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Massimo GIRARDIS

Professore Ordinario
Dipartimento Chirurgico, Medico, Odontoiatrico e di Scienze Morfologiche con interesse Trapiantologico, Oncologico e di Medicina Rigenerativa

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Pubblicazioni

2024 - Advances and Challenges in Sepsis Management: Modern Tools and Future Directions [Articolo su rivista]
Santacroce, Elena; D’Angerio, Miriam; Ciobanu, Alin Liviu; Masini, Linda; Lo Tartaro, Domenico; Coloretti, Irene; Busani, Stefano; Rubio, Ignacio; Meschiari, Marianna; Franceschini, Erica; Mussini, Cristina; Girardis, Massimo; Gibellini, Lara; Cossarizza, Andrea; De Biasi, Sara
abstract

: Sepsis, a critical condition marked by systemic inflammation, profoundly impacts both innate and adaptive immunity, often resulting in lymphopenia. This immune alteration can spare regulatory T cells (Tregs) but significantly affects other lymphocyte subsets, leading to diminished effector functions, altered cytokine profiles, and metabolic changes. The complexity of sepsis stems not only from its pathophysiology but also from the heterogeneity of patient responses, posing significant challenges in developing universally effective therapies. This review emphasizes the importance of phenotyping in sepsis to enhance patient-specific diagnostic and therapeutic strategies. Phenotyping immune cells, which categorizes patients based on clinical and immunological characteristics, is pivotal for tailoring treatment approaches. Flow cytometry emerges as a crucial tool in this endeavor, offering rapid, low cost and detailed analysis of immune cell populations and their functional states. Indeed, this technology facilitates the understanding of immune dysfunctions in sepsis and contributes to the identification of novel biomarkers. Our review underscores the potential of integrating flow cytometry with omics data, machine learning and clinical observations to refine sepsis management, highlighting the shift towards personalized medicine in critical care. This approach could lead to more precise interventions, improving outcomes in this heterogeneously affected patient population.

2024 - INTRAVENOUS FOSFOMYCIN IN COMBINATION REGIMENS AS A TREATMENT OPTION FOR DIFFICULT-TO-TREAT INFECTIONS DUE TO MULTIDRUG-RESISTANT GRAM-NEGATIVE ORGANISMS: A REAL-LIFE EXPERIENCE [Articolo su rivista]
Meschiari, Marianna; Faltoni, Matteo; Kaleci, Shaniko; Tassoni, Giovanni; Orlando, Gabriella; Franceschini, Erica; Burastero, Giulia; Bedini, Andrea; Serio, Lucia; Biagioni, Emanuela; Melegari, Gabriele; Venturelli, Claudia; Sarti, Mario; Bertellini, Elisabetta; Girardis, Massimo; Mussini, Cristina
abstract

Background: We aim to investigate the efficacy of intravenous (IV) Fosfomycin as combination therapy for treatment of difficult-to-treat (DTT) multidrug-resistant (MDR) gram negative bacteria (GNB) acute and subacute infections and risk factors associated with 90-day mortality. Methods: A retrospective, observational, monocentric study enrolled patients treated with IV Fosfomycin in combination regimens (>/= 72 h) for proven DTT-MDR-GNB based infection . Multivariate regression analysis identified independent risk factors for 90-day mortality. A propensity score for receiving Fosfomycin was performed to control for confounding factors. Results: 70 patients were included: 54.3% carbapenem-resistant isolates, 31.4% resistant to ceftazidime/avibactam and 28.6% to ceftolozane/tazobactam. The main pathogens were Pseudomonas aeruginosa (57.1%) and Klebsiella pneumoniae (22.9%). The most prevalent infections were nosocomial pneumonia (42.9%), followed by osteomyelitis (17.1%) and intra-abdominal infections (IAI). All-cause 30 and 90-day mortality were 15.7% and 31.4% (18.9% and 50%, considering only DTT-MDR-GNB acute infections). Relapse at 30 days occurred in 22.9% of cases (29% with emergence of fosfomycin resistance). Mortality at 90 days was independently associated with septic shock, and the evidence of ceftolozane/tazobactam resistance., Resistance to ceftolozane/tazobactam was confirmed significant after adjustment by propensity score analysis (HR 5.84, 95%CI 1.65-20.68, p=0.006). Conclusions: Fosfomycin seems a promising salvage, combination treatment in DTT- MDR-GNB infections. Resistance to ceftolozane/tazobactam seems to be independently associated with treatment failure. Randomized clinical trials focusing on pathogen and infection sites are urgently required to demonstrate the superiority of fosfomycin in combination with other agents for the resolution of difficult to treat GNB infections.

2023 - A Fatal Case of Pseudomonas aeruginosa Community-Acquired Pneumonia in an Immunocompetent Patient: Clinical and Molecular Characterization and Literature Review [Articolo su rivista]
Barp, Nicole; Marcacci, Matteo; Biagioni, Emanuela; Serio, Lucia; Busani, Stefano; Ventura, Paolo; Franceschini, Erica; Orlando, Gabriella; Venturelli, Claudia; Menozzi, Ilaria; Tambassi, Martina; Scaltriti, Erika; Pongolini, Stefano; Sarti, Mario; Pietrangelo, Antonello; Girardis, Massimo; Mussini, Cristina; Meschiari, Marianna
abstract

Rare cases of Pseudomonas aeruginosa community-acquired pneumonia (PA-CAP) were reported in non-immunocompromised patients. We describe a case of Pseudomonas aeruginosa (PA) necrotizing cavitary CAP with a fatal outcome in a 53-year-old man previously infected with SARS-CoV-2, who was admitted for dyspnea, fever, cough, hemoptysis, acute respiratory failure and a right upper lobe opacification. Six hours after admission, despite effective antibiotic therapy, he experienced multi-organ failure and died. Autopsy confirmed necrotizing pneumonia with alveolar hemorrhage. Blood and bronchoalveolar lavage cultures were positive for PA serotype O:9 belonging to ST1184. The strain shares the same virulence factor profile with reference genome PA01. With the aim to better investigate the clinical and molecular characteristics of PA-CAP, we considered the literature of the last 13 years concerning this topic. The prevalence of hospitalized PA-CAP is about 4% and has a mortality rate of 33–66%. Smoking, alcohol abuse and contaminated fluid exposure were the recognized risk factors; most cases presented the same symptoms described above and needed intensive care. Co-infection of PA-influenza A is described, which is possibly caused by influenza-inducing respiratory epithelial cell dysfunction: the same pathophysiological mechanism could be assumed with SARS-CoV-2 infection. Considering the high rate of fatal outcomes, additional studies are needed to identify sources of infections and new risk factors, along with genetic and immunological features. Current CAP guidelines should be revised in light of these results.

2023 - Association Between Pulmonary Aspergillosis And Cytomegalovirus Reactivation In Critically Ill Covid-19 Patients: A Prospective Observational Cohort Study. [Articolo su rivista]
Caciagli, Valeria; Coloretti, Irene; Talamonti, Marta; Farinelli, Carlotta; Gatto, Ilenia; Biagioni, Emanuela; Sarti, Mario; Franceschini, Erica; Meschiari, Marianna; Mussini, Cristina; Tonelli, Roberto; Clini, Enrico; Girardis, Massimo; Busani, Stefano
abstract

COVID-19-associated invasive pulmonary aspergillosis (CAPA) is common and is associated with poor outcomes in critically ill patients. This prospective observational study aimed to ex-plore the association between CAPA development and the incidence and prognosis of cytomegalo-virus (CMV) reactivation in critically ill COVID-19 patients. We included all consecutive criti-cally ill adult patients with confirmed COVID-19 infection who were admitted to three COVID-19 intensive care units (ICUs) in an Italian hospital from February 25, 2020, to May 8, 2022. A standardized procedure was employed for early detection of CAPA. Risk factors associ-ated with CAPA and CMV reactivation and the association between CMV recurrence and mor-tality were estimated using adjusted Cox proportional hazard regression models. CAPA oc-curred in 96 patients (16,6%) of the 579 patients analyzed. Among the CAPA population, 40 (41,7%) patients developed CMV blood reactivation with a median time of 18 days (IQR 7-27). The CAPA+CMV group did not exhibit a significantly higher 90-day mortality rate (62.5% vs. 48.2%) than the CAPA alone group (p=0.166). The CAPA+CMV group had a longer ICU stay, few-er ventilation-free days, and a higher rate of secondary bacterial infections than the control group of CAPA alone. In the CAPA population, prior immunosuppression was the only independent risk factor for CMV reactivation (HR 2.33, 95% C.I. 1.21-4.48, p=0.011). In critically ill COVID-19 pa-tients, CMV reactivation is common in those with a previous CAPA diagnosis. Basal immuno-suppression before COVID-19 appeared to be the primary independent variable affecting CMV reactivation in patients with CAPA. Furthermore, the association of CAPA+CMV versus CAPA alone appears to impact ICU length of stay and secondary bacterial infections but not mortality.

2023 - Critical COVID-19 Patients Through First, Second And Third Wave: Retrospective Observational Study Comparing Outcomes In ICU. [Articolo su rivista]
Coloretti, Irene; Farinelli, Carlotta; Biagioni, Emanuela; Gatto, Ilenia; Munari, Elena; Dall'Ara, Lorenzo; Busani, Stefano; Meschiari, Marianna; Tonelli, Roberto; Mussini, Cristina; Guaraldi, Giovanni; Cossarizza, Andrea; Clini, Enrico; Girardis, Massimo
abstract

Introduction- The time-course of the COVID-19 pandemic was characterized by subsequent waves identified by peaks of Intensive Care Unit (ICU) admission rates. During these periods, progressive knowledge of the disease led to the development of specific therapeutic strategies. This retrospective study investigates whether this led to improvement in outcomes of COVID-19 patients admitted to ICU. Methods- Outcomes were evaluated in consecutive adult COVID19 patients admitted to our ICU, divided into three waves based on the admission period: the first wave from February 25th, 2020, to July 6th, 2020; the second wave from September 20th, 2020, to February 13th, 2021; the third wave from February 14th, 2021 to April 30th, 2021. Differences were assessed comparing outcomes and by using different multivariable Cox models adjusted for variables related to outcome. Further sensitivity analysis was performed in patients undergoing invasive mechanical ventilation. Results- Overall, 428 patients were included in the analysis: 102, 169 and 157 patients in the first, second and third wave. The ICU and in-hospital crude mortalities were lower by 7% and 10% in the third wave compared to the other 2 waves (p>0.05). A higher number of ICU and hospital free days at day 90 was found in the third wave when compared to the other 2 waves (p=0.001). Overall, 62.6% underwent invasive ventilation, with decreasing requirement during the waves (p=0.002). The adjusted Cox model showed no difference in the Hazard Ratio for mortality among the waves. In the propensity-matched analysis the hospital mortality rate was reduced by 11% in the third wave (p=0.044). Conclusions - With application of best practice as known by the time of the first three waves of the pandemic, our study failed to identify a significant improvement in mortality rate when comparing the different waves of the COVID-19 pandemic, notwithstanding, the sub-analyses showed a trend in mortality reduction in the third wave. Rather, our study identified a possible positive effect of dexamethasone on mortality rate reduction and the increased risk of death related to bacterial infections in the three waves.

2023 - Detailed characterization of SARS-CoV-2-specific T and B cells after infection or heterologous vaccination [Articolo su rivista]
Lo Tartaro, Domenico; Paolini, Annamaria; Mattioli, Marco; Swatler, Julian; Neroni, Anita; Borella, Rebecca; Santacroce, Elena; Di Nella, Alessia; Gozzi, Licia; Busani, Stefano; Cuccorese, Michela; Trenti, Tommaso; Meschiari, Marianna; Guaraldi, Giovanni; Girardis, Massimo; Mussini, Cristina; Piwocka, Katarzyna; Gibellini, Lara; Cossarizza, Andrea; De Biasi, Sara
abstract

: The formation of a robust long-term antigen (Ag)-specific memory, both humoral and cell-mediated, is created following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination. Here, by using polychromatic flow cytometry and complex data analyses, we deeply investigated the magnitude, phenotype, and functionality of SARS-CoV-2-specific immune memory in two groups of healthy subjects after heterologous vaccination compared to a group of subjects who recovered from SARS-CoV-2 infection. We find that coronavirus disease 2019 (COVID-19) recovered patients show different long-term immunological profiles compared to those of donors who had been vaccinated with three doses. Vaccinated individuals display a skewed T helper (Th)1 Ag-specific T cell polarization and a higher percentage of Ag-specific and activated memory B cells expressing immunoglobulin (Ig)G compared to those of patients who recovered from severe COVID-19. Different polyfunctional properties characterize the two groups: recovered individuals show higher percentages of CD4+ T cells producing one or two cytokines simultaneously, while the vaccinated are distinguished by highly polyfunctional populations able to release four molecules, namely, CD107a, interferon (IFN)-γ, tumor necrosis factor (TNF), and interleukin (IL)-2. These data suggest that functional and phenotypic properties of SARS-CoV-2 adaptive immunity differ in recovered COVID-19 individuals and vaccinated ones.

2023 - Do all critically ill patients with COVID-19 disease benefit from adding tocilizumab to glucocorticoids? A retrospective cohort study. [Articolo su rivista]
Mussini, Cristina; Cozzi-Lepri, Alessandro; Meschiari, Marianna; Franceschini, Erica; Jole Burastero, Giulia; Faltoni, Matteo; Franceschi, Giacomo; Iadisernia, Vittorio; Volpi, Sara; Dessilani, Andrea; Gozzi, Licia; Conti, Jacopo; DEL MONTE, Martina; Milic, Jovana; Borghi, Vanni; Tonelli, Roberto; Brugioni, Lucio; Romagnoli, Elisa; Pietrangelo, Antonello; Corradini, Elena; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Clini, Enrico; Guaraldi, Giovanni
abstract

2023 - Extracorporeal CO 2 Removal During Renal Replacement Therapy to Allow Lung-Protective Ventilation in Patients With COVID-19-Associated Acute Respiratory Distress Syndrome [Articolo su rivista]
Alessandri, F.; Tonetti, T.; Pistidda, L.; Busani, S.; Borrazzo, C.; Fanelli, V.; Polzoni, M.; Piazza, O.; Lorini, L.; Cattaneo, S.; Ricci, D.; Zanoni, A.; Girardis, M.; Terragni, P.; Tempesta, M.; Di Luca, M.; Pugliese, F.; Ranieri, V. M.
abstract

The aim of this retrospective multicenter observational study is to test the feasibility and safety of a combined extracorporeal CO 2 removal (ECCO 2 R) plus renal replacement therapy (RRT) system to use an ultraprotective ventilator setting while maintaining (1) an effective support of renal function and (2) values of pH within the physiologic limits in a cohort of coronavirus infectious disease 2019 (COVID-19) patients. Among COVID-19 patients admitted to the intensive care unit of 9 participating hospitals, 27 patients with acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI) requiring invasive mechanical ventilation undergoing ECCO 2 R-plus-RRT treatment were included in the analysis. The treatment allowed to reduce V T from 6.0 ± 0.6 mL/kg at baseline to 4.8 ± 0.8, 4.6 ± 1.0, and 4.3 ± 0.3 mL/kg, driving pressure (ΔP) from 19.8 ± 2.5 cm H 2 O to 14.8 ± 3.6, 14.38 ± 4.1 and 10.2 ± 1.6 cm H 2 O after 24 hours, 48 hours, and at discontinuation of ECCO 2 R-plus-RRT (T3), respectively ( p < 0.001). PaCO 2 and pH remained stable. Plasma creatinine decreased over the study period from 3.30 ± 1.27 to 1.90 ± 1.30 and 1.27 ± 0.90 mg/dL after 24 and 48 hours of treatment, respectively ( p < 0.01). No patient-related events associated with the extracorporeal system were reported. These data show that in patients with COVID-19-induced ARDS and AKI, ECCO 2 R-plus-RRT is effective in allowing ultraprotective ventilator settings while maintaining an effective support of renal function and values of pH within physiologic limits.

2023 - Pneumocystis jirovecii pneumonia in patients with decompensated cirrhosis: a case series [Articolo su rivista]
Franceschini, Erica; Dolci, Giovanni; Santoro, Antonella; Meschiari, Marianna; Riccò, Alice; Menozzi, Marianna; Burastero, Giulia Jole; Cuffari, Biagio; De Maria, Nicola; Serio, Lucia; Biagioni, Emanuela; Catellani, Barbara; Sandro, Stefano Di; Colecchia, Antonio; Girardis, Massimo; Benedetto, Fabrizio Di; Mussini, Cristina
abstract

Objectives: Pneumocystis jirovecii pneumonia (PCP) incidence is increasing in people without HIV. Decompensated liver cirrhosis is not currently considered a risk factor for PCP. The aim of this paper is to describe a case series of patients with decompensated liver cirrhosis and PCP. Methods: All consecutive patients hospitalized with decompensated cirrhosis and microbiology-confirmed PCP at Policlinico Modena University Hospital from January 1, 2016 to December 31, 2021 were included in our series. Results: Eight patients were included. All patients had advanced-stage liver disease with a model for end-stage liver disease score above 15 (6/8 above 20). Four were on an active orthotopic liver transplant waiting list at the time of PCP diagnosis. Five patients did not have any traditional risk factor for PCP, whereas the other three were on glucocorticoid treatment for acute-on-chronic liver failure. All patients were treated with cotrimoxazole, except two who died before the diagnosis. Five patients died (62.5%), four of them within 30 days from PCP diagnosis. Of the remaining three, one patient underwent liver transplantation. Conclusion: Although further studies are needed, liver cirrhosis can be an independent risk factor for PCP in patients with decompensated cirrhosis that is mainly due to severe alcoholic hepatitis and who are on corticosteroids therapy, and primary prophylaxis for PCP should be considered.

2023 - Prognostic immune markers identifying patients with severe COVID-19 who respond to tocilizumab [Articolo su rivista]
DE BIASI, Sara; Mattioli, Marco; Meschiari, Marianna; LO TARTARO, Domenico; Paolini, Annamaria; Borella, Rebecca; Neroni, Anita; Fidanza, LUCIA MICHELA PIA; Busani, Stefano; Girardis, Massimo; Coppi, Francesca; Mattioli, Anna Vittoria; Guaraldi, Giovanni; Mussini, Cristina; Cossarizza, Andrea; Gibellini, Lara
abstract

Introduction: A growing number of evidences suggest that the combination of hyperinflammation, dysregulated T and B cell response and cytokine storm play a major role in the immunopathogenesis of severe COVID-19. IL-6 is one of the main pro-inflammatory cytokines and its levels are increased during SARS-CoV-2 infection. Several observational and randomized studies demonstrated that tocilizumab, an IL-6R blocker, improves survival in critically ill patients both in infectious disease and intensive care units. However, despite transforming the treatment options for COVID-19, IL-6R inhibition is still ineffective in a fraction of patients. Methods: In the present study, we investigated the impact of two doses of tocilizumab in patients with severe COVID-19 who responded or not to the treatment by analyzing a panel of cytokines, chemokines and other soluble factors, along with the composition of peripheral immune cells, paying a particular attention to T and B lymphocytes. Results: We observed that, in comparison with non-responders, those who responded to tocilizumab had different levels of several cytokines and different T and B cells proportions before starting therapy. Moreover, in these patients, tocilizumab was further able to modify the landscape of the aforementioned soluble molecules and cellular markers. Conclusions: We found that tocilizumab has pleiotropic effects and that clinical response to this drug remain heterogenous. Our data suggest that it is possible to identify patients who will respond to treatment and that the administration of tocilizumab is able to restore the immune balance through the re-establishment of different cell populations affected by SARS-COV-2 infection, highlighting the importance of temporal examination of the pathological features from the diagnosis.

2023 - Quality of Life in COVID-Related ARDS Patients One Year after Intensive Care Discharge (Odissea Study): A Multicenter Observational Study [Articolo su rivista]
Deana, C.; Vetrugno, L.; Cortegiani, A.; Mongodi, S.; Salve, G.; Mangiagalli, M.; Boscolo, A.; Pettenuzzo, T.; Miori, S.; Sanna, A.; Lassola, S.; Magnoni, S.; Ferrari, E.; Biagioni, E.; Bassi, F.; Castaldo, N.; Fantin, A.; Longhini, F.; Corradi, F.; Forfori, F.; Cammarota, G.; De Robertis, E.; Buonsenso, D.; Spadaro, S.; Grieco, D. L.; Martino De, M.; Isola, M.; Mojoli, F.; Girardis, M.; Giarratano, A.; Bignami, E. G.; Navalesi, P.; Cecconi, M.; Maggiore, S. M.
abstract

Background: Investigating the health-related quality of life (HRQoL) after intensive care unit (ICU) discharge is necessary to identify possible modifiable risk factors. The primary aim of this study was to investigate the HRQoL in COVID-19 critically ill patients one year after ICU discharge. Methods: In this multicenter prospective observational study, COVID-19 patients admitted to nine ICUs from 1 March 2020 to 28 February 2021 in Italy were enrolled. One year after ICU discharge, patients were required to fill in short-form health survey 36 (SF-36) and impact of event-revised (IES-R) questionnaire. A multivariate linear or logistic regression analysis to search for factors associated with a lower HRQoL and post-traumatic stress disorded (PTSD) were carried out, respectively. Results: Among 1003 patients screened, 343 (median age 63 years [57–70]) were enrolled. Mechanical ventilation lasted for a median of 10 days [2–20]. Physical functioning (PF 85 [60–95]), physical role (PR 75 [0–100]), emotional role (RE 100 [33–100]), bodily pain (BP 77.5 [45–100]), social functioning (SF 75 [50–100]), general health (GH 55 [35–72]), vitality (VT 55 [40–70]), mental health (MH 68 [52–84]) and health change (HC 50 [25–75]) describe the SF-36 items. A median physical component summary (PCS) and mental component summary (MCS) scores were 45.9 (36.5–53.5) and 51.7 (48.8–54.3), respectively, considering 50 as the normal value of the healthy general population. In all, 109 patients (31.8%) tested positive for post-traumatic stress disorder, also reporting a significantly worse HRQoL in all SF-36 domains. The female gender, history of cardiovascular disease, liver disease and length of hospital stay negatively affected the HRQoL. Weight at follow-up was a risk factor for PTSD (OR 1.02, p = 0.03). Conclusions: The HRQoL in COVID-19 ARDS (C-ARDS) patients was reduced regarding the PCS, while the median MCS value was slightly above normal. Some risk factors for a lower HRQoL have been identified, the presence of PTSD is one of them. Further research is warranted to better identify the possible factors affecting the HRQoL in C-ARDS.

2023 - Refractory septic shock and alternative wordings: A systematic review of literature [Articolo su rivista]
Antonucci, E.; Polo, T.; Giovini, M.; Girardis, M.; Martin-Loeches, I.; Nielsen, N. D.; Lozsan, F. J. C.; Ferrer, R.; Lakbar, I.; Leone, M.
abstract

Background: We reviewed the different studies using the terms “refractory septic shock” and/or “catecholamine resistance” and/or “high dose norepinephrine” so as to highlight the heterogeneity of the definitions used by authors addressing such concepts. Method: A systematic review was conducted assessing the papers reporting data on refractory septic shock. We used keywords as exact phrases and subject headings according to database syntax. Results: Of 276 papers initially reviewed, we included 8 studies – 3 randomized controlled trials, 3 prospective studies and 2 retrospective studies, representing a total of 562 patients with septic shock. Catecholamine resistance was generally defined as “a decreased vascular responsiveness to catecholamine independently of the administered norepinephrine dose”. Refractory septic shock was broadly defined as “a clinical condition characterized by persistent hyperdynamic shock even though adequate fluid resuscitation (individualized doses) and high doses of norepinephrine (≥ 1 μg/kg/min)”. Reported “high doses” of norepinephrine were often ≥1 μg/kg/min. However, wide variability was found throughout the literature on the use of these terms. Discussion: Marked inconsistencies were identified in the usage of the terms for refractory septic shock. There is a pressing need to determine consensus definitions so as to establish a common language in the medical literature and to harmonize future studies.

2023 - Rezafungin versus caspofungin for treatment of candidaemia and invasive candidiasis (ReSTORE): a multicentre, double-blind, double-dummy, randomised phase 3 trial [Articolo su rivista]
Thompson, G. R.; Soriano, A.; Cornely, O. A.; Kullberg, B. J.; Kollef, M.; Vazquez, J.; Honore, P. M.; Bassetti, M.; Pullman, J.; Chayakulkeeree, M.; Poromanski, I.; Dignani, C.; Das, A. F.; Sandison, T.; Pappas, P. G.; Akova, M.; Alagha, R.; Alangaden, G.; Albrecht, S. J.; Alexander, B.; Al-Obaidi, M.; Ambasch, G.; Armestar Rodriguez, F.; Azap, A.; Baffoe-Bonnie, A.; Belkhir, L.; Ben-Ami, R.; Boutoille, D.; Cascio, A.; Chai, L. Y.; Chaiwarith, R.; Chen, S.; Chen, Y. -C.; Chen, Y. -H.; Choi, J. Y.; Choi, Y. H.; Chotiprasitsakul, D.; Chung, J. W.; Danion, F.; Denis, B.; Diaz Santos, E.; Dictar, M. O.; Diltoer, M.; Dupont, H.; Feng, S.; Ferre Colomer, M. A.; Ferrer, R.; Forel, J. -M. F. R.; Fortun-Abete, J.; Garcia-Diaz, J.; Girardis, M.; He, F.; Hites, M.; Ho, M. -W.; Honore, P.; Horcajada Gallego, J. P.; Huang, H.; Huang, P. -Y.; Huang, Y.; Hussein, O.; Intalapaporn, P.; Jaruratanasirikul, S.; Jauregui-Peredo, L.; Johnson, M.; Jung, D. S.; Jutivorakool, K.; Kern, W. V.; Kett, D. H.; Khawcharoenporn, T.; Kim, Y. K.; Koehler, P.; Kotanidou, A.; Lachiewicz, A.; Lin, Q.; Lopez Cortes, L. E.; Luo, H.; Luzzati, R.; Maor, Y.; Mccarty, T.; Merelli, M.; Merino Amador, P.; Midturi, J.; Migliorino, G. M.; Mira, J. -P.; Mootsikapun, P.; Morrissey, O.; Munoz Garcia de Paredes, P.; Mussini, C.; Mylonakis, E.; Nseir, S.; Nseir, W.; Odabasi, Z.; Papastamopoulos, V.; Paterson, D.; Patterson, T. F.; Peck, K. R.; Peng, Z.; Permpalung, N.; Plantefeve, G. J.; Poromanski, I. G.; Powell, D.; Psichogiou, M.; Puah, S. H.; Rahav, G.; Martinez, A. R.; Ramos Ramos, J. C.; Raz-Pasteur, A.; Restrepo Castro, C. A.; Riera, F.; Roblot, F.; Rodriguez Alvarez, R. J.; Rogers, B.; Roilides, E.; Sanchez Vallejo, G.; Sganga, G.; Sipsas, N.; Slavin, M.; Spec, A.; Strahilevitz, J.; Tancheva, D. M.; Tao, Z.; Teschner, D.; Van Wijngaerden, E.; Vergidis, P.; Viale, P.; Wang, F. -D.; Wang, S.; Weber, G.; Weng, J.; Xu, J.; Yao, L.; Yavuz, S.; Yilmaz, M.; Young, J. -A.; Zarate, A. H.; Zeng, J.; Zhang, Y.
abstract

Background: Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with candidaemia and invasive candidiasis. Methods: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial done at 66 tertiary care centres in 15 countries. Adults (≥18 years) with systemic signs and mycological confirmation of candidaemia or invasive candidiasis were eligible for inclusion and randomly assigned (1:1) to receive intravenous rezafungin once a week (400 mg in week 1, followed by 200 mg weekly, for a total of two to four doses) or intravenous caspofungin (70 mg loading dose on day 1, followed by 50 mg daily) for no more than 4 weeks. The primary endpoints were global cure (consisting of clinical cure, radiological cure, and mycological eradication) at day 14 for the European Medical Agency (EMA) and 30-day all-cause mortality for the US Food and Drug Administration (FDA), both with a target non-inferiority margin of 20%, assessed in the modified intention-to-treat population (all patients who received one or more doses of study drug and had documented Candida infection based on a culture from blood or another normally sterile site obtained within 96 h before randomisation). Safety was evaluated by the incidence and type of adverse events and deaths in the safety population, defined as all patients who received any amount of study drug. The trial is registered with ClinicalTrials.gov, NCT03667690, and is complete. Findings: Between Oct 12, 2018, and Aug 29, 2021, 222 patients were screened for inclusion, and 199 patients (118 [59%] men; 81 [41%] women; mean age 61 years [SD 15·2]) were randomly assigned (100 [50%] patients to the rezafungin group and 99 [50%] patients to the caspofungin group). 55 (59%) of 93 patients in the rezafungin group and 57 (61%) of 94 patients in the caspofungin group had a global cure at day 14 (weighted treatment difference −1·1% [95% CI −14·9 to 12·7]; EMA primary endpoint). 22 (24%) of 93 patients in the rezafungin group and 20 (21%) of 94 patients in the caspofungin group died or had an unknown survival status at day 30 (treatment difference 2·4% [95% CI −9·7 to 14·4]; FDA primary endpoint). In the safety analysis, 89 (91%) of 98 patients in the rezafungin group and 83 (85%) of 98 patients in the caspofungin group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events that occurred in at least 5% of patients in either group were pyrexia, hypokalaemia, pneumonia, septic shock, and anaemia. 55 (56%) patients in the rezafungin group and 52 (53%) patients in the caspofungin group had serious adverse events. Interpretation: Our data show that rezafungin was non-inferior to caspofungin for the primary endpoints of day-14 global cure (EMA) and 30-day all-cause mortality (FDA). Efficacy in the initial days of treatment warrants evaluation. There were no concerning trends in treatment-emergent or serious adverse events. These phase 3 results show the efficacy and safety of rezafungin and support its ongoing development. Funding: Cidara Therapeutics and Mundipharma.

2023 - Role of selective digestive decontamination in the prevention of VAP in COVID-19 patients: a pre-post observational study. [Articolo su rivista]
Biagioni, Emanuela; Ferrari, Elena; Gatto, Ilenia; Serio, Lucia; Farinelli, Carlotta; Coloretti, Irene; Talamonti, Marta; Tosi, Martina; Meschiari, Marianna; Tonelli, Roberto; Venturelli, Claudia; Mussini, Cristina; Clini, Enrico; Sarti, Mario; Cossarizza, Andrea; Busani, Stefano; Girardis, Massimo.
abstract

The aim of our study was to evaluate whether the introduction of SDD in a structured protocol for VAP prevention was effective in reducing the occurrence of ventilator associated pneumonia (VAP) in COVID19 patients without changes in the microbiological pattern of antibiotic resistances. This observational pre-post study including adult patients requiring invasive mechanical ventilation (IMV) for severe respiratory failure related to SARS-CoV-2 admitted in three COVID19 intensive care units (ICUs) in an Italian hospital from February 22, 2020, to March 8, 2022. Selective digestive decontamination (SDD) was introduced from the end of April 2021 in the structured protocol for VAP prevention. The SDD consisted of a tobramycin sulphate, colistin sulphate and amphotericin B suspension applied in the patient oropharynx and the stomach via nasogastric tube. Three-hundred forty-eight patients were included in the study. In the 86 patients (32,9%) who received SDD the occurrence of VAP decreased by 7,7% (p = 0,192) compared to patients who did not receive SDD. Onset time of VAP, the occurrence of multidrug-resistant microorganisms AP, the length of invasive mechanical ventilation and hospital mortality were similar in patients who received and who did not receive SDD. The multivariate analysis adjusted for confounders showed that the use of SDD reduces the occurrence of VAP (HR 0,536, CI 0,338-0,851; p = 0,017) Our pre-post observational study indicates that the use of SDD in a structured protocol for VAP prevention seems to reduce the occurrence of VAP without changes in the incidence of multidrug-resistant bacteria in COVID19 patients.

2023 - Sex-related mortality differences in young adult septic shock patients [Articolo su rivista]
Zangrillo, A.; Morselli, F.; Biagioni, E.; Stella, R. D.; Coloretti, I.; Moizo, E.; Plumari, V. P.; Monti, G.; Borghi, G.; Salonia, A.; Almirante, G.; Maraggia, D.; Zambon, M.; Langiano, N.; Roasio, A.; Pasin, L.; Mucci, M.; Beccaria, P. F.; Pasculli, N.; Redaelli, M. B.; Pallanch, O.; Gallo, G.; Real, G.; Nava, M.; Venturelli, S.; Tosi, M.; Munari, E.; Visconti, M. G.; Perno, S.; Girardis, M.; Landoni, G.
abstract

Septic shock survival rate and host immune response are intimately interlaced. In the last years, biological and pre-clinical studies demonstrated sex-specific differences in the immune response to infection. In the hypothesis that survival rate is related to the hormonal framework, the aim of the present study was to observe sex-specific differences in 28-day mortality rate between women of childbearing potential and same-age men. This multicenter study was conducted in six Italian intensive care units (ICUs). We enrolled consecutive patients ≤ 55 years old admitted to the Intensive Care Unit from January 2011 to January 2020, who were diagnosed with septic shock at the time of ICU admission or during the ICU stay. We gathered baseline characteristics and outcomes. The primary outcome was 28-day mortality; secondary outcomes included ICU mortality, in-hospital mortality and length of stay in the ICU and in the hospital. Moreover, data from >55 years old patients were collected and analyzed. We enrolled 361 young patients with septic shock: 215 were males (60%) and 146 females (40%). While baseline and ICU characteristics were similar between the two groups, males had a higher 28-day mortality rate (39.5% vs. 29%, p = 0.035), ICU mortality rate (49% vs. 38%, p = 0.040) and hospital mortality rate (61% vs. 50%, p = 0.040) as compared to females. Findings were confirmed in patients with septic shock at ICU admission. Young adult females developed septic shock less frequently than young males, displaying a reduced mortality rate as compared to that of their same-age male counterpart. These findings may stimulate future research and therapies.

2023 - The association of procalcitonin and C- reactive protein with bacterial infections acquired during ICU stay in COVID-19 critically ill patients. [Articolo su rivista]
Campani, Simone; Talamonti, Marta; Dall’Ara, Lorenzo; Coloretti, Irene; Gatto, Ilenia; Biagioni, Emanuela; Tosi, Martina; Meschiari, Marianna; Tonelli, Roberto; Clini, Enrico; Cossarizza, Andrea; Guaraldi, Giovanni; Mussini, Cristina; Sarti, Mario; Trenti, Tommaso; Girardis, Massimo
abstract

In COVID-19 patients, procalcitonin (PCT) and C-reactive protein (CRP) performance in identify-ing bacterial infections remains unclear. Our study aimed to evaluate the association of PCT and CRP with secondary infections acquired during ICU stay in critically ill COVID-19. This observa-tional study included adult patients admitted to three COVID-19 intensive care units (ICU) from February 2020 to May 2022 with respiratory failure caused by SARS-CoV-2 infection and ICU stay≥ 11 days. The values of PCT and CRP collected on the day of infection diagnosis were com-pared to those collected on day 11 after ICU admission, the median time for infection occurrence, in patients without secondary infection. The receiver operating characteristic curve (ROC) and multivariate logistic model were used to assess PCT and CRP association with secondary infec-tions. Two hundred and seventy-nine patients were included, of whom 169 (60,6%) developed secondary infection after ICU admission. The PCT and CRP values observed on the day of the in-fection diagnosis were larger (p< 0,001) than those observed on day 11 after ICU admission in pa-tients without secondary infections. The ROC analysis calculated an AUC of 0,744 (95%CI 0,685-0,803) and 0,754 (95%CI 0,695-0,812) for PCT and CRP, respectively. Multivariate logistic models showed that PCT ≥ 0,16 ng/ml and CRP≥ 1,35 mg/dl were associated (p<0,001) with infections acquired during ICU stay. Our results indicated that PCT and CRP values were associated with developing secondary infections in COVID-19 patients with an ICU stay > 11 days with an ac-ceptable level of diagnostic accuracy using cut-off values lower than those commonly used in no-COVID-19 patients.

2023 - Trials on oxygen targets in the critically ill patients: do they change our knowledge and practice? [Articolo su rivista]
Girardis, M.; de Man, A. M. E.; Singer, M.
abstract

2023 - Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder [Articolo su rivista]
Bergantini, L.; Baldassarri, M.; D'Alessandro, M.; Brunelli, G.; Fabbri, G.; Zguro, K.; Degl'Innocenti, A.; Mari, F.; Daga, S.; Meloni, I.; Bruttini, M.; Croci, S.; Lista, M.; Maffeo, D.; Pasquinelli, E.; Serio, V. B.; Antolini, E.; Basso, S. L.; Minetto, S.; Tita, R.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Emiliozzi, A.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Lorubbio, M.; Pancrazzi, A.; Vaghi, M.; Monforte, A. D. A.; Miraglia, F. G.; Mondelli, M. U.; Mantovani, S.; Bruno, R.; Vecchia, M.; Maffezzoni, M.; Martinelli, E.; Girardis, M.; Busani, S.; Venturelli, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Pallotto, C.; Parisi, S. G.; Basso, M.; Panese, S.; Baratti, S.; Scotton, P. G.; Andretta, F.; Giobbia, M.; Scaggiante, R.; Gatti, F.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; Di Florio, A.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Mussini, C.; Tavecchia, L.; Crotti, L.; Parati, G.; Mene, R.; Sanarico, M.; Gori, M.; Raimondi, F.; Stella, A.; Biscarini, F.; Bachetti, T.; La Rovere, M. T.; Bussotti, M.; Ludovisi, S.; Capitani, K.; Dei, S.; Ravaglia, S.; Giliberti, A.; Gori, G.; Artuso, R.; Andreucci, E.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Micheli, G.; Falcone, M.; Urso, D.; Tiseo, G.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Bellucci, A.; Colaneri, M.; Casprini, P.; Pomara, C.; Esposito, M.; Leoncini, R.; Cirianni, M.; Galasso, L.; Bellini, M. A.; Gabbi, C.; Picchiotti, N.; Furini, S.; Fallerini, C.; Bargagli, E.; Renieri, A.
abstract

Background: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. Methods: A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Results: Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. Conclusion: RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 (www.clinicaltrial.org)

2022 - A first update on mapping the human genetic architecture of COVID-19 [Articolo su rivista]
Pathak, Ga; Polimanti, R; Karjalainen, J; Daly, M; Ganna, A; Daly, Mj; Stevens, C; Kanai, M; Liao, Rg; Trankiem, A; Balaconis, Mk; Nguyen, H; Solomonson, M; Veerapen, K; Ripatti, S; Nkambul, L; Bryant, S; Sankaran, Vg; Neale, Bm; Karczewski, Kj; Martin, Ar; Atkinson, Eg; Tsuo, K; Baya, N; Turley, P; Gupta, R; Walters, Rk; Palmer, Ds; Sarma, G; Cheng, N; Lu, W; Churchhouse, C; Goldstein, Ji; King, D; Zhou, W; Seed, C; Finucane, H; Satterstrom, Fk; Andrews, Sj; Sloofman, Lg; Sealfon, Sc; Hoggart, C; Underwood, Sj; Cordioli, M; Pirinen, M; Donner, K; Kivinen, K; Palotie, A; Kaunisto, M; Harerimana, N; Chwialkowska, K; Wolford, B; Roberts, G; Park, D; Ball, Ca; Coignet, M; Mccurdy, S; Knight, S; Partha, R; Rhead, B; Zhang, M; Berkowitz, N; Gaddis, M; Noto, K; Ruiz, L; Pavlovic, M; Hong, El; Rand, K; Girshick, A; Guturu, H; Baltzell, Ah; Niemi, Mek; Pigazzini, S; Rahmouni, S; Georges, M; Belhaj, Y; Guntz, J; Claassen, S; Beguin, Y; Gofflot, S; Nkambule, L; Nkambul, L; Cusick, C; Moutschen, M; Misset, B; Darcis, G; Guiot, J; Azarzar, S; Malaise, O; Huynen, P; Meuris, C; Thys, M; Jacques, J; Leonard, P; Frippiat, F; Giot, Jb; Sauvage, As; Von Frenckell, C; Lambermont, B; Nakanishi, T; Morrison, Dr; Richards, Jb; Butler-Laporte, G; Forgetta, V; Ghosh, B; Laurent, L; Henry, D; Abdullah, T; Adeleye, O; Mamlouk, N; Kimchi, N; Afrasiabi, Z; Rezk, N; Vulesevic, B; Bouab, M; Guzman, C; Petitjean, L; Tselios, C; Xue, Xq; Afilalo, J; Adra, D; Mooser, V; Li, R; Belisle, A; Lepage, P; Ragoussis, J; Auld, D; Lathrop, Gm; Afilalo, M; Oliveira, M; Brenner, B; Brassard, N; Durand, M; Chasse, M; Kaufmann, De; Schurr, E; Hayward, C; Richmond, A; Baillie, Jk; Glessner, Jt; Hakonarson, H; Chang, X; Shaw, Dm; Below, J; Polikowski, H; Lauren, Pe; Chen, Hh; Zhu, Wy; Davis, L; Kerchberger, Ve; Campbell, A; Porteous, Dj; Fawns-Ritchie, C; Morris, M; Mccormick, Jb; North, K; Glessner, Jr; Gignoux, Cr; Wicks, Sj; Crooks, K; Barnes, Kc; Daya, M; Shortt, J; Rafaels, N; Chavan, S; Timmers, Prhj; Wilson, Jf; Tenesa, A; Kerr, Sm; D'Mellow, K; Shahin, D; El-Sherbiny, Ym; El-Jawhari, Jj; von Hohenstaufen, Ka; Sobh, A; Eltoukhy, Mm; Mohamed, Aas; Elhadidy, Ta; Abd Elghafar, Ms; Elnagdy, Mh; Samir, A; Hegazy, Maf; Abdel-Aziz, M; Khafaga, Wt; El-Lawaty, Wm; Torky, Ms; Moahmed, Hs; El-shanshory, Mr; Yassen, Am; Okasha, K; Eid, Ma; Medina-Gomez, C; Uitterlinden, Ag; Ikram, Ma; Magi, R; Milani, L; Metspalu, A; Laisk, T; Lall, K; Lepamets, M; Esko, T; Reimann, E; Alavere, H; Metsalu, K; Puusepp, M; Naaber, P; Laane, E; Pesukova, J; Peterson, P; Kisand, K; Tabri, J; Allos, R; Hensen, K; Starkopf, J; Ringmets, I; Tamm, A; Kallaste, A; Batini, C; Tobin, Md; Venn, Ld; Lee, Ph; Shrine, N; Williams, At; Guyatt, Al; John, C; Packer, Rj; Ali, A; Wang, X; Wain, Lv; Bee, Ce; Adams, El; Free, Rc; Hollox, Ej; Ruotsalainen, S; Kristiansson, K; Koskelainen, S; Perola, M; Rivolta, C; Quinodoz, M; Kamdar, D; Bochud, Py; Boillat, N; Bibert, S; Nussle, Sg; Albrich, W; Suh, N; Neofytos, D; Erard, V; Voide, C; Friolet, R; Vollenweider, P; Pagani, Jl; Oddo, M; zu Bentrup, Fm; Conen, A; Clerc, O; Marchetti, O; Guillet, A; Guyat-Jacques, C; Foucras, S; Rime, M; Chassot, J; Jaquet, M; Viollet, Rm; Lannepoudenx, Y; Portopena, L; Bochud, Py; Desgranges, F; Filippidis, P; Guery, B; Haefliger, D; Kampouri, Ee; Manuel, O; Munting, A; Papadimitriou-Olivgeris, M; Regina, J; Rochat-Stettler, L; Suttels, V; Tadini, E; Tschopp, J; Van Singer, M; Viala, B; Boillat-Blanco, N; Brahier, T; Hugli, O; Meuwly, Jy; Pantet, O; Nussle, Sg; Bochud, M; D'Acremont, V; Younes, Se; Albrich, Wc; Suh, N; Cerny, A; O'Mahony, L; von Mering, C; Frischknecht, M; Kleger, Gr; Filipovic, M; Kahlert, Cr; Wozniak, H; Negro, Tr; Pugin, J; Bouras, K; Knapp, C; Egger, T; Perret, A; Montillier, P; di Bartolomeo, C; Barda, B; de Cid, R; Carreras, A; Galvan-Femenia, I; Blay, N; Farre, X; Sumoy, L; Cortes, B; Moreno, V; Kogevinas, M; Garcia-Aymerich, J; Castano-Vinyals, G; Dobano, C; Mercader, Jm; Mercader, J; Guindo-Martinez, M; Torrents
abstract

2022 - An explainable model of host genetic interactions linked to COVID-19 severity [Articolo su rivista]
Onoja, A.; Picchiotti, N.; Fallerini, C.; Baldassarri, M.; Fava, F.; Mari, F.; Daga, S.; Benetti, E.; Bruttini, M.; Palmieri, M.; Croci, S.; Amitrano, S.; Meloni, I.; Frullanti, E.; Doddato, G.; Lista, M.; Beligni, G.; Valentino, F.; Zguro, K.; Tita, R.; Giliberti, A.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Di Sarno, L.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Rossetti, B.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Pancrazzi, A.; Lorubbio, M.; Vaghi, M.; D'Arminio Monforte, A.; Miraglia, F. G.; Bruno, R.; Vecchia, M.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Tommasi, A.; Zuccon, U.; Vietri, L.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; De Vivo, O.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Coviello, D. A.; Mussini, C.; Martinelli, E.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Sanarico, M.; Biscarini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; La Rovere, M. T.; Sarzi-Braga, S.; Bussotti, M.; Capitani, K.; Dei, S.; Ravaglia, S.; Artuso, R.; Andreucci, E.; Gori, G.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Segala, F. V.; Menichetti, F.; Falcone, M.; Tiseo, G.; Barbieri, C.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Mene, R.; Colaneri, M.; Casprini, P.; Merla, G.; Squeo, G. M.; Maffezzoni, M.; Mantovani, S.; Mondelli, M. U.; Ludovisi, S.; Colombo, F.; Chiaromonte, F.; Renieri, A.; Furini, S.; Raimondi, F.
abstract

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

2022 - Association between respiratory distress time and invasive mechanical ventilation in COVID-19 patients: a multicentre regional cohort study. [Articolo su rivista]
Busani, Stefano; Coloretti, Irene; Baciarello, Marco; Bellini, Valentina; Sarti, Marco; Biagioni, Emanuela; Tonelli, Roberto; Marchioni, Alessandro; Clini, Enrico; Guaraldi, Giovanni; Mussini, Cristina; Meschiari, Marianna; Tonetti, Tommaso; Pisani, Lara; Nava, Stefano; Bignami, Elena; Ranieri, Marco; Girardis, Massimo
abstract

Aim: to determine whether the duration of respiratory distress symptoms in severe COVID-19 pneumonia affects the need for invasive mechanical ventilation and clinical outcomes. Materials and methods: an observational multicentre cohort study of patients hospitalised in five COVID-19–designated ICUs of the University Hospitals of Emilia-Romagna Region. Patients included were adults with pneumonia due to SARS-CoV-2 with PaO₂/FiO₂ ratio <300 mmHg, respiratory distress symptoms, and need for mechanical ventilation (invasive or non-invasive). Exclusion criteria were an uncertain time of respiratory distress, end-of-life decision, and mechanical respiratory support before hospital admission. Measurements and main results: we analysed 171 patients stratified into tertiles according to respiratory distress duration (distress time, DT) before application of mechanical ventilation support. The rate of patients requiring invasive mechanical ventilation was significantly different (p<0.001) among the tertiles: 17/57 patients in the shortest duration, 29/57 in the intermediate duration, and 40/57 in the longest duration. The respiratory distress time significantly increased the risk of invasive ventilation in the univariate analysis (OR 5.5 [CI 2.48–12.35], p = 0.003). Multivariable regression analysis confirmed this association (OR 10.7 [CI 2.89–39.41], p <0.001). Clinical outcomes (mortality and hospital stay) did not show significant differences between DT tertiles. Discussion: albeit preliminary and retrospective, our data raised the hypothesis that the duration of respiratory distress symptoms may play a role in COVID-19 patients’ need for invasive mechanical ventilation. Furthermore, our observations suggested that specific strategies may be directed towards identifying and managing early symptoms of respiratory distress, regardless of the levels of hypoxemia and the severity of the dyspnoea itself.

2022 - Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19 [Articolo su rivista]
Zguro, K.; Baldassarri, M.; Fava, F.; Beligni, G.; Daga, S.; Leoncini, R.; Galasso, L.; Cirianni, M.; Rusconi, S.; Siano, M.; Francisci, D.; Schiaroli, E.; Luchi, S.; Morelli, G.; Martinelli, E.; Girardis, M.; Busani, S.; Parisi, S. G.; Panese, S.; Piscopo, C.; Capasso, M.; Tacconi, D.; Raffaelli, C. S.; Giliberti, A.; Gori, G.; Katsikis, P. D.; Lorubbio, M.; Calzoni, P.; Ognibene, A.; Bocchia, M.; Tozzi, M.; Bucalossi, A.; Marotta, G.; Furini, S.; Renieri, A.; Fallerini, C.
abstract

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF–platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage.

2022 - Ceftazidime/Avibactam in Ventilator-Associated Pneumonia Due to Difficult-to-Treat Non-Fermenter Gram-Negative Bacteria in COVID-19 Patients: A Case Series and Review of the Literature [Articolo su rivista]
Burastero, Giulia Jole; Orlando, Gabriella; Santoro, Antonella; Menozzi, Marianna; Franceschini, Erica; Bedini, Andrea; Cervo, Adriana; Faltoni, Matteo; Bacca, Erica; Biagioni, Emanuela; Coloretti, Irene; Melegari, Gabriele; Maccieri, Jessica; Busani, Stefano; Bertellini, Elisabetta; Girardis, Massimo; Ferrarini, Giulia; Rofrano, Laura; Sarti, Mario; Mussini, Cristina; Meschiari, Marianna
abstract

Ventilator-associated pneumonia (VAP) in critically ill patients with COVID-19 represents a very huge global threat due to a higher incidence rate compared to non-COVID-19 patients and almost 50% of the 30-day mortality rate. Pseudomonas aeruginosa was the first pathogen involved but uncommon non-fermenter gram-negative organisms such as Burkholderia cepacea and Stenotrophomonas maltophilia have emerged as other potential etiological causes. Against carbapenem-resistant gram-negative microorganisms, Ceftazidime/avibactam (CZA) is considered a first-line option, even more so in case of a ceftolozane/tazobactam resistance or shortage. The aim of this report was to describe our experience with CZA in a case series of COVID-19 patients hospitalized in the ICU with VAP due to difficult-to-treat (DTT) P. aeruginosa, Burkholderia cepacea, and Stenotrophomonas maltophilia and to compare it with data published in the literature. A total of 23 patients were treated from February 2020 to March 2022: 19/23 (82%) VAPs were caused by Pseudomonas spp. (16/19 DTT), 2 by Burkholderia cepacea, and 6 by Stenotrophomonas maltophilia; 12/23 (52.1%) were polymicrobial. Septic shock was diagnosed in 65.2% of the patients and VAP occurred after a median of 29 days from ICU admission. CZA was prescribed as a combination regimen in 86% of the cases, with either fosfomycin or inhaled amikacin or cotrimoxazole. Microbiological eradication was achieved in 52.3% of the cases and the 30-day overall mortality rate was 14/23 (60.8%). Despite the high mortality of critically ill COVID-19 patients, CZA, especially in combination therapy, could represent a valid treatment option for VAP due to DTT non-fermenter gram-negative bacteria, including uncommon pathogens such as Burkholderia cepacea and Stenotrophomonas maltophilia.

2022 - Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity [Articolo su rivista]
Fallerini, C.; Picchiotti, N.; Baldassarri, M.; Zguro, K.; Daga, S.; Fava, F.; Benetti, E.; Amitrano, S.; Bruttini, M.; Palmieri, M.; Croci, S.; Lista, M.; Beligni, G.; Valentino, F.; Meloni, I.; Tanfoni, M.; Minnai, F.; Colombo, F.; Cabri, E.; Fratelli, M.; Gabbi, C.; Mantovani, S.; Frullanti, E.; Gori, M.; Crawley, F. P.; Butler-Laporte, G.; Richards, B.; Zeberg, H.; Lipcsey, M.; Hultstrom, M.; Ludwig, K. U.; Schulte, E. C.; Pairo-Castineira, E.; Baillie, J. K.; Schmidt, A.; Frithiof, R.; Mari, F.; Renieri, A.; Furini, S.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Rossetti, B.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Pancrazzi, A.; Lorubbio, M.; Vaghi, M.; Monforte, A. D.; Miraglia, F. G.; Mondelli, M. U.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Tommasi, A.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; Vivo, O. D.; Doddato, G.; Tita, R.; Giliberti, A.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Perticaroli, V.; Ariani, F.; Carriero, M. L.; Sarno, L. D.; Alaverdian, D.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, L. G.; Coviello, D. A.; Mussini, C.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Sanarico, M.; Raimondi, F.; Biscarini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Capitani, K.; Dei, S.; Ravaglia, S.; Artuso, R.; Andreucci, E.; Gori, G.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Segala, F. V.; Menichetti, F.; Falcone, M.; Tiseo, G.; Barbieri, C.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Stefania, L.; Lenzi, M.; Pietro, M. A. D.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Roberto, M.; Zuccon, U.; Vietri, L.; Ceri, S.; Pinoli, P.; Casprini, P.; Merla, G.; Squeo, G. M.; Maffezzoni, M.; Bruno, R.; Vecchia, M.; Colaneri, M.; Ludovisi, S.; Marincevic-Zuniga, Y.; Nordlund, J.; Luther, T.; Larsson, A.; Hanslin, K.; Gradin, A.; Galien, S.; Anderberg, S. B.; Rosen, J.; Rubertsson, S.; Clohisey, S.; Horby, P.; Millar, J.; Knight, J.; Montgomery, H.; Maslove, D.; Ling, L.; Nichol, A.; Summers, C.; Walsh, T.; Hinds, C.; Semple, M. G.; Openshaw, P. J. M.; Shankar-Hari, M.; Ho, A.; Mcauley, D.; Ponting, C.; Rowan, K.; Griffiths, F.; Oosthuyzen, W.; Meikle, J.; Finernan, P.; Furniss, J.; Mcmaster, E.; Law, A.; Paterson, T.; Wackett, T.; Armstrong, R.; Murphy, L.; Fawkes, A.; Clark, R.; Coutts, A.; Donnelly, L.; Gilchrist, T.; Hafezi, K.; Macgillivray, L.; Maclean, A.; Mccafferty, S.; Morrice, K.; Weaver, J.; Boz, C.; Golightly, A.; Ward, M.; Mal, H.; Szoor-McElhinney, H.; Brown, A.; Hendry, R.; Stenhouse, A.; Cullum, L.; Law, D.; Law, S.; Law, R.; Swets, M.; Day, N.; Taneski, F.; Duncan, E.; Zechner, M.; Parkinson, N.; Klaric, L.; Bretherick, A.
abstract

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

2022 - Communication and visiting policies in Italian intensive care units during the first COVID-19 pandemic wave and lockdown: a nationwide survey [Articolo su rivista]
Langer, T.; Depalo, F. C.; Forlini, C.; Landini, S.; Mezzetti, A.; Previtali, P.; Monti, G.; de Toma, C.; Biscardi, D.; Giannini, A.; Fumagalli, R.; Mistraletti, G.; Lissoni, B.; De Martini, A.; Mareto, N.; Rossitto, C.; Zummo, U.; Taverna, M.; Machieraldo, P.; Navarra, M.; Parlanti Garbero, M.; Scaletti, C.; Perno, S.; Amendolia, L.; Montrucchio, G.; Veliaj, D.; Barbarello, G.; Alesci, M.; Bolgiaghi, L.; Vailati, D.; Pezzi, A.; Boselli, E.; Piccoli, F.; Greco, M.; Gemma, M.; Resta, M.; Crotti, S.; Bottino, N.; Abruzzese, C.; Savioli, M.; Migliorino, G.; Muttini, S.; Umbrello, M.; Borghi, B.; Greco, S.; Dizeo, M.; Bottiroli, M.; Mondino, M. G.; Prosepri, M.; Casella, G.; Curto, F.; Zaniboni, M.; Giudici, R.; Gentile, C.; Bombino, M.; Rona, R.; Cortinovis, B.; Benini, A.; Avalli, L.; Tavola, M.; Ferrario, M.; Preda, R.; Primerano, E.; Russo, G.; Porta, V.; Valdambrini, F.; Fassini, P.; Orando, S.; Beck, E.; Pedeferri, M.; Cogliati, G.; Testini, D.; Moroni, B.; Codeluppi, V.; Ruggeri, P.; Milanesi, E.; Belliato, M.; Besozzi, A.; Riccio, M.; Zerbi, S.; Corbella, D.; Ferri, F.; Grazioli, L.; Bonanomi, E.; Giacomini, M.; Sacchi, N.; Codognola, C.; Ambrosini, A.; Guatteri, L.; Subert, M.; Castelli, G. P.; Borelli, M.; Venier, E.; Dittura, L.; Buttera, S.; Bigai, R.; Magnoni, S.; Rauch, S.; Colombo, A.; Fullin, G.; Donolato, C.; Cattin, S.; State, V.; Redeghieri, E.; Russo, A.; Pastorini, S.; Allena, S.; Munari, M.; Turchet, F.; Peta, M.; De Santis, V.; Scala, C.; Facondini, F.; Marangoni, E.; Tassinati, T.; Zanzani, C.; Russo, E.; Marchio, A.; Barbagallo, M.; Girardis, M.; Taffache, P.; Mordacci, M.; Vincenzi, M.; Pennica, M.; Bracciotti, G.; Iori, P.; Gambi, D.; Cappellini, I.; Vegnuti, L.; De Luca, A.; Romagnoli, S.; Mosti, G.; Carla, R.; Roticiani, V.; Pelagalli, L.; Fuselli, E.; D'Avino, E.; De Bellis, M.; Gianni, G.; Leonardis, F.; Rossi, M.; Lorusso, R.; Magnanimi, E.; Martelli, S.; Baisi, F.; Balsamo, D.; Cotticelli, V.; Mattei, A.; Farinelli, I.; Riccini, T.; Cola, L.; Jorio, A.; Iacobone, E.; Domizi, R.; Pizzi, S.; Nasso, A.; Graziani, R.; Monaco, A.; Manno, M.; Ottelio, C. M.; Del Rio, M.; Serra, A.; Enna, B.; Loddo, F. M.; Galbiati, R.; Mellea, S.; Kimberly, M. B.; Vissani, M.; Romito, F. M.; Baccari, L.; Zarrillo, N.; Esposito, C.; Murino, P.; Notaro, S.; Ausiello, C.; Marra, A.; Policastro, C.; Cafora, C.; De Benedectis, G.; Di Falco, V.; Sciddurlo, M.; Negro, G.; Vetuschi, P.; Recchia, A.; Pasquariello, R.; Squillace, R.; Ciambrone, A.; Bencivenga, C.; Camiolo, M.; Agozzino, C.; Oliveri, F.; Notarrigo, T.; Castiglione, G.; Mo, A.; Condorelli, L.; Favarato, M.
abstract

Background: During the first coronavirus disease 2019 (COVID-19) pandemic wave, an unprecedented number of patients with respiratory failure due to a new, highly contagious virus needed hospitalization and intensive care unit (ICU) admission. The aim of the present study was to describe the communication and visiting policies of Italian intensive care units (ICUs) during the first COVID-19 pandemic wave and national lockdown and compare these data with prepandemic conditions. Methods: A national web-based survey was conducted among 290 Italian hospitals. Each ICU (active between February 24 and May 31, 2020) was encouraged to complete an individual questionnaire inquiring the hospital/ICU structure/organization, communication/visiting habits and the role of clinical psychology prior to, and during the first COVID-19 pandemic wave. Results: Two hundred and nine ICUs from 154 hospitals (53% of the contacted hospitals) completed the survey (202 adult and 7 pediatric ICUs). Among adult ICUs, 60% were dedicated to COVID-19 patients, 21% were dedicated to patients without COVID-19 and 19% were dedicated to both categories (Mixed). A total of 11,102 adult patients were admitted to the participating ICUs during the study period and only approximately 6% of patients received at least one visit. Communication with family members was guaranteed daily through an increased use of electronic devices and was preferentially addressed to the same family member. Compared to the prepandemic period, clinical psychologists supported physicians more often regarding communication with family members. Fewer patients received at least one visit from family members in COVID and mixed-ICUs than in non-COVID ICUs, l (0 [0–6]%, 0 [0–4]% and 11 [2–25]%, respectively, p < 0.001). Habits of pediatric ICUs were less affected by the pandemic. Conclusions: Visiting policies of Italian ICUs dedicated to adult patients were markedly altered during the first COVID-19 wave. Remote communication was widely adopted as a surrogate for family meetings. New strategies to favor a family-centered approach during the current and future pandemics are warranted.

2022 - Correction: Endobronchial valve positioning for alveolar-pleural fistula following ICU management complicating COVID-19 pneumonia (BMC Pulmonary Medicine, (2021), 21, 1, (307), 10.1186/s12890-021-01653-w) [Articolo su rivista]
Donatelli, P.; Trentacosti, F.; Pellegrino, M. R.; Tonelli, R.; Bruzzi, G.; Andreani, A.; Cappiello, G. F.; Andrisani, D.; Gozzi, F.; Mussini, C.; Busani, S.; Cavaliere, G. V.; Girardis, M.; Bertellini, E.; Clini, E.; Marchioni, A.
abstract

2022 - Cytomegalovirus blood reactivation in COVID-19 critically ill patients: risk factors and impact on mortality. [Articolo su rivista]
Gatto, Ilenia; Biagioni, Emanuela; Coloretti, Irene; Farinelli, Carlotta; Avoni, Camilla; Caciagli, Valeria; Busani, Stefano; Sarti, Mario; Pecorari, Monica; Gennari, William; Guaraldi, Giovanni; Franceschini, Erica; Meschiari, Marianna; Mussini, Cristina; Tonelli, Roberto; Clini, Enrico; Cossarizza, Andrea; Girardis, Massimo; Gibellini, Lara
abstract

Purpose: Cytomegalovirus (CMV) reactivation in immunocompetent critically ill patients is common and relates to a worsening outcome. In this large observational study, we evaluated the incidence and the risk factors associated with CMV reactivation and its effects on mortality in a large cohort of COVID-19 patients admitted to the intensive care unit (ICU). Methods: Consecutive patients with confirmed SARS-CoV-2 infection and acute respiratory distress syndrome admitted to three ICUs from February 2020 to July 2021 were included. The patients were screened at ICU admission and once or twice per week for quantitative CMV-DNAemia in the blood. The risk factors associated with CMV blood reactivation and its association with mortality were estimated by adjusted Cox proportional hazards regression models. Results: CMV blood reactivation was observed in 88 patients (20,4%) of the 431 patients studied. SAPS II score (HR 1,031, 95% CI 1,010-1,053, p=0,006), platelet count (HR 0,0996, 95% CI 0,993-0,999, p=0,004), invasive mechanical ventilation (HR 2,611, 95% CI 1,223-5,571, p=0,013) and secondary bacterial infection (HR 5,041; 95% CI 2,852-8,911, p<0,0001) during ICU stay were related to CMV reactivation. Hospital mortality was higher in patients with (67,0%) than in patients without (24,5%) CMV reactivation but the adjusted analysis did not confirm this association (HR 1,141, 95% CI 0,757-1,721, p=0,528). Conclusion: The severity of illness and the occurrence of secondary bacterial infections were associated with an increased risk of CMV blood reactivation, which, however, does not seem to influence the outcome of COVID-19 ICU patients independently.

2022 - Early awake proning in critical and severe COVID-19 patients undergoing noninvasive respiratory support: A retrospective multicenter cohort study [Articolo su rivista]
Tonelli, R; Pisani, L; Tabbì, L; Comellini, V; Prediletto, I; Fantini, R; Marchioni, A; Andrisani, D; Gozzi, F; Bruzzi, G; Manicardi, L; Busani, S; Mussini, C; Castaniere, I; Bassi, I; Carpano, M; Tagariello, F; Corsi, G; D' amico, R; Girardis, M; Nava, S; Clini, E.
abstract

Introduction- In non-intubated patients with COVID-19 pneumonia, awake prone position associated with non-invasive respiratory support (NRS) demonstrated only physiological benefits. Nonetheless, it might be arguable that at least a selected subset of these patients is going to obtain significant clinical gains. Methods- This retrospective cohort study was conducted in two teaching hospitals comparing effects of awake prone position in addition to usual care (PP) with standard care alone (SC)in severe and critical COVID-19 patients undergoing NRS. Primary outcome was endotracheal intubation (ETI) rate. In-hospital mortality, time to ETI, tracheostomy, length of RICU and hospital stay served as secondary outcomes. Risk factors associated with ETI were also investigated in PP group. Results- A cohort of 114 patients (38 and 76 in PP and SC group, respectively) was analyzed. Greater ETI risk reduction rate was observed in PP as compared with SC both at unadjusted estimates (HR=0.45 95%CI [0.2-0.9], p=0.02), and even after adjustment for confounders (HR=0.59 95%CI[0.3-0.94], p=0.03). Compared with SC, PP group also showed a favorable difference in terms of days free from respiratory support, length of RICU and hospital stay, but not in mortality or tracheostomy rate. Conclusion- Early awake proning in spontaneously breathing Covid-19 patients is associated with a risk reduction of intubation rate.Findings prompt further randomized controlled trials to answer the pending questions on the real efficacy of PP in this setting.

2022 - Editorial: Putting the Spotlight on the Role of Oxygen in Critically-Ill Patients: From Basic Mechanisms to Clinical Effects [Articolo su rivista]
Busani, S.; Munari, E.; Taccone, F. S.; Donati, A.; Girardis, M.
abstract

2022 - Epidemiology and age-related mortality in critically ill patients with intra-abdominal infection or sepsis: an international cohort study [Articolo su rivista]
Arvaniti, K.; Dimopoulos, G.; Antonelli, M.; Blot, K.; Creagh-Brown, B.; Deschepper, M.; de Lange, D.; De Waele, J.; Dikmen, Y.; Eckmann, C.; Einav, S.; Francois, G.; Fjeldsoee-Nielsen, H.; Girardis, M.; Jovanovic, B.; Lindner, M.; Koulenti, D.; Labeau, S.; Lipman, J.; Lipovestky, F.; Makikado, L. D. U.; Maseda, E.; Mikstacki, A.; Montravers, P.; Paiva, J. A.; Pereyra, C.; Rello, J.; Timsit, J. -F.; Tomescu, D.; Vogelaers, D.; Blot, S.
abstract

Objective: To describe epidemiology and age-related mortality in critically ill older adults with intra-abdominal infection. Methods: A secondary analysis was undertaken of a prospective, multi-national, observational study (Abdominal Sepsis Study, ClinicalTrials.gov #NCT03270345) including patients with intra-abdominal infection from 309 intensive care units (ICUs) in 42 countries between January and December 2016. Mortality was considered as ICU mortality, with a minimum of 28 days of observation when patients were discharged earlier. Relationships with mortality were assessed by logistic regression analysis. Results: The cohort included 2337 patients. Four age groups were defined: middle-aged patients [reference category; 40–59 years; n=659 (28.2%)], young-old patients [60–69 years; n=622 (26.6%)], middle-old patients [70–79 years; n=667 (28.5%)] and very old patients [≥80 years; n=389 (16.6%)]. Secondary peritonitis was the predominant infection (68.7%) and was equally prevalent across age groups. Mortality increased with age: 20.9% in middle-aged patients, 30.5% in young-old patients, 31.2% in middle-old patients, and 44.7% in very old patients (P<0.001). Compared with middle-aged patients, young-old age [odds ratio (OR) 1.62, 95% confidence interval (CI) 1.21–2.17], middle-old age (OR 1.80, 95% CI 1.35–2.41) and very old age (OR 3.69, 95% CI 2.66–5.12) were independently associated with mortality. Other independent risk factors for mortality included late-onset hospital-acquired intra-abdominal infection, diffuse peritonitis, sepsis/septic shock, source control failure, liver disease, congestive heart failure, diabetes and malnutrition. Conclusions: For ICU patients with intra-abdominal infection, age >60 years was associated with mortality; patients aged ≥80 years had the worst prognosis. Comorbidities and overall disease severity further compromised survival. As all of these factors are non-modifiable, it remains unclear how to improve outcomes.

2022 - First and second wave among hospitalized COVID-19 patients with severe pneumonia: a comparison of 28-day mortality over 1-year pandemic in a tertiary university hospital in Italy. [Articolo su rivista]
Meschiari, M; Cozzi-Lepri, A; Tonelli, R; Bacca, E; Menozzi, M; Franceschini, E; Cuomo, G; Bedini, A; Volpi, S; Milic, J; Brugioni, L; Romagnoli, E; Pietrangelo, A; Corradini, E; Coloretti, I; Biagioni, E; Busani, S; Girardis, M; Cossarizza, A; Clini, E; Guaraldi, G; Mussini, C.
abstract

Objectives: The first COVID-19-19 epidemic wave was over the period February-May 2020. Since October 1st, 2020 Italy, as many other European countries, faced a second wave. The aim of this analysis was to compare the 28-day mortality between the two waves among COVID-19 hospitalised patients. Design: Observational cohort study. Standard survival analysis was performed to compare all-cause mortality within 28 days after hospital admission in the two waves. Kaplan-Meier curves as well as Cox regression model analysis were used. The effect of wave on risk of death was shown by means of hazard ratios (HRs) with 95% confidence intervals (CI). A sensitivity analysis around the impact of the circulating variant as a potential unmeasured confounder was performed. Setting: University Hospital of Modena, Italy. Patients admitted to hospital for severe COVID-19 pneumonia during the first (February 22nd – May 31st, 2020) and second wave (October 1st- December 31st, 2020) were included. Results: During the two study periods, a total of 1,472 patients with severe COVID-19 pneumonia were admitted to our hospital, 449 during the first wave and 1,023 during the second. Median age was 70 years (IQR:56-80), 37% females, 49% with PaO /FiO < 250 mmHg, 82% with ≥1 comorbidity, median duration of symptoms was 6 days. 28-day mortality rate was 20.0% (95% CI:16.3-23.7) during the first wave vs. 14.2% (95% CI:12.0-16.3) in the second (log-rank test p-value= 0.03). After including key predictors of death in the multivariable Cox regression model, the data still strongly suggested a lower 28-day mortality rate in the 2nd wave (aHR=0.64, 95% CI: 0.45, 0.90, p- value=0.01). Conclusions: In our hospitalized COVID-19 patients with severe pneumonia, the 28-day mortality appeared to be reduced by 36% during the second as compared to the first wave. Further studies are needed to identify factors that may have contributed to this improved survival.

2022 - Inspiratory effort and respiratory mechanics in spontaneously breathing patients with acute exacerbation of idiopathic pulmonary fibrosis: a retrospective matched control study. [Articolo su rivista]
Tonelli, Roberto; Castaniere, Ivana; Cortegiani, Andrea; Tabbì, Luca; Fantini, Riccardo; Andrisani, Dario; Gozzi, Filippo; Moretti, Antonio; Bruzzi, Giulia; Manicardi, Linda; Cerbone, Caterina; Nani, Chiara; Biagioni, Emanuela; Cerri, Stefania; Samarelli, Valeria; Busani, Stefano; Girardis, Massimo; Marchioni, Alessandro; Clini, Enrico
abstract

Background- Patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) may experience severe acute respiratory failure, even requiring ventilatory assistance. Physiological data on lung mechanics during these events are lacking. Methods- Patients with AE-IPF admitted to Respiratory Intensive Care Unit to receive noninvasive ventilation (NIV) were retrospectively analyzed. Esophageal pressure swing (ΔP es ) and respiratory mechanics before and 2 hours after NIV start were collected as primary outcome. Correlation between positive end-expiratory pressure (PEEP) levels and changes of dynamic compliance (dynC RS ) and PaO 2 /FiO 2 ratio was assessed. Further, an exploratory comparison with a historic cohort of ARDS patients matched 1:1 by age, sequential organ failure assessment score, body mass index and PaO 2 /FiO 2 level was performed. Results- At baseline, AE-IPF presented high respiratory drive activation with ΔPes = 27 (21–34) cmH2O, respiratory rate (RR) = 34 (30–39) bpm and minute ventilation (VE) = 21 (20–26) L/min. Two hours after NIV application, ΔPes, RR and VE showed a significant reduction (16 [14–24] cmH2O, p<0.0001, 27 [25–30] bpm, p=0.001, and 18 [17–20] L/min, p=0.003, respectively) while no significant change was found for dynamic transpulmonary pressure (27 [21–34] VS 27 [25–36] cmH2O, p=0.2) expiratory tidal volume (Vte) (9.1 [8.7–10.1] VS 9.3 [8.7 – 9.9] mL/kg of predicted boy weight, p=0.2), dynCRS (28 [19–31] VS 26 [18–28] mL/cmH2O, p=0.1) and dynamic mechanical power (71 [49–94] VS 60 [51–74] J/min, p=0.1). PEEP levels negatively correlated with PaO 2 /FiO 2 ratio and dynC RS (r=–0.67, p=0.03 and r=–0.27, p=0.4, respectively). When compared to AE-IPF, ARDS patients presented lower baseline ΔP es , RR, VE and dynamic mechanical power. At difference with AE-IPF, Vte and dynC RS increased significantly following NIV (p=0.01 and p=0.004 respectively) with PEEP levels directly associated with PaO 2 /FiO 2 ratio and dynC RS (r=0.24, p=0.5 and r=0.65, p=0.04, respectively). Conclusions- In this study, patients with AE-IPF showed a high inspiratory effort, whose intensity was reduced by NIV application without significant improvement in respiratory mechanics. In an exploratory analysis, AE-IPF patients showed a different mechanical behavior under spontaneous unassisted and assisted breathing compared with ARDS of similar severity.

2022 - Long-Term Impact of the COVID-19 Pandemic on In-Hospital Antibiotic Consumption and Antibiotic Resistance: A Time Series Analysis (2015-2021) [Articolo su rivista]
Meschiari, Marianna; Onorato, Lorenzo; Bacca, Erica; Orlando, Gabriella; Menozzi, Marianna; Franceschini, Erica; Bedini, Andrea; Cervo, Adriana; Santoro, Antonella; Sarti, Mario; Venturelli, Claudia; Biagioni, Emanuela; Coloretti, Irene; Busani, Stefano; Girardis, Massimo; Lòpez-Lozano, José-María; Mussini, Cristina
abstract

The coronavirus disease 2019 (COVID-19)-pandemic-related overload of health systems has compromised the application of antimicrobial stewardship (AS) models and infection prevention and control (IPC) programs. We aimed to evaluate the impact of COVID-19 on antimicrobial consumption (AC) and antimicrobial resistance (AMR) in the University Hospital of Modena. A time series analysis with an autoregressive integrated moving average model was conducted from January 2015 to October 2021 to evaluate the AC in the whole hospital and the intensive care unit (ICU), the incidence density (ID) of bloodstream infections (BSIs) due to the main multidrug-resistant organisms, and of C. difficile infections (CDIs). After an initial peak during the COVID-19 period, a decrease in the trend of AC was observed, both at the hospital (CT: -1.104, p = 0.025) and ICU levels (CT: -4.47, p = 0.047), with no significant difference in the single classes. Among the Gram-negative isolates, we observed a significant increase only in the level of BSIs due to carbapenem-susceptible Pseudomonas aeruginosa (CL: 1.477, 95% CI 0.130 to 2.824, p = 0.032). Considering Gram-positive bacteria, an increase in the level of BSIs due to methicillin-resistant Staphylococcus aureus and in the trend of CDIs were observed, though they did not reach statistical significance (CL: 0.72, 95% CI -0.039 to 1.48, p = 0.062; CT: 1.43, 95% CI -0.002 to 2.863, p = 0.051; respectively). Our findings demonstrated that the increases in AMR and AC that appeared in the first COVID-19 wave may be later controlled by restoring IPC and AS programs to pre-epidemic levels. A coordinated healthcare effort is necessary to address the longer-term impact of COVID-19 on AC to avoid irreversible consequences on AMR.

2022 - Metabolic reprograming shapes neutrophil functions in severe COVID-19 [Articolo su rivista]
Borella, Rebecca; De Biasi, Sara; Paolini, Annamaria; Boraldi, Federica; Tartaro, Domenico Lo; Mattioli, Marco; Fidanza, Lucia; Neroni, Anita; Caro-Maldonado, Alfredo; Meschiari, Marianna; Franceschini, Erica; Quaglino, Daniela; Guaraldi, Giovanni; Bertoldi, Carlo; Sita, Marco; Busani, Stefano; Girardis, Massimo; Mussini, Cristina; Cossarizza, Andrea; Gibellini, Lara
abstract

: To better understand the mechanisms at the basis of neutrophil functions during SARS-CoV-2 we studied patients with severe COVID-19 pneumonia. They had high blood proportion of degranulated neutrophils and elevated plasma levels of myeloperoxidase (MPO), elastase and MPO-DNA complexes, which are typical markers of neutrophil extracellular traps (NET). Their neutrophils display dysfunctional mitochondria, defective oxidative burst, increased glycolysis, glycogen accumulation in the cytoplasm, and increase glycogenolysis. Hypoxia-inducible factor 1α (ΗΙF-1α) is stabilized in such cells, and it controls the level of glycogen phosphorylase L (PYGL), a key enzyme in glycogenolysis. Inhibiting PYGL abolishes the ability of neutrophils to produce NET. Patients displayed significant increases of plasma levels of molecules involved in the regulation of neutrophils' function, including CCL2, CXCL10, CCL20, IL-18, IL-3, IL-6, G-CSF, GM-CSF, IFN-γ. Our data suggest that metabolic remodelling is vital for the formation of NET and for boosting neutrophil inflammatory response, thus suggesting that modulating ΗΙF-1α or PYGL could represent a novel approach for innovative therapies. This article is protected by copyright. All rights reserved.

2022 - Molecular and cellular immune features of aged patients with severe COVID-19 pneumonia [Articolo su rivista]
Lo Tartaro, D.; Neroni, A.; Paolini, A.; Borella, R.; Mattioli, M.; Fidanza, L.; Quong, A.; Petes, C.; Awong, G.; Douglas, S.; Lin, D.; Nieto, J.; Gozzi, L.; Franceschini, E.; Busani, S.; Nasi, M.; Mattioli, A. V.; Trenti, T.; Meschiari, M.; Guaraldi, G.; Girardis, M.; Mussini, C.; Gibellini, L.; Cossarizza, A.; De Biasi, S.
abstract

Aging is a major risk factor for developing severe COVID-19, but few detailed data are available concerning immunological changes after infection in aged individuals. Here we describe main immune characteristics in 31 patients with severe SARS-CoV-2 infection who were >70 years old, compared to 33 subjects <60 years of age. Differences in plasma levels of 62 cytokines, landscape of peripheral blood mononuclear cells, T cell repertoire, transcriptome of central memory CD4+ T cells, specific antibodies are reported along with features of lung macrophages. Elderly subjects have higher levels of pro-inflammatory cytokines, more circulating plasmablasts, reduced plasmatic level of anti-S and anti-RBD IgG3 antibodies, lower proportions of central memory CD4+ T cells, more immature monocytes and CD56+ pro-inflammatory monocytes, lower percentages of circulating follicular helper T cells (cTfh), antigen-specific cTfh cells with a less activated transcriptomic profile, lung resident activated macrophages that promote collagen deposition and fibrosis. Our study underlines the importance of inflammation in the response to SARS-CoV-2 and suggests that inflammaging, coupled with the inability to mount a proper anti-viral response, could exacerbate disease severity and the worst clinical outcome in old patients.

2022 - Nasal pressure swings as the measure of inspiratory effort in spontaneously breathing patients with de novo acute respiratory failure [Articolo su rivista]
Tonelli, Roberto; Cortegiani, Andrea; Marchioni, Alessandro; Fantini, Riccardo; Tabbì, Luca; Castaniere, Ivana; Biagioni, Emanuela; Busani, Stefano; Nani, Chiara; Cerbone, Caterina; Vermi, Morgana; Gozzi, Filippo; Bruzzi, Giulia; Manicardi, Linda; Rosaria Pellegrino, Maria; Beghè, Bianca; Girardis, Massimo; Pelosi, Paolo; Gregoretti, Cesare; Ball, Lorenzo; Clini, Enrico
abstract

Background- Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (ΔP es ) and nasal (ΔP nos ) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF. Methods- From January 1 st , 2021 to September 1 st , 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of noninvasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 hours after starting NRS. Correlation between ΔP es and ΔP nos served as primary outcome. The effect of ΔP nos measurements on respiratory rate and ΔP es was also assessed. Results- ΔP es and ΔP nos were strongly correlated at admission (R 2 =0.88, p<0.001) and 24 hours apart (R 2 =0.94, p<0.001). The nasal plug insertion and the mouth closure required for ΔP nos measurement did not result in significant change of respiratory rate and ΔP es . The correlation between measures at 24 hours remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [R 2 =0.79, p<0.001] or non-invasive ventilation [R 2 =0.95, p<0.001]). Conclusions- In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. ΔP nos might warrant further investigation as a measure of inspiratory effort in patients with ARF.

2022 - Patients Recovering from Severe COVID-19 Develop a Polyfunctional Antigen-Specific CD4+ T Cell Response [Articolo su rivista]
Paolini, A.; Borella, R.; Neroni, A.; Lo Tartaro, D.; Mattioli, M.; Fidanza, L.; Di Nella, A.; Santacroce, E.; Gozzi, L.; Busani, S.; Trenti, T.; Meschiari, M.; Guaraldi, G.; Girardis, M.; Mussini, C.; Gibellini, L.; De Biasi, S.; Cossarizza, A.
abstract

Specific T cells are crucial to control SARS-CoV-2 infection, avoid reinfection and confer protection after vaccination. We have studied patients with severe or moderate COVID-19 pneumonia, compared to patients who recovered from a severe or moderate infection that had occurred about 4 months before the analyses. In all these subjects, we assessed the polyfunctionality of virus-specific CD4+ and CD8+ T cells by quantifying cytokine production after in vitro stimulation with different SARS-CoV-2 peptide pools covering different proteins (M, N and S). In particular, we quantified the percentage of CD4+ and CD8+ T cells simultaneously producing interferon-γ, tumor necrosis factor, interleukin (IL)-2, IL-17, granzyme B, and expressing CD107a. Recovered patients who experienced a severe disease display high proportions of antigen-specific CD4+ T cells producing Th1 and Th17 cytokines and are characterized by polyfunctional SARS-CoV-2-specific CD4+ T cells. A similar profile was found in patients experiencing a moderate form of COVID-19 pneumonia. No main differences in polyfunctionality were observed among the CD8+ T cell compartments, even if the proportion of responding cells was higher during the infection. The identification of those functional cell subsets that might influence protection can thus help in better understanding the complexity of immune response to SARS-CoV-2.

2022 - Plasma Cytokine Atlas Reveals the Importance of TH2 Polarization and Interferons in Predicting COVID-19 Severity and Survival [Articolo su rivista]
Gibellini, L.; De Biasi, S.; Meschiari, M.; Gozzi, L.; Paolini, A.; Borella, R.; Mattioli, M.; Lo Tartaro, D.; Fidanza, L.; Neroni, A.; Busani, S.; Girardis, M.; Guaraldi, G.; Mussini, C.; Cozzi-Lepri, A.; Cossarizza, A.
abstract

Although it is now widely accepted that host inflammatory response contributes to COVID-19 immunopathogenesis, the pathways and mechanisms driving disease severity and clinical outcome remain poorly understood. In the effort to identify key soluble mediators that characterize life-threatening COVID-19, we quantified 62 cytokines, chemokines and other factors involved in inflammation and immunity in plasma samples, collected at hospital admission, from 80 hospitalized patients with severe COVID-19 disease who were stratified on the basis of clinical outcome (mechanical ventilation or death by day 28). Our data confirm that age, as well as neutrophilia, lymphocytopenia, procalcitonin, D-dimer and lactate dehydrogenase are strongly associated with the risk of fatal COVID-19. In addition, we found that cytokines related to TH2 regulations (IL-4, IL-13, IL-33), cell metabolism (lep, lep-R) and interferons (IFNα, IFNβ, IFNγ) were also predictive of life-threatening COVID-19.

2022 - Poor timing and failure of source control are risk factors for mortality in critically ill patients with secondary peritonitis [Articolo su rivista]
De Pascale, G.; Antonelli, M.; Deschepper, M.; Arvaniti, K.; Blot, K.; Brown, B. C.; de Lange, D.; De Waele, J.; Dikmen, Y.; Dimopoulos, G.; Eckmann, C.; Francois, G.; Girardis, M.; Koulenti, D.; Labeau, S.; Lipman, J.; Lipovetsky, F.; Maseda, E.; Montravers, P.; Mikstacki, A.; Paiva, J. A.; Pereyra, C.; Rello, J.; Timsit, J. F.; Vogelaers, D.; Blot, S.; Lamrous, A.; Lipovestky, F.; Rezende-Neto, J.; Vymazal, T.; Fjeldsoee-Nielsen, H.; Kott, M.; Kostoula, A.; Javeri, Y.; Einav, S.; Makikado, L. D. U.; Tomescu, D.; Gritsan, A.; Jovanovic, B.; Venkatesan, K.; Mirkovic, T.; Creagh-Brown, B.; Emmerich, M.; Canale, M.; Dietz, L. S.; Ilutovich, S.; Miñope, J. T. S.; Silva, R. B.; Montenegro, M. A.; Martin, P.; Saul, P.; Chediack, V.; Sutton, G.; Couce, R.; Balasini, C.; Gonzalez, S.; Lascar, F. M.; Descotte, E. J.; Gumiela, N. S.; Pino, C. A.; Cesio, C.; Valgolio, E.; Cunto, E.; Dominguez, C.; Lipovestky, F.; Nelson, N. F.; Abegao, E. M.; Pozo, N. C.; Bianchi, L.; Correger, E.; Pastorino, M. L.; Miyazaki, E. A.; Grubissich, N.; Garcia, M.; Bonetto, N.; Quevedo, N. E.; Gomez, C. D.; Queti, F.; Estevarena, L. G.; Fernandez, R.; Santolaya, I.; Pozo, N. C.; Grangeat, S. H.; Doglia, J.; Zakalik, G.; Pellegrini, C.; Lloria, M. M.; Chacon, M. E.; Fumale, M.; Leguizamon, M.; Hidalgo, I. B.; Tiranti, R. J. a.; Capponi, P.; Tita, A.; Cardonnet, L.; Bettini, L.; Ramos, A.; Lovesio, L.; Miranda, E. M.; Farfan, A. B.
abstract

Purpose To describe data on epidemiology, microbiology, clinical characteristics and outcome of adult patients admitted in the intensive care unit (ICU) with secondary peritonitis, with special emphasis on antimicrobial therapy and source control. Methods Post hoc analysis of a multicenter observational study (Abdominal Sepsis Study, AbSeS) including 2621 adult ICU patients with intra-abdominal infection in 306 ICUs from 42 countries. Time-till-source control intervention was calculated as from time of diagnosis and classified into 'emergency' (< 2 h), 'urgent' (2-6 h), and 'delayed' (> 6 h). Relationships were assessed by logistic regression analysis and reported as odds ratios (OR) and 95% confidence interval (CI). Results The cohort included 1077 cases of microbiologically confirmed secondary peritonitis. Mortality was 29.7%. The rate of appropriate empiric therapy showed no difference between survivors and non-survivors (66.4% vs. 61.3%, p = 0.1). A stepwise increase in mortality was observed with increasing Sequential Organ Failure Assessment (SOFA) scores (19.6% for a value <= 4-55.4% for a value > 12, p < 0.001). The highest odds of death were associated with septic shock (OR 3.08 [1.42-7.00]), late-onset hospital-acquired peritonitis (OR 1.71 [1.16-2.52]) and failed source control evidenced by persistent inflammation at day 7 (OR 5.71 [3.99-8.18]). Compared with 'emergency' source control intervention (< 2 h of diagnosis), 'urgent' source control was the only modifiable covariate associated with lower odds of mortality (OR 0.50 [0.34-0.73]). Conclusion 'Urgent' and successful source control was associated with improved odds of survival. Appropriateness of empirical antimicrobial treatment did not significantly affect survival suggesting that source control is more determinative for outcome.

2022 - Risk Factors for Intra-Abdominal Candidiasis in Intensive Care Units: Results from EUCANDICU Study [Articolo su rivista]
Bassetti, M.; Vena, A.; Giacobbe, D. R.; Trucchi, C.; Ansaldi, F.; Antonelli, M.; Adamkova, V.; Alicino, C.; Almyroudi, M. -P.; Atchade, E.; Azzini, A. M.; Brugnaro, P.; Carannante, N.; Peghin, M.; Berruti, M.; Carnelutti, A.; Castaldo, N.; Corcione, S.; Cortegiani, A.; Dimopoulos, G.; Dubler, S.; Garcia-Garmendia, J. L.; Girardis, M.; Cornely, O. A.; Ianniruberto, S.; Kullberg, B. J.; Lagrou, K.; Lebihan, C.; Luzzati, R.; Malbrain, M.; Merelli, M.; Marques, A. J.; Martin-Loeches, I.; Mesini, A.; Paiva, J. -A.; Raineri, S. M.; Rautemaa-Richardson, R.; Schouten, J.; Spapen, H.; Tasioudis, P.; Timsit, J. -F.; Tisa, V.; Tumbarello, M.; Van den Berg, C. H. S. B.; Veber, B.; Venditti, M.; Voiriot, G.; Wauters, J.; Zappella, N.; Montravers, P.
abstract

Introduction: Intra-abdominal infections represent the second most frequently acquired infection in the intensive care unit (ICU), with mortality rates ranging from 20% to 50%. Candida spp. may be responsible for up to 10–30% of cases. This study assesses risk factors for development of intra-abdominal candidiasis (IAC) among patients admitted to ICU. Methods: We performed a case–control study in 26 European ICUs during the period January 2015–December 2016. Patients at least 18 years old who developed an episode of microbiologically documented IAC during their stay in the ICU (at least 48 h after admission) served as the case cohort. The control group consisted of adult patients who did not develop episodes of IAC during ICU admission. Matching was performed at a ratio of 1:1 according to time at risk (i.e. controls had to have at least the same length of ICU stay as their matched cases prior to IAC onset), ICU ward and period of study. Results: During the study period, 101 case patients with a diagnosis of IAC were included in the study. On univariate analysis, severe hepatic failure, prior receipt of antibiotics, prior receipt of parenteral nutrition, abdominal drain, prior bacterial infection, anastomotic leakage, recurrent gastrointestinal perforation, prior receipt of antifungal drugs and higher median number of abdominal surgical interventions were associated with IAC development. On multivariate analysis, recurrent gastrointestinal perforation (OR 13.90; 95% CI 2.65–72.82, p = 0.002), anastomotic leakage (OR 6.61; 95% CI 1.98–21.99, p = 0.002), abdominal drain (OR 6.58; 95% CI 1.73–25.06, p = 0.006), prior receipt of antifungal drugs (OR 4.26; 95% CI 1.04–17.46, p = 0.04) or antibiotics (OR 3.78; 95% CI 1.32–10.52, p = 0.01) were independently associated with IAC. Conclusions: Gastrointestinal perforation, anastomotic leakage, abdominal drain and prior receipt of antifungals or antibiotics may help to identify critically ill patients with higher probability of developing IAC. Prospective studies are needed to identify which patients will benefit from early antifungal treatment.

2022 - Risk factors for pulmonary air leak and clinical prognosis in patients with COVID-19 related acute respiratory failure: a retrospective matched control study. [Articolo su rivista]
Tonelli, Roberto; Bruzzi, Giulia; Manicardi, Linda; Tabbì, Luca; Fantini, Riccardo; Castaniere, Ivana; Andrisani, Dario; Gozzi, Filippo; Rosaria Pellegrino, Maria; Trentacosti, Fabiana; Dall'Ara, Lorenzo; Busani, Stefano; Franceschini, Erica; Baroncini, Serena; Manco, Gianrocco; Meschiari, Marianna; Mussini, Cristina; Girardis, Massimo; Beghe', Bianca; Marchioni, Alessandro; Clini, Enrico
abstract

Background- The role of excessive inspiratory effort in promoting alveolar and pleural rupture resulting in air leak (AL) in patients with SARS-CoV-2 induced acute respiratory failure (ARF) while on spontaneous breathing is undetermined. Methods- Among all patients with COVID-19 related ARF admitted to a respiratory intensive care unit (RICU) and receiving non-invasive respiratory support, those developing an AL were and matched 1:1 (by means of PaO2/FiO2 ratio, age, body mass index-BMI and subsequent organ failure assessment [SOFA]) with a comparable population who did not (NAL group). Esophageal pressure (ΔPes) and dynamic transpulmonary pressure (ΔPL) swings were compared between groups. Risk factors affecting AL onset were evaluated. The composite outcome of ventilator-free-days (VFD) at day 28 (including ETI, mortality, tracheostomy) was compared between groups. Results- AL and NAL groups (n=28) showed similar ΔPes, whereas AL had higher ΔPL (20 [16‐21] and 17 [11‐20], p=0.01 respectively). Higher ΔPL (OR=1.5 95%CI[1‐1.8], p=0.01), positive end‐expiratory pressure (OR=2.4 95%CI[1.2‐5.9], p=0.04) and pressure support (OR=1.8 95%CI[1.1-3.5], p=0.03), D-dimer on admission (OR=2.1 95%CI[1.3-9.8], p=0.03), and features suggestive of consolidation on computed tomography scan (OR=3.8 95%CI[1.1-15], p= 0.04) were all significantly associated with AL. A lower VFD score resulted in a higher risk (HR=3.7 95%CI [1.2-11.3], p=0.01) in the AL group compared with NAL. RICU stay and 90-day mortality were also higher in the AL group compared with NAL. Conclusions- In spontaneously breathing patients with COVID‐19 related ARF, higher levels of ΔPL, blood D‐dimer, NIV delivery pressures and a consolidative lung pattern were associated with AL onset.

2022 - Source control in the management of sepsis and septic shock [Articolo su rivista]
De Waele, J. J.; Girardis, M.; Martin-Loeches, I.
abstract

2022 - The PROVENT-C19 registry: A study protocol for international multicenter SIAARTI registry on the use of prone positioning in mechanically ventilated patients with COVID-19 ARDS [Articolo su rivista]
De Rosa, S.; Sella, N.; Rezoagli, E.; Lorenzoni, G.; Gregori, D.; Bellani, G.; Foti, G.; Pettenuzzo, T.; Baratto, F.; Fullin, G.; Papaccio, F.; Peta, M.; Poole, D.; Toffoletto, F.; Maggiore, S. M.; Navales, P.; Navalesi, P.; Tiberio, I.; Pasin, L.; Godi, I.; Serra, E.; Zarantonello, F.; Andreatta, G.; Boscolo, A.; Persona, P.; Cattin, L.; Forin, E.; Boni, E.; Golino, G.; Danzi, V.; Vetrugno, L.; Cornacchia, N.; Donadello, K.; Gottin, L.; Polati, E.; Campagnolo, M.; Linassi, F.; Panciera, G.; Garofalo, E.; Bruni, A.; Carlon, R.; Pipitone, M.; Serra, E.; Candosin, A.; Badii, F.; Role, S. D.; Girardis, M.; Busani, S.; Gamberini, E.; Tartivita, C. N.; Gamberini, L.; Cortegiani, A.; Frisella, S.; Ippolito, M.; Salvo, F.; Greco, M.; Cecconi, M.; Aceto, R.; Langer, T.; Repishti, M.; Zeduri, A.; Ottolina, D.; Fossali, T.; Colombo, R.; Predonzani, N.; Ferluga, M.; Blasi, S. D.; Zardin, M.; Vergine, S.; Luccarelli, G.; Tritapepe, L.; Francesconi, A. G.; Pagani, M.; Mojoli, F.; Orlando, A.; Mongodi, S.; Bitondo, M.; Johnathan, M.; Maugeri, J.; Bellissima, A.; Guzzardella, A.; Vallecoccia, M. S.; Spadaro, S.; Cricca, V.; Andriolo, E.; Bianchin, A.; Alampi, D.; Rocco, M.; Anchisi, S.; Tenaglia, T.; Nicoletti, R.; Antonini, B.; Zanaty, M.; Mogahed, M.; Ali, A.; Emara, M.; Abdullah, E.; Awad, A. K.; Abdel-Maboud, M.; Hussein, A. M.; Hussein, A. A. R. M.; Mosleh, A. A.; Ahmed, M. G.; Aziz, M. G.; Elsayed, A.; Aldhalia, A.; Elkhatid, A.; Abodina, A. M.; Khalleefah, A.; Shalabi, L. E.; Shamed, H.; Bakeer, H. B.; Hawad, A.; Abuzaid, T.; Alqandouz, R. A. S.; Saliga, A. A.; Haddud, A.; Kredan, A. A.; Shaban, M. S.; Salama, A. A.; Altabit, A. E. R. M.; Alflite, A. O. S.; Hashim, H. T.; Kadhim, Q. M.; Abd-Alreda, A. H.; Al-Juifari, M. A.; Al-Gburi, S. M.; Akram, A.; Laila, A.; Bakri, A.; Abdelmageed, A.; Binnawara, M.; Mohamed, M.; Esaadi, H.; Othman, E.; Said, A.; Alarabi, R.; Alameen, H.; Albouishi, N.; Babaa, K. A.; Salih, R.; Elbakheet, D. E.; Abuelyamen, A.; Perez-Torres, D.; Mattson, J.; Al-Sadawi, M.; Elseidy, S.
abstract

Background The worldwide use of prone position (PP) for invasively ventilated patients with COVID-19 is progressively increasing from the first pandemic wave in everyday clinical practice. Among the suggested treatments for the management of ARDS patients, PP was recommended in the Surviving Sepsis Campaign COVID-19 guidelines as an adjuvant therapy for improving ventilation. In patients with severe classical ARDS, some authors reported that early application of prolonged PP sessions significantly decreases 28-day and 90-day mortality. Methods and analysis Since January 2021, the COVID19 Veneto ICU Network research group has developed and implemented nationally and internationally the "PROVENT-C19 Registry", endorsed by the Italian Society of Anesthesia Analgesia Resuscitation and Intensive Care. . .'(SIAARTI). The PROVENT-C19 Registry wishes to describe 1. The real clinical practice on the use of PP in COVID-19 patients during the pandemic at a National and International level; and 2. Potential baseline and clinical characteristics that identify subpopulations of invasively ventilated patients with COVID-19 that may improve daily from PP therapy. This web-based registry will provide relevant information on how the database research tools may improve our daily clinical practice. Conclusions This multicenter, prospective registry is the first to identify and characterize the role of PP on clinical outcome in COVID-19 patients. In recent years, data emerging from large registries have been increasingly used to provide real-world evidence on the effectiveness, quality, and safety of a clinical intervention. Indeed observation-based registries could be effective tools aimed at identifying specific clusters of patients within a large study population with widely heterogeneous clinical characteristics. Copyright:

2022 - The effect of non-invasive ventilation on intra-abdominal pressure [Articolo su rivista]
Regli, A.; Nanda, R.; Braun, J. P.; Girardis, M.; Max, M.; Malbrain, M. L.; De Keulenaer, B. L.
abstract

Background: Non-invasive ventilation is a well-established treatment modality in patients with respiratory failure of different aetiologies. A previous case report described how non-invasive ventilation caused gastric distension and intra-abdominal hypertension with subsequent cardio-respiratory arrest and clinical recovery following resuscitative efforts including gastric decompression with a nasogastric tube. Methods: The aim of this prospective multicentre observational study was to assess the effect of non-invasive ventilation on intra-abdominal pressure. Following informed consent, intra-abdominal pressure and PaCO2were measured before and after the application of non-invasive ventilation for up to three days in critically ill patients requiring non-invasive ventilation. Results: Thirty-five patients were enrolled; mean (±SD) age of 67.8 (±12.5) years, median (interquartile range) body mass index of 27.9 (24.5-30.0) kg m-2, Acute Physiology and Chronic Health Evaluation II score of 15.8 (±6.4). On admission and after 24 hours of non-invasive ventilation, intra-abdominal pressure was 11.0 (7.5-15.0) mm Hg and 11.0 (8.5-14.5) mm Hg (P = 0.82) and PaCO2was 44.4 (±11.4) mm Hg and 51.3 (±14.3) mm Hg (P = 0.19), respectively. Conclusions: The application of non-invasive ventilation was not associated with an increase in intra-abdominal pressure over 72 hours in this small observational study. Thus, it appears that intra-abdominal pressure does not frequently increase when applying non-invasive ventilation in critically ill patients with respiratory failure.

2022 - The effects of exposure to severe hyperoxemia on neurological outcome and mortality after cardiac arrest [Articolo su rivista]
la Via, L.; Astuto, M.; Bignami, E. G.; Busalacchi, D.; Dezio, V.; Girardis, M.; Lanzafame, B.; Ristagno, G.; Pelosi, P.; Sanfilippo, F.
abstract

INTRODUCTION: Hyperoxemia during cardiac arrest (CA) may increase chances of successful resuscitation. However, episodes of severe hyperoxemia after intensive care unit admission occurs frequently (up to 60%), and these have been associated with higher mortality in CA patients. The impact of severe hyperoxemia on neurological outcome is more unclear. EVIDENCE ACQUISITION: We conducted a systematic review and meta-analysis on Pubmed and EMBASE to evaluate the effects of severe hyperoxemia according to arterial blood gas analysis on neurological outcome and mortality in patients resuscitated from CA and admitted to intensive care unit. EVIDENCE SYNTHESIS: Thirteen observational studies were included, eight of them reporting data on neurological outcome and ten on mortality. Most studies reported odds ratio adjusted for confounders. Severe hyperoxemia was associated with worse neurological outcome (OR 1.37 [95%CI 1.01,1.86], P=0.04) and higher mortality at longest follow-up (OR 1.32 [95%CI 1.11,1.57], P=0.002). Subgroup analyses according to timing of hyperoxemia showed that any hyperoxemia during the first 36 hours was associated with worse neurological outcome (OR 1.52 [95%CI 1.12,2.08], P=0.008) and higher mortality (OR 1.40 [95%CI 1.18,1.66], P=0.0001), whilst early hyperoxemia was not (neurological: P=0.29; mortality: P=0.19). Sensitivity analyses mostly confirmed the results of the primary analyses. CONCLUSIONS: Severe hyperoxemia is associated with worse neurological outcome and lower survival in CA survivors admitted to intensive care unit. Clinical efforts should be made to avoid severe hyperoxemia during at least the first 36 hours after cardiac arrest.

2022 - Whole-genome sequencing reveals host factors underlying critical COVID-19 [Articolo su rivista]
Kousathanas, A.; Pairo-Castineira, E.; Rawlik, K.; Stuckey, A.; Odhams, C. A.; Walker, S.; Russell, C. D.; Malinauskas, T.; Wu, Y.; Millar, J.; Shen, X.; Elliott, K. S.; Griffiths, F.; Oosthuyzen, W.; Morrice, K.; Keating, S.; Wang, B.; Rhodes, D.; Klaric, L.; Zechner, M.; Parkinson, N.; Siddiq, A.; Goddard, P.; Donovan, S.; Maslove, D.; Nichol, A.; Semple, M. G.; Zainy, T.; Maleady-Crowe, F.; Todd, L.; Salehi, S.; Knight, J.; Elgar, G.; Chan, G.; Arumugam, P.; Patch, C.; Rendon, A.; Bentley, D.; Kingsley, C.; Kosmicki, J. A.; Horowitz, J. E.; Baras, A.; Abecasis, G. R.; Ferreira, M. A. R.; Justice, A.; Mirshahi, T.; Oetjens, M.; Rader, D. J.; Ritchie, M. D.; Verma, A.; Fowler, T. A.; Shankar-Hari, M.; Summers, C.; Hinds, C.; Horby, P.; Mcauley, D.; Montgomery, H.; Openshaw, P. J. M.; Elliott, P.; Walsh, T.; Tenesa, A.; Fawkes, A.; Murphy, L.; Rowan, K.; Ponting, C. P.; Vitart, V.; Wilson, J. F.; Yang, J.; Bretherick, A. D.; Scott, R. H.; Hendry, S. C.; Moutsianas, L.; Law, A.; Caulfield, M. J.; Baillie, J. K.; Begg, C.; Ling, L.; Millar, J.; Pereira, A. C.; Aravindan, L.; Armstrong, R.; Biggs, H.; Boz, C.; Brown, A.; Clark, R.; Coutts, A.; Coyle, J.; Cullum, L.; Das, S.; Day, N.; Donnelly, L.; Duncan, E.; Finernan, P.; Fourman, M. H.; Furlong, A.; Furniss, J.; Gallagher, B.; Gilchrist, T.; Golightly, A.; Hafezi, K.; Hamilton, D.; Hendry, R.; Law, D.; Law, R.; Law, S.; Lidstone-Scott, R.; Macgillivray, L.; Maclean, A.; Mal, H.; Mccafferty, S.; Mcmaster, E.; Meikle, J.; Moore, S. C.; Murphy, S.; Hellen, M.; Zheng, C.; Chen, J.; Paterson, T.; Schon, K.; Stenhouse, A.; Das, M.; Swets, M.; Szoor-McElhinney, H.; Taneski, F.; Turtle, L.; Wackett, T.; Ward, M.; Weaver, J.; Wrobel, N.; Arbane, G.; Bociek, A.; Campos, S.; Grau, N.; Jones, T. O.; Lim, R.; Marotti, M.; Ostermann, M.; Whitton, C.; Alldis, Z.; Astin-Chamberlain, R.; Bibi, F.; Biddle, J.; Blow, S.; Bolton, M.; Borra, C.; Bowles, R.; Burton, M.; Choudhury, Y.; Collier, D.; Cox, A.; Easthope, A.; Ebano, P.; Fotiadis, S.; Gurasashvili, J.; Halls, R.; Hartridge, P.; Kallon, D.; Kassam, J.; Lancoma-Malcolm, I.; Matharu, M.; May, P.; Mitchelmore, O.; Newman, T.; Patel, M.; Pheby, J.; Pinzuti, I.; Prime, Z.; Prysyazhna, O.; Shiel, J.; Taylor, M.; Tierney, C.; Wood, S.; Zak, A.; Zongo, O.; Bonner, S.; Hugill, K.; Jones, J.; Liggett, S.; Headlam, E.; Bandla, N.; Gellamucho, M.; Davies, M.; Thompson, C.; Abdelrazik, M.; Bakthavatsalam, D.; Elhassan, M.; Ganesan, A.; Haldeos, A.; Moreno-Cuesta, J.; Purohit, D.; Vincent, R.; Xavier, K.; Kumar, R.; Frater, A.; Saleem, M.; Carter, D.; Jenkins, S.; Lamond, Z.; Wall, A.; Fernandez-Roman, J.; Hamilton, D. O.; Johnson, E.; Johnston, B.; Martinez, M. L.; Mulla, S.; Shaw, D.; Waite, A. A. C.; Waugh, V.; Welters, I. D.; Williams, K.; Cavazza, A.; Cockrell, M.; Corcoran, E.; Depante, M.; Finney, C.; Jerome, E.; Mcphail, M.; Nayak, M.; Noble, H.; O'Reilly, K.; Pappa, E.; Saha, R.; Saha, S.; Smith, J.; Knighton, A.; Antcliffe, D.; Banach, D.; Brett, S.; Coghlan, P.; Fernandez, Z.; Gordon, A.; Rojo, R.; Arias, S. S.; Templeton, M.; Meredith, M.; Morris, L.; Ryan, L.; Clark, A.; Sampson, J.; Peters, C.; Dent, M.; Langley, M.; Ashraf, S.; Wei, S.; Andrew, A.; Bashyal, A.; Davidson, N.; Hutton, P.; Mckechnie, S.; Wilson, J.; Baptista, D.; Crowe, R.; Fernandes, R.; Herdman-Grant, R.; Joseph, A.; O'Connor, D.; Allen, M.; Loveridge, A.; Mckenley, I.; Morino, E.; Naranjo, A.; Simms, R.; Sollesta, K.; Swain, A.; Venkatesh, H.; Khera, J.; Fox, J.; Andrew, G.; Barclay, L.; Callaghan, M.; Campbell, R.; Clark, S.; Hope, D.; Marshall, L.; Mcculloch, C.; Briton, K.; Singleton, J.; Birch, S.; Brimfield, L.; Daly, Z.; Pogson, D.; Rose, S.; Nown, A.; Battle, C.; Brinkworth, E.; Harford, R.; Murphy, C.; Newey, L.; Rees, T.; Williams, M.; Arnold, S.; Polgarova, P.; Stroud, K.; Meaney, E.; Jones, M.; Ng, A.; Agrawal, S.; Pathan, N.; White, D.; Daubney, E.; Elston, K.; Grauslyte, L.; Hussain, M.; Phull, M.; Pogreban, T.; Rosaroso, L.; Salciute, E.; Franke, G.; Wong, J.
abstract

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

2021 - A five-component infection control bundle to permanently eliminate a carbapenem-resistant Acinetobacter baumannii spreading in an intensive care unit [Articolo su rivista]
Meschiari, Marianna; Lòpez-Lozano, José-María; Di Pilato, Vincenzo; Gimenez-Esparza, Carola; Vecchi, Elena; Bacca, Erica; Orlando, Gabriella; Franceschini, Erica; Sarti, Mario; Pecorari, Monica; Grottola, Antonella; Venturelli, Claudia; Busani, Stefano; Serio, Lucia; Girardis, Massimo; Rossolini, Gian Maria; Gyssens, Inge C; Monnet, Dominique L; Mussini, Cristina
abstract

Carbapenem-resistant Acinetobacter baumannii (CRAB) infection outbreaks are difficult to control and sometimes require cohorting of CRAB-positive patients or temporary ward closure for environmental cleaning. We aimed at controlling the deadly 2018 CRAB outbreak in a 12 bed- intensive care unit (ICU) including 9 beds in a 220 m2 open space. We implemented a new multimodal approach without ward closure, cohorting or temporarily limiting admissions.

2021 - A pandemic recap: lessons we have learned [Articolo su rivista]
Coccolini, F.; Cicuttin, E.; Cremonini, C.; Tartaglia, D.; Viaggi, B.; Kuriyama, A.; Picetti, E.; Ball, C.; Abu-Zidan, F.; Ceresoli, M.; Turri, B.; Jain, S.; Palombo, C.; Guirao, X.; Rodrigues, G.; Gachabayov, M.; Machado, F.; Eftychios, L.; Kanj, S. S.; Di Carlo, I.; Di Saverio, S.; Khokha, V.; Kirkpatrick, A.; Massalou, D.; Forfori, F.; Corradi, F.; Delibegovic, S.; Machain Vega, G. M.; Fantoni, M.; Demetriades, D.; Kapoor, G.; Kluger, Y.; Ansari, S.; Maier, R.; Leppaniemi, A.; Hardcastle, T.; Vereczkei, A.; Karamagioli, E.; Pikoulis, E.; Pistello, M.; Sakakushev, B. E.; Navsaria, P. H.; Galeiras, R.; Yahya, A. I.; Osipov, A. V.; Dimitrov, E.; Doklestic, K.; Pisano, M.; Malacarne, P.; Carcoforo, P.; Sibilla, M. G.; Kryvoruchko, I. A.; Bonavina, L.; Kim, J. I.; Shelat, V. G.; Czepiel, J.; Maseda, E.; Marwah, S.; Chirica, M.; Biancofiore, G.; Podda, M.; Cobianchi, L.; Ansaloni, L.; Fugazzola, P.; Seretis, C.; Gomez, C. A.; Tumietto, F.; Malbrain, M.; Reichert, M.; Augustin, G.; Amato, B.; Puzziello, A.; Hecker, A.; Gemignani, A.; Isik, A.; Cucchetti, A.; Nacoti, M.; Kopelman, D.; Mesina, C.; Ghannam, W.; Ben-Ishay, O.; Dhingra, S.; Coimbra, R.; Moore, E. E.; Cui, Y.; Quiodettis, M. A.; Bala, M.; Testini, M.; Diaz, J.; Girardis, M.; Biffl, W. L.; Hecker, M.; Sall, I.; Boggi, U.; Materazzi, G.; Ghiadoni, L.; Matsumoto, J.; Zuidema, W. P.; Ivatury, R.; Enani, M. A.; Litvin, A.; Al-Hasan, M. N.; Demetrashvili, Z.; Baraket, O.; Ordonez, C. A.; Negoi, I.; Kiguba, R.; Memish, Z. A.; Elmangory, M. M.; Tolonen, M.; Das, K.; Ribeiro, J.; O'Connor, D. B.; Tan, B. K.; Van Goor, H.; Baral, S.; De Simone, B.; Corbella, D.; Brambillasca, P.; Scaglione, M.; Basolo, F.; De'Angelis, N.; Bendinelli, C.; Weber, D.; Pagani, L.; Monti, C.; Baiocchi, G.; Chiarugi, M.; Catena, F.; Sartelli, M.
abstract

On January 2020, the WHO Director General declared that the outbreak constitutes a Public Health Emergency of International Concern. The world has faced a worldwide spread crisis and is still dealing with it. The present paper represents a white paper concerning the tough lessons we have learned from the COVID-19 pandemic. Thus, an international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making. With the present paper, international and heterogenous multidisciplinary panel of very differentiated people would like to share global experiences and lessons with all interested and especially those responsible for future healthcare decision making.

2021 - Acquisition of skills in critical emergency medicine: An experimental study on the SIAARTI Academy CREM experience [Articolo su rivista]
Battaglini, D.; Ionescu Maddalena, A.; Caporusso, R. R.; Garofalo, E.; Bruni, A.; Bocci, M. G.; Cingolani, E.; Giarratano, A.; Petrini, F.; Astuto, M.; Barelli, A.; Bressan, F.; Cinnella, G.; Girardis, M.; Grasselli, G.; Ingrassia, P. L.; Menarini, M.; Pelaia, P.; Pelosi, P.; Rocco, M.; Tritapepe, L.
abstract

BACKGROUND: In 2019 the SIAARTI developed a seven-days course for residents, focused on critical emergency medicine (CREM) in a hostile environment, that grounds on simulation-based education and training with hands-on simulation, high-fidelity simulators and part-task trainers. This project aimed to evaluate the efficacy of this course in comparison to traditional learning programs in term of technical (TS) and non-technical (NTS) skills. We assessed the improvement in TS and NTS over time, and the ability to involve trainees in corporate activities. METHODS: Three-hundred and twenty-seven trainees completed the study. Trainees were allocated into three groups: those who joined the SIAARTI-Academy-CREM course and received a study kit (SA-kit, N.=124), those who received only a study kit (kit, N.=108), and control (N.=95). Eighty-five tests were administered to investigate skills at three time-points: T0 (baseline), T1 (post-training/kit), and T2 (four months later). RESULTS: TS differed among groups (P<0.0001), with the highest points in the SA-kit group at T1 (post-hoc comparison, P<0.0001 vs. kit; P<0.0001 vs. control), and T2 (post-hoc comparison, P<0.0001 vs. kit; P<0.0001 vs. control). NTS differed among groups (P=0.0406), with the highest points in the SA-kit group at T1 (post-hoc comparison, P=0.0337 vs. kit; P=0.0416 vs. control), and T2 (post-hoc comparison, P=0.0073 vs. kit; P=0.3308 vs. control). SA-kit group significantly improved TS (P<0.0001) and NTS (P=0.0006) over time. Involvement in corporate activities of SA-kit was significantly higher than kit and control (P=0.0012). CONCLUSIONS: SA-kit improvement in TS and NTS was higher than kit and control and was maintained over time. Participation in this course implemented participation in corporate activities among attendees.

2021 - Adjunctive IgM-enriched immunoglobulin therapy with a personalised dose based on serum igm-titres versus standard dose in the treatment of septic shock: A randomised controlled trial (igm-fat trial) [Articolo su rivista]
Biagioni, E.; Tosi, M.; Berlot, G.; Castiglione, G.; Corona, A.; De Cristofaro, M. G.; Donati, A.; Feltracco, P.; Forfori, F.; Fragranza, F.; Murino, P.; Piazza, O.; Tullo, L.; Grasselli, G.; D'Amico, R.; Girardis, M.
abstract

Introduction In patients with septic shock, low levels of circulating immunoglobulins are common and their kinetics appear to be related to clinical outcome. The pivotal role of immunoglobulins in the host immune response to infection suggests that additional therapy with polyclonal intravenous immunoglobulins may be a promising option in patients with septic shock. Immunoglobulin preparations enriched with the IgM component have largely been used in sepsis, mostly at standard dosages (250 mg/kg per day), regardless of clinical severity and without any dose adjustment based on immunoglobulin serum titres or other biomarkers. We hypothesised that a personalised dose of IgM enriched preparation based on patient IgM titres and aimed to achieve a specific threshold of IgM titre is more effective in decreasing mortality than a standard dose. Methods and analysis The study is designed as a multicentre, interventional, randomised, single-blinded, prospective, investigator sponsored, two-armed study. Patients with septic shock and IgM titres <60 mg/dL will be randomly assigned to an IgM titre-based treatment or a standard treatment group in a ratio of 1:1. The study will involve 12 Italian intensive care units and 356 patients will be enrolled. Patients assigned to the IgM titre-based treatment will receive a personalised daily dose based on an IgM serum titre aimed at achieving serum titres above 100 mg/dL up to discontinuation of vasoactive drugs or day 7 after enrolment. Patients assigned to the IgM standard treatment group will receive IgM enriched preparation daily for three consecutive days at the standard dose of 250 mg/kg. The primary endpoint will be all-cause mortality at 28 days. Ethics and dissemination The study protocol was approved by the ethics committees of the coordinating centre (Comitato Etico dell'Area Vasta Emilia Nord) and collaborating centres. The results of the trial will be published within 12 months from the end of the study and the steering committee has the right to present them at public symposia and conferences. Trial registration details The trial protocol and information documents have received a favourable opinion from the Area Vasta Emilia Nord Ethical Committee on 12 September 2019. The trial protocol has been registered on EudraCT (2018-001613-33) on 18 April 2018 and on ClinicalTrials.gov (NCT04182737) on 2 December 2019.

2021 - Adjunctive Immunotherapy With Polyclonal Ig-M Enriched Immunoglobulins for Septic Shock: From Bench to Bedside. The Rationale for a Personalized Treatment Protocol [Articolo su rivista]
Busani, Stefano; Roat, Erika; Tosi, Martina; Biagioni, Emanuela; Coloretti, Irene; Meschiari, Marianna; Gelmini, Roberta; Brugioni, Lucio; DE BIASI, Sara; Girardis, Massimo
abstract

Septic shock still has a high mortality rate which has not hinted at decreasing in recent years. Unfortunately, randomized trials failed mainly because the septic patient was considered as a homogeneous entity. All this creates a sort of therapeutic impotence in everyday clinical practice in treating patients with septic shock. The need to customize therapy on each patient with sepsis has now become an established necessity. In this scenario, adjuvant therapies can help if interpreted as modulators of the immune system. Indeed, the host’s immune response differs from patient to patient based on the virulence of the pathogen, comorbidity, infection site, and prolonged hospitalization. In this review, we summarize the rationale for using immunoglobulins as an adjunctive treatment. Furthermore, we would like to suggest a possible protocol to personalize treatment in the different clinical scenarios of the host’s response to serious infectious events.

2021 - An update on levosimendan in acute cardiac care: applications and recommendations for optimal efficacy and safety [Articolo su rivista]
Heringlake, M.; Alvarez, J.; Bettex, D.; Bouchez, S.; Fruhwald, S.; Girardis, M.; Grossini, E.; Guarracino, F.; Herpain, A.; Toller, W.; Tritapepe, L.; Pollesello, P.
abstract

Introduction: In the 20 years since its introduction to the palette of intravenous hemodynamic therapies, the inodilator levosimendan has established itself as a valuable asset for the management of acute decompensated heart failure. Its pharmacology is notable for delivering inotropy via calcium sensitization without an increase in myocardial oxygen consumption. Areas covered: Experience with levosimendan has led to its applications expanding into perioperative hemodynamic support and various critical care settings, as well as an array of situations associated with acutely decompensated heart failure, such as right ventricular failure, cardiogenic shock with multi-organ dysfunction, and cardio-renal syndrome. Evidence suggests that levosimendan may be preferable to milrinone for patients in cardiogenic shock after cardiac surgery or for weaning from extracorporeal life support and may be superior to dobutamine in terms of short-term survival, especially in patients on beta-blockers. Positive effects on kidney function have been noted, further differentiating levosimendan from catecholamines and phosphodiesterase inhibitors. Expert opinion:Levosimendan can be a valuable resource in the treatment of acute cardiac dysfunction, especially in the presence of beta-blockers or ischemic cardiomyopathy. When attention is given to avoiding or correcting hypovolemia and hypokalemia, an early use of the drug in the treatment algorithm is preferred.

2021 - Association of toll-like receptor 7 variants with life-threatening COVID-19 disease in males: Findings from a nested case-control study [Articolo su rivista]
Fallerini, C.; Daga, S.; Mantovani, S.; Benetti, E.; Picchiotti, N.; Francisci, D.; Paciosi, F.; Schiaroli, E.; Baldassarri, M.; Fava, F.; Palmieri, M.; Ludovisi, S.; Castelli, F.; Quiros-Roldan, E.; Vaghi, M.; Rusconi, S.; Siano, M.; Bandini, M.; Spiga, O.; Capitani, K.; Furini, S.; Mari, F.; Renieri, A.; Mondelli, M. U.; Frullanti, E.; Valentino, F.; Doddato, G.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Croci, S.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Sarno, L. D.; Beligni, G.; Tommasi, A.; Iuso, N.; Montagnani, F.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bargagli, E.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Romani, D.; Piacentini, P.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; D'Arminio Monforte, A.; Miraglia, F. G.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Gabrieli, A.; Riva, A.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Baratti, S.; Antoni, M. D.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Gori, M.; Crotti, L.; Parati, G.; Gabbi, C.; Zanella, I.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Chiariello, M.; Belli, M. A.; Dei, S.
abstract

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients. Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.

2021 - Author Correction: Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection (Nature Communications, (2021), 12, 1, (4677), 10.1038/s41467-021-24940-w) [Articolo su rivista]
De Biasi, S.; Tartaro, D. L.; Gibellini, L.; Paolini, A.; Quong, A.; Petes, C.; Awong, G.; Douglas, S.; Lin, D.; Nieto, J.; Galassi, F. M.; Borella, R.; Fidanza, L.; Mattioli, M.; Leone, C.; Neri, I.; Meschiari, M.; Cicchetti, L.; Iannone, A.; Trenti, T.; Sarti, M.; Girardis, M.; Guaraldi, G.; Mussini, C.; Facchinetti, F.; Cossarizza, A.
abstract

The original version of this Article contained an error in Table 1. The correct version of the first row of the 2nd, 3rd, 5th and 7th columns states ‘CTR’, ‘PN’, ‘CTR vs PN’ and ‘PN vs PP’, instead of the original, incorrect ‘HD’, ‘NP’, ‘CTR vs NP’ and ‘CTR vs PP’. This has been corrected in both the PDF and HTML versions of the Article.

2021 - Better prognosis in females with severe COVID-19 pneumonia: possible role of inflammation as potential mediator. [Articolo su rivista]
Mussini, C; Cozzi-Lepri, A; Menozzi, M; Meschiari, M; Franceschini, E; Rogati, C; Cuomo, G; Bedini, A; Iadisernia, M; Volpi, S; Milic, J; Tonelli, R; Brugioni, L; Pietrangelo, A; Girardis, M; Cossarizza, A; Clini, E; Guaraldi, G.; De biasi, S; Gibellini, Lara
abstract

Objectives: Sex differences in COVID-19 severity and mortality have been described. Key aims of this analysis were to compare the risk of invasive mechanical ventilation (IMV) and mortality by sex and to explore whether variation in specific biomarkers could mediate this difference. Methods: This was a retrospective, observational cohort study among patients with severe COVID- 19 pneumonia. A survival analysis was conducted to compare time to the composite endpoint of IMV or death by sex. Interaction was formally tested to compare the risk difference by sex in subsets. Mediation analysis with a binary endpoint IMV or death (yes/no) by end of follow-up for a number of inflammation/coagulation biomarkers in the context of counterfactual prediction was also conducted. Results: Among 415 patients, 134 were females (32%) and 281 males (67%), median age 66 years (IQR 54-77). At admission, females showed a significantly less severe clinical and respiratory profiles with a higher PaO2/FiO2 (254 mmHg vs 191 mmHg; p=0.023). By 28 days from admission, 49.2% (95% CI: 39.6-58.9%) of males vs. 31.7% (17.9-45.4%) of females underwent IMV or death (log-rank pvalue<0.0001) and this amounted to a difference in HR of 0.40 (0.26-0.63, p=0.0001). The AUC in Creactive protein (CRP) over the study period appeared to explain 85% of this difference in risk by sex. Conclusions: Our analysis confirms a difference in the risk of COVID-19 clinical progression by sex and provides a hypothesis for potential mechanisms leading to this. CRP showed a predominant role to mediate the difference in risk by sex.

2021 - Bridging animal and clinical research during SARS-CoV-2 pandemic: A new-old challenge [Articolo su rivista]
Winkler, M. S.; Skirecki, T.; Brunkhorst, F. M.; Cajander, S.; Cavaillon, J. -M.; Ferrer, R.; Flohe, S. B.; Garcia-Salido, A.; Giamarellos-Bourboulis, E. J.; Girardis, M.; Kox, M.; Lachmann, G.; Martin-Loeches, I.; Netea, M. G.; Spinetti, T.; Schefold, J. C.; Torres, A.; Uhle, F.; Venet, F.; Weis, S.; Scherag, A.; Rubio, I.; Osuchowski, M. F.
abstract

Many milestones in medical history rest on animal modeling of human diseases. The SARS-CoV-2 pandemic has evoked a tremendous investigative effort primarily centered on clinical studies. However, several animal SARS-CoV-2/COVID-19 models have been developed and pre-clinical findings aimed at supporting clinical evidence rapidly emerge. In this review, we characterize the existing animal models exposing their relevance and limitations as well as outline their utility in COVID-19 drug and vaccine development. Concurrently, we summarize the status of clinical trial research and discuss the novel tactics utilized in the largest multi-center trials aiming to accelerate generation of reliable results that may subsequently shape COVID-19 clinical treatment practices. We also highlight areas of improvement for animal studies in order to elevate their translational utility. In pandemics, to optimize the use of strained resources in a short time-frame, optimizing and strengthening the synergy between the preclinical and clinical domains is pivotal.

2021 - C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age [Articolo su rivista]
Zanella, I.; Zacchi, E.; Piva, S.; Filosto, M.; Beligni, G.; Alaverdian, D.; Amitrano, S.; Fava, F.; Baldassarri, M.; Frullanti, E.; Meloni, I.; Renieri, A.; Castelli, F.; Quiros-Roldan, E.; Mari, F.; Daga, S.; Benetti, E.; Furini, S.; Fallerini, C.; Valentino, F.; Doddato, G.; Giliberti, A.; Tita, R.; Bruttini, M.; Croci, S.; Pinto, A. M.; Mencarelli, M. A.; Rizzo, C. L.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Sarno, L. D.; Palmieri, M.; Carriero, M. L.; Fabbiani, M.; Rossetti, B.; Bargagli, E.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canac-Cini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Pancrazi, A.; Lorubbio, M.; Vaghi, M.; Monforte, A. D.; Miraglia, F. G.; Mondelli, M. U.; Bruno, R.; Marco, V.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Tommasi, A.; Paciosi, F.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Antoni, M. D.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Squeo, G. M.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Biagio, A. D.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Picchiotti, N.; Gori, M.; Gabbi, C.; Sanarico, M.; Ceri, S.; Pinoli, P.; Raimondi, F.; Bis-Carini, F.; Stella, A.; Rizzi, M.; Maggiolo, F.; Ripamonti, D.; Suardi, C.; Bachetti, T.; Rovere, M. T. L.; Sarzi-Braga, S.; Bussotti, M.; Capitani, K.; Zguro, K.; Dei, S.; Ravaglia, S.; Artuso, R.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Perticaroli, V.; Gennarelli, M.; Magri, C.; Basiotto, G.; Zizioli, D.; Giliani, S.; Monti, E.; Foca, E.; Carriero, C.; Latronico, N.; Padovani, A.; Brugnoni, D.
abstract

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lyso-some functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

2021 - Cluster analysis identifies patients at risk of catheter-associated urinary tract infections in intensive care units: findings from the SPIN-UTI Network [Articolo su rivista]
Barchitta, M.; Maugeri, A.; Favara, G.; Riela, P. M.; La Mastra, C.; La Rosa, M. C.; Magnano San Lio, R.; Gallo, G.; Mura, I.; Agodi, A.; Salesia, F.; Ennio, S.; Montagna, M. T.; Squeri, R.; Di Bartolo, R. M.; Salvatore, T.; Mattaliano, A. R.; Bellocchi, P.; Castiglione, G.; Astuto, M.; Longhitano, A. M.; Monea, M. C.; Scrofani, G.; Di Benedetto, A.; Carmela, R. M.; Manta, G.; Tetamo, R.; Dei, I.; Pandiani, I.; Antonino, C.; Piotti, P.; Girardis, M.; Righi, E.; Pierangelo, S.; Arnoldo, L.; Brusaferro, S.; Coniglio, S.; Albino, B.; Pintaudi, S.; Minerva, M.; Milazzo, M.; Bissolo, E.; Rigo, A.; Fabiani, L.; Marinangeli, F.; Stefanini, P.; D'Errico, M. M.; Donati, A.; Tardivo, S.; Moretti, F.; Carli, A.; Pagliarulo, R.; Bianco, A.; Pavia, M.; Pasculli, M.; Vittori, C.; Orsi, G. B.; Arrigoni, C.; Laurenti, P.; Ingala, F.; Farruggia, P.
abstract

Background: Although preventive strategies have been proposed against catheter-associated urinary tract infections (CAUTIs) in intensive care units (ICUs), more efforts are needed to control the incidence rate. Aim: To distinguish patients according to their characteristics at ICU admission, and to identify clusters of patients at higher risk for CAUTIs. Methods: A two-step cluster analysis was conducted on 9656 patients from the Italian Nosocomial Infections Surveillance in Intensive Care Units project. Findings: Three clusters of patients were identified. Type of admission, patient origin and administration of antibiotics had the greatest weight on the clustering model. Cluster 1 comprised more patients with a medical type of ICU admission who came from the community. Cluster 2 comprised patients who were more likely to come from other wards/hospitals, and to report administration of antibiotics 48 h before or after ICU admission. Cluster 3 was similar to Cluster 2 but was characterized by a lower percentage of patients with administration of antibiotics 48 h before or after ICU admission. Patients in Clusters 1 and 2 had a longer duration of urinary catheterization [median 7 days, interquartile range (IQR) 12 days for Cluster 1; median 7 days, IQR 11 days for Cluster 2] than patients in Cluster 3 (median 6 days, IQR 8 days; P<0.001). Interestingly, patients in Cluster 1 had a higher incidence of CAUTIs (3.5 per 100 patients) compared with patients in the other two clusters (2.5 per 100 patients in both clusters; P=0.033). Conclusion: To the authors' knowledge, this is the first study to use cluster analysis to identify patients at higher risk of CAUTIs who could gain greater benefit from preventive strategies.

2021 - Correction to: Tocilizumab for patients with COVID-19 pneumonia. The single-arm TOCIVID-19 prospective trial (Journal of Translational Medicine, (2020), 18, 1, (405), 10.1186/s12967-020-02573-9) [Articolo su rivista]
Perrone, F.; Piccirillo, M. C.; Ascierto, P. A.; Salvarani, C.; Parrella, R.; Marata, A. M.; Popoli, P.; Ferraris, L.; Marrocco-Trischitta, M. M.; Ripamonti, D.; Binda, F.; Bonfanti, P.; Squillace, N.; Castelli, F.; Muiesan, M. L.; Lichtner, M.; Calzetti, C.; Salerno, N. D.; Atripaldi, L.; Cascella, M.; Costantini, M.; Dolci, G.; Facciolongo, N. C.; Fraganza, F.; Massari, M.; Montesarchio, V.; Mussini, C.; Negri, E. A.; Botti, G.; Cardone, C.; Gargiulo, P.; Gravina, A.; Schettino, C.; Arenare, L.; Chiodini, P.; Gallo, C.; Piccirillo, M. C.; Schettino, C.; Gravina, A.; Gargiulo, P.; Arenare, L.; Ascierto, P. A.; Vitale, M. G.; Trojaniello, C.; Palla, M.; Bianchi, A. A. M.; Botti, G.; De Feo, G.; Miscio, L.; Gallo, C.; Chiodiniy, P.; Ferraris, L.; Marrocco-Trischitta, M. M.; Froldi, M.; Menicanti, L.; Cuppone, M. T.; Gobbo, G.; Baldessari, C.; Valenti, V.; Castelvecchio, S.; Poli, F.; Giacomazzi, F.; Piccinni, R.; Annnunziata, M. L.; Biondi, A.; Bussolari, C.; Mazzoleni, M.; Giachi, A.; Filtz, A.; Manini, A.; Poletti, E.; Masserini, F.; Conforti, F.; Gaudiano, G.; Favero, V.; Moroni, A.; Viva, T.; Fancoli, F.; Ferrari, D.; Niro, D.; Resta, M.; Ballotta, A.; Poli, M. D.; Ranucci, M.; Ripamonti, D.; Binda, F.; Tebaldi, A.; Gritti, G.; Pasulo, L.; Gaglio, L.; Del Fabbro, R.; Alborghetti, L.; Giustinetti, G.; Columpsi, P.; Cazzaniga, M.; Capici, S.; Sala, L.; Di Sciacca, R.; Mosca, G.; Pirozzi, M. R.; Castelli, F.; Muiesan, M. L.; Franceschini, F.; Roccaro, A.; Salvetti, M.; Paini, A.; Corda, L.; Ricci, C.; Tomasoni, L.; Nasta, P.; Lorenzotti, S.; Odolini, S.; Foca, E.; Roldan, E. Q.; Metra, M.; Magrini, S.; Borghetti, P.; Latronico, N.; Piva, S.; Filippini, M.; Tomasi, G.; Zuccala, F.; Cattaneo, S.; Scolari, F.; Bossini, N.; Gaggiotti, M.; Properzi, M.; Lichtner, M.; Del Borgo, C.; Marocco, R.; Belvisi, V.; Tieghi, T.; De Masi, M.; Zuccala, P.; Fabietti, P.; Vetica, A.; Mercurio, V. S.; Carraro, A.; Fondaco, L.; Kertusha, B.; Curtolo, A.; Del Giudice, E.; Lubrano, R.; Zotti, M. G.; Puorto, A.; Ciuffreda, M.; Sarni, A.; Monteforte, G.; Romeo, D.; Viola, E.; Damiani, C.; Barone, A.; Mantovani, B.; Di Sanzo, D.; Gentili, V.; Carletti, M.; Aiuti, M.; Gallo, A.; Meliante, P. G.; Martellucci, S.; Riggio, O.; Cardinale, V.; Ridola, L.; Bragazzi, M. C.; Gioia, S.; Valenzi, E.; Graziosi, C.; Bina, N.; Fasolo, M.; Ricci, S.; Gioacchini, M. T.; Lucci, A.; Corso, L.; Tornese, D.; Nijhawan, P.; Equitani, F.; Cosentino, C.; Palladino, M.; Leonetti, F.; Leto, G.; Gnessi, C.; Campagna, G.; Cesareo, R.; Marrocco, F.; Straface, G.; Mecozzi, A.; Cerbo, L.; Isgro, V.; Parrocchia, S.; Visconti, G.; Casati, G.; Calzetti, C.; Ariani, A.; Donghi, L.; Salerno, N. D.; Tacconelli, E.; Bertoldi, M.; Cattaneo, P.; Lambertenghi, L.; Motta, L.; Omega, L.; Albano, G.; Parrella, R.; Fraganza, F.; Atripaldi, L.; Montesarchio, V.; Scarano, F.; De Rosa, A.; Buglione, A.; Lavoretano, S.; Gaglione, G.; De Marco, M.; Sangiovanni, V.; Fusco, F. M.; Viglietti, R.; Manzillo, E.; Rescigno, C.; Pisapia, R.; Plamieri, G.; Maraolo, A.; Calabria, G.; Catalano, M.; Fiorentino, G.; Annunziata, A.; Polistina, G.; Imitazione, P.; Mollica, M.; Esposito, V.; D'Abraccio, M.; Punzi, R.; Bianco, V.; Sbreglia, C.; Del Vecchio, R. F.; Bordonali, A.; Franco, A.; Massari, M.; Salsi, P.; Fontana, M.; Virzi, G.; Calderone, O.; Molteni, A.; Gennarini, S.; Gnudi, U.; Ricci, M. A.; Titolo, G.; Mensi, G.; Vuotto, P.; Gasperini, B.; Mancini, M.; Pasquini, Z.; Spanu, P.; Clementi, S.; Pierini, S.; Bokor, D.; Gori, D.; Ciofetti, M.; Caimi, M.; Bettazzi, L.; Allevi, E.; Furiani, S.; Capitanio, C.; Mastropasqua, B.; Fara, C.; Pulitano, G.; Matsuno, J. S.; Porta, F. D.; Dolfini, V.; Beyene, N. B.; Bezzi, M.; Novali, M.; Viale, P.; Tedeschi, S.; Pascale, R.; Bruno, R.; Di Filippo, A.; Sachs, M.; Oggionni, T.; Di Stefano, M.; Mengoli, C.; Facchini, C.; De Nardo, D.; Frausini, G.; Mucci, L.; Tedesco, S.; Girolimetti, R.; Manfredini, E.; Di Carlo, A. M.; Espinosa, E.; Dennetta, D.; Ticinesi, A.; Meschi, T.
abstract

Following publication of the original article [1] the authors identified that the collaborators of the TOCIVID-19 investigators, Italy were only available in the supplementary file. The original article has been updated so that the collaborators are correctly acknowledged. For clarity, all collaborators are listed in this correction article.

2021 - Development and validation of a prediction model for tocilizumab failure in hospitalized patients with SARS-CoV-2 infection [Articolo su rivista]
Mussini, C; Cozzi-Lepri, A; Menozzi, M; Meschiari, M; Franceschini, E; Milic, J; Brugioni, L; Pietrangelo, A; Girardis, M; Cossarizza, A; Tonelli, R; Clini, E; Massari, M; Bartoletti, M; Ferrari, A; Cattelan, Am; Zuccalà, P; Lichtner, M; Rossotti, R; Girardi, E; Nicastri, E; Puoti, M; Antinori, A; Viale, Pl; Guaraldi, G.
abstract

Background: The aim of this secondary analysis of the TESEO cohort is to identify, early in the course of treatment with tocilizumab, factors associated with the risk of progressing to mechanical ventilation and death and develop a risk score to estimate the risk of this outcome according to patients’ profile. Methods: Patients with COVID-19 severe pneumonia receiving standard of care + tocilizumab who were alive and free from mechanical ventilation at day6 after treatment initiation were included in this retrospective, multicenter cohort study. Multivariable logistic regression models were built to identify predictors of mechanical ventilation or death by day-28 from treatment initiation and β-coefficients were used to develop a risk score. Secondary outcome was mortality. Patients with the same inclusion criteria as the derivation cohort from 3 independent hospitals were used as validation cohort. Results: 266 patients treated with tocilizumab were included. By day 28 of hospital follow-up post treatment initiation, 40 (15%) underwent mechanical ventilation or died [26 (10%)]. At multivariable analysis, sex, day-4 PaO2/FiO2 ratio, platelets and CRP were independently associated with the risk of developing the study outcomes and were used to generate the proposed risk score. The accuracy of the score in AUC was 0.80 and 0.70 in internal validation and test for the composite endpoint and 0.92 and 0.69 for death, respectively. Conclusions: Our score could assist clinicians in identifying, early after tocilizumab, patients who are likely to progress to mechanical ventilation or death so that they could be selected for eventual rescue therapies.

2021 - Development of post-COVID-19 cardiovascular events: An analysis of clinical features and risk factors from a single hospital retrospective study [Articolo su rivista]
Cuomo, G.; Puzzolante, C.; Iadisernia, V.; Santoro, A.; Menozzi, M.; Carli, F.; Digaetano, M.; Orlando, G.; Franceschini, E.; Bedini, A.; Meschiari, M.; Manzini, L.; Corradi, L.; Milic, J.; Borghi, V.; Brugioni, L.; Pietrangelo, A.; Clini, E.; Girardis, M.; Guaraldi, G.; Mussini, C.
abstract

Cardiovascular complications after a SARS-CoV-2 infection are a phenomenon of relevant scientific inter-est. The aim of this study was to analyze the onset of post-COVID-19 cardiovascular events in patients hospitalized in a tertiary care center. This is a retrospective study conducted on patients hospitalized over a period of three months. The patients were older than 18 years of age and had a diagnosis of COVID-19 infection confirmed from a nasopharyngeal swab sample. Anamnestic and clinical-laboratory data were collected. Cardiovascular events at 30 days were defined as follows: arrhythmias, myocardial infarction, myocarditis, and pulmonary embolism. Univariate analysis (Student’s t-test or Mann-Whitney U test, as appropriate) and multivariate analysis (multinomial logistic regression) were applied to the data. A total of 394 patients were included; they were mostly males and had a median age of 65.5 years. Previous cardiovascular disease was present in 14.7% of patients. Oxygen therapy was required for 77.9%, and 53% received anticoagulant therapy. The overall 30-day mortality was 20.3%. A cardiovascular event developed in 15.7% of the subjects. These were mainly pulmonary embolism (9.4%), followed by arrhythmias (3.3%), myocardial infarction (2.3%), and myocarditis (0.8%). Patients who developed cardiovascular events upon univariate analysis were significantly older, with major comorbidities, a more compromised respiratory situation, and a higher mortality rate. Multivariate analysis revealed independent factors that were significantly associated with the development of cardiovascular events: hypertension, endotracheal intubation, and age older than 75 years. In patients with COVID-19, the development of a cardiovascular event occurs quite frequently and is mainly seen in elderly subjects with comorbidities (especially hypertension) in the presence of a severe respiratory picture.

2021 - Effects of cytokine blocking agents on hospital mortality in patients admitted to ICU with acute respiratory distress syndrome by SARS-CoV2 infection: retrospective cohort study. [Articolo su rivista]
Coloretti, I; Busani, S; Biagioni, E; Venturelli, S; Munari, E; Marco, S; Dall’Ara, L; Tosi, M; Clini, E; Tonelli, R; Fantini, R; Mussini, C; Meschiari, M; Guaraldi, G; Cossarizza, A; Alfano, G; Girardis, M; Gibellini, Lara
abstract

Background- The use of cytokine-blocking agents has been proposed to modulate the inflammatory response in patients with COVID19. Tocilizumab and Anakinra were included in the local protocol as an optional treatment in critically ill patients with acute respiratory distress syndrome (ARDS) by SARS-CoV2 infection. This cohort study evaluated the effects of therapy with cytokine blocking agents on in-hospital mortality in COVID19 patients requiring mechanical ventilation and admitted to intensive care unit. Methods- The association between therapy with Tocilizumab or Anakinra and in-hospital mortality was assessed in consecutive adult COVID19 patients admitted to our ICU with moderate to severe ARDS. The association was evaluated by comparing patients who receive to those who did not receive Tocilizumab or Anakinra and by using different multivariable Cox models adjusted for variables related to poor outcome, for the propensity to be treated with Tocilizumab or Anakinra and after patient matching. Results- Sixty-six patients who received immunotherapy (49 Tocilizumab, 17 Anakinra) and 28 patients who did not receive immunotherapy were included. The in-hospital crude mortality was 30,3% in treated patients and 50% in non-treated (OR 0,77, 95% CI 0,56-1,05, p=0,069). The adjusted Cox model showed an association between therapy with immunotherapy and in-hospital mortality (HR 0,40, 95% CI 0,19-0,83, p=0,015). This protective effect was further confirmed in the analysis adjusted for propensity score, in the propensity-matched cohort and in the cohort of patients with invasive mechanical ventilation within 2 hours after ICU admission. Conclusions- Although important limitations, our study showed that cytokine-blocking agents seem to be safe and to improve survival in COVID-19 patients admitted to ICU with ARDS and the need of mechanical ventilation.

2021 - Employing a systematic approach to biobanking and analyzing clinical and genetic data for advancing COVID-19 research [Articolo su rivista]
Daga, S.; Fallerini, C.; Baldassarri, M.; Fava, F.; Valentino, F.; Doddato, G.; Benetti, E.; Furini, S.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Meloni, I.; Pinto, A. M.; Raimondi, F.; Stella, A.; Biscarini, F.; Picchiotti, N.; Gori, M.; Pinoli, P.; Ceri, S.; Sanarico, M.; Crawley, F. P.; Birolo, G.; Montagnani, F.; Di Sarno, L.; Tommasi, A.; Palmieri, M.; Croci, S.; Emiliozzi, A.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennet, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Vaghi, M.; D'Arminio Monforte, A.; Merlini, E.; Mondelli, M. U.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Sita, M.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, M. E.; Magro, P.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Gabbi, C.; Valente, S.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Mancarella, S.; Tavecchia, L.; Renieri, A.; Mari, F.; Frullanti, E.
abstract

Within the GEN-COVID Multicenter Study, biospecimens from more than 1000 SARS-CoV-2 positive individuals have thus far been collected in the GEN-COVID Biobank (GCB). Sample types include whole blood, plasma, serum, leukocytes, and DNA. The GCB links samples to detailed clinical data available in the GEN-COVID Patient Registry (GCPR). It includes hospitalized patients (74.25%), broken down into intubated, treated by CPAP-biPAP, treated with O2 supplementation, and without respiratory support (9.5%, 18.4%, 31.55% and 14.8, respectively); and non-hospitalized subjects (25.75%), either pauci- or asymptomatic. More than 150 clinical patient-level data fields have been collected and binarized for further statistics according to the organs/systems primarily affected by COVID-19: heart, liver, pancreas, kidney, chemosensors, innate or adaptive immunity, and clotting system. Hierarchical clustering analysis identified five main clinical categories: (1) severe multisystemic failure with either thromboembolic or pancreatic variant; (2) cytokine storm type, either severe with liver involvement or moderate; (3) moderate heart type, either with or without liver damage; (4) moderate multisystemic involvement, either with or without liver damage; (5) mild, either with or without hyposmia. GCB and GCPR are further linked to the GCGDR, which includes data from whole-exome sequencing and high-density SNP genotyping. The data are available for sharing through the Network for Italian Genomes, found within the COVID-19 dedicated section. The study objective is to systematize this comprehensive data collection and begin identifying multi-organ involvement in COVID-19, defining genetic parameters for infection susceptibility within the population, and mapping genetically COVID-19 severity and clinical complexity among patients.

2021 - Endobronchial valve positioning for alveolar-pleural fistula following ICU management of severe COVID-19 pneumonia. [Articolo su rivista]
Donatelli, P; Trentacosti, F; Pellegrino, Mr; Tonelli, R; Bruzzi, G; Andreani, A; Cappiello, Gf; Andrisani, D; Gozzi, F; Mussini, C; Busani, S; Cavaliere, Gv; Girardis, M; Bertellini, E; Clini, E; Marchioni, A.
abstract

Background- Since December 2019 the outbreak of novel Coronavirus (Severe Acute Respiratory Sindrome-2, SARS-CoV2) has spread across the world. The main clinical consequences are respiratory failure even requiring mechanical ventilation, and pneumonia frequently sharing clinical and radiologic similarities to Acute Respiratory Distress Syndrome (ARDS). In this context the lung parenchyma is highly prone to ventilator-related injury, with pneumothorax and persistent air leak as the most serious adverse events. So far, endobronchial valve (EBV) positioning has proved efficacy in treating air leaks with high success rate. Case presentation- We report, for the first time, two cases of patients affected by SARS-CoV2-related pneumonia suffering from pneumothorax and persistent air leaks after invasive mechanical ventilation, and successfully treated through EBV positioning. Conclusions- Persistent air leaks may result from lung tissue damage due to a complex interaction between inflammation and ventilator-related injury (VILI), especially in the advanced stages of ARDS. EBV positioning seems to be a feasible and effective least-invasive therapeutic option for caring this subset of patients.

2021 - Endogenous control of inflammation characterizes pregnant women with asymptomatic or paucisymptomatic SARS-CoV-2 infection [Articolo su rivista]
De Biasi, S.; Tartaro, D. L.; Gibellini, L.; Paolini, A.; Quong, A.; Petes, C.; Awong, G.; Douglas, S.; Lin, D.; Nieto, J.; Galassi, F. M.; Borella, R.; Fidanza, L.; Mattioli, M.; Leone, C.; Neri, I.; Meschiari, M.; Cicchetti, L.; Iannone, A.; Trenti, T.; Sarti, M.; Girardis, M.; Guaraldi, G.; Mussini, C.; Facchinetti, F.; Cossarizza, A.
abstract

SARS-CoV-2 infection can affect all human beings, including pregnant women. Thus, understanding the immunological changes induced by the virus during pregnancy is nowadays of pivotal importance. Here, using peripheral blood from 14 pregnant women with asymptomatic or mild SARS-CoV-2 infection, we investigate cell proliferation and cytokine production, measure plasma levels of 62 cytokines, and perform a 38-parameter mass cytometry analysis. Our results show an increase in low density neutrophils but no lymphopenia or gross alterations of white blood cells, which display normal levels of differentiation, activation or exhaustion markers and show well preserved functionality. Meanwhile, the plasma levels of anti-inflammatory cytokines such as interleukin (IL)-1RA, IL-10 and IL-19 are increased, those of IL-17, PD-L1 and D-dimer are decreased, but IL-6 and other inflammatory molecules remain unchanged. Our profiling of antiviral immune responses may thus help develop therapeutic strategies to avoid virus-induced damages during pregnancy.

2021 - Exogenous pulmonary surfactant in COVID-19 ARDS. The similarities to neonatal RDS suggest a new scenario for an 'old' strategy [Articolo su rivista]
Bhatt, R. M.; Clark, H. W.; Girardis, M.; Busani, S.
abstract

Acute respiratory distress syndrome (ARDS) related to SARS-CoV-2 infection has some unusual characteristics that differentiate it from the pathophysiology described in the more 'typical' ARDS. Among multiple hypotheses, a close similarity has been suggested between COVID-19 ARDS and neonatal respiratory distress syndrome (RDS). With this opinion paper, we investigated the pathophysiological similarities between infant respiratory diseases (RDS and direct neonatal ARDS (NARDS)) and COVID-19 in adults. We also analysed, for the first time, similarities in the response to exogenous surfactant administration in terms of improved static compliance in RDS and direct NARDS, and adult COVID-19 ARDS. In conclusion, we believe that if the pathological processes are similar both from the pathophysiological point of view and from the response in respiratory mechanics to a recruitment treatment such as surfactant, perhaps the latter could be considered a plausible option and lead to recruitment in clinical trials currently ongoing on patients with COVID-19.

2021 - Genetic mechanisms of critical illness in COVID-19 [Articolo su rivista]
Pairo-Castineira, E.; Clohisey, S.; Klaric, L.; Bretherick, A. D.; Rawlik, K.; Pasko, D.; Walker, S.; Parkinson, N.; Fourman, M. H.; Russell, C. D.; Furniss, J.; Richmond, A.; Gountouna, E.; Wrobel, N.; Harrison, D.; Wang, B.; Wu, Y.; Meynert, A.; Griffiths, F.; Oosthuyzen, W.; Kousathanas, A.; Moutsianas, L.; Yang, Z.; Zhai, R.; Zheng, C.; Grimes, G.; Beale, R.; Millar, J.; Shih, B.; Keating, S.; Zechner, M.; Haley, C.; Porteous, D. J.; Hayward, C.; Yang, J.; Knight, J.; Summers, C.; Shankar-Hari, M.; Klenerman, P.; Turtle, L.; Ho, A.; Moore, S. C.; Hinds, C.; Horby, P.; Nichol, A.; Maslove, D.; Ling, L.; Mcauley, D.; Montgomery, H.; Walsh, T.; Pereira, A. C.; Renieri, A.; Millar, J.; Nichol, A.; Walsh, T.; Shankar-Hari, M.; Ponting, C.; Meikle, J.; Finernan, P.; Mcmaster, E.; Law, A.; Baillie, J. K.; Paterson, T.; Wackett, T.; Armstrong, R.; Clark, R.; Coutts, A.; Donnelly, L.; Gilchrist, T.; Hafezi, K.; Macgillivray, L.; Maclean, A.; Mccafferty, S.; Morrice, K.; Weaver, J.; Boz, C.; Golightly, A.; Ward, M.; Mal, H.; Szoor-McElhinney, H.; Brown, A.; Hendry, R.; Stenhouse, A.; Cullum, L.; Law, D.; Law, S.; Law, R.; Swets, M.; Day, N.; Taneski, F.; Duncan, E.; Parkinson, N.; Collier, D.; Wood, S.; Zak, A.; Borra, C.; Matharu, M.; May, P.; Alldis, Z.; Mitchelmore, O.; Bowles, R.; Easthope, A.; Bibi, F.; Lancoma-Malcolm, I.; Gurasashvili, J.; Pheby, J.; Shiel, J.; Bolton, M.; Patel, M.; Taylor, M.; Zongo, O.; Ebano, P.; Harding, P.; Astin-Chamberlain, R.; Choudhury, Y.; Cox, A.; Kallon, D.; Burton, M.; Hall, R.; Blowes, S.; Prime, Z.; Biddle, J.; Prysyazhna, O.; Newman, T.; Tierney, C.; Kassam, J.; Shankar-Hari, M.; Ostermann, M.; Campos, S.; Bociek, A.; Lim, R.; Grau, N.; Jones, T. O.; Whitton, C.; Marotti, M.; Arbane, G.; Bonner, S.; Hugill, K.; Reid, J.; Welters, I.; Waugh, V.; Williams, K.; Shaw, D.; Roman, J. F.; Martinez, M. L.; Johnson, E.; Waite, A.; Johnston, B.; Hamilton, D.; Mulla, S.; Mcphail, M.; Smith, J.; Baillie, J. K.; Barclay, L.; Hope, D.; Mcculloch, C.; Mcquillan, L.; Clark, S.; Singleton, J.; Priestley, K.; Rea, N.; Callaghan, M.; Campbell, R.; Andrew, G.; Marshall, L.; Mckechnie, S.; Hutton, P.; Bashyal, A.; Davidson, N.; Summers, C.; Polgarova, P.; Stroud, K.; Pathan, N.; Elston, K.; Agrawal, S.; Battle, C.; Newey, L.; Rees, T.; Harford, R.; Brinkworth, E.; Williams, M.; Murphy, C.; White, I.; Croft, M.; Bandla, N.; Gellamucho, M.; Tomlinson, J.; Turner, H.; Davies, M.; Quinn, A.; Hussain, I.; Thompson, C.; Parker, H.; Bradley, R.; Griffiths, R.; Scriven, J.; Nilsson, A.; Bates, M.; Dasgin, J.; Gill, J.; Puxty, A.; Cathcart, S.; Salutous, D.; Turner, L.; Duffy, K.; Puxty, K.; Joseph, A.; Herdman-Grant, R.; Simms, R.; Swain, A.; Naranjo, A.; Crowe, R.; Sollesta, K.; Loveridge, A.; Baptista, D.; Morino, E.; Davey, M.; Golden, D.; Jones, J.; Moreno Cuesta, J.; Haldeos, A.; Bakthavatsalam, D.; Vincent, R.; Elhassan, M.; Xavier, K.; Ganesan, A.; Purohit, D.; Abdelrazik, M.; Morgan, J.; Akeroyd, L.; Bano, S.; Lawton, T.; Warren, D.; Bromley, M.; Sellick, K.; Gurr, L.; Wilkinson, B.; Nagarajan, V.; Szedlak, P.; Cupitt, J.; Stoddard, E.; Benham, L.; Preston, S.; Laha, S.; Slawson, N.; Bradshaw, Z.; Brown, J.; Caswell, M.; Melling, S.; Bamford, P.; Faulkner, M.; Cawley, K.; Jeffrey, H.; London, E.; Sainsbury, H.; Nagra, I.; Nasir, F.; Dunmore, C.; Jones, R.; Abraheem, A.; Al-Moasseb, M.; Girach, R.; Padden, G.; Egan, J.; Brantwood, C.; Alexander, P.; Bradley-Potts, J.; Allen, S.; Felton, T.; Manna, S.; Farnell-Ward, S.; Leaver, S.; Queiroz, J.; Maccacari, E.; Dawson, D.; Delgado, C. C.; Saluzzio, R. P.; Ezeobu, O.; Ding, L.; Sicat, C.; Kanu, R.; Durrant, G.; Texeira, J.; Harrison, A.; Samakomva, T.; Scriven, J.; Willis, H.; Hopkins, B.; Thrasyvoulou, L.; Jackson, M.; Zaki, A.; Tibke, C.; Bennett, S.; Woodyatt, W.; Kent, A.; Goodwin, E.; Brandwood, C.; Clark, R.; Smith, L.; Rooney, K.; Thomson, N.; Rodden, N.; Hughes, E.; Mcglynn, D.; Clark, C.; Clark, P.; Abel, L.; Sundaram, R.; Gemmell, L.; Brett, M.; Hornsby, J.;
abstract

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10−8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10−8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 × 10−12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10−8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte–macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice.

2021 - Good clinical practice for the use of vasopressor and inotropic drugs in critically ill patients: State-of-the-art and expert consensus [Articolo su rivista]
Carsetti, A.; Bignami, E.; Cortegiani, A.; Donadello, K.; Donati, A.; Foti, G.; Grasselli, G.; Romagnoli, S.; Antonelli, M.; De Blasio, E.; Forfori, F.; Guarracino, F.; Scolletta, S.; Pepe, L. T.; Scudeller, L.; Cecconi, M.; Girardis, M.
abstract

Vasopressors and inotropic agents are widely used in critical care. However, strong evidence supporting their use in critically ill patients is lacking in many clinical scenarios. Thus, the Italian Society of Anesthesia and Intensive Care (SIAARTI) promoted a project aimed to provide indications for good clinical practice on the use of vasopressors and inotropes, and on the management of critically ill patients with shock. A panel of 16 experts in the field of intensive care medicine and hemodynamics has been established. Systematic review of the available literature was performed based on PICO questions. Basing on available evidence, the panel prepared a summary of evidence and then wrote the clinical questions. A modified semi-quantitative RAND/UCLA appropriateness method has been used to determine the appropriateness of specific clinical scenarios. The panel identified 29 clinical questions for the use of vasopressors and inotropes in patients with septic shock and cardiogenic shock. High level of agreement exists among the panel members about appropriateness of inotropes/vasopressors' use in patients with septic shock and cardiogenic shock.

2021 - Guide-wire replacement of a mini-midline catheter with a central venous catheter: A retrospective study on 63 cases [Articolo su rivista]
Brugioni, L.; Bertellini, E.; Ravazzini, M.; Barchetti, M.; Borsatti, A.; Martella, P.; Girardis, M.; Serra, F.; Tricoli, A.; Nicolini, M.; Bianchini, M.; Schepis, F.; Tazzioli, G.; Pinelli, G.; Romagnoli, E.; Gelmini, R.
abstract

Background: Achieving a reliable venous access in a particular subset of patients and/or in emergency settings can be challenging and time-consuming. Furthermore, many hospitalized patients do not meet the criteria for central venous catheter positioning, unless an upgrade of the treatment is further needed. The mini-midline catheter has already showed to be reliable and safe as a stand-alone device, since it is easily and rapidly inserted and can indwell up to 1 month. Methods: In this further case series, we retrospectively evaluated data from 63 patients where a previously inserted mini-midline catheter was upgraded to a central venous catheter (the devices inserted in the arm replaced by peripherally inserted central catheter and others inserted “off-label” in the internal jugular replaced by single lumen centrally inserted central catheter), being used as introducer for the Seldinger guidewire. Results: The guidewire replacement was been made even early (after 1 day) or late (more than 10 days), usually following a need for an upgrade in treatment. No early or late complications were reported. Conclusion: According to the preliminary data we collected, this converting procedure seems to be feasible and risk-free, since neither infectious nor thrombotic complications were reported.

2021 - Herpes Simplex re-activation in patients with SARS-CoV2 pneumonia: a prospective observational study. [Articolo su rivista]
Franceschini, E; Cozzi-Lepri, A; Santoro, A; Bacca, E; Lancellotti, G; Menozzi, M; Gennari, W; Meschiari, M; Bedini, A; Orlando, G; Puzzolante, C; Digaetano, M; Milic, J; Codeluppi, M; Pecorari, M; Carli, F; Cuomo, G; Alfano, G; Corradi, L; Tonelli, R; De Maria, N; Busani, S; Biagioni, E; Coloretti, I; Guaraldi, G; Sarti, M; Luppi, M; Clini, E; Girardis, M; Gyssens, I; Mussini, C.
abstract

Background: Herpes simplex 1 co-infections in patients with COVID-19 are considered relatively uncommon; some reports on re-activations in patients in intensive-care unit have been published. The aim of the study was to analyze herpetic re-activations and their clinical manifestations in hospitalized COVID-19 patients, performing HSV-1 PCR on plasma twice a week. Methods: We conducted a prospective, observational, single-center study involving 70 consecutive patients with severe/critical SARS-CoV-2 pneumonia tested for HSV-1 hospitalized at Azienda Ospedaliero-Universitaria of Modena. Results: Of these 70 patients, 21 (30.0%) showed detectable viremia and 13 (62%) had clinically relevant manifestations of HSV-1 infection corresponding to 15 events (4 pneumonia, 5 herpes labialis, 3 gingivostomatitis, one encephalitis and two hepatitis). HSV-1 positive patients were more frequently treated with steroids than HSV-1 negative patients (76.2% vs 49.0%, p 0.036) and more often underwent mechanical ventilation (IMV) (57.1% vs 22.4%, p 0.005). In the unadjusted logistic regression analysis, steroid treatment, IMV, and higher LDH were significantly associated with an increased risk of HSV1 re-activation (odds ratio 3.33, 4.61, and 16.9, respectively). The association with use of steroids was even stronger after controlling for previous use of both tocilizumab and IMV (OR=5.13, 95% CI:1.36-19.32, p=0.016). The effect size was larger when restricting to participants who were treated with high dose of steroids while there was no evidence to support an association with use of tocilizumab. Conclusions: Our study shows a high incidence of HSV-1 reactivation both virologically and clinically in patients with SARS-CoV-51 2 severe pneumonia, especially in those treated with steroids.

2021 - Hospital-Acquired Infections in Critically Ill Patients With COVID-19 [Articolo su rivista]
Grasselli, G.; Scaravilli, V.; Mangioni, D.; Scudeller, L.; Alagna, L.; Bartoletti, M.; Bellani, G.; Biagioni, E.; Bonfanti, P.; Bottino, N.; Coloretti, I.; Cutuli, S. L.; De Pascale, G.; Ferlicca, D.; Fior, G.; Forastieri, A.; Franzetti, M.; Greco, M.; Guzzardella, A.; Linguadoca, S.; Meschiari, M.; Messina, A.; Monti, G.; Morelli, P.; Muscatello, A.; Redaelli, S.; Stefanini, F.; Tonetti, T.; Antonelli, M.; Cecconi, M.; Foti, G.; Fumagalli, R.; Girardis, M.; Ranieri, M.; Viale, P.; Raviglione, M.; Pesenti, A.; Gori, A.; Bandera, A.
abstract

Background: Few small studies have described hospital-acquired infections (HAIs) occurring in patients with COVID-19. Research Question: What characteristics in critically ill patients with COVID-19 are associated with HAIs and how are HAIs associated with outcomes in these patients? Study Design and Methods: Multicenter retrospective analysis of prospectively collected data including adult patients with severe COVID-19 admitted to eight Italian hub hospitals from February 20, 2020, through May 20, 2020. Descriptive statistics and univariate and multivariate Weibull regression models were used to assess incidence, microbial cause, resistance patterns, risk factors (ie, demographics, comorbidities, exposure to medication), and impact on outcomes (ie, ICU discharge, length of ICU and hospital stays, and duration of mechanical ventilation) of microbiologically confirmed HAIs. Results: Of the 774 included patients, 359 patients (46%) demonstrated 759 HAIs (44.7 infections/1,000 ICU patient-days; 35% multidrug-resistant [MDR] bacteria). Ventilator-associated pneumonia (VAP; n = 389 [50%]), bloodstream infections (BSIs; n = 183 [34%]), and catheter-related BSIs (n = 74 [10%]) were the most frequent HAIs, with 26.0 (95% CI, 23.6-28.8) VAPs per 1,000 intubation-days, 11.7 (95% CI, 10.1-13.5) BSIs per 1,000 ICU patient-days, and 4.7 (95% CI, 3.8-5.9) catheter-related BSIs per 1,000 ICU patient-days. Gram-negative bacteria (especially Enterobacterales) and Staphylococcus aureus caused 64% and 28% of cases of VAP, respectively. Variables independently associated with infection were age, positive end expiratory pressure, and treatment with broad-spectrum antibiotics at admission. Two hundred thirty-four patients (30%) died in the ICU (15.3 deaths/1,000 ICU patient-days). Patients with HAIs complicated by septic shock showed an almost doubled mortality rate (52% vs 29%), whereas noncomplicated infections did not affect mortality. HAIs prolonged mechanical ventilation (median, 24 days [interquartile range (IQR), 14-39 days] vs 9 days [IQR, 5-13 days]; P < .001), ICU stay (24 days [IQR, 16-41 days] vs 9 days [IQR, 6-14 days]; P = .003), and hospital stay (42 days [IQR, 25-59 days] vs 23 days [IQR, 13-34 days]; P < .001). Interpretation: Critically ill patients with COVID-19 are at high risk for HAIs, especially VAPs and BSIs resulting from MDR organisms. HAIs prolong mechanical ventilation and hospitalization, and HAIs complicated by septic shock almost double mortality. Trial Registry: ClinicalTrials.gov; No.: NCT04388670; URL: www.clinicaltrials.gov

2021 - Hypokalemia in Patients with COVID-19 [Articolo su rivista]
Alfano, G.; Ferrari, A.; Fontana, F.; Perrone, R.; Mori, G.; Ascione, E.; Magistroni, R.; Venturi, G.; Pederzoli, S.; Margiotta, G.; Romeo, M.; Piccinini, F.; Franceschi, G.; Volpi, S.; Faltoni, M.; Ciusa, G.; Bacca, E.; Tutone, M.; Raimondi, A.; Menozzi, M.; Franceschini, E.; Cuomo, G.; Orlando, G.; Santoro, A.; Di Gaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Milic, J.; Meschiari, M.; Mussini, C.; Cappelli, G.; Guaraldi, G.; Borghi, V.; Burastero, G.; Corradi, L.; Di Gaetano, M.; Dolci, G.; Fantini, R.; Iadisernia, V.; Larne, D.; Pellegrino, F.; Rogati, C.; Santoro, A.; Tonelli, R.; Yaacoub, D.; Alfan, S.; Marco, B.; Pulizzi, R.; Leonelli, M.; Facchini, F.; Damiano, F.; Girardis, M.; Andreotti, A.; Biagioni, E.; Bondi, F.; Busani, S.; Chierego, G.; Scotti, M.; Cossarizza, L. S. A.; Bellinazzi, C.; Borella, R.; De Biasi, S.; De Gaetano, A.; Fidanza, L.; Gibellini, L.; Iannone, A.; Tartaro, D. L.; Mattioli, M.; Nasi, M.; Paolini, A.; Pinti, M.
abstract

Background: Patients with COVID-19 experience multiple clinical conditions that may cause electrolyte imbalances. Hypokalemia is a concerning electrolyte disorder closely associated with severe complications. This study aimed to estimate prevalence, risk factors and outcome of hypokalemia in a cohort of patients with confirmed COVID-19. Methods: A retrospective analysis was conducted on 290 non-ICU admitted patients with COVID-19 at the tertiary teaching hospital of Modena, Italy, from February 16 to April 14, 2020. Results: Hypokalemia was detected in 119 out of 290 patients (41%) during hospitalization. Mean serum potassium was 3.1 ± 0.1 meq/L. The majority of patients (90.7%) patients experienced only a mild decrease in serum potassium level (3–3.4 mEq/L). Hypokalemia was associated with hypocalcemia, which was detected in 50% of subjects. Urine potassium-to-creatinine ratio, measured in a small number of patients (n = 45; 36.1%), revealed an increase of urinary potassium excretion in most cases (95.5%). Risk factors for hypokalemia were female sex (odds ratio (OR) 2.44; 95% CI 1.36–4.37; P 0.003) and diuretic therapy (OR 1.94, 95% CI 1.08–3.48; P 0.027). Hypokalemia, adjusted for sex, age and SOFA score, was not associated with ICU transfer (OR 0.52; 95% CI 0.228–1.212; P = 0.131), in-hospital mortality (OR, 0.47; 95% CI 0.170–1.324; P = 0.154) and composite outcome of ICU transfer or in-hospital mortality (OR 0.48; 95% CI 0.222–1.047; P = 0.065) in our cohort of patients. Conclusions: Hypokalemia was a frequent disorder in subjects with COVID-19. Female sex and diuretic therapy were identified as risk factors for low serum potassium levels. Hypokalemia was unrelated to ICU transfer and death in this cohort of patients.

2021 - Identification and characterization of a SARS-CoV-2 specific CD8+ T cell response with immunodominant features [Articolo su rivista]
Gangaev, Anastasia; Ketelaars, Steven L C; Isaeva, Olga I; Patiwael, Sanne; Dopler, Anna; Hoefakker, Kelly; De Biasi, Sara; Gibellini, Lara; Mussini, Cristina; Guaraldi, Giovanni; Girardis, Massimo; Ormeno, Cami M P Talavera; Hekking, Paul J M; Lardy, Neubury M; Toebes, Mireille; Balderas, Robert; Schumacher, Ton N; Ovaa, Huib; Cossarizza, Andrea; Kvistborg, Pia
abstract

The COVID-19 pandemic caused by SARS-CoV-2 is a continuous challenge worldwide, and there is an urgent need to map the landscape of immunogenic and immunodominant epitopes recognized by CD8+ T cells. Here, we analyze samples from 31 patients with COVID-19 for CD8+ T cell recognition of 500 peptide-HLA class I complexes, restricted by 10 common HLA alleles. We identify 18 CD8+ T cell recognized SARS-CoV-2 epitopes, including an epitope with immunodominant features derived from ORF1ab and restricted by HLA-A*01:01. In-depth characterization of SARS-CoV-2-specific CD8+ T cell responses of patients with acute critical and severe disease reveals high expression of NKG2A, lack of cytokine production and a gene expression profile inhibiting T cell re-activation and migration while sustaining survival. SARS-CoV-2-specific CD8+ T cell responses are detectable up to 5 months after recovery from critical and severe disease, and these responses convert from dysfunctional effector to functional memory CD8+ T cells during convalescence.

2021 - Incidence and prognosis of ventilator-associated pneumonia in critically ill patients with covid-19: A multicenter study [Articolo su rivista]
Giacobbe, D. R.; Battaglini, D.; Enrile, E. M.; Dentone, C.; Vena, A.; Robba, C.; Ball, L.; Bartoletti, M.; Coloretti, I.; Di Bella, S.; Di Biagio, A.; Brunetti, I.; Mikulska, M.; Carannante, N.; De Maria, A.; Magnasco, L.; Maraolo, A. E.; Mirabella, M.; Montrucchio, G.; Patroniti, N.; Taramasso, L.; Tiseo, G.; Fornaro, G.; Fraganza, F.; Monastra, L.; Roman-Pognuz, E.; Paluzzano, G.; Fiorentino, G.; Corcione, A.; Bussini, L.; Pascale, R.; Corcione, S.; Tonetti, T.; Rinaldi, M.; Falcone, M.; Biagioni, E.; Ranieri, V. M.; Giannella, M.; De Rosa, F. G.; Girardis, M.; Menichetti, F.; Viale, P.; Pelosi, P.; Bassetti, M.
abstract

The primary objective of this multicenter, observational, retrospective study was to assess the incidence rate of ventilator-associated pneumonia (VAP) in coronavirus disease 2019 (COVID-19) patients in intensive care units (ICU). The secondary objective was to assess predictors of 30-day case-fatality of VAP. From 15 February to 15 May 2020, 586 COVID-19 patients were admitted to the participating ICU. Of them, 171 developed VAP (29%) and were included in the study. The incidence rate of VAP was of 18 events per 1000 ventilator days (95% confidence intervals [CI] 16–21). Deep respiratory cultures were available and positive in 77/171 patients (45%). The most frequent organisms were Pseudomonas aeruginosa (27/77, 35%) and Staphylococcus aureus (18/77, 23%). The 30-day case-fatality of VAP was 46% (78/171). In multivariable analysis, septic shock at VAP onset (odds ratio [OR] 3.30, 95% CI 1.43–7.61, p = 0.005) and acute respiratory distress syndrome at VAP onset (OR 13.21, 95% CI 3.05–57.26, p < 0.001) were associated with fatality. In conclusion, VAP is frequent in critically ill COVID-19 patients. The related high fatality is likely the sum of the unfavorable prognostic impacts of the underlying viral and the superimposed bacterial diseases.

2021 - Incidence, risk factors and outcome of acute kidney injury (AKI) in patients with COVID-19 [Articolo su rivista]
Alfano, Gaetano; Ferrari, Annachiara; Fontana, Francesco; Mori, Giacomo; Magistroni, Riccardo; Meschiari, Marianna; Franceschini, Erica; Menozzi, Marianna; Cuomo, Gianluca; Orlando, Gabriella; Santoro, Antonella; Digaetano, Margherita; Puzzolante, Cinzia; Carli, Federica; Bedini, Andrea; Milic, Jovana; Coloretti, Irene; Raggi, Paolo; Mussini, Cristina; Girardis, Massimo; Cappelli, Gianni; Guaraldi, Giovanni
abstract

Background Acute kidney injury (AKI) is a severe complication of coronavirus disease-2019 (COVID-19). This study aims to evaluate incidence, risk factors and case-fatality rate of AKI in patients with COVID-19. Methods We reviewed the health medical records of 307 consecutive patients with COVID-19 hospitalized at the University Hospital of Modena, Italy. Results AKI was diagnosed in 69 out of 307 (22.4%) COVID-19 patients. Stages 1, 2, or 3 AKI accounted for 57.9%, 24.6% and 17.3%, respectively. AKI patients had a mean age of 74.7 +/- 9.9 years. These patients showed higher serum levels of the main markers of inflammation and higher rate of severe pneumonia than non-AKI patients. Kidney injury was associated with a higher rate of urinary abnormalities including proteinuria (0.44 +/- 0.85 vs 0.18 +/- 0.29 mg/mg; P = < 0.0001) and microscopic hematuria (P = 0.032) compared to non-AKI patients. Hemodialysis was performed in 7.2% of the subjects and 33.3% of the survivors did not recover kidney function after AKI. Risk factors for kidney injury were age, male sex, CKD and higher non-renal SOFA score. Patients with AKI had a mortality rate of 56.5%. Adjusted Cox regression analysis revealed that COVID-19-associated AKI was independently associated with in-hospital death (hazard ratio [HR] = 4.82; CI 95%, 1.36-17.08) compared to non-AKI patients. Conclusion AKI was a common and harmful consequence of COVID-19. It manifested with urinary abnormalities (proteinuria, microscopic hematuria) and conferred an increased risk for death. Given the well-known short-term sequelae of AKI, prevention of kidney injury is imperative in this vulnerable cohort of patients.

2021 - Inspiratory effort and lung mechanics in spontaneously breathing patients with acute respiratory failure due to COVID-19. A matched control study. [Articolo su rivista]
Tonelli, R; Busani, S; Tabbì, L; Fantini, R; Castaniere, I; Biagioni, E; Mussini, C; Girardis, M; Clini, E; Marchioni, A.
abstract

Several physical and biological mechanisms can drive progression between the different phases of lung injury due to SARS-CoV-2 infection, thus modifying the mechanical properties and behavior of COVID-19 over time. In this research letter we have presented the findings of a registered clinical trial aimed at describing and comparing the inspiratory effort (primary outcome) and the breathing pattern of spontaneously breathing patients with ARF in COVID-19 and historically matched non-COVID-19 patients, either candidate to NIV. Moreover, we reported the response to a 2 hours NIV trial in the two groups. Spontaneously breathing COVID-19 at their early onset of acute respiratory failure with indication for NIV showed different mechanical characteristics and breathing pattern when compared with non-COVID-19.

2021 - Mapping the human genetic architecture of COVID-19 [Articolo su rivista]
Niemi, M. E. K.; Karjalainen, J.; Liao, R. G.; Neale, B. M.; Daly, M.; Ganna, A.; Pathak, G. A.; Andrews, S. J.; Kanai, M.; Veerapen, K.; Fernandez-Cadenas, I.; Schulte, E. C.; Striano, P.; Marttila, M.; Minica, C.; Marouli, E.; Karim, M. A.; Wendt, F. R.; Savage, J.; Sloofman, L.; Butler-Laporte, G.; Kim, H. -N.; Kanoni, S.; Okada, Y.; Byun, J.; Han, Y.; Uddin, M. J.; Smith, G. D.; Willer, C. J.; Buxbaum, J. D.; Mehtonen, J.; Finucane, H.; Cordioli, M.; Martin, A. R.; Zhou, W.; Pasaniuc, B.; Julienne, H.; Aschard, H.; Shi, H.; Yengo, L.; Polimanti, R.; Ghoussaini, M.; Schwartzentruber, J.; Dunham, I.; Chwialkowska, K.; Francescatto, M.; Trankiem, A.; Balaconis, M. K.; Davis, L.; Lee, S.; Priest, J.; Renieri, A.; Sankaran, V. G.; van Heel, D.; Deelen, P.; Brent Richards, J.; Nakanishi, T.; Biesecker, L.; Eric Kerchberger, V.; Kenneth Baillie, J.; Mari, F.; Bernasconi, A.; Ceri, S.; Canakoglu, A.; Wolford, B.; Faucon, A.; Dutta, A. K.; Schurmann, C.; Harry, E.; Birney, E.; Nguyen, H.; Nasir, J.; Kaunisto, M.; Solomonson, M.; Dueker, N.; Vadgama, N.; Limou, S.; Rahmouni, S.; Mbarek, H.; Darwish, D.; Uddin, M. M.; Albertos, R.; Perez-Tur, J.; Li, R.; Folkersen, L.; Moltke, I.; Koelling, N.; Teumer, A.; Kousathanas, A.; Utrilla, A.; Verdugo, R. A.; Zarate, R.; Medina-Gomez, C.; Gomez-Cabrero, D.; Carnero-Montoro, E.; Cadilla, C. L.; Moreno-Estrada, A.; Garmendia, A.; Moya, L.; Sedaghati-Khayat, B.; Boua, P. R.; Fave, M. -J.; Francioli, L.; Lemacon, A.; Migeotte, I.; Patel, S.; Varnai, R.; Szentpeteri, J. L.; Sipeky, C.; Colombo, F.; von Hohenstaufen, K.; Lio, P.; Vallerga, C.; Wang, Q.; Tanigawa, Y.; Im, H.; Han, C.; Song, H.; Lim, J.; Lee, Y.; Kim, S.; Im, S.; Atanasovska, B.; Ahmad, H. F.; Boer, C.; Jansen, P.; Kaja, E.; Pasko, D.; Kennis-Szilagyi, I.; Kornilov, S. A.; Prijatelj, V.; Prokic, I.; Sivanadhan, I.; Perumal, S.; Esmaeeli, S.; Pearson, N. M.; Auton, A.; Shelton, J. F.; Shastri, A. J.; Filshtein-Sonmez, T.; Coker, D.; Symons, A.; Esparza-Gordillo, J.; Aslibekyan, S.; O'Connell, J.; Ye, C.; Weldon, C. H.; Perera, M.; O'Leary, K.; Tuck, M.; O'Brien, T.; Meltzer, D.; O'Donnell, P.; Nutescu, E.; Yang, G.; Alarcon, C.; Herrmann, S.; Mazurek, S.; Banagan, J.; Hamidi, Z.; Barbour, A.; Raffat, N.; Moreno, D.; Friedman, P.; Ferwerda, B.; van de Beek, D.; Brouwer, M. C.; Vlaar, A. P. J.; Joost Wiersinga, W.; Posthuma, D.; Tissink, E.; Koos Zwinderman, A. H.; Uffelmann, E.; van Agtmael, M.; Algera, A. G.; van Baarle, F.; Bax, D.; Beudel, M.; Bogaard, H. J.; Bomers, M.; Bonta, P. I.; Bos, L.; Botta, M.; de Brabander, J.; de Bree, G.; de Bruin, S.; Bugiani, M.; Bulle, E.; Chouchane, O.; Cloherty, A.; Dongelmans, D.; Elbers, P.; Fleuren, L.; Geerlings, S.; Geerts, B.; Geijtenbeek, T.; Girbes, A.; Goorhuis, B.; Grobusch, M. P.; Hafkamp, F.; Hagens, L.; Hamann, J.; Harris, V.; Hemke, R.; Hermans, S. M.; Heunks, L.; Hollmann, M.; Horn, J.; Hovius, J. W.; de Jong, M. D.; Koning, R.; van Mourik, N.; Nellen, J.; Nossent, E. J.; Paulus, F.; Peters, E.; van der Poll, T.; Preckel, B.; Prins, J. M.; Raasveld, J.; Reijnders, T.; Schinkel, M.; Schultz, M. J.; Schuurman, A.; Sigaloff, K.; Smit, M.; Stijnis, C. S.; Stilma, W.; Teunissen, C.; Thoral, P.; Tsonas, A.; van der Valk, M.; Veelo, D.; de Vries, H.; van Vugt, M.; Wouters, D.; Minnaar, R. P.; Kromhout, A.; van Uffelen, K. W. J.; Wolterman, R. A.; Roberts, G.; Park, D.; Ball, C. A.; Coignet, M.; Mccurdy, S.; Knight, S.; Partha, R.; Rhead, B.; Zhang, M.; Berkowitz, N.; Gaddis, M.; Noto, K.; Ruiz, L.; Pavlovic, M.; Hong, E. L.; Rand, K.; Girshick, A.; Guturu, H.; Baltzell, A. H.; Guntz, J.; Beguin, Y.; Pigazzini, S.; Nkambule, L.; Bouysran, Y.; Busson, A.; Peyrassol, X.; Wilkin, F.; Pichon, B.; Smits, G.; Vandernoot, I.; Goffard, J. -C.; Georges, M.; Moutschen, M.; Misset, B.; Darcis, G.; Guiot, J.; Jadot, L.; Azarzar, S.; Dellot, P.; Gofflot, S.; Claassen, S.; Bertrand, A.; Parzibut, G.; Clarinval, M.; Moermans, C.; Malaise, O.; El Kandoussi, K.; Thonon, R.; Huynen, P.; Mesdagh, A.; Melo, S.
abstract

The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-191,2, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases3–7. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

2021 - Methylprednisolone as rescue therapy after tocilizumab failure in patients with severe COVID-19 pneumonia [Articolo su rivista]
Guaraldi, Giovanni; Banchelli, Federico; Milic, Jovana; Dolci, Giovanni; Massari, Marco; Corsini, Romina; Meschiari, Marianna; Girardis, Massimo; Busani, Stefano; Cossarizza, Andrea; Salvarani, Carlo; Mussini, Cristina; D'Amico, Roberto
abstract

2021 - Monocyte Distribution Width (MDW) as novel inflammatory marker with prognostic significance in COVID-19 patients [Articolo su rivista]
Riva, G.; Castellano, S.; Nasillo, V.; Ottomano, A. M.; Bergonzini, G.; Paolini, A.; Lusenti, B.; Milic, J.; De Biasi, S.; Gibellini, L.; Cossarizza, A.; Busani, S.; Girardis, M.; Guaraldi, G.; Mussini, C.; Manfredini, R.; Luppi, M.; Tagliafico, E.; Trenti, T.
abstract

Monocyte Distribution Width (MDW), a new cytometric parameter correlating with cytomorphologic changes occurring upon massive monocyte activation, has recently emerged as promising early biomarker of sepsis. Similar to sepsis, monocyte/macrophage subsets are considered key mediators of the life-threatening hyper-inflammatory disorder characterizing severe COVID-19. In this study, we longitudinally analyzed MDW values in a cohort of 87 COVID-19 patients consecutively admitted to our hospital, showing significant correlations between MDW and common inflammatory markers, namely CRP (p < 0.001), fibrinogen (p < 0.001) and ferritin (p < 0.01). Moreover, high MDW values resulted to be prognostically associated with fatal outcome in COVID-19 patients (AUC = 0.76, 95% CI: 0.66–0.87, sensitivity 0.75, specificity 0.70, MDW threshold 26.4; RR = 4.91, 95% CI: 1.73–13.96; OR = 7.14, 95% CI: 2.06–24.71). This pilot study shows that MDW can be useful in the monitoring of COVID-19 patients, as this innovative hematologic biomarker is: (1) easy to obtain, (2) directly related to the activation state of a fundamental inflammatory cell subset (i.e. monocytes, pivotal in both cytokine storm and sepsis immunopathogenesis), (3) well correlated with clinical severity of COVID-19-associated inflammatory disorder, and, in turn, (4) endowed with relevant prognostic significance. Additional studies are needed to define further the clinical impact of MDW testing in the management of COVID-19 patients.

2021 - Prone position in intubated, mechanically ventilated patients with COVID-19: a multi-centric study of more than 1000 patients [Articolo su rivista]
Langer, T.; Brioni, M.; Guzzardella, A.; Carlesso, E.; Cabrini, L.; Castelli, G.; Dalla Corte, F.; De Robertis, E.; Favarato, M.; Forastieri, A.; Forlini, C.; Girardis, M.; Grieco, D. L.; Mirabella, L.; Noseda, V.; Previtali, P.; Protti, A.; Rona, R.; Tardini, F.; Tonetti, T.; Zannoni, F.; Antonelli, M.; Foti, G.; Ranieri, M.; Pesenti, A.; Fumagalli, R.; Grasselli, G.; Berselli, A.; Bove, T.; Calligari, P.; Coloretti, I.; Coluccello, A.; Costantini, E.; Fanelli, V.; Gagliardi, G.; Longhini, F.; Mariani, F.; Mascarello, A.; Menga, L.; Ottaviani, I.; Pasero, D.; Pedeferri, M.; Pezzi, A.; Servillo, G.; Severgnini, P.; Spadaro, S.; Zambelli, V.
abstract

Background: Limited data are available on the use of prone position in intubated, invasively ventilated patients with Coronavirus disease-19 (COVID-19). Aim of this study is to investigate the use and effect of prone position in this population during the first 2020 pandemic wave. Methods: Retrospective, multicentre, national cohort study conducted between February 24 and June 14, 2020, in 24 Italian Intensive Care Units (ICU) on adult patients needing invasive mechanical ventilation for respiratory failure caused by COVID-19. Clinical data were collected on the day of ICU admission. Information regarding the use of prone position was collected daily. Follow-up for patient outcomes was performed on July 15, 2020. The respiratory effects of the first prone position were studied in a subset of 78 patients. Patients were classified as Oxygen Responders if the PaO2/FiO2 ratio increased ≥ 20 mmHg during prone position and as Carbon Dioxide Responders if the ventilatory ratio was reduced during prone position. Results: Of 1057 included patients, mild, moderate and severe ARDS was present in 15, 50 and 35% of patients, respectively, and had a resulting mortality of 25, 33 and 41%. Prone position was applied in 61% of the patients. Patients placed prone had a more severe disease and died significantly more (45% vs. 33%, p < 0.001). Overall, prone position induced a significant increase in PaO2/FiO2 ratio, while no change in respiratory system compliance or ventilatory ratio was observed. Seventy-eight % of the subset of 78 patients were Oxygen Responders. Non-Responders had a more severe respiratory failure and died more often in the ICU (65% vs. 38%, p = 0.047). Forty-seven % of patients were defined as Carbon Dioxide Responders. These patients were older and had more comorbidities; however, no difference in terms of ICU mortality was observed (51% vs. 37%, p = 0.189 for Carbon Dioxide Responders and Non-Responders, respectively). Conclusions: During the COVID-19 pandemic, prone position has been widely adopted to treat mechanically ventilated patients with respiratory failure. The majority of patients improved their oxygenation during prone position, most likely due to a better ventilation perfusion matching. Trial registration: clinicaltrials.gov number: NCT04388670

2021 - Rare variants in Toll-like receptor 7 results in functional impairment and downregulation of cytokine-mediated signaling in COVID-19 patients [Articolo su rivista]
Mantovani, S.; Daga, S.; Fallerini, C.; Baldassarri, M.; Benetti, E.; Picchiotti, N.; Fava, F.; Galli, A.; Zibellini, S.; Bruttini, M.; Palmieri, M.; Croci, S.; Amitrano, S.; Alaverdian, D.; Capitani, K.; Furini, S.; Mari, F.; Meloni, I.; Montagnani, F.; Tumbarello, M.; Rancan, I.; Fabbiani, M.; Rossetti, B.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Raffaelli, C. S.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Romani, D.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Pisani, M.; Ognibene, A.; Pancrazzi, A.; Lorubbio, M.; Vaghi, M.; D'Arminio Monforte, A.; Miraglia, F. G.; Bruno, R.; Vecchia, M.; Girardis, M.; Venturelli, S.; Busani, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Tommasi, A.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Aucella, F.; Raggi, P.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Guarnaccia, A.; Valente, S.; De Vivo, O.; Doddato, G.; Lista, M.; Beligni, G.; Valentino, F.; Zguro, K.; Tita, R.; Giliberti, A.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.; Ariani, F.; Di Sarno, L.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Lacerenza, G.; Mussini, C.; Martinelli, E.; Tavecchia, L.; Belli, M. A.; Crotti, L.; Parati, G.; Sanarico, M.; Raimondi, F.; Biscarini, F.; Stella, A.; Bachetti, T.; La Rovere, M. T.; Ludovisi, S.; Bussotti, M.; Dei, S.; Ravaglia, S.; Artuso, R.; Andreucci, E.; Gori, G.; Pagliazzi, A.; Fiorentini, E.; Perrella, A.; Bianchi, F.; Bergomi, P.; Catena, E.; Colombo, R.; Luchi, S.; Morelli, G.; Petrocelli, P.; Iacopini, S.; Modica, S.; Baroni, S.; Segala, F. V.; Falcone, M.; Tiseo, G.; Barbieri, C.; Matucci, T.; Grassi, D.; Ferri, C.; Marinangeli, F.; Brancati, F.; Vincenti, A.; Borgo, V.; Lombardi, S.; Lenzi, M.; Di Pietro, M. A.; Vichi, F.; Romanin, B.; Attala, L.; Costa, C.; Gabbuti, A.; Mene, R.; Colaneri, M.; Casprini, P.; Merla, G.; Squeo, G. M.; Maffezzoni, M.; Frullanti, E.; Mondelli, M. U.; Renieri, A.
abstract

Toll-like receptors (TLR) are crucial components in the initiation of innate immune responses to a variety of pathogens, triggering the production of pro-inflammatory cytokines and type I and II interferons, which are responsible for innate antiviral responses. Among the different TLRs, TLR7 recognizes several single-stranded RNA viruses including SARS-CoV-2. We and others identified rare loss-of-function variants in X-chromosomal TLR7 in young men with severe COVID-19 and with no prior history of major chronic diseases, that were associated with impaired TLR7 signaling as well as type I and II IFN responses. Here, we performed RNA sequencing to investigate transcriptome variations following imiquimod stimulation of peripheral blood mononuclear cells isolated from patients carrying previously identified hypomorphic, hypofunctional, and loss-of-function TLR7 variants. Our investigation revealed a profound impairment of the TLR7 pathway in patients carrying loss-of-function variants. Of note, a failure in IFNγ upregulation following stimulation was also observed in cells harboring the hypofunctional and hypomorphic variants. We also identified new TLR7 variants in severely affected male patients for which a functional characterization of the TLR7 pathway was performed demonstrating a decrease in mRNA levels in the IFNα, IFNγ, RSAD2, ACOD1, IFIT2, and CXCL10 genes.

2021 - Rationale for polyclonal intravenous immunoglobulin adjunctive therapy in covid-19 patients: Report of a structured multidisciplinary consensus [Articolo su rivista]
Coloretti, I.; Berlot, G.; Busani, S.; De Rosa, F. G.; Donati, A.; Forfori, F.; Grasselli, G.; Mirabella, L.; Tascini, C.; Viale, P.; Girardis, M.
abstract

Introduction: Adjunctive therapy with polyclonal intravenous immunoglobins (IVIg) is currently used for preventing or managing infections and sepsis, especially in immunocompro-mised patients. The pathobiology of COVID-19 and the mechanisms of action of Ig led to the con-sideration of this adjunctive therapy, including in patients with respiratory failure due to the SARSCoV-2 infection. This manuscript reports the rationale, the available data and the results of a structured consensus on intravenous Ig therapy in patients with severe COVID-19. Methods: A panel of multidisciplinary experts defined the clinical phenotypes of COVID-19 patients with severe respiratory failure and, after literature review, voted for the agreement on the rationale and the potential role of IVIg therapy for each phenotype. Due to the scarce evidence available, a modified RAND/UCLA appropriateness method was used. Results: Three different phenotypes of COVID19 patients with severe respiratory failure were identified: patients with an abrupt and dysregulated hyperinflammatory response (early phase), patients with suspected immune paralysis (late phase) and patients with sepsis due to a hospital-acquired superinfection (sepsis by bacterial superinfec-tion). The rationale for intravenous Ig therapy in the early phase was considered uncertain whereas the panelists considered its use in the late phase and patients with sepsis/septic shock by bacterial superinfection appropriate. Conclusion: As with other immunotherapies, IVIg adjunctive therapy may have a potential role in the management of COVID-19 patients. The ongoing trials will clarify the appropriate target population and the true effectiveness.

2021 - Revisited Hyperoxia Pathophysiology in the Perioperative Setting: A Narrative Review [Articolo su rivista]
Busani, Stefano; Sarti, Marco; Serra, Francesco; Gelmini, Roberta; Venturelli, Sophie; Munari, Elena; Girardis, Massimo
abstract

2021 - SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues [Articolo su rivista]
D'Antonio, M.; Nguyen, J. P.; Arthur, T. D.; Matsui, H.; D'Antonio-Chronowska, A.; Frazer, K. A.; Neale, B. M.; Daly, M.; Ganna, A.; Stevens, C.; Pathak, G. A.; Andrews, S. J.; Kanai, M.; Cordioli, M.; Ganna, A.; Karjalainen, J.; Pathak, G. A.; Polimanti, R.; Andrews, S. J.; Cordioli, M.; Pirinen, M.; Kanai, M.; Harerimana, N.; Veerapen, K.; Wolford, B.; Nguyen, H.; Solomonson, M.; Stevens, C.; Liao, R. G.; Chwialkowska, K.; Trankiem, A.; Balaconis, M. K.; Hayward, C.; Richmond, A.; Campbell, A.; Morris, M.; Fawns-Ritchie, C.; Glessner, J. T.; Shaw, D. M.; Chang, X.; Polikowski, H.; Lauren, P. E.; Chen, H. -H.; Wanying, Z.; Hakonarson, H.; Porteous, D. J.; Below, J.; North, K.; Mccormick, J. B.; Timmers, P. R. H. J.; Wilson, J. F.; Tenesa, A.; D'Mellow, K.; Kerr, S. M.; Niemi, M. E. K.; Cordioli, M.; Nkambul, L.; von Hohenstaufen, K. A.; Sobh, A.; Eltoukhy, M. M.; Yassen, A. M.; Hegazy, M. A. F.; Okasha, K.; Eid, M. A.; Moahmed, H. S.; Shahin, D.; El-Sherbiny, Y. M.; Elhadidy, T. A.; Abd Elghafar, M. S.; El-Jawhari, J. J.; Mohamed, A. A. S.; Elnagdy, M. H.; Samir, A.; Abdel-Aziz, M.; Khafaga, W. T.; El-Lawaty, W. M.; Torky, M. S.; El-Shanshory, M. R.; Batini, C.; Lee, P. H.; Shrine, N.; Williams, A. T.; Tobin, M. D.; Guyatt, A. L.; John, C.; Packer, R. J.; Ali, A.; Free, R. C.; Wang, X.; Wain, L. V.; Hollox, E. J.; Venn, L. D.; Bee, C. E.; Adams, E. L.; Niemi, M. E. K.; Niavarani, A.; Cordioli, M.; Nkambul, L.; Sharififard, B.; Aliannejad, R.; Amirsavadkouhi, A.; Naderpour, Z.; Tadi, H. A.; Aleagha, A. E.; Ahmadi, S.; Moghaddam, S. B. M.; Adamsara, A.; Saeedi, M.; Abdollahi, H.; Hosseini, A.; Chariyavilaskul, P.; Chamnanphon, M.; Suttichet, T. B.; Shotelersuk, V.; Pongpanich, M.; Phokaew, C.; Chetruengchai, W.; Jantarabenjakul, W.; Putchareon, O.; Torvorapanit, P.; Puthanakit, T.; Suchartlikitwong, P.; Hirankarn, N.; Nilaratanakul, V.; Sodsai, P.; Brumpton, B. M.; Hveem, K.; Willer, C.; Wolford, B.; Zhou, W.; Rogne, T.; Solligard, E.; Asvold, B. O.; Abedalthagafi, M.; Alaamery, M.; Alqahtani, S.; Baraka, D.; Al Harthi, F.; Alsolm, E.; Safieh, L. A.; Alowayn, A. M.; Alqubaishi, F.; Al Mutairi, A.; Mangul, S.; Alshareef, A.; Sawaji, M.; Almutairi, M.; Aljawini, N.; Albesher, N.; Arabi, Y. M.; Mahmoud, E. S.; Khattab, A. K.; Halawani, R. T.; Alahmadey, Z. Z.; Albakri, J. K.; Felemban, W. A.; Suliman, B. A.; Hasanato, R.; Al-Awdah, L.; Alghamdi, J.; Alzahrani, D.; Aljohani, S.; Al-Afghani, H.; Alrashed, M.; Aldhawi, N.; Albardis, H.; Alkwai, S.; Alswailm, M.; Almalki, F.; Albeladi, M.; Almohammed, I.; Barhoush, E.; Albader, A.; Massadeh, S.; Almalik, A.; Alotaibi, S.; Alghamdi, B.; Jung, J.; Fawzy, M. S.; Lee, Y.; Magnus, P.; Trogstad, L. -I. S.; Helgeland, O.; Harris, J. R.; Mangino, M.; Spector, T. D.; Emma, D.; Smieszek, S. P.; Przychodzen, B. P.; Polymeropoulos, C.; Polymeropoulos, V.; Polymeropoulos, M. H.; Fernandez-Cadenas, I.; Perez-Tur, J.; Llucia-Carol, L.; Cullell, N.; Muino, E.; Carcel-Marquez, J.; Dediego, M. L.; Iglesias, L. L.; Planas, A. M.; Soriano, A.; Rico, V.; Aguero, D.; Bedini, J. L.; Lozano, F.; Domingo, C.; Robles, V.; Ruiz-Jaen, F.; Marquez, L.; Gomez, J.; Coto, E.; Albaiceta, G. M.; Garcia-Clemente, M.; Dalmau, D.; Arranz, M. J.; Dietl, B.; Serra-Llovich, A.; Soler, P.; Colobran, R.; Martin-Nalda, A.; Martinez, A. P.; Bernardo, D.; Rojo, S.; Fiz-Lopez, A.; Arribas, E.; de la Cal-Sabater, P.; Segura, T.; Gonzalez-Villa, E.; Serrano-Heras, G.; Marti-Fabregas, J.; Jimenez-Xarrie, E.; de Felipe Mimbrera, A.; Masjuan, J.; Garcia-Madrona, S.; Dominguez-Mayoral, A.; Villalonga, J. M.; Menendez-Valladares, P.; Chasman, D. I.; Buring, J. E.; Ridker, P. M.; Franco, G.; Sesso, H. D.; Manson, J. E.; Chang, X.; Glessner, J. R.; Hakonarson, H.; Hayward, C.; Richmond, A.; Porteous, D. J.; Campbell, A.; Fawns-Ritchie, C.; Medina-Gomez, C.; Uitterlinden, A. G.; Arfan Ikram, M.; Kristiansson, K.; Koskelainen, S.; Perola, M.; Donner, K.; Kivinen, K.; Palotie, A.; Ripatti, S.; Ruotsalainen, S.; Kaunisto, M.; Nakanishi, T.; B
abstract

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.

2021 - Shorter androgen receptor polyQ alleles protect against life-threatening COVID-19 disease in European males [Articolo su rivista]
Baldassarri, M.; Picchiotti, N.; Fava, F.; Fallerini, C.; Benetti, E.; Daga, S.; Valentino, F.; Doddato, G.; Furini, S.; Giliberti, A.; Tita, R.; Amitrano, S.; Bruttini, M.; Croci, S.; Meloni, I.; Pinto, A. M.; Iuso, N.; Gabbi, C.; Sciarra, F.; Venneri, M. A.; Gori, M.; Sanarico, M.; Crawley, F. P.; Pagotto, U.; Fanelli, F.; Mezzullo, M.; Dominguez-Garrido, E.; Planas-Serra, L.; Schluter, A.; Colobran, R.; Soler-Palacin, P.; Lapunzina, P.; Tenorio, J.; Pujol, A.; Castagna, M. G.; Marcelli, M.; Isidori, A. M.; Renieri, A.; Frullanti, E.; Mari, F.; Montagnani, F.; Di Sarno, L.; Tommasi, A.; Palmieri, M.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Sestini, F.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennett, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Guerrini, S.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Cappelli, S.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Vaghi, M.; Monforte, A. D.; Merlini, E.; Miraglia, F. G.; Mondelli, M. U.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Sita, M.; Cossarizza, A.; Antinori, A.; Vergori, A.; Emiliozzi, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Paciosi, F.; Scotton, P. G.; Andretta, F.; Panese, S.; Baratti, S.; Scaggiante, R.; Gatti, F.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, E.; Antoni, M. D.; Zanella, I.; Monica, M. D.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Fiorentino, G.; Carella, M.; Castori, M.; Merla, G.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Valente, S.; Mencarelli, M. A.; Lo Rizzo, C.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Zucchi, P.; Parravicini, P.; Menatti, E.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Bosio, G.; Martinelli, E.; Mancarella, S.; Tavecchia, L.; Crotti, L.; Parati, G.; Aguilera-Albesa, S.; Albu, S.; Casasnovas, C.; Velez-Santamaria, V.; Horcajada, J. P.; Villar, J.; Rodriguez-Palmero, A.; Ruiz, M.; Seijo, L. M.; Troya, J.; Valencia-Ramos, J.; Gut, M.
abstract

Background: While SARS-CoV-2 similarly infects men and women, COVID-19 outcome is less favorable in men. Variability in COVID-19 severity may be explained by differences in the host genome. Methods: We compared poly-amino acids variability from WES data in severely affected COVID-19 patients versus SARS-CoV-2 PCR-positive oligo-asymptomatic subjects. Findings: Shorter polyQ alleles (≤22) in the androgen receptor (AR) conferred protection against severe outcome in COVID-19 in the first tested cohort (both males and females) of 638 Italian subjects. The association between long polyQ alleles (≥23) and severe clinical outcome (p = 0.024) was also validated in an independent cohort of Spanish men <60 years of age (p = 0.014). Testosterone was higher in subjects with AR long-polyQ, possibly indicating receptor resistance (p = 0.042 Mann-Whitney U test). Inappropriately low serum testosterone level among carriers of the long-polyQ alleles (p = 0.0004 Mann-Whitney U test) predicted the need for intensive care in COVID-19 infected men. In agreement with the known anti-inflammatory action of testosterone, patients with long-polyQ and age ≥60 years had increased levels of CRP (p = 0.018, not accounting for multiple testing). Interpretation: We identify the first genetic polymorphism that appears to predispose some men to develop more severe disease. Failure of the endocrine feedback to overcome AR signaling defects by increasing testosterone levels during the infection leads to the polyQ tract becoming dominant to serum testosterone levels for the clinical outcome. These results may contribute to designing reliable clinical and public health measures and provide a rationale to test testosterone as adjuvant therapy in men with COVID-19 expressing long AR polyQ repeats. Funding: MIUR project “Dipartimenti di Eccellenza 2018-2020” to Department of Medical Biotechnologies University of Siena, Italy (Italian D.L. n.18 March 17, 2020) and “Bando Ricerca COVID-19 Toscana” project to Azienda Ospedaliero-Universitaria Senese. Private donors for COVID-19 research and charity funds from Intesa San Paolo.

2021 - Synergistic effect of static compliance and d-dimers to predict outcome of patients with covid-19-ards: A prospective multicenter study [Articolo su rivista]
Tonetti, T.; Grasselli, G.; Rucci, P.; Alessandri, F.; Dell'Olio, A.; Boscolo, A.; Pasin, L.; Sella, N.; Mega, C.; Melotti, R. M.; Girardis, M.; Busani, S.; Bellani, G.; Foti, G.; Grieco, D. L.; Scaravilli, V.; Protti, A.; Langer, T.; Mascia, L.; Pugliese, F.; Cecconi, M.; Fumagalli, R.; Nava, S.; Antonelli, M.; Slutsky, A. S.; Navalesi, P.; Pesenti, A.; Ranieri, V. M.
abstract

The synergic combination of D-dimer (as proxy of thrombotic/vascular injury) and static compliance (as proxy of parenchymal injury) in predicting mortality in COVID-19-ARDS has not been systematically evaluated. The objective is to determine whether the combination of elevated D-dimer and low static compliance can predict mortality in patients with COVID-19-ARDS. A “training sample” (March–June 2020) and a “testing sample” (September 2020–January 2021) of adult patients invasively ventilated for COVID-19-ARDS were collected in nine hospitals. D-dimer and compliance in the first 24 h were recorded. Study outcome was all-cause mortality at 28-days. Cutoffs for D-dimer and compliance were identified by receiver operating characteristic curve analysis. Mutually exclusive groups were selected using classification tree analysis with chi-square automatic interaction detection. Time to death in the resulting groups was estimated with Cox regression adjusted for SOFA, sex, age, PaO2/FiO2 ratio, and sample (training/testing). “Training” and “testing” samples amounted to 347 and 296 patients, respectively. Three groups were identified: D-dimer ≤ 1880 ng/mL (LD); D-dimer > 1880 ng/mL and compliance > 41 mL/cmH2O (LD-HC); D-dimer > 1880 ng/mL and compliance ≤ 41 mL/cmH2O (HD-LC). 28-days mortality progressively increased in the three groups (from 24% to 35% and 57% (training) and from 27% to 39% and 60% (testing), respectively; p < 0.01). Adjusted mortality was significantly higher in HD-LC group compared with LD (HR = 0.479, p < 0.001) and HD-HC (HR = 0.542, p < 0.01); no difference was found between LD and HD-HC. In conclusion, combination of high D-dimer and low static compliance identifies a clinical phenotype with high mortality in COVID-19-ARDS.

2021 - Temporal changes in the epidemiology, management, and outcome from acute respiratory distress syndrome in European intensive care units: a comparison of two large cohorts [Articolo su rivista]
Sakr, Y.; Francois, B.; Sole-Violan, J.; Kotfis, K.; Jaschinski, U.; Estella, A.; Leone, M.; Jakob, S. M.; Wittebole, X.; Fontes, L. E.; de Melo Gurgel, M.; Midega, T.; Vincent, J. -L.; Ranieri, V. M.; Karth, G. D.; Draxler, V.; Filzwieser, G.; Heindl, W.; Kellner, G.; Bauer, T.; Lenz, K.; Rossmann, E.; Wiedermann, C.; Biston, P.; Chochrad, D.; Collin, V.; Damas, P.; Decruyenaere, J.; Hoste, E.; Devriendt, J.; Espeel, B.; Fraipont, V.; Installe, E.; Malbrain, M.; Nollet, G.; Preiser, J. -C.; Raemaekers, J.; Roman, A.; Simon, M.; Spapen, H.; Swinnen, W.; Vallot, F.; Vincent, J. -L.; Chytra, I.; Dadak, L.; Herold, I.; Polak, F.; Sterba, M.; Bestle, M.; Espersen, K.; Guldager, H.; Welling, K. -L.; Nyman, D.; Ruokonen, E.; Saarinen, K.; Annane, D.; Catogni, P.; Colas, G.; Coulomb, F.; Dorne, R.; Garrouste, M.; Isetta, C.; Larche, J.; Le Gall, J. -R.; Lessire, H.; Malledant, Y.; Mateu, P.; Ossart, M.; Payen, D.; Schlossmacher, P.; Timsit, J. -F.; Winnock, S.; Sollet, J. -P.; Mallet, L.; Maurer, P.; Sab, J. -M.; Aykut, G.; Brunkhorst, F.; Nierhaus, A.; Lauterbach, M.; Ragaller, M.; Gatz, R.; Gerlach, H.; Henzler, D.; Hopf, H. -B.; Hueneburg, H.; Karzai, W.; Keller, A.; Kuhlmann, U.; Langgartner, J.; Manhold, C.; Reith, B.; Schuerholz, T.; Spies, C.; Stogbauer, R.; Unterburger, J.; Clouva-Molyvdas, P. -M.; Giokas, G.; Ioannidou, E.; Lahana, A.; Liolios, A.; Marathias, K.; Nakos, G.; Tasiou, A.; Tsangaris, H.; Tamasi, P.; Marsh, B.; Power, M.; Sprung, C.; Biagioli, B.; Pallavicini, F. B.; Pesenti, A.; Capra, C.; Corte, F. D.; Donadio, P.; Donati, A.; Giarratano, A.; Giorgio, T.; Giudici, D.; Greco, S.; Guadagnucci, A.; Lapichino, G.; Livigni, S.; Moise, G.; Nardi, G.; Panascia, E.; Pizzamiglio, M.; Ranieri, V. M.; Rosi, R.; Sicignano, A.; Solca, M.; Vignali, G.; Rinonapoli, I. V.; Barnas, M.; De Bel, E. E.; De Pont, A. -C.; Groeneveld, J.; Nijsten, M.; Sie, L. -H.; Zandstra, D. F.; Harboe, S.; Linden, S.; Lovstad, R. Z.; Moen, H.; Smith-Erichsen, N.; Piotrowski, A.; Karpel, E.; Almeida, E.; Moreno, R.; Pais-De-Lacerda, A.; Paiva, J. A.; Serra, I.; Pimentel, J. M.; Filipescu, D.; Jovanovic, K.; Malik, P.; Lucka, K.; Voga, G.; Alvarez-Santullano, C. A.; Artigas, A.; Zavala, E.; Escorsell, A.; Nicolas, J.; Cea, J. J. I.; Marina, L.; Montejo, J.; Palencia, E.; Santos, F.; Sierra-Camerino, R.; Sipmann, F.; Brodersen, K.; Haggqvist, J.; Hermansson, D.; Hjelmqvist, H.; Heer, K.; Loderer, G.; Maggiorini, M.; Zender, H.; Andrews, P.; Appadu, B.; Groba, C. B.; Bewley, J.; Burchett, K.; Chambers, P.; Coakley, J.; Doberenz, D.; Eastwood, N.; Ferguson, A.; Fielden, J.; Gedney, J.; Gunning, K.; Harling, D.; Jankowski, S.; Jayson, D.; Kilner, A.; Krishna-Kumar, V.; Lei, K.; Mackenzie, S.; Macnaughton, P.; Marx, G.; Mcculloch, C.; Morgan, P.; Rhodes, A.; Roberts, C.; Russell, M.; Tupper-Carey, D.; Wright, M.; Twohey, L.; Watts, J.; Webster, R.; Williams, D.; Urbanek, P.; Schlieber, J.; Reisinger, J.; Auer, J.; Hartjes, A.; Lerche, A.; Janous, T.; Kink, E.; Krahulec, W.; Smolle, K. -H.; Van Der Schueren, M.; Thibo, P.; Vanhoof, M.; Ahmet, I.; Gadisseux, P.; Dufaye, P.; Jacobs, O.; Dive, A.; Bouckaert, Y.; Gilbert, E.; Gressens, B.; Pinck, E.; De Waele, J. J.; Rimachi, R.; Gusu, D.; De Decker, K.; Mandianga, K.; Heytens, L.; Van Collie, O.; Vandenheede, W.; Rogiers, P.; Pavlik, P.; Manak, J.; Kieslichova, E.; Turek, R.; Fischer, M.; Valkova, R.; Dostal, P.; Malaska, J.; Hajek, R.; Zidkova, A.; Lavicka, P.; Kolodzeike, P.; Kruse, M.; Andersen, T.; Harjola, V. -P.; Durocher, A.; Moulront, S.; Lepape, A.; Losser, M. -R.; Cabaret, P.; Kalaitzis, E.; Zogheib, E.; Charve, P.; Lefrant, J. -Y.; Beilouny, B.; Forceville, X.; Misset, B.; Jacobs, F.; Floccard, B.; Wynckel, A.; Castelain, V.; Faure, A.; Lavagne, P.; Lepoivre, T.; Moussa, M. D.; Vieillard-Baron, A.; Durand, M.; Gainnier, M.; Ichai, C.; Arens, S.; Hoffmann, C.; Kaffarnik, M.; Scharnofske, C. -J.; Voigt, I.; Peckelsen, C.; Weber, M.; Gille, J.; Lange, A.; Schoser, G.; Sablotzki, A.; Bluethgen, A.; Vo
abstract

Background: Mortality rates for patients with ARDS remain high. We assessed temporal changes in the epidemiology and management of ARDS patients requiring invasive mechanical ventilation in European ICUs. We also investigated the association between ventilatory settings and outcome in these patients. Methods: This was a post hoc analysis of two cohorts of adult ICU patients admitted between May 1–15, 2002 (SOAP study, n = 3147), and May 8–18, 2012 (ICON audit, n = 4601 admitted to ICUs in the same 24 countries as the SOAP study). ARDS was defined retrospectively using the Berlin definitions. Values of tidal volume, PEEP, plateau pressure, and FiO2 corresponding to the most abnormal value of arterial PO2 were recorded prospectively every 24 h. In both studies, patients were followed for outcome until death, hospital discharge or for 60 days. Results: The frequency of ARDS requiring mechanical ventilation during the ICU stay was similar in SOAP and ICON (327[10.4%] vs. 494[10.7%], p = 0.793). The diagnosis of ARDS was established at a median of 3 (IQ: 1–7) days after admission in SOAP and 2 (1–6) days in ICON. Within 24 h of diagnosis, ARDS was mild in 244 (29.7%), moderate in 388 (47.3%), and severe in 189 (23.0%) patients. In patients with ARDS, tidal volumes were lower in the later (ICON) than in the earlier (SOAP) cohort. Plateau and driving pressures were also lower in ICON than in SOAP. ICU (134[41.1%] vs 179[36.9%]) and hospital (151[46.2%] vs 212[44.4%]) mortality rates in patients with ARDS were similar in SOAP and ICON. High plateau pressure (> 29 cmH2O) and driving pressure (> 14 cmH2O) on the first day of mechanical ventilation but not tidal volume (> 8 ml/kg predicted body weight [PBW]) were independently associated with a higher risk of in-hospital death. Conclusion: The frequency of and outcome from ARDS remained relatively stable between 2002 and 2012. Plateau pressure > 29 cmH2O and driving pressure > 14 cmH2O on the first day of mechanical ventilation but not tidal volume > 8 ml/kg PBW were independently associated with a higher risk of death. These data highlight the continued burden of ARDS and provide hypothesis-generating data for the design of future studies.

2021 - The COVID-19 puzzle: deciphering pathophysiology and phenotypes of a new disease entity [Articolo su rivista]
Osuchowski, M. F.; Winkler, M. S.; Skirecki, T.; Cajander, S.; Shankar-Hari, M.; Lachmann, G.; Monneret, G.; Venet, F.; Bauer, M.; Brunkhorst, F. M.; Weis, S.; Garcia-Salido, A.; Kox, M.; Cavaillon, J. -M.; Uhle, F.; Weigand, M. A.; Flohe, S. B.; Wiersinga, W. J.; Almansa, R.; de la Fuente, A.; Martin-Loeches, I.; Meisel, C.; Spinetti, T.; Schefold, J. C.; Cilloniz, C.; Torres, A.; Giamarellos-Bourboulis, E. J.; Ferrer, R.; Girardis, M.; Cossarizza, A.; Netea, M. G.; van der Poll, T.; Bermejo-Martin, J. F.; Rubio, I.
abstract

The zoonotic SARS-CoV-2 virus that causes COVID-19 continues to spread worldwide, with devastating consequences. While the medical community has gained insight into the epidemiology of COVID-19, important questions remain about the clinical complexities and underlying mechanisms of disease phenotypes. Severe COVID-19 most commonly involves respiratory manifestations, although other systems are also affected, and acute disease is often followed by protracted complications. Such complex manifestations suggest that SARS-CoV-2 dysregulates the host response, triggering wide-ranging immuno-inflammatory, thrombotic, and parenchymal derangements. We review the intricacies of COVID-19 pathophysiology, its various phenotypes, and the anti-SARS-CoV-2 host response at the humoral and cellular levels. Some similarities exist between COVID-19 and respiratory failure of other origins, but evidence for many distinctive mechanistic features indicates that COVID-19 constitutes a new disease entity, with emerging data suggesting involvement of an endotheliopathy-centred pathophysiology. Further research, combining basic and clinical studies, is needed to advance understanding of pathophysiological mechanisms and to characterise immuno-inflammatory derangements across the range of phenotypes to enable optimum care for patients with COVID-19.

2021 - The impact of tocilizumab on respiratory support states transition and clinical outcomes in COVID-19 patients. A Markov model multi-state study [Articolo su rivista]
Milic, J.; Banchelli, F.; Meschiari, M.; Franceschini, E.; Ciusa, G.; Gozzi, L.; Volpi, S.; Faltoni, M.; Franceschi, G.; Iadisernia, V.; Yaacoub, D.; Dolci, G.; Bacca, E.; Rogati, C.; Tutone, M.; Burastero, G.; Raimondi, A.; Menozzi, M.; Cuomo, G.; Corradi, L.; Orlando, G.; Santoro, A.; Digaetano, M.; Puzzolante, C.; Carli, F.; Bedini, A.; Busani, S.; Girardis, M.; Cossarizza, A.; Miglio, R.; Mussini, C.; Guaraldi, G.; D'Amico, R.
abstract

Background The benefit of tocilizumab on mortality and time to recovery in people with severe COVID pneumonia may depend on appropriate timing. The objective was to estimate the impact of tocilizumab administration on switching respiratory support states, mortality and time to recovery. Methods In an observational study, a continuous-time Markov multi-state model was used to describe the sequence of respiratory support states including: no respiratory support (NRS), oxygen therapy (OT), non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), OT in recovery, NRS in recovery. Results Two hundred seventy-one consecutive adult patients were included in the analyses contributing to 695 transitions across states. The prevalence of patients in each respiratory support state was estimated with stack probability plots, comparing people treated with and without tocilizumab since the beginning of the OT state. A positive effect of tocilizumab on the probability of moving from the invasive and non-invasive mechanical NIV/IMV state to the OT in recovery state (HR = 2.6, 95% CI = 1.2–5.2) was observed. Furthermore, a reduced risk of death was observed in patients in NIV/IMV (HR = 0.3, 95% CI = 0.1–0.7) or in OT (HR = 0.1, 95% CI = 0.0–0.8) treated with tocilizumab. Conclusion To conclude, we were able to show the positive impact of tocilizumab used in different disease stages depicted by respiratory support states. The use of the multi-state Markov model allowed to harmonize the heterogeneous mortality and recovery endpoints and summarize results with stack probability plots. This approach could inform randomized clinical trials regarding tocilizumab, support disease management and hospital decision making.

2021 - Time course of risk factors associated with mortality of 1260 critically ill patients with COVID-19 admitted to 24 Italian intensive care units [Articolo su rivista]
Zanella, A.; Florio, G.; Antonelli, M.; Bellani, G.; Berselli, A.; Bove, T.; Cabrini, L.; Carlesso, E.; Castelli, G. P.; Cecconi, M.; Citerio, G.; Coloretti, I.; Corti, D.; Dalla Corte, F.; De Robertis, E.; Foti, G.; Fumagalli, R.; Girardis, M.; Giudici, R.; Guiotto, L.; Langer, T.; Mirabella, L.; Pasero, D.; Protti, A.; Ranieri, M. V.; Rona, R.; Scudeller, L.; Severgnini, P.; Spadaro, S.; Stocchetti, N.; Vigano, M.; Pesenti, A.; Grasselli, G.; Aspesi, M.; Baccanelli, F.; Bassi, F.; Bet, A.; Biagioni, E.; Biondo, A.; Bonenti, C.; Bottino, N.; Brazzi, L.; Buquicchio, I.; Busani, S.; Calini, A.; Calligaro, P.; Cantatore, L. P.; Carelli, S.; Carsetti, A.; Cavallini, S.; Cimicchi, G.; Coppadoro, A.; Dall'Ara, L.; Di Gravio, V.; Erba, M.; Evasi, G.; Facchini, A.; Fanelli, V.; Feliciotti, G.; Fusarini, C. F.; Ferraro, G.; Gagliardi, G.; Garberi, R.; Gay, H.; Giacche, L.; Grieco, D.; Guzzardella, A.; Longhini, F.; Manzan, A.; Maraggia, D.; Milani, A.; Mischi, A.; Montalto, C.; Mormina, S.; Noseda, V.; Paleari, C.; Pedeferri, M.; Pezzi, A.; Pizzilli, G.; Pozzi, M.; Properzi, P.; Rauseo, M.; Russotto, V.; Saccarelli, L.; Servillo, G.; Spano, S.; Tagliabue, P.; Tonetti, T.; Tullo, L.; Vetrugno, L.; Vivona, L.; Volta, C. A.; Zambelli, V.; Zanoni, A.
abstract

Purpose: To evaluate the daily values and trends over time of relevant clinical, ventilatory and laboratory parameters during the intensive care unit (ICU) stay and their association with outcome in critically ill patients with coronavirus disease 19 (COVID-19). Methods: In this retrospective–prospective multicentric study, we enrolled COVID-19 patients admitted to Italian ICUs from February 22 to May 31, 2020. Clinical data were daily recorded. The time course of 18 clinical parameters was evaluated by a polynomial maximum likelihood multilevel linear regression model, while a full joint modeling was fit to study the association with ICU outcome. Results: 1260 consecutive critically ill patients with COVID-19 admitted in 24 ICUs were enrolled. 78% were male with a median age of 63 [55–69] years. At ICU admission, the median ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) was 122 [89–175] mmHg. 79% of patients underwent invasive mechanical ventilation. The overall mortality was 34%. Both the daily values and trends of respiratory system compliance, PaO2/FiO2, driving pressure, arterial carbon dioxide partial pressure, creatinine, C-reactive protein, ferritin, neutrophil, neutrophil–lymphocyte ratio, and platelets were associated with survival, while for lactate, pH, bilirubin, lymphocyte, and urea only the daily values were associated with survival. The trends of PaO2/FiO2, respiratory system compliance, driving pressure, creatinine, ferritin, and C-reactive protein showed a higher association with survival compared to the daily values. Conclusion: Daily values or trends over time of parameters associated with acute organ dysfunction, acid–base derangement, coagulation impairment, or systemic inflammation were associated with patient survival.

2021 - Vertebral artery dissection in term pregnancy after cervical spine manipulation: a case report and review the literature [Articolo su rivista]
Monari, F.; Busani, S.; Imbrogno, M. G.; Neri, I.; Girardis, M.; Ghirardini, A.; Cavalleri, F.; Facchinetti, F.
abstract

Background: Vertebral artery dissection is an uncommon, but potentially fatal, vascular event. This case aimed to describe the pathogenesis and clinical presentation of vertebral artery dissection in a term pregnant patient. Moreover, we focused on the differential diagnosis, reviewing the available evidence. Case presentation: A 39-year-old Caucasian woman presented at 38 + 4 weeks of gestation with a short-term history of vertigo, nausea, and vomiting. Symptoms appeared a few days after cervical spine manipulation by an osteopathic specialist. Urgent magnetic resonance imaging of the head was obtained and revealed an ischemic lesion of the right posterolateral portion of the brain bulb. A subsequent computed tomography angiographic scan of the head and neck showed a right vertebral artery dissection. Based on the correlation of the neurological manifestations and imaging findings, a diagnosis of vertebral artery dissection was established. The patient started low-dose acetylsalicylic acid and prophylactic enoxaparin following an urgent cesarean section. Conclusion: Vertebral artery dissection is a rare but potential cause of neurologic impairments in pregnancy and during the postpartum period. It should be considered in the differential diagnosis for women who present with headache and/or vertigo. Women with a history of migraines, hypertension, or autoimmune disorders in pregnancy are at higher risk, as well as following cervical spine manipulations. Prompt diagnosis and management of vertebral artery dissection are essential to ensure favorable outcomes.

2020 - A case of splenic artery pseudoaneurysm rupture in a bulimic patient with gastric ulcer [Articolo su rivista]
Brugioni, L.; Petri, J.; Cirino, S. S.; Amidei, L.; Scarabottini, S.; de Niederhausern, F.; Vivoli, D.; Girardis, M.
abstract

Splenic artery pseudoaneurysm is a rarely described condition and it is even more rarely considered as a complication of peptic disease. The most common etiologies are pancreatitis, both chronic and acute, and trauma. Diagnosis can be challenging, including ultrasonography, computed tomography scan and angiography, the latter being useful also for therapy (embolization). Given her history of bulimia nervosa and the stress related to hospitalization, our patient was particularly predisposed to peptic ulcer.

2020 - ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population [Articolo su rivista]
Benetti, E.; Tita, R.; Spiga, O.; Ciolfi, A.; Birolo, G.; Bruselles, A.; Doddato, G.; Giliberti, A.; Marconi, C.; Musacchia, F.; Pippucci, T.; Torella, A.; Trezza, A.; Valentino, F.; Baldassarri, M.; Brusco, A.; Asselta, R.; Bruttini, M.; Furini, S.; Seri, M.; Nigro, V.; Matullo, G.; Tartaglia, M.; Mari, F.; Elisa, F.; Chiara, F.; Sergio, D.; Susanna, C.; Sara, A.; Francesca, F.; Montagnani, F.; Di Sarno, L.; Tommasi, A.; Palmieri, M.; Emiliozzi, A.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Bergantini, L.; D'Alessandro, M.; Cameli, P.; Bennet, D.; Anedda, F.; Marcantonio, S.; Scolletta, S.; Franchi, F.; Mazzei, M. A.; Conticini, E.; Cantarini, L.; Frediani, B.; Tacconi, D.; Feri, M.; Scala, R.; Spargi, G.; Corridi, M.; Nencioni, C.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Bandini, M.; Desanctis, E.; Canaccini, A.; Spertilli, C.; Donati, A.; Guidelli, L.; Croci, L.; Verzuri, A.; Anemoli, V.; Ognibene, A.; Vaghi, M.; D'Arminio Monforte, A.; Merlini, E.; Mondelli, M. U.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Sita, M.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Riva, A.; Francisci, D.; Schiaroli, E.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Parisi, S. G.; Castelli, F.; Quiros-Roldan, M. E.; Magro, P.; Minardi, C.; Castelli, D.; Polesini, I.; Della Monica, M.; Piscopo, C.; Capasso, M.; Russo, R.; Andolfo, I.; Iolascon, A.; Carella, M.; Castori, M.; Merla, G.; Aucella, F.; Raggi, P.; Marciano, C.; Perna, R.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Gabbi, C.; Valente, S.; Guerrini, S.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Bargagli, E.; Mandala, M.; Giorli, A.; Salerni, L.; Fiorentino, G.; Zucchi, P.; Parravicini, P.; Menatti, E.; Baratti, S.; Trotta, T.; Giannattasio, F.; Coiro, G.; Lena, F.; Coviello, D. A.; Mussini, C.; Renieri, A.; Pinto, A. M.
abstract

In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.

2020 - Adjunctive therapy with vitamin c and thiamine in patients treated with steroids for refractory septic shock: A propensity matched before-after, case-control study [Articolo su rivista]
Coloretti, I.; Biagioni, E.; Venturelli, S.; Munari, E.; Tosi, M.; Roat, E.; Brugioni, L.; Gelmini, R.; Venturelli, C.; Girardis, M.
abstract

Purpose: Triple therapy with steroids, vitamin C and thiamine has been recently proposed as a safe and beneficial in patients with sepsis. In 2017, we added the use of intravenous vitamin C and thiamine in septic shock patients receiving low dose hydrocortisone because poorly responsive to vasopressors. Aim of this study is to verify whether triple therapy rather than steroids alone can improve outcome in patients with refractory shock. Materials and methods: In this before-after retrospective analysis, we compared septic shock patients admitted to our intensive care unit (ICU) who received triple therapy from June 2017 to November 2019 to septic shock patients who received only hydrocortisone from January 2015 to June 2017. Patients of the two study periods were matched 1:1 using a propensity score model. Results: A final cohort of 56 patients treated with triple therapy were matched to 56 patients treated only with steroids. Triple therapy reduced the length of mechanical ventilation (p = 0,01) and showed a trend in lowering the 30-day and hospital mortality compared to therapy with only hydrocortisone. Conclusions: Although with significant limitations, our experience indicated that triple therapy seems to provide an improvement of clinical outcomes in patients with refractory septic shock.

2020 - Altered bioenergetics and mitochondrial dysfunction of monocytes in patients with COVID-19 pneumonia [Articolo su rivista]
Gibellini, L.; De Biasi, S.; Paolini, A.; Borella, R.; Boraldi, F.; Mattioli, M.; Lo Tartaro, D.; Fidanza, L.; Caro-Maldonado, A.; Meschiari, M.; Iadisernia, V.; Bacca, E.; Riva, G.; Cicchetti, L.; Quaglino, D.; Guaraldi, G.; Busani, S.; Girardis, M.; Mussini, C.; Cossarizza, A.
abstract

In patients infected by SARS-CoV-2 who experience an exaggerated inflammation leading to pneumonia, monocytes likely play a major role but have received poor attention. Thus, we analyzed peripheral blood monocytes from patients with COVID-19 pneumonia and found that these cells show signs of altered bioenergetics and mitochondrial dysfunction, had a reduced basal and maximal respiration, reduced spare respiratory capacity, and decreased proton leak. Basal extracellular acidification rate was also diminished, suggesting reduced capability to perform aerobic glycolysis. Although COVID-19 monocytes had a reduced ability to perform oxidative burst, they were still capable of producing TNF and IFN-γ in vitro. A significantly high amount of monocytes had depolarized mitochondria and abnormal mitochondrial ultrastructure. A redistribution of monocyte subsets, with a significant expansion of intermediate/pro-inflammatory cells, and high amounts of immature monocytes were found, along with a concomitant compression of classical monocytes, and an increased expression of inhibitory checkpoints like PD-1/PD-L1. High plasma levels of several inflammatory cytokines and chemokines, including GM-CSF, IL-18, CCL2, CXCL10, and osteopontin, finally confirm the importance of monocytes in COVID-19 immunopathogenesis.

2020 - Antimicrobial de-escalation in the critically ill patient and assessment of clinical cure: the DIANA study [Articolo su rivista]
De Bus, L.; Depuydt, P.; Steen, J.; Dhaese, S.; De Smet, K.; Tabah, A.; Akova, M.; Cotta, M. O.; De Pascale, G.; Dimopoulos, G.; Fujitani, S.; Garnacho-Montero, J.; Leone, M.; Lipman, J.; Ostermann, M.; Paiva, J. -A.; Schouten, J.; Sjovall, F.; Timsit, J. -F.; Roberts, J. A.; Zahar, J. -R.; Zand, F.; Zirpe, K.; De Waele, J. J.; Rios, F.; Vazquez, A. R.; Vidal, M. G.; Zakalik, G.; Attokaran, A. G.; Banakh, I.; Dey-Chatterjee, S.; Ewan, J.; Ferrier, J.; Forbes, L.; Fourie, C.; Leditschke, A.; Murray, L.; Eller, P.; Biston, P.; Bracke, S.; De Crop, L.; De Schryver, N.; Frans, E.; Spapen, H.; Van Malderen, C.; Vansteelandt, S.; Vermeiren, D.; Arevalo, E. P.; Crespo, M.; Flores, R. Z.; Piza, P.; Tutillo, D. M.; Elme, A.; Kallaste, A.; Starkopf, J.; Bourenne, J.; Calypso, M.; Cohen, Y.; Dahyot-Fizelier, C.; Depret, F.; Guillot, M.; Imzi, N.; Jochmans, S.; Kouatchet, A.; Lepape, A.; Martin, O.; Heim, M.; Schaller, S. J.; Arvaniti, K.; Bekridelis, A.; Ioannidis, P.; Mitrakos, C.; Papanikolaou, M. N.; Pouriki, S.; Vemvetsou, A.; Abraham, B.; Bhattacharya, P. K.; Budugu, A.; Dixit, S.; Gurav, S.; Kandanuri, P.; Prabhu, D. A.; Rathod, D.; Savaru, K.; Udupa, A. N.; Varghese, S. B.; Bakhodaei, H. H.; Dabiri, G.; Fallahi, M. J.; Feiz, F.; Firoozifar, M.; Khaloo, V.; Maghsudi, B.; Masjedi, M.; Nikandish, R.; Sabetian, G.; Marsh, B.; Martin-Loeches, I.; Steiner, J.; Barbagallo, M.; Caricato, A.; Cortegiani, A.; D'Andrea, R.; Deana, C.; Donati, A.; Girardis, M.; Mandala, G.; Panarello, G.; Pasero, D.; Pelagalli, L.; Soave, P. M.; Spadaro, S.; Fujita, Y.; Fujiwara, S.; Hara, Y.; Hashi, H.; Hashimoto, S.; Hashimoto, H.; Hayakawa, K.; Inoue, M.; Isokawa, S.; Kameda, S.; Kamohara, H.; Kanamoto, M.; Katayama, S.; Kawagishi, T.; Kawano, Y.; Kida, Y.; Kita, M.; Kobayashi, A.; Kuriyama, A.; Naito, T.; Nashiki, H.; Nishiyama, K.; Shindo, S.; Suzuki, T.; Takaba, A.; Tanaka, C.; Tetsuya, K.; Tomioka, Y.; Yanagawa, Y.; Yoshida, H.; Adnan, S.; Hasan, M. S.; Sulaiman, H.; Gasca Lopez, G. A.; Hernandez-Cardenas, C. M.; Namendys-Silva, S. A.; Bethlehem, C.; de Lange, D.; Hunfeld, N.; Numan, S.; van Leeuwen, H.; Owens, D.; Almeida, M.; Fragoso, E.; Leonor, T.; Pereira, J. -M.; Filipescu, D.; Grigoras, I.; Popescu, M.; Tomescu, D.; Alshahrani, M. S.; Alvarez-Gonzalez, M.; Barrero-Garcia, I.; Blasco-Navalpotro, M. A.; Claverias, L.; Estella, A.; Espina, L. F.; Garmendia, J. L. G.; Prieto, E. G.; Gomez-Prieto, G.; Conde, C. J.; Sagasti, F. M.; Cantero, A. M.; Orejas-Gallego, A.; Papiol, E.; Perez-Civantos, D.; Laderas, J. C. P.; Alvarez, J. T.; Vera-Artazcoz, P.; Cortes, P. V.; Oldner, A.; Spangfors, M.; Alp, E.; Koksal, I.; Korten, V.; Ozveren, A.; Hall, A.; Hatton, K. W.; Laudanski, K.
abstract

Purpose: The DIANA study aimed to evaluate how often antimicrobial de-escalation (ADE) of empirical treatment is performed in the intensive care unit (ICU) and to estimate the effect of ADE on clinical cure on day 7 following treatment initiation. Methods: Adult ICU patients receiving empirical antimicrobial therapy for bacterial infection were studied in a prospective observational study from October 2016 until May 2018. ADE was defined as (1) discontinuation of an antimicrobial in case of empirical combination therapy or (2) replacement of an antimicrobial with the intention to narrow the antimicrobial spectrum, within the first 3 days of therapy. Inverse probability (IP) weighting was used to account for time-varying confounding when estimating the effect of ADE on clinical cure. Results: Overall, 1495 patients from 152 ICUs in 28 countries were studied. Combination therapy was prescribed in 50%, and carbapenems were prescribed in 26% of patients. Empirical therapy underwent ADE, no change and change other than ADE within the first 3 days in 16%, 63% and 22%, respectively. Unadjusted mortality at day 28 was 15.8% in the ADE cohort and 19.4% in patients with no change [p = 0.27; RR 0.83 (95% CI 0.60–1.14)]. The IP-weighted relative risk estimate for clinical cure comparing ADE with no-ADE patients (no change or change other than ADE) was 1.37 (95% CI 1.14–1.64). Conclusion: ADE was infrequently applied in critically ill-infected patients. The observational effect estimate on clinical cure suggested no deleterious impact of ADE compared to no-ADE. However, residual confounding is likely.

2020 - Best-practice IgM- and IgA-enriched immunoglobulin use in patients with sepsis [Articolo su rivista]
Nierhaus, A.; Berlot, G.; Kindgen-Milles, D.; Muller, E.; Girardis, M.
abstract

Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Despite treatment being in line with current guidelines, mortality remains high in those with septic shock. Intravenous immunoglobulins represent a promising therapy to modulate both the pro- and anti-inflammatory processes and can contribute to the elimination of pathogens. In this context, there is evidence of the benefits of immunoglobulin M (IgM)- and immunoglobulin A (IgA)-enriched immunoglobulin therapy for sepsis. This manuscript aims to summarize current relevant data to provide expert opinions on best practice for the use of an IgM- and IgA-enriched immunoglobulin (Pentaglobin) in adult patients with sepsis. Main text: Sepsis patients with hyperinflammation and patients with immunosuppression may benefit most from treatment with IgM- and IgA-enriched immunoglobulin (Pentaglobin). Patients with hyperinflammation present with phenotypes that manifest throughout the body, whilst the clinical characteristics of immunosuppression are less clear. Potential biomarkers for hyperinflammation include elevated procalcitonin, interleukin-6, endotoxin activity and C-reactive protein, although thresholds for these are not well-defined. Convenient biomarkers for identifying patients in a stage of immune-paralysis are still matter of debate, though human leukocyte antigen–antigen D related expression on monocytes, lymphocyte count and viral reactivation have been proposed. The timing of treatment is potentially more critical for treatment efficacy in patients with hyperinflammation compared with patients who are in an immunosuppressed stage. Due to the lack of evidence, definitive dosage recommendations for either population cannot be made, though we suggest that patients with hyperinflammation should receive an initial bolus at a rate of up to 0.6 mL (30 mg)/kg/h for 6 h followed by a continuous maintenance rate of 0.2 mL (10 mg)/kg/hour for ≥ 72 h (total dose ≥ 0.9 g/kg). For immunosuppressed patients, dosage is more conservative (0.2 mL [10 mg]/kg/h) for ≥ 72 h, without an initial bolus (total dose ≥ 0.72 g/kg). Conclusions: Two distinct populations that may benefit most from Pentaglobin therapy are described in this review. However, further clinical evidence is required to strengthen support for the recommendations given here regarding timing, duration and dosage of treatment.

2020 - COVID-19-associated vasculitis and thrombotic complications: from pathological findings to multidisciplinary discussion [Articolo su rivista]
Vacchi, Caterina; Meschiari, Marianna; Milic, Jovana; Marietta, Marco; Tonelli, Roberto; Alfano, Gaetano; Volpi, Sara; Faltoni, Matteo; Franceschi, Giacomo; Ciusa, Giacomo; Bacca, Erica; Tutone, Marco; Raimondi, Alessandro; Menozzi, Marianna; Franceschini, Erica; Cuomo, Gianluca; Orlando, Gabriella; Santoro, Antonella; Di Gaetano, Margherita; Puzzolante, Cinzia; Carli, Federica; Bedini, Andrea; Cossarizza, Andrea; Castaniere, Ivana; Ligabue, Guido; De Ruvo, Nicola; Manco, Gianrocco; Rolando, Giovanni; Gelmini, Roberta; Maiorana, Antonino; Girardis, Massimo; Mascia, Maria Teresa; Mussini, Cristina; Salvarani, Carlo; Guaraldi, Giovanni
abstract

Neutrophilic arterial vasculitis in COVID-19 represents a novel finding and could be responsible for thrombotic complications.

2020 - Case report of a patient who survived after cardiac arrest and cardiogenic shock by anaphylactic reaction to gadolinium during magnetic resonance imaging [Articolo su rivista]
Biagioni, Emanuela; Coloretti, Irene; Disalvo, Fabrizio; Andreotti, Alberto; Sani, Francesco; Torricelli, Pietro; Gelmini, Roberta; Girardis, Massimo
abstract

We report the case of a young adult which survived to anaphylactic shock caused by gadolinium-based contrast agent (GBCA) contrast agent infusion. The patient had no comorbidities and previous history of allergic reactions to contrast agents and underwent elective magnetic resonance imaging (MRI) for parotid swelling. Seven years before he received intravenous GBCA administration during an MRI, which exact chemical composition is unknown, without any allergic reaction. After intravenous injection of GBCA for MRI the patient developed anaphylactic shock, causing respiratory failure, cardiac arrest, and cardiogenic shock after return of spontaneous circulation. Because of the rarity of the described event, this report has the aim to raise awareness in the healthcare personnel of the possibility of these life-threatening adverse reactions from GBCAs also in a patient without history of allergy to contrast agents and suggest a possible clinical management of these patients.

2020 - Clinical and molecular characterization of COVID-19 hospitalized patients [Articolo su rivista]
Benetti, E.; Giliberti, A.; Emiliozzi, A.; Valentino, F.; Bergantini, L.; Fallerini, C.; Anedda, F.; Amitrano, S.; Conticini, E.; Tita, R.; D'Alessandro, M.; Fava, F.; Marcantonio, S.; Baldassarri, M.; Bruttini, M.; Mazzei, M. A.; Montagnani, F.; Mandala, M.; Bargagli, E.; Furini, S.; Renieri, A.; Mari, F.; Doddato, G.; Croci, S.; Di Sarno, L.; Tommasi, A.; Daga, S.; Palmieri, M.; Fabbiani, M.; Rossetti, B.; Zanelli, G.; Cameli, P.; Bennett, D.; Scolletta, S.; Franchi, F.; Cantarini, L.; Frediani, B.; Tacconi, D.; Spertilli, C.; Feri, M.; Donati, A.; Scala, R.; Guidelli, L.; Ognibene, A.; Spargi, G.; Corridi, M.; Nencioni, C.; Croci, L.; Caldarelli, G. P.; Spagnesi, M.; Piacentini, P.; Canaccini, A.; Verzuri, A.; Anemoli, V.; Vaghi, M.; Monforte, A. D.; Merlini, E.; Mondelli, M. U.; Mantovani, S.; Ludovisi, S.; Girardis, M.; Venturelli, S.; Cossarizza, A.; Antinori, A.; Vergori, A.; Rusconi, S.; Siano, M.; Gabrieli, A.; Francisci, D.; Schiaroli, E.; Scotton, P. G.; Andretta, F.; Panese, S.; Scaggiante, R.; Parisi, S. G.; Castelli, F.; Roldan, M. E. Q.; Magro, P.; Minardi, C.; della Monica, M.; Piscopo, C.; Capasso, M.; Carella, M.; Castori, M.; Merla, G.; Aucella, F.; Raggi, P.; Bassetti, M.; Di Biagio, A.; Sanguinetti, M.; Masucci, L.; Gabbi, C.; Valente, S.; Guerrini, S.; Frullanti, E.; Meloni, I.; Mencarelli, M. A.; Rizzo, C. L.; Pinto, A. M.
abstract

Clinical and molecular characterization by Whole Exome Sequencing (WES) is reported in 35 COVID-19 patients attending the University Hospital in Siena, Italy, from April 7 to May 7, 2020. Eighty percent of patients required respiratory assistance, half of them being on mechanical ventilation. Fiftyone percent had hepatic involvement and hyposmia was ascertained in 3 patients. Searching for common genes by collapsing methods against 150 WES of controls of the Italian population failed to give straightforward statistically significant results with the exception of two genes. This result is not unexpected since we are facing the most challenging common disorder triggered by environmental factors with a strong underlying heritability (50%). The lesson learned from Autism-Spectrum-Disorders prompted us to re-analyse the cohort treating each patient as an independent case, following a Mendelian-like model. We identified for each patient an average of 2.5 pathogenic mutations involved in virus infection susceptibility and pinpointing to one or more rare disorder(s). To our knowledge, this is the first report on WES and COVID-19. Our results suggest a combined model for COVID-19 susceptibility with a number of common susceptibility genes which represent the favorite background in which additional host private mutations may determine disease progression.

2020 - Early inspiratory effort assessment by esophageal manometry early predicts noninvasive ventilation outcome in de novo respiratory failure: a pilot study. [Articolo su rivista]
Tonelli, Roberto; Fantini, Riccardo; Tabbì, Luca; Castaniere, Ivana; Pisani, Lara; Pellegrino, Maria Rosaria; DELLA CASA, Giovanni; D'Amico, Roberto; Girardis, Massimo; Nava, Stefano; Clini, Enrico M.; Marchioni, Alessandro
abstract

Rationale: The role of inspiratory effort has still to be determined as a potential predictors of non-invasive mechanical ventilation (NIV) failure in acute hypoxic de novo respiratory failure (AHRF). Objectives: We explore the hypothesis that inspiratory effort might be a major determinant of NIV failure in these patients. Methods: Thirty consecutive patients with AHRF admitted to a single center and candidates for a 24-hour NIV trial were enrolled. Clinical features, tidal changes in esophageal (ΔPes) and dynamic transpulmonary pressure (ΔPL), expiratory tidal volume, and respiratory rate were recorded on admission and 2-4-12-24 hours after NIV start, and were tested for correlation with outcomes. Measurements and Main Results: ΔPes and ΔPes/ΔPL were significantly lower 2 hours after NIV start in patients who successfully completed the NIV trial (n=18) compared to those who needed endotracheal intubation (n=12) [median=11 (IQR=8–15) cmH2O vs 31.5 (30–36) cmH2O, p<0.0001] while other variables differed later. ΔPes was not related to other predictors of NIV failure at baseline. NIV-induced reduction in ΔPes of 10 cmH2O or more after 2 hours of treatment was strongly associated to avoidance of intubation, and represented the most accurate predictor of treatment success (OR=15, 95%CI 2.8-110, p=0.001, AUC=0.97, 95%CI 0.91–1, p<0.0001). Conclusions: The magnitude of inspiratory effort relief as assessed by ΔPes variation within the first 2 hours of NIV was an early and accurate predictor of NIV outcome at 24 hours.

2020 - Expansion of plasmablasts and loss of memory B cells in peripheral blood from COVID-19 patients with pneumonia [Articolo su rivista]
De Biasi, S.; Lo Tartaro, D.; Meschiari, M.; Gibellini, L.; Bellinazzi, C.; Borella, R.; Fidanza, L.; Mattioli, M.; Paolini, A.; Gozzi, L.; Jaacoub, D.; Faltoni, M.; Volpi, S.; Milic, J.; Sita, M.; Sarti, M.; Pucillo, C.; Girardis, M.; Guaraldi, G.; Mussini, C.; Cossarizza, A.
abstract

Studies on the interactions between SARS-CoV-2 and humoral immunity are fundamental to elaborate effective therapies including vaccines. We used polychromatic flow cytometry, coupled with unsupervised data analysis and principal component analysis (PCA), to interrogate B cells in untreated patients with COVID-19 pneumonia. COVID-19 patients displayed normal plasma levels of the main immunoglobulin classes, of antibodies against common antigens or against antigens present in common vaccines. However, we found a decreased number of total and naïve B cells, along with decreased percentages and numbers of memory switched and unswitched B cells. On the contrary, IgM+ and IgM− plasmablasts were significantly increased. In vitro cell activation revealed that B lymphocytes showed a normal proliferation index and number of dividing cells per cycle. PCA indicated that B-cell number, naive and memory B cells but not plasmablasts clustered with patients who were discharged, while plasma IgM level, C-reactive protein, D-dimer, and SOFA score with those who died. In patients with pneumonia, the derangement of the B-cell compartment could be one of the causes of the immunological failure to control SARS-Cov2, have a relevant influence on several pathways, organs and systems, and must be considered to develop vaccine strategies.

2020 - Handling and processing of blood specimens from patients with Covid-19 for safe studies on cell phenotype and cytokine storm [Articolo su rivista]
Cossarizza, Andrea; Gibellini, Lara; DE BIASI, Sara; LO TARTARO, Domenico; Mattioli, Marco; Paolini, Annamaria; Fidanza, Lucia; Bellinazzi, Caterina; Borella, Rebecca; Castaniere, Ivana; Meschiari, Marianna; Sita, Marco; Manco, Gianrocco; Clini, Enrico; Gelmini, Roberta; Girardis, Massimo; Guaraldi, Giovanni; Mussini, Cristina
abstract

The pandemic caused by SARS-CoV-2 heavily involves all those working in a laboratory. Samples from known infected patients or donors who are considered healthy can arrive, and a colleague might be asymptomatic but able to transmit the virus. Working in a clinical laboratory is posing several safety challenges. Few years ago, ISAC published guidelines to safely analyze and sort human samples that were revised in these days. We describe the procedures that we have been following since the first patient appeared in Italy, which have only slightly modified our standard one, being all human samples associated with risks.

2020 - Increased Plasma Levels of Mitochondrial DNA and Normal Inflammasome Gene Expression in Monocytes Characterize Patients With Septic Shock Due to Multidrug Resistant Bacteria [Articolo su rivista]
Busani, Stefano; De Biasi, Sara; Nasi, Milena; Paolini, Annamaria; Venturelli, Sophie; Tosi, Martina; Girardis, Massimo; Cossarizza, Andrea
abstract

Introduction: The activity and regulation of inflammasome is receiving increasing attention in septic shock. Moreover, there is a growing body of evidence suggesting that mitochondrial DNA (mtDNA) can play a role as biomarker of disease severity and even mortality both in adults and children in critically ill setting. However, no data are available on the amount of circulating mtDNA and inflammasome gene expression in multi-drug resistant (MDR) bacteria septic shock. For this reason, the aim of this study was to determine whether plasma mtDNA levels and inflammasome gene expression in monocytes could be related to severity in patients admitted to intensive care unit (ICU) with septic shock due to MDR pathogens. Materials and Methods: Peripheral blood mononuclear cells (PBMC) and plasma were isolated from up to 20 ml of venous blood by density gradient centrifugation in patients admitted to ICU with the diagnosis of septic shock due to MDR-bacteria. Then, CD14+ monocytes were sorted, and RNA and DNA were extracted. NLRP3, PYCARD, AIM2 and NAIP expression level was analyzed by RT-PCR. Plasma circulating mtDNA levels were quantified by digital droplet PCR. Basal and outcome characteristics of the patients were collected. Age-matched healthy subjects were chosen as controls. Results: Nineteen patients with septic shock and 20 healthy subjects were enrolled in the study. A small trend toward an increased expression of inflammasome genes was observed in septic shock patients, who also displayed a marked tendency to an increased expression of IL-18 and IL-1β genes. Circulating mtDNA levels were significantly higher in septic shock patients if compared to healthy subjects, and patients who died in ICU were characterized by higher level of mtDNA if compared to those who were dismissed after 7 days. No correlations were found between mtDNA and inflammasome level and other clinical variables. Conclusion: Despite many limitations, our data suggest that in patients with septic shock caused by MDR pathogens the expression of main inflammasome genes was comparable to that of healthy patients without infection. Furthermore, our data evidence a possible role of mtDNA as a prognostic marker of severity in septic shock from MDR.

2020 - Levosimendan Efficacy and Safety: 20 Years of SIMDAX in Clinical Use [Articolo su rivista]
Papp, Z.; Agostoni, P.; Alvarez, J.; Bettex, D.; Bouchez, S.; Brito, D.; Cerny, V.; Comin-Colet, J.; Crespo-Leiro, M. G.; Delgado, J. F.; Edes, I.; Eremenko, A. A.; Farmakis, D.; Fedele, F.; Fonseca, C.; Fruhwald, S.; Girardis, M.; Guarracino, F.; Harjola, V. -P.; Heringlake, M.; Herpain, A.; Heunks, L. M. A.; Husebye, T.; Ivancan, V.; Karason, K.; Kaul, S.; Kivikko, M.; Kubica, J.; Masip, J.; Matskeplishvili, S.; Mebazaa, A.; Nieminen, M. S.; Oliva, F.; Papp, J. G.; Parissis, J.; Parkhomenko, A.; Poder, P.; Polzl, G.; Reinecke, A.; Ricksten, S. -E.; Riha, H.; Rudiger, A.; Sarapohja, T.; Schwinger, R. H. G.; Toller, W.; Tritapepe, L.; Tschope, C.; Wikstrom, G.; Lewinski, D. V.; Vrtovec, B.; Pollesello, P.
abstract

Levosimendan was first approved for clinical use in 2000, when authorization was granted by Swedish regulatory authorities for the hemodynamic stabilization of patients with acutely decompensated chronic heart failure (HF). In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitization and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced HF, right ventricular failure, pulmonary hypertension, cardiac surgery, critical care, and emergency medicine. Levosimendan is currently in active clinical evaluation in the United States. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and noncardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, the United Kingdom, and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute HF arena in recent times and charts a possible development trajectory for the next 20 years.

2020 - Machine learning in predicting respiratory failure in patients with COVID-19 pneumonia - challenges, strengths, and opportunities in a global health emergency. [Articolo su rivista]
Ferrari, D; Milic, J; Tonelli, R; Ghinelli, F; Meschiari, M; Volpi, S; Faltoni, M; Franceschi, G; Iadisernia, V; Yaacoub, D; Ciusa, G; Bacca, E; Rogati, C; Tutone, M; Burastero, G; Raimondi, A; Menozzi, M; Franceschini, E; Cuomo, G; Corradi, L; Orlando, G; Santoro, A; Di Gaetano, M; Puzzolante, C; Carli, F; Borghi, V; Bedini, A; Fantini, R; Tabbì, L; Castaniere, I; Busani, S; Clini, E; Girardis, M; Sarti, M; Cossarizza, A; Mussini, C; Mandreoli, F; Missier, P; Guaraldi, G.
abstract

Aims- The aim of this study was to estimate a 48 hour prediction of moderate to severe respiratory failure, requiring mechanical ventilation, in hospitalized patients with COVID-19 pneumonia. Methods- This was an observational study that comprised consecutive patients with COVID-19 pneumonia admitted to hospital from 21 February to 6 April 2020. The patients’ medical history, demographic, epidemiologic and clinical data were collected in an electronic patient chart. The dataset was used to train predictive models using an established machine learning framework leveraging a hybrid approach where clinical expertise is applied alongside a data-driven analysis. The study outcome was the onset of moderate to severe respiratory failure defined as PaO 2 /FiO 2 ratio <150 mmHg in at least one of two consecutive arterial blood gas analyses in the following 48 hours. Shapley Additive exPlanations values were used to quantify the positive or negative impact of each variable included in each model on the predicted outcome. Results- A total of 198 patients contributed to generate 1068 usable observations which allowed to build 3 predictive models based respectively on 31-variables signs and symptoms, 39-variables laboratory biomarkers and 91-variables as a composition of the two. A fourth “boosted mixed model” included 20 variables was selected from the model 3, achieved the best predictive performance (AUC=0.84) without worsening the FN rate. Its clinical performance was applied in a narrative case report as an example. Conclusion- This study developed a machine model with 84% prediction accuracy, which is able to assist clinicians in decision making process and contribute to develop new analytics to improve care at high technology readiness levels.

2020 - Marked T cell activation, senescence, exhaustion and skewing towards TH17 in patients with Covid-19 pneumonia. [Articolo su rivista]
De Biasi, S; Meschiari, M; Gibellini, L; Bellinazzi, C; Borella, R; Fidanza, L; Gozzi, L; Iannone, A; Lo Tartaro, D; Mattioli, M; Paolini, A; Menozzi, M; Milić, J; Franceschi, G; Fantini, R; Tonelli, R; Sita, M; Sarti, M; Trenti, T; Brugioni, L; Cicchetti, L; Facchinetti, F; Pietrangelo, A; Clini, E; Girardis, M; Guaraldi, G; Mussini, C; Cossarizza, A.
abstract

We provide an in-depth investigation of the T cell compartment and functionality, cytokine production and plasma levels in a total of 39 patients affected by Covid-19 pneumonia. At admission, patients were lymphopenic; for all, SARS-CoV-2 was detected in a nasopharyngeal swab specimen by real-time RT-PCR, and pneumonia was subsequently confirmed by X-rays. Detailed 18-parameter flow cytometry coupled with unsupervised data analysis revealed that patients showed similar percentages of CD4+ and CD8+ T cells, but a decreased absolute number in both populations. For CD4+ T lymphocytes, we found a significant decrease in the number of naïve, central and effector memory cells and an increased percentage of terminally differentiated cells, regulatory T cells, and of those that were activated or that were expressing PD1 and CD57 markers. Studies on chemokine receptors and lineage-specifying transcription factors revealed that, among CD4+ T cells, patients displayed a lower percentage of cells expressing CCR6 or CXCR3, and of those co-expressing CCR6 and CD161, but higher percentages of 62 CXCR4+ or CCR4+ cells. No differences were noted in the expression of T-bet or GATA-3. Analyses of patients' CD8+ T cells showed decreased numbers of naïve and central memory and increased amounts of activated cells, accompanied by increased percentages of activated cells and of lymphocytes expressing CD57, PD1, or both. CD8+ T cells expressed lower percentages of CCR6+, CXCR3+ or T-bet+ cells and of CXCR3+,T-bet+ or CCR6+,CD161+ lymphocytes. We also found higher percentages of cells expressing CCR4+, CXCR4 or GATA-3. Analyses of lymphocyte proliferation revealed that terminally differentiated CD4+ and CD8+ T cell from patients had a lower proliferative index than controls, whereas cellular bioenergetics, measured by the quantification of mitochondrial oxygen consumption and extracellular acidification rate, was similar in CD4+ T cells from both groups. We measured plasma level of 31 cytokines linked to inflammation, including T helper (TH)type-1 and TH2 cytokines, chemokines, galectins, pro- and anti-inflammatory mediators, finding that most were dramatically increased in Covid-19 patients, confirming the presence of a massive cytokine storm. Analysis of the production of different cytokines after stimulation by anti-CD3/CD28 monoclonal antibodies revealed that patients not only had a high capacity to produce tumour necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-2, but also showed a significant skewing of CD4+ T cells towards the TH17 phenotype. A therapeutic approach now exists based on the administration of drugs that block IL-6pathway, and seems to improve the disease. IL-17 is crucial in recruiting and activating neutrophils, cells that can migrate to the lung and are heavily involved in the pathogenesis of Covid-19. We show here that a skewing of activated T cells towards the TH17 functional phenotype exists in Covid-19 patients. We therefore suggest that blocking the IL-17 pathway by biological drugs that are already used to treat different pathologies could provide a novel, additional strategy to improve the health of patients infected by SARS-CoV-2.

2020 - Multi-centre, three arm, randomized controlled trial on the use of methylprednisolone and unfractionated heparin in critically ill ventilated patients with pneumonia from SARS-CoV-2 infection: A structured summary of a study protocol for a randomised controlled trial [Articolo su rivista]
Busani, S.; Tosi, M.; Mighali, P.; Vandelli, P.; D'Amico, R.; Marietta, M.; Forfori, F.; Donati, A.; Cinnella, G.; De Monte, A.; Pasero, D.; Bellani, G.; Tascini, C.; Foti, G.; Ranieri, M.; Girardis, M.
abstract

OBJECTIVES: To assess the hypothesis that an adjunctive therapy with methylprednisolone and unfractionated heparin (UFH) or with methylprednisolone and low molecular weight heparin (LMWH) are more effective in reducing any-cause mortality in critically-ill ventilated patients with pneumonia from SARS-CoV-2 infection compared to LMWH alone. TRIAL DESIGN: The study is designed as a multi-centre, interventional, parallel group, superiority, randomized, investigator sponsored, three arms study. Patients, who satisfy all inclusion criteria and no exclusion criteria, will be randomly assigned to one of the three treatment groups in a ratio 1:1:1. PARTICIPANTS: Inpatients will be recruited from 8 Italian Academic and non-Academic Intensive Care Units INCLUSION CRITERIA (ALL REQUIRED): 1. Positive SARS-CoV-2 diagnostic (on pharyngeal swab of deep airways material) 2. Positive pressure ventilation (either non-invasive or invasive) from > 24 hours 3. Invasive mechanical ventilation from < 96 hours 4. PaO2/FiO2 ratio lower than 150 mmHg 5. D-dimer level > 6 times the upper limit of normal reference range 6. C-reactive Protein > 6-fold upper the limit of normal reference range EXCLUSION CRITERIA: 1. Age < 18 years 2. On-going treatment with anticoagulant drugs 3. Platelet count < 100.000/mm3 4. History of heparin-induced thrombocytopenia 5. Allergy to sodium enoxaparin or other LMWH, UFH or methylprednisolone 6. Active bleeding or on-going clinical condition deemed at high risk of bleeding contraindicating anticoagulant treatment 7. Recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery 8. Chronic assumption or oral corticosteroids 9. Pregnancy or breastfeeding or positive pregnancy test. In childbearing age women, before inclusion, a pregnancy test will be performed if not available 10. Clinical decision to withhold life-sustaining treatment or "too sick to benefit" 11. Presence of other severe diseases impairing life expectancy (e.g. patients are not expected to survive 28 days given their pre-existing medical condition) 12. Lack or withdrawal of informed consent INTERVENTION AND COMPARATOR: • LMWH group: patients in this group will be administered enoxaparin at standard prophylactic dosage. • LMWH + steroid group: patients in this group will receive enoxaparin at standard prophylactic dosage and methylprednisolone. • UFH + steroid group: patients in this group will receive UFH at therapeutic dosages and methylprednisolone. UFH will be administered intravenously in UFH + steroid group at therapeutic doses. The infusion will be started at an infusion rate of 18 UI/kg/hour and then modified to obtain aPTT Ratio in between the range of 1.5-2.0. aPTT will be periodically checked at intervals no longer than 12 hours. The treatment with UFH will be administered up to ICU discharge. After ICU discharge anticoagulant therapy may be interrupted or switched to prophylaxis with LMWH in the destination ward up to clinical judgement of the attending physician. Enoxaparin will be administered in both LMWH group and LMWH + steroid group at standard prophylactic dose (i.e., 4000 UI once day, increased to 6000 UI once day for patients weighting more than 90 kg). The treatment will be administered subcutaneously once a day up to ICU discharge. After ICU discharge it may be continued or interrupted in the destination ward up to clinical judgement of the attending physician. Methylprednisolone will be administered in both LMWH + steroid group and UHF + steroid group intravenously with an initial bolus of 0,5 mg/kg followed by administration of 0,5 mg/kg 4 times daily for 7 days, 0,5 mg/kg 3 times daily from day 8 to day 10, 0,5 mg/kg 2 times daily at days 11 and 12 and 0,5 mg/kg once daily at days 13 and 14. MAIN OUTCOMES: Primary Efficacy Endpoint: All-cause mortality at day 28 Secondary Efficacy Endpoints: - Ventilation free days (VFDs) at day 28, defined

2020 - Never Give Up: lesson learned from a severe COVID-19 patient. [Articolo su rivista]
Tonelli, Roberto; Iattoni, Andrea; Girardis, Massimo; De Pietri, Lesley; Clini, Enrico; Mussini, Cristina
abstract

We here report the clinical course of a 72-year old Caucasian male (M.A.) admitted for SARS-CoV2 pneumonia at our University Hospital in Modena. A multidisciplinary medical staff composed by different specialists (infectious diseases, pulmonology, intensive care) was in charge for caring and assuming shared clinical decisions.

2020 - Pathophysiology of COVID-19-associated acute respiratory distress syndrome: a multicentre prospective observational study [Articolo su rivista]
Grasselli, G.; Tonetti, T.; Protti, A.; Langer, T.; Girardis, M.; Bellani, G.; Laffey, J.; Carrafiello, G.; Carsana, L.; Rizzuto, C.; Zanella, A.; Scaravilli, V.; Pizzilli, G.; Grieco, D. L.; Di Meglio, L.; de Pascale, G.; Lanza, E.; Monteduro, F.; Zompatori, M.; Filippini, C.; Locatelli, F.; Cecconi, M.; Fumagalli, R.; Nava, S.; Vincent, J. -L.; Antonelli, M.; Slutsky, A. S.; Pesenti, A.; Ranieri, V. M.; Lissoni, A.; Rossi, N.; Guzzardella, A.; Valsecchi, C.; Madotto, F.; Bevilacqua, F.; Di Laudo, M.; Querci, L.; Seccafico, C.
abstract

Background: Patients with COVID-19 can develop acute respiratory distress syndrome (ARDS), which is associated with high mortality. The aim of this study was to examine the functional and morphological features of COVID-19-associated ARDS and to compare these with the characteristics of ARDS unrelated to COVID-19. Methods: This prospective observational study was done at seven hospitals in Italy. We enrolled consecutive, mechanically ventilated patients with laboratory-confirmed COVID-19 and who met Berlin criteria for ARDS, who were admitted to the intensive care unit (ICU) between March 9 and March 22, 2020. All patients were sedated, paralysed, and ventilated in volume-control mode with standard ICU ventilators. Static respiratory system compliance, the ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air, ventilatory ratio (a surrogate of dead space), and D-dimer concentrations were measured within 24 h of ICU admission. Lung CT scans and CT angiograms were done when clinically indicated. A dataset for ARDS unrelated to COVID-19 was created from previous ARDS studies. Survival to day 28 was assessed. Findings: Between March 9 and March 22, 2020, 301 patients with COVID-19 met the Berlin criteria for ARDS at participating hospitals. Median static compliance was 41 mL/cm H2O (33–52), which was 28% higher than in the cohort of patients with ARDS unrelated to COVID-19 (32 mL/cm H2O [25–43]; p<0·0001). 17 (6%) of 297 patients with COVID-19-associated ARDS had compliances greater than the 95th percentile of the classical ARDS cohort. Total lung weight did not differ between the two cohorts. CT pulmonary angiograms (obtained in 23 [8%] patients with COVID-19-related ARDS) showed that 15 (94%) of 16 patients with D-dimer concentrations greater than the median had bilateral areas of hypoperfusion, consistent with thromboembolic disease. Patients with D-dimer concentrations equal to or less than the median had ventilatory ratios lower than those of patients with D-dimer concentrations greater than the median (1·66 [1·32–1·95] vs 1·90 [1·50–2·33]; p=0·0001). Patients with static compliance equal to or less than the median and D-dimer concentrations greater than the median had markedly increased 28-day mortality compared with other patient subgroups (40 [56%] of 71 with high D-dimers and low compliance vs 18 [27%] of 67 with low D-dimers and high compliance, 13 [22%] of 60 with low D-dimers and low compliance, and 22 [35%] of 63 with high D-dimers and high compliance, all p=0·0001). Interpretation: Patients with COVID-19-associated ARDS have a form of injury that, in many aspects, is similar to that of those with ARDS unrelated to COVID-19. Notably, patients with COVID-19-related ARDS who have a reduction in respiratory system compliance together with increased D-dimer concentrations have high mortality rates. Funding: None.

2020 - Peritoneal dialysis in the time of coronavirus disease 2019 [Articolo su rivista]
Alfano, Gaetano; Fontana, Francesco; Ferrari, Annachiara; Guaraldi, Giovanni; Mussini, Cristina; Magistroni, Riccardo; Cappelli, Gianni; Bacca, Erica; Bedini, Andrea; Borghi, Vanni; Burastero, Giulia; Carli, Federica; Ciusa, Giacomo; Corradi, Luca; Cuomo, Gianluca; Digaetano, Margherita; Dolci, Giovanni; Faltoni, Matteo; Fantini, Riccardo; Franceschi, Giacomo; Franceschini, Ericad; Iadisernia, Vittorio; Larnõ, Damiano; Menozzi, Marianna; Meschiari, Marianna; Milic, Jovana; Orlando, Gabriella; Pellegrino, Francesco; Raimondi, Alessandro; Rogati, Carlotta; Santoro, Antonella; Tonelli, Roberto; Tutone, Marco; Volpi, Sara; Yaacoub, Dina; Aten, G.; Marco, Ballestri; Mori, Giacomo; Girardis, Massimo; Andreotti, Alberto; Biagioni, Emanuela; Bondi, Filippo; Busani, Stefano; Chierego, Giovanni; Scotti, Marzia; Serio, Lucia; Cossarizza, Andrea; Bellinazzi, Caterina; Borella, Rebecca; de Biasi, Sara; de Gaetano, Anna; Fidanza, Lucia; Gibellini, Lara; Iannone, Anna; Lo Tartaro, Domenico; Mattioli, Marco; Nasi, Milena; Paolini, Annamariag; Pinti, Marcello
abstract

In the current setting of global containment, peritoneal dialysis (PD) and home haemodialysis are the best modalities of renal replacement therapy (RRT) to reduce the rate of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the shorter and easier training programme of PD compared to home haemodialysis, PD appears a practical solution for patients with end-stage renal disease to reduce the risk of hospital-acquired infection. PD offers the advantage of minimizing the risk of viral transmission through interpersonal contact that commonly occurs during the haemodialysis session and while travelling from home to the haemodialysis facility using public transport services. To overcome barriers to health care access due to the containment measures for this emerging disease, telemedicine is a useful and reliable tool for delivering health care without exposing patients to the risk of contact. However, novel issues including handling of potentially infected dialysate, caregivers' infectious risk and adequacy of PD in critically ill patients with acute respiratory distress syndrome remain to be clarified. In conclusion, PD should be preferred to the other modalities of RRT during the coronavirus disease 2019 (COVID-19) outbreak because it can be a solution to cope with the increased number of infected patients worldwide.

2020 - Reply to “Indications and timing for tracheostomy in patients with SARS CoV2‐related” by Ferri et al [Articolo su rivista]
Mattioli, F.; Marudi, A.; Ghirelli, M.; Molteni, G.; Sgarbi, N.; Valerini, S.; Girardis, M.; Presutti, L.; Fermi, M.
abstract

2020 - SARS-CoV-2, the Virus that Causes COVID-19: Cytometry and the New Challenge for Global Health [Articolo su rivista]
Cossarizza, A.; De Biasi, S.; Guaraldi, G.; Girardis, M.; Mussini, C.
abstract

2020 - Surfactant replacement might help recovery of low-compliance lung in severe COVID-19 pneumonia. [Articolo su rivista]
Busani, S; Dall’Ara, L; Tonelli, R; Clini, E; Munari, E; Venturelli, S; Meschiari, M; Guaraldi, G; Cossarizza, A; Ranieri, Mv; Girardis, M.
abstract

It has been hypothesized that there is a reduced AT2 cells number with low ability to synthesize and secrete endogenous surfactant in COVID-19 patients. To our knowledge, exogenous surfactant replacement has not been described so far in COVID-19 patients. We here report five cases of critically ill COVID-19 undergoing exogenous surfactant instillation through the airways.

2020 - Testicular pain as an unusual presentation of COVID-19: a brief review of SARS-CoV-2 and the testis [Articolo su rivista]
La Marca, Antonio; Busani, Stefano; Donno, Valeria; Guaraldi, Giovanni; Ligabue, Guido; Girardis, Massimo
abstract

Can the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus induce testis damage and dysfunction?

2020 - The clinical relevance of oliguria in the critically ill patient: Analysis of a large observational database [Articolo su rivista]
Vincent, J. -L.; Ferguson, A.; Pickkers, P.; Jakob, S. M.; Jaschinski, U.; Almekhlafi, G. A.; Leone, M.; Mokhtari, M.; Fontes, L. E.; Bauer, P. R.; Sakr, Y.; Tomas, E.; Bibonge, E. A.; Charra, B.; Faroudy, M.; Doedens, L.; Farina, Z.; Adler, D.; Balkema, C.; Kok, A.; Alaya, S.; Gharsallah, H.; Muzha, D.; Temelkov, A.; Georgiev, G.; Simeonov, G.; Tsaryanski, G.; Georgiev, S.; Seliman, A.; Vrankovic, S.; Vucicevic, Z.; Gornik, I.; Barsic, B.; Husedzinovic, I.; Pavlik, P.; Manak, J.; Kieslichova, E.; Turek, R.; Fischer, M.; Valkova, R.; Dadak, L.; Dostal, P.; Malaska, J.; Hajek, R.; Zidkova, A.; Lavicka, P.; Starkopf, J.; Kheladze, Z.; Chkhaidze, M.; Kaloiani, V.; Medve, L.; Sarkany, A.; Kremer, I.; Marjanek, Z.; Tamasi, P.; Krupnova, I.; Vanags, I.; Liguts, V.; Pilvinis, V.; Vosylius, S.; Kekstas, G.; Balciunas, M.; Kolbusz, J.; Kubler, A.; Mielczarek, B.; Mikaszewska-Sokolewicz, M.; Kotfis, K.; Tamowicz, B.; Sulkowski, W.; Smuszkiewicz, P.; Pihowicz, A.; Trejnowska, E.; Hagau, N.; Filipescu, D.; Droc, G.; Lupu, M. N.; Nica, A.; Stoica, R.; Tomescu, D. R.; Constantinescu, D. L.; Valcoreanu Zbaganu, G. M.; Slavcovici, A.; Bagin, V.; Belsky, D.; Palyutin, S.; Shlyapnikov, S.; Bikkulova, D.; Gritsan, A.; Natalia, G.; Makarenko, E.; Kokhno, V.; Tolkach, A.; Kokarev, E.; Belotserkovskiy, B.; Zolotukhin, K.; Kulabukhov, V.; Soskic, L.; Palibrk, I.; Jankovic, R.; Jovanovic, B.; Pandurovic, M.; Bumbasirevic, V.; Uljarevic, B.; Surbatovic, M.; Ladjevic, N.; Slobodianiuk, G.; Sobona, V.; Cikova, A.; Gebhardtova, A.; Jun, C.; Yunbo, S.; Dong, J.; Feng, S.; Duan, M.; Xu, Y.; Xue, X.; Gao, T.; Xing, X. Z.; Zhao, X.; Li, C. H.; Gengxihua, G.; Tan, H.; Xu, J.; Jiang, L.; Tiehe, Q.; Bingyu, Q.; Shi, Q.; Lv, Z.; Zhang, L.; Jingtao, L.; Zhen, Z.; Wang, Z.; Wang, T. H.; Yuhong, L.; Zhai, Q.; Chen, Y.; Wang, C.; Jiang, W.; Ruilan, W.; Chen, Y.; Xiaobo, H.; Ge, H.; Yan, T.; Yuhui, C.; Zhang, J.; Jian-Hong, F.; Zhu, H.; Huo, F.; Wang, Y.; Li, C.; Zhuang, M.; Ma, Z.; Sun, J.; Liuqingyue, L.; Yang, M.; Meng, J.; Ma, S.; Kang, Y.; Yu, L.; Peng, Q.; Wei, Y.; Zhang, W.; Sun, R.; Yeung, A.; Wan, W. L.; Sin, K. K. C.; Lee, K. L.; Wijanti, M.; Widodo, U.; Samsirun, H.; Sugiman, T.; Wisudarti, C.; Maskoen, T. T.; Hata, N.; Kobe, Y.; Nishida, O.; Miyazaki, D.; Nunomiya, S.; Uchino, S.; Kitamura, N.; Yamashita, K.; Hashimoto, S.; Fukushima, H.; Adib, N. A. N.; Tai, L. L.; Tony, B.; Bigornia, R. R.; Bigornia, R. R.; Palo, J. E.; Chatterjee, S.; Tan, B. H.; Kong, A.; Goh, S.; Lee, C. -C.; Pothirat, C.; Khwannimit, B.; Theerawit, P.; Pornsuriyasak, P.; Piriyapatsom, A.; Mukhtar, A.; Hamdy, A. N.; Hosny, H.; Ashraf, A.; Mokhtari, M.; Nowruzinia, S.; Lotfi, A. H.; Zand, F.; Nikandish, R.; Moghaddam, O. M.; Cohen, J.; Sold, O.; Sfeir, T.; Hasan, A. Y.; Abugaber, D.; Ahmad, H.; Tantawy, T.; Baharoom, S.; Algethamy, H.; Amr, A.; Almekhlafi, G.; Coskun, R.; Sungur, M.; Cosar, A.; Gucyetmez, B.; Demirkiran, O.; Senturk, E.; Ulusoy, H.; Atalan, H. K.; Serin, S.; Kati, I.; Alnassrawi, Z.; Almemari, A.; Krishnareddy, K.; Kashef, S.; Alsabbah, A.; Poirier, G.; Marshall, J. C.; Herridge, M.; Fernandez-Medero, R.; Fulda, G.; Banschbach, S.; Quintero, J.; Schroeder, E.; Sicoutris, C.; Gueret, R.; Kashyap, R.; Bauer, P.; Nanchal, R.; Wunderink, R. G.; Jimenez, E.; Ryan, A.; Prince, D.; Edington, J.; Van Haren, F.; Bersten, A.; Hawkins, D. J.; Kilminster, M.; Sturgess, D.; Ziegenfuss, M.; O' Connor, S.; Lipman, J.; Campbell, L.; McAllister, R.; Roberts, B.; Williams, P.; Parke, R.; Seigne, P.; Freebairn, R.; Nistor, D.; Oxley, C.; Young, P.; Valentini, R.; Wainsztein, N.; Comignani, P.; Casaretto, M.; Sutton, G.; Villegas, P.; Galletti, C.; Neira, J.; Rovira, D.; Hidalgo, J.; Sandi, F.; Caser, E.; Thompson, M. M.; D'Agostino Dias, M.; Fontes, L. E.; Lunardi, M. C.; Youssef, N. C.; Lobo, S.; Silva, R.; Sales, J. A.; Melo, L. M. C.; Oliveira, M.; Fonte, M.; Grion, C.; Feijo, C.; Rezende, V.; Assuncao, M.; Neves, A. P.; Gusman, P.; Dalcomune, D.; Teixeira, C.; Kaefer, K.; Maia, I.;
abstract

Background: Urine output is widely used as one of the criteria for the diagnosis and staging of acute renal failure, but few studies have specifically assessed the role of oliguria as a marker of acute renal failure or outcomes in general intensive care unit (ICU) patients. Using a large multinational database, we therefore evaluated the occurrence of oliguria (defined as a urine output < 0.5 ml/kg/h) in acutely ill patients and its association with the need for renal replacement therapy (RRT) and outcome. Methods: International observational study. All adult (> 16 years) patients in the ICON audit who had a urine output measurement on the day of admission were included. To investigate the association between oliguria and mortality, we used a multilevel analysis. Results: Of the 8292 patients included, 2050 (24.7%) were oliguric during the first 24 h of admission. Patients with oliguria on admission who had at least one additional 24-h urine output recorded during their ICU stay (n = 1349) were divided into three groups: transient - oliguria resolved within 48 h after the admission day (n = 390 [28.9%]), prolonged - oliguria resolved > 48 h after the admission day (n = 141 [10.5%]), and permanent - oliguria persisting for the whole ICU stay or again present at the end of the ICU stay (n = 818 [60.6%]). ICU and hospital mortality rates were higher in patients with oliguria than in those without, except for patients with transient oliguria who had significantly lower mortality rates than non-oliguric patients. In multilevel analysis, the need for RRT was associated with a significantly higher risk of death (OR = 1.51 [95% CI 1.19-1.91], p = 0.001), but the presence of oliguria on admission was not (OR = 1.14 [95% CI 0.97-1.34], p = 0.103). Conclusions: Oliguria is common in ICU patients and may have a relatively benign nature if only transient. The duration of oliguria and need for RRT are associated with worse outcome.

2020 - The predictive value of fruit juice in the esophagus-pleural fistula. [Articolo su rivista]
Brugioni, Lucio; De Niederhausern, Francesca; Romagnoli, Elisa; Aramini, Beatrice; Girardis, Massimo; Bertani, Angela; Fontana, Francesco; Gramolini, Manuel
abstract

Esophageal-pleural fistula is a rare and challenging condition to diagnose and requires strong clinical suspicion in order to be recognized promptly. Chest computed tomography (CT) with contrast medium for explain abbreviation (OS) is the gold standard for diagnosis. The definitive therapy is purely surgical, except for a few selected cases that benefit from endoscopic therapy. Our case involves a 45-year-old woman who came to the Emergency Department with dyspnea and thoracalgia. Chest X-ray and high-resolution CT showed empyema and pleural effusion to the left hemithorax. The lack of improvement despite the therapy and a subsequent clinical finding gave rise to the suspicion of esophageal-pleural fistula, confirmed with CT with contrast medium for OS. In this case, we opted for endoscopy correction of the esophageal defects. The diagnostic delay and the pre-existing comorbidities (previous kidney transplant for chronic kidney disease from lupus nephritis, high blood pressure, familiarity with Ischemic cardiomyopathy) could justify the inauspicious course of our case.

2020 - Tocilizumab in patients with severe COVID-19: a retrospective cohort study [Articolo su rivista]
Guaraldi, G; Meschiari, M; Cozzi-Lepri, A; Milic, J; Tonelli, R; Menozzi, M; Franceschini, E; Cuomo, G; Orlando, G; Borghi, V; Santoro, A; Di Gaetano, M; Puzzolante, C; Carli, F; Bedini, A; Corradi, L; Fantini, R; Castaniere, I; Tabbì, L; Girardis, M; Tedeschi, S; Giannella, M; Bartoletti, M; Pascale, R; Dolci, G; Brugioni, L; Pietrangelo, A; Cossarizza, A; Pea, F; Clini, E; Salvarani, C; Massari, M; Viale, Pl; Mussini, C.
abstract

Background- There is no approved therapy for COVID-19 pneumonia. The aim of this multicentre cohort study was to assess the role of tocilizumab in reducing the risk of invasive mechanical ventilation and/or death in patients with severe COVID-19 pneumonia who received standard of care (SoC) treatment. Methods- The TESEO Cohort Study is a retrospective, multicentre observational cohort study of patients with COVID-19 severe pneumonia treated with SoC with or without tocilizumab using intravenous (IV) or subcutaneous (SC) formulations, identifying respectively treated and comparator groups. Survival analysis was performed with participants’ follow-up accruing from the date of entry into clinics until initiation of invasive mechanical ventilation or death, used as a composite outcome. Treatment groups were compared using Kaplan-Meier curves and Cox regression analysis after adjusting for gender, age and baseline Sequential Organ Failure Assessment (SOFA) score. Findings- Of 544 patients included, 179 patients were treated with tocilizumab: 88 with the IV (16.1%) and 91 with SC formulation (16.7%). Mortality was significantly higher in the comparator group (20%) as opposed to tocilizumab IV (6.8%) and tocilizumab SC (7.7%) (p<0.001). A reduced risk of invasive mechanical ventilation/death was shown for participants treated with tocilizumab from fitting a Cox regression analysis adjusted for gender, age and SOFA score (aHR=0.61, 95% CI:0.40-0.92; p=0.02). We found no evidence for a difference between IV and SC administration route of tocilizumab. With regards to the mortality endpoint alone, a reduced risk was observed comparing tocilizumab with the comparator group (aHR=0.38 95% CI:0.17-0.83, p=0.02) . Interpretation- Tocilizumab, regardless of IV or SC administration may be capable of reducing invasive mechanical ventilation or death in severe COVID-19 pneumonia. Our observations should be confirmed in randomised studies. Funding- This study was not funded.

2020 - Tracheostomy in the COVID-19 pandemic [Articolo su rivista]
Mattioli, F.; Fermi, M.; Ghirelli, M.; Molteni, G.; Sgarbi, N.; Bertellini, E.; Girardis, M.; Presutti, L.; Marudi, A.
abstract

Purpose: The role of tracheostomy in COVID-19-related ARDS is unknown. Nowadays, there is no clear indication regarding the timing of tracheostomy in these patients. Methods: We describe our synergic experience between ENT and ICU Departments at University Hospital of Modena underlining some controversial aspects that would be worth discussing tracheostomies in these patients. During the last 2 weeks, we performed 28 tracheostomies on patients with ARDS due to COVID-19 infection who were treated with IMV. Results: No differences between percutaneous and surgical tracheostomy in terms of timing and no case of team virus infection. Conclusion: In our experience, tracheostomy should be performed only in selected patients within 7- and 14-day orotracheal intubation.

2020 - Two fatal cases of acute liver failure due to HSV-1 infection in COVID-19 patients following immunomodulatory therapies. [Articolo su rivista]
Busani, S; Bedini, A; Biagioni, E; Serio, L; Tonelli, R; Meschiari, M; Franceschini, E; Guaraldi, G; Cossarizza, A; Clini, E; Maiorana, A; Gennari, W; De Maria, N; Luppi, M; Mussini, C; Girardis, M.; Gibellini, Lara
abstract

We reported two fatal cases of acute liver failure secondary to Herpes Simplex Virus 1 infection in COVID-19 patients, following tocilizumab and corticosteroid therapy. Screening for and prompt recognition of Herpes Simplex Virus 1 reactivation in these patients, undergoing immunomodulatory treatment, may have potentially relevant clinical consequences.

2020 - Use of critical care resources during the first 2 weeks (February 24–March 8, 2020) of the Covid-19 outbreak in Italy [Articolo su rivista]
Tonetti, T.; Grasselli, G.; Zanella, A.; Pizzilli, G.; Fumagalli, R.; Piva, S.; Lorini, L.; Iotti, G.; Foti, G.; Colombo, S.; Vivona, L.; Rossi, S.; Girardis, M.; Agnoletti, V.; Campagna, A.; Gordini, G.; Navalesi, P.; Boscolo, A.; Graziano, A.; Valeri, I.; Vianello, A.; Cereda, D.; Filippini, C.; Cecconi, M.; Locatelli, F.; Bartoletti, M.; Giannella, M.; Viale, P.; Antonelli, M.; Nava, S.; Pesenti, A.; Ranieri, V. M.; Albano, G.; Alborghetti, A.; Aldegheri, G.; Antonini, B.; Belgiorno, N.; Bellani, G.; Beretta, E.; Bonazzi, S.; Borelli, M.; Cabrini, L.; Carnevale, L.; Carnevale, S.; Castelli, G.; Catena, E.; Chiumello, D.; Coluccello, A.; Coppini, D.; Covello, D.; Defilippi, G.; Deipoli, M.; Dughi, P.; Gallioli, G.; Gnesin, P.; Greco, S.; Guatteri, L.; Guzzon, D.; Keim, R.; Landoni, G.; Langer, T.; Lombardo, A.; Marino, G.; Merli, G.; Merlo, D.; Mojoli, F.; Muttini, S.; Natalini, G.; Petrucci, N.; Pezzi, A.; Radrizzani, D.; Raimondi, M.; Riccio, M.; Storti, E.; Tavola, M.; Vitale, G.; Bosco, E.; Calo, M. A.; Danzi, V.; Derosa, S.; Farnia, A.; Lazzari, F.; Meggiolaro, M.; Munari, M.; Saia, M.; Sella, N.; Serra, E.; Tiberio, I.; Baiocchi, M.; Benedetto, M.; Bordini, M.; Caramelli, F.; Cilloni, N.; Dellagiovampaola, M.; Fanelli, A.; Frascaroli, G.; Fusari, M.; Gordini, G.; Maitan, S.; Martino, C.; Melotti, R. M.; Merola, R.; Minardi, F.; Moro, F.; Nardi, G.; Nolli, M.; Pierucci, E.; Potalivo, A.; Repetti, F.; Salsi, P.; Terzitta, M.; Tosi, M.; Venturi, S.; Volta, C. A.; Zani, G.; Zanoni, A.
abstract

Background: A Covid-19 outbreak developed in Lombardy, Veneto and Emilia-Romagna (Italy) at the end of February 2020. Fear of an imminent saturation of available ICU beds generated the notion that rationing of intensive care resources could have been necessary. Results: In order to evaluate the impact of Covid-19 on the ICU capacity to manage critically ill patients, we performed a retrospective analysis of the first 2 weeks of the outbreak (February 24–March 8). Data were collected from regional registries and from a case report form sent to participating sites. ICU beds increased from 1545 to 1989 (28.7%), and patients receiving respiratory support outside the ICU increased from 4 (0.6%) to 260 (37.0%). Patients receiving respiratory support outside the ICU were significantly older [65 vs. 77 years], had more cerebrovascular (5.8 vs. 13.1%) and renal (5.3 vs. 10.0%) comorbidities and less obesity (31.4 vs. 15.5%) than patients admitted to the ICU. PaO2/FiO2 ratio, respiratory rate and arterial pH were higher [165 vs. 244; 20 vs. 24 breath/min; 7.40 vs. 7.46] and PaCO2 and base excess were lower [34 vs. 42 mmHg; 0.60 vs. 1.30] in patients receiving respiratory support outside the ICU than in patients admitted to the ICU, respectively. Conclusions: Increase in ICU beds and use of out-of-ICU respiratory support allowed effective management of the first 14 days of the Covid-19 outbreak, avoiding resource rationing.

2019 - A Position Paper on IgM-Enriched Intravenous Immunoglobulin Adjunctive Therapy in Severe Acute Bacterial Infections: The TO-PIRO SCORE Proposal [Articolo su rivista]
De Rosa, Francesco Giuseppe; Corcione, Silvia; Tascini, Carlo; Pasero, Daniela; Rocchetti, Andrea; Massaia, Massimo; Berlot, Giorgio; Solidoro, Paolo; Girardis, Massimo
abstract

IgM-enriched immunoglobulins (e-IgM) may be useful in patients with severe acute bacterial infections. The evidence for the administration of e-IgM is not extensive and a definitive consensus has never been reached on its best use in patients with acute infections as well as in critically ill patients. However, the official indication in several countries, including Italy, is quite wide and mainly refers to supportive treatment of patients with acute severe bacterial infections. A multidisciplinary meeting of Italian Experts in Infectious Diseases, Anesthesia and Critical Care, Pneumology, Microbiology and Oncohaematology aimed to produce a statement on the best practical methodological score that could improve the use of e-IgM in patients with different infections, variable severity of disease and etiology. The Expert Panel reviewed the literature and the available guidelines, discussed the experience and eventually proposed to adapt the PIRO score to the practical methodological needs of a simple tool that could guide the administration of e-IgM.

2019 - A new device for ultrasound-guided peripheral venous access [Articolo su rivista]
Brugioni, Lucio; Marco, Barchetti; Tazzioli, Giovanni; Gelmini, Roberta; Girardis, Massimo; Bianchini, Marcello; Schepis, Filippo; Nicolini, Matteo; Giovanni, Pinelli; Pietro, Martella; Marco, Barozzi; Mori, Francesca; Scarabottini, Serena; Righetti, Andrea; Mirco Ravazzini and Elisabetta Bertellini,
abstract

Background: In patients with difficult peripheral venous access, alternative techniques require expertise and are invasive, expensive, and prone to serious adverse events. This brought us to designing a new venous catheter (JLB® Deltamed, Inc.) for the cannulation of medium and large bore veins; it is echogenic, and available in different lengths (60 / 70 / 80 mm) and Gauges (14 / 16 / 17 / 18). Methods: We led a multi-center observational convenience sampling study to evaluate safety and effectiveness of JLB. Data was collected from June 2015 to February 2018. Inclusion criteria were age ⩾ 18, difficulty in obtaining superficial venous access in the veins of the arm, need for rapid infusion, or patient’s preference. Results: We enrolled 1000 patients, mean age 66.8 years. In total, 951 (95.1%) had the device placed in internal jugular vein, 28 in basilic or cephalic vein, 15 in femoral vein, 5 in axillary vein (infra-clavicular tract), and 1 in the external jugular vein. The procedure was performed by attending physicians or emergency medicine residents under US guidance. Mean procedure time (from disinfection to securing) was approximately 240 s. Mean attempts number was 1.21. Early complications (<24 h) occurred in four patients, consisting in two soft tissue hematoma, one phlebitis, and one atrial tachyarrhythmia. No major complications (such as pneumothorax) were reported. Mean indwelling time was 168 h (7 days); early occlusion/dislocation occurred in four cases. Conclusion: According to preliminary data, the application of JLB appears to be safe, cost-effective, and rapid to place bedside.

2019 - CYTOREDUCTIVE SURGERY AND HIPEC IN A 14 YEARS OLD PATIENT WITH PERITONEAL RECURRENCE OF ADENOCARCINOMA OF THE RIGHT COLON [Articolo su rivista]
Sorrentino, Lorena; Serra, Francesco; Cabry, Francesca; De Julis, Stefano; Barbieri, Elisa; Girardis, Massimo; Ceccarelli, Pier Luca; Gelmini, Roberta
abstract

Introduction Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is nowadays a feasible and effective treatment for peritoneal metastasis. We present a case of a 14 years old child with peritoneal metastasis from recurrent colorectal cancer. Presentation of case Colonoscopy and CT-scan were performed leading to the diagnosis of a stenosing adenocarcinoma of the right colon in 2015. Two pelvic lesions were found at the total body PET scan, suspected for peritoneal metastasis. Neoadjuvant chemotherapy was administered, and restaging CT-scan and magnetic resonance (MRI) highlighted a partial response. The patient underwent right laparoscopic hemicolectomy. The postoperative staging was T4 N1 G3. Seven months after the last cycle of adjuvant chemotherapy, CT-scan revealed two huge abdominal masses. The patient underwent explorative laparotomy and bilateral oophorectomy, positive for metastasis from colorectal cancer and peritoneal washing cytology was positive for neoplastic cells. A CT-scan was performed on December 2017 showed a suspect lesion below the anterior abdominal wall. The case was discussed at the tumour board and the indication for CRS and HIPEC was given. In January 2018 the child underwent complete CRS and HIPEC with no complications. No adjuvant chemotherapy was administered. After 11 months the follow up is negative for the recurrent disease. Discussion and Conclusion Cytoreduction and HIPEC can be performed even in children as a feasible and safe treatment with successful outcomes. As for adults, an appropriate multidisciplinary pre-operative work up and a correct cases selection is needed to have the best results even regarding the quality of life.

2019 - Current gaps in sepsis immunology: new opportunities for translational research [Articolo su rivista]
Rubio, Ignacio; Osuchowski, Marcin F; Shankar-Hari, Manu; Skirecki, Tomasz; Winkler, Martin Sebastian; Lachmann, Gunnar; La Rosée, Paul; Monneret, Guillaume; Venet, Fabienne; Bauer, Michael; Brunkhorst, Frank M; Kox, Matthijs; Cavaillon, Jean-Marc; Uhle, Florian; Weigand, Markus A; Flohé, Stefanie B; Wiersinga, W Joost; Martin-Fernandez, Marta; Almansa, Raquel; Martin-Loeches, Ignacio; Torres, Antoni; Giamarellos-Bourboulis, Evangelos J; Girardis, Massimo; Cossarizza, Andrea; Netea, Mihai G; van der Poll, Tom; Scherag, André; Meisel, Christian; Schefold, Joerg C; Bermejo-Martín, Jesús F
abstract

Increasing evidence supports a central role of the immune system in sepsis, but the current view of how sepsis affects immunity, and vice versa, is still rudimentary. The European Group on Immunology of Sepsis has identified major gaps that should be addressed with high priority, such as understanding how immunological alterations predispose to sepsis, key aspects of the immunopathological events during sepsis, and the long-term consequences of sepsis on patient's immunity. We discuss major unmet topics in those three categories, including the role of key immune cells, the cause of lymphopenia, organ-specific immunology, the dynamics of sepsis-associated immunological alterations, the role of the microbiome, the standardisation of immunological tests, the development of better animal models, and the opportunities offered by immunotherapy. Addressing these gaps should help us to better understand sepsis physiopathology, offering translational opportunities to improve its prevention, diagnosis, and care.

2019 - Epidemiology of intra-abdominal infection and sepsis in critically ill patients: "AbSeS", a multinational observational cohort study and ESICM Trials Group Project [Articolo su rivista]
Blot, Stijn; Antonelli, Massimo; Arvaniti, Kostoula; Blot, Koen; Creagh-Brown, Ben; de Lange, Dylan; De Waele, Jan; Deschepper, Mieke; Dikmen, Yalim; Dimopoulos, George; Eckmann, Christian; Francois, Guy; Girardis, Massimo; Koulenti, Despoina; Labeau, Sonia; Lipman, Jeffrey; Lipovestky, Fernando; Maseda, Emilio; Montravers, Philippe; Mikstacki, Adam; Paiva, José-Artur; Pereyra, Cecilia; Rello, Jordi; Timsit, Jean-Francois; Vogelaers, Dirk; Abdominal Sepsis Study (AbSeS) group on behalf of the Trials Group of the European Society of Intensive Care, Medicine
abstract

PURPOSE: To describe the epidemiology of intra-abdominal infection in an international cohort of ICU patients according to a new system that classifies cases according to setting of infection acquisition (community-acquired, early onset hospital-acquired, and late-onset hospital-acquired), anatomical disruption (absent or present with localized or diffuse peritonitis), and severity of disease expression (infection, sepsis, and septic shock). METHODS: We performed a multicenter (n = 309), observational, epidemiological study including adult ICU patients diagnosed with intra-abdominal infection. Risk factors for mortality were assessed by logistic regression analysis. RESULTS: The cohort included 2621 patients. Setting of infection acquisition was community-acquired in 31.6%, early onset hospital-acquired in 25%, and late-onset hospital-acquired in 43.4% of patients. Overall prevalence of antimicrobial resistance was 26.3% and difficult-to-treat resistant Gram-negative bacteria 4.3%, with great variation according to geographic region. No difference in prevalence of antimicrobial resistance was observed according to setting of infection acquisition. Overall mortality was 29.1%. Independent risk factors for mortality included late-onset hospital-acquired infection, diffuse peritonitis, sepsis, septic shock, older age, malnutrition, liver failure, congestive heart failure, antimicrobial resistance (either methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Gram-negative bacteria, or carbapenem-resistant Gram-negative bacteria) and source control failure evidenced by either the need for surgical revision or persistent inflammation. CONCLUSION: This multinational, heterogeneous cohort of ICU patients with intra-abdominal infection revealed that setting of infection acquisition, anatomical disruption, and severity of disease expression are disease-specific phenotypic characteristics associated with outcome, irrespective of the type of infection. Antimicrobial resistance is equally common in community-acquired as in hospital-acquired infection.

2019 - Incidence and outcome of invasive candidiasis in intensive care units (ICUs) in Europe: results of the EUCANDICU project [Articolo su rivista]
Bassetti, Matteo; Giacobbe, Daniele R; Vena, Antonio; Trucchi, Cecilia; Ansaldi, Filippo; Antonelli, Massimo; Adamkova, Vaclava; Alicino, Cristiano; Almyroudi, Maria-Panagiota; Atchade, Enora; Azzini, Anna M; Carannante, Novella; Carnelutti, Alessia; Corcione, Silvia; Cortegiani, Andrea; Dimopoulos, George; Dubler, Simon; García-Garmendia, José L; Girardis, Massimo; Cornely, Oliver A; Ianniruberto, Stefano; Kullberg, Bart Jan; Lagrou, Katrien; Le Bihan, Clement; Luzzati, Roberto; Malbrain, Manu L N G; Merelli, Maria; Marques, Ana J; Martin-Loeches, Ignacio; Mesini, Alessio; Paiva, José-Artur; Peghin, Maddalena; Raineri, Santi Maurizio; Rautemaa-Richardson, Riina; Schouten, Jeroen; Brugnaro, Pierluigi; Spapen, Herbert; Tasioudis, Polychronis; Timsit, Jean-François; Tisa, Valentino; Tumbarello, Mario; van den Berg, Charlotte H S B; Veber, Benoit; Venditti, Mario; Voiriot, Guillaume; Wauters, Joost; Montravers, Philippe
abstract

BACKGROUND: The objective of this study was to assess the cumulative incidence of invasive candidiasis (IC) in intensive care units (ICUs) in Europe. METHODS: A multinational, multicenter, retrospective study was conducted in 23 ICUs in 9 European countries, representing the first phase of the candidemia/intra-abdominal candidiasis in European ICU project (EUCANDICU). RESULTS: During the study period, 570 episodes of ICU-acquired IC were observed, with a cumulative incidence of 7.07 episodes per 1000 ICU admissions, with important between-center variability. Separated, non-mutually exclusive cumulative incidences of candidemia and IAC were 5.52 and 1.84 episodes per 1000 ICU admissions, respectively. Crude 30-day mortality was 42%. Age (odds ratio [OR] 1.04 per year, 95% CI 1.02-1.06, p < 0.001), severe hepatic failure (OR 3.25, 95% 1.31-8.08, p 0.011), SOFA score at the onset of IC (OR 1.11 per point, 95% CI 1.04-1.17, p 0.001), and septic shock (OR 2.12, 95% CI 1.24-3.63, p 0.006) were associated with increased 30-day mortality in a secondary, exploratory analysis. CONCLUSIONS: The cumulative incidence of IC in 23 European ICUs was 7.07 episodes per 1000 ICU admissions. Future in-depth analyses will allow explaining part of the observed between-center variability, with the ultimate aim of helping to improve local infection control and antifungal stewardship projects and interventions.

2019 - La presenza dei familiari durante le manovre di rianimazione: un’indagine qualitativa in una Terapia Intensiva Generale [Articolo su rivista]
Giovannetti, M; Boni, Davide; Ferri, P; Girardis, M
abstract

Introduction: although many studies confirm the will of relatives to remain during cardiopulmonary resuscitation of their loved ones who are hospitalized in ICU, this rarely happens in Italy, even in the case of “open ICU”. Nurses and physicians are often against these people’s will for various reasons that have never been fully clarified. Purpose: the purpose is to analyse the experiences, opinions and emotions of nurses and physicians about the presence of family members during resuscitation. Materials and methods: for the aim of this research, it has been conducted a qualitative, phenomenological study that has involved 24 health professionals:17 nurses and 7 physicians all operating in an ICU in Northern Italy, that is open 24 hours a day to the relatives and allows them to attend CPR. Each attendee was given a personal and professional sheet, that they would need in order to describe the features of the sample. Subsequently, a semi-structured interview was conducted with the help of five guidance questions, created after an analysis of the reference literature. Results: 6 dominant themes and 20 recurrent secondary themes emerged from data analysis amongst the attendees. The majority of health professionals say that they agree with the presence of the family during CPR, and they explained some of the advantages and benefits. Nevertheless, some fears persist, even amongst the most experienced professionals, even though negative experiences are not related to these. Discussion and Conclusions: The presence of the family during CPR appears to be well accepted by health professionals. Defusing courses and clinical audits in teams may be useful to reduce difficulties and fears in managing family presence, as well as a specific training that allows the professional to be able to handle any problematic situation.

2019 - Mortality in Patients With Septic Shock by Multidrug Resistant Bacteria: Risk Factors and Impact of Sepsis Treatments [Articolo su rivista]
Busani, Stefano; Serafini, Giulia; Mantovani, Elena; Venturelli, Claudia; Giannella, Maddalena; Viale, Pierluigi; Mussini, Cristina; Cossarizza, Andrea; Girardis, Massimo
abstract

Background: Patients with septic shock by multidrug resistant (MDR) microorganism maybe considered a specific population of critical patients at very high risk of death in whom the effects of standard sepsis treatment has never been assessed. The objective of this retrospective analysis was to evaluate the risk factors for 30-day mortality and the impact of sepsis management in patients with septic shock caused by MDR bacteria. Methods: Patients with septic shock by MDR bacteria admitted to the mixed intensive care unit (ICU) of Modena University Hospital during a 6-year period were studied. The clinical and microbiological characteristics and sepsis treatments provided were analyzed and compared between survivors (S) and nonsurvivors (NS) at 30 days after septic shock appearance. Results: Ninety-four patients were studied. All therapeutic interventions applied to patients during their ICU stay did not show statistical significance between S and NS groups, except for administration of immunoglobulin M (IgM) preparation which were provided more frequently in S group (P <.05). At the multivariate adjusted analysis, preexisting cancer (odds ratio [OR] = 2.965) and Acinetobacter baumannii infections (OR = 3.197) were independently correlated with an increased risk of 30-day mortality, whereas treatment with IgM preparation was protective (OR = 0.283). Conclusions: This retrospective study showed that in patients with septic shock caused by MDR bacteria, history of cancer and infection sustained by A baumannii increase the risk of mortality and that standard sepsis treatments do not seem to provide any protective effect. Adjunctive therapy with IgM preparation seems to be beneficial, but further appropriate studies are needed to confirm the results observed.

2019 - Oxygen: a powerful drug to handle with care [Articolo su rivista]
Coloretti, Irene; Tosi, Martina; Biagioni, Emanuela; Girardis, Massimo
abstract

2019 - Prognostic Potential of the Panfungal Marker (1 → 3)-β-D-Glucan in Invasive Mycoses Patients [Articolo su rivista]
Pini, P; Venturelli, C; Girardis, M; Forghieri, F; Blasi, E
abstract

We analyze the prognostic potential of (1 → 3)-β-D-glucan (BG) levels in predicting clinical outcomes in patients with invasive fungal infections, on a population undergoing 253 episodes (177 with positive and 76 with negative outcome). Using linear regression analysis, we assessed the prognostic potential of kinetically evaluated BG levels and we found an overall sensitivity and specificity of 68 and 82%, respectively. Moreover, using an interpretative algorithm based on two distinct cutoff values, we were able to predict the outcome in 84% of the studied population with a diagnostic accuracy of 82%.

2019 - University of Modena Experience With Liver Grafts From Donation After Circulatory Death: What Really Matters in Organ Selection? [Articolo su rivista]
Olivieri, T.; Magistri, P.; Guidetti, C.; Baroni, S.; Rinaldi, S.; Assirati, G.; Catellani, B.; Chierego, G.; Cantaroni, C.; Bondi, F.; Campagna, A.; Sangiorgi, G.; Pecchi, A.; Serra, V.; Tarantino, G.; Ballarin, R.; Guerrini, G. P.; Girardis, M.; Bertellini, E.; Di Benedetto, F.
abstract

Introduction: The use of grafts from donation after circulatory death (DCD) is an important additional source to implement within the donor pool. We herein report the outcomes of our early experience with DCD grafts for liver transplantation (LT). Methods: Ten patients successfully underwent LT with grafts from DCD donors between August 2017 and January 2019 at the Hepato-Pancreato-Biliary Surgery and Liver Transplant Unit of University of Modena and Reggio Emilia. All donors underwent normothermic regional perfusion after death declaration and, after the procurement, all the suitable grafts underwent ex situ hypothermic perfusion prior to transplantation. Results: Mean postoperative hospital stay after transplant was 12.7 days (range, 5-26), and in 5 cases we placed a biliary drainage (Kehr tube) during surgery. Primary graft nonfunction did not occur after LT in this cohort, although, we registered one case of biliary anastomosis stricture that was managed endoscopically by endoscopic retrograde cholangiopancreatography. All patients are alive and none required retransplantation. Conclusions: In our experience with controlled DCD donors, the demonstration of: (1) a negative trend of lactate during normothermic regional perfusion; (2) an aspartate aminotransferase and alanine aminotransferase level lower than 2000 mU/dL; and (3) less than 1 hour of functional warm ischemia time along with no signs of microscopic or macroscopic ischemia of the grafts, are related to positive outcomes in the first year after transplant. A DCD risk score based on Italian population characteristics and regulations on death observation may improve donor-recipient match and avoid futile transplants.

2019 - Use of Levosimendan in Intensive Care Unit Settings: An Opinion Paper [Articolo su rivista]
Herpain, Antoine; Bouchez, Stefaan; Girardis, Massimo; Guarracino, Fabio; Knotzer, Johann; Levy, Bruno; Liebregts, Tobias; Pollesello, Piero; Ricksten, Sven-Erik; Riha, Hynek; Rudiger, Alain; Sangalli, Fabio
abstract

Levosimendan is an inodilator that promotes cardiac contractility primarily through calcium sensitization of cardiac troponin C and vasodilatation via opening of adenosine triphosphate-sensitive potassium (KATP) channels in vascular smooth muscle cells; the drug also exerts organ-protective effects through a similar effect on mitochondrial KATP channels. This pharmacological profile identifies levosimendan as a drug that may have applications in a wide range of critical illness situations encountered in intensive care unit medicine: hemodynamic support in cardiogenic or septic shock; weaning from mechanical ventilation or from extracorporeal membrane oxygenation; and in the context of cardiorenal syndrome. This review, authored by experts from 9 European countries (Austria, Belgium, Czech republic, Finland, France, Germany, Italy, Sweden, and Switzerland), examines the clinical and experimental data for levosimendan in these situations and concludes that, in most instances, the evidence is encouraging, which is not the case with other cardioactive and vasoactive drugs routinely used in the intensive care unit. The size of the available studies is, however, limited and the data are in need of verification in larger controlled trials. Some proposals are offered for the aims and designs of these additional studies.

2019 - What's new in oxygen therapy? [Articolo su rivista]
Girardis, Massimo; Alhazzani, Waleed; Rasmussen, Bodil Steen
abstract

2018 - Common practice and guidelines for sedation in critically ill patients [Capitolo/Saggio]
Girardis, M.; Rossi, B.; Dall'Ara, L.; Cantaroni, C.
abstract

2018 - Comparison of European ICU patients in 2012 (ICON) versus 2002 (SOAP) [Articolo su rivista]
Vincent, Jean-Louis; Lefrant, Jean-Yves; Kotfis, Katarzyna; Nanchal, Rahul; Martin-Loeches, Ignacio; Wittebole, Xavier; Sakka, Samir G.; Pickkers, Peter; Moreno, Rui; Sakr, Yasser; Pavlik, P.; Manak, J.; Kieslichova, E.; Turek, R.; Fischer, M.; Valkova, R.; Dadak, L.; Dostal, P.; Malaska, J.; Hajek, R.; Židková, A.; Lavicka, P.; Medve, L.; Sarkany, A.; Kremer, I.; Marjanek, Z.; Tamasi, P.; Kolbusz, J.; Kübler, A.; Mielczarek, B.; Mikaszewska-Sokolewicz, M.; Kotfis, K.; Tamowicz, B.; Sulkowski, W.; Smuszkiewicz, P.; Pihowicz, A.; Trejnowska, E.; Hagau, N.; Filipescu, D.; Droc, G.; Lupu, M.; Nica, A.; Stoica, R.; Tomescu, D.; Constantinescu, D.; Valcoreanu Zbaganu, G.; Slavcovici, A.; Soskic, L.; Palibrk, I.; Jankovic, R.; Jovanovic, B.; Pandurovic, M.; Bumbasirevic, V.; Uljarevic, B.; Surbatovic, M.; Ladjevic, N.; Slobodianiuk, G.; Sobona, V.; Cikova, A.; Gebhardtova, A.; Cohen, J.; Sold, O.; Urbanek, P.; Schlieber, J.; Reisinger, J.; Auer, J.; Hartjes, A.; Lerche, A.; Janous, T.; Kink, E.; Krahulec, W.; Smolle, K.; van der Schueren, M.; Thibo, P.; Vanhoof, M.; Ahmet, I.; Philippe, G.; Dufaye, P.; Jacobs, O.; Fraipont, V.; Biston, P.; Dive, A.; Bouckaert, Y.; Gilbert, E.; Gressens, B.; Pinck, E.; Collin, V.; Vincent, J. L.; de Waele, J.; Rimachi, R.; Gusu, D.; de decker, K.; Mandianga, K.; Heytens, L.; Wittebole, X.; Herbert, S.; Olivier, V.; Vandenheede, W.; Rogiers, P.; Kolodzeike, P.; Kruse, M.; Andersen, T.; Harjola, V.; Saarinen, K.; Leone, M.; Durocher, A.; Moulront, S.; Lepape, A.; Losser, M.; Cabaret, P.; Kalaitzis, E.; Zogheib, E.; Charve, P.; Francois, B.; Lefrant, J. Y.; Beilouny, B.; Forceville, X.; Misset, B.; Jacobs, F.; Bernard, F.; Payen, D.; Wynckel, A.; Castelain, V.; Faure, A.; Lavagne, P.; Thierry, L.; Moussa, M.; Vieillard-Baron, A.; Durand, M.; Gainnier, M.; Ichai, C.; Arens, S.; Hoffmann, C.; Kaffarnik, M.; Scharnofske, C.; Voigt, I.; Peckelsen, C.; Weber, M.; Gille, J.; Lange, A.; Schoser, G.; Sablotzki, A.; Jaschinski, U.; Bluethgen, A.; Vogel, F.; Tscheu, A.; Fuchs, T.; Wattenberg, M.; Helmes, T.; Scieszka, S.; Heintz, M.; Sakka, S.; Kohler, J.; Fiedler, F.; Danz, M.; Sakr, Y.; Riessen, R.; Kerz, T.; Kersten, A.; Tacke, F.; Marx, G.; Volkert, T.; Schmutz, A.; Nierhaus, A.; Kluge, S.; Abel, P.; Janosi, R.; Utzolino, S.; Bracht, H.; Toussaint, S.; Giannakou Peftoulidou, M.; Myrianthefs, P.; Armaganidis, A.; Routsi, C.; Xini, A.; Mouloudi, E.; Kokoris, I.; Kyriazopoulos, G.; Vlachos, S.; Lavrentieva, A.; Partala, P.; Nakos, G.; Barry, J.; O’Leary, R.; Motherway, C.; Faheem, M.; Dunne, E.; Donnelly, M.; Konrad, T.; Bonora, E.; Achilli, C.; Rossi, S.; Castiglione, G.; Peris, A.; Albanese, D.; Stocchetti, N.; Citerio, G.; Mozzoni, L.; Sisillo, E.; de Negri, P.; Savioli, M.; Vecchiarelli, P.; Puflea, F.; Stankovic, V.; Minoja, G.; Montibeller, S.; Calligaro, P.; Sorrentino, R.; Feri, M.; Zambon, M.; Colombaroli, E.; Giarratano, A.; Pellis, T.; Capra, C.; Antonelli, M.; Gullo, A.; Chelazzi, C.; de Capraris, A.; Patroniti, N.; Girardis, M.; Franchi, F.; Berlot, G.; Ponssen, H.; Ten Cate, J.; Bormans, L.; Husada, S.; Buise, M.; van der Hoven, B.; Reidinga, A.; Kuiper, M.; Pickkers, P.; Kluge, G.; Den Boer, S.; Kesecioglu, J.; van Leeuwen, H.; Flaatten, H.; Mo, S.; Branco, V.; Rua, F.; Lafuente, E.; Sousa, M.; Catorze, N.; Barros, M.; Pereira, L.; Vintém de Oliveira, A.; Gomes, J.; Gaspar, I.; Pereira, M.; Cymbron, M.; Dias, A.; Almeida, E.; Beirao, S.; Serra, I.; Ribeiro, R.; Povoa, P.; Faria, F.; Costa-E-Silva, Z.; Nóbrega, J.; Fernandes, F.; Gabriel, J.; Voga, G.; Rupnik, E.; Kosec, L.; Kerin Povšic, M.; Osojnik, I.; Tomic, V.; Sinkovic, A.; González, J.; Zavala, E.; Pérez Valenzuela, J.; Marina, L.; Vidal-Cortés, P.; Posada, P.; Ignacio Martin-Loeches, A.; Muñoz Guillén, N.; Palomar, M.; Sole-Violan, J.; Torres, A.; Gonzalez Gallego, M.; Aguilar, G.; Montoiro Allué, R.; Argüeso, M.; Parejo, M.; Palomo Navarro, M.; Jose, A.; Nin, N.; Alvarez Lerma, F.; Martinez
abstract

Purpose: To evaluate differences in the characteristics and outcomes of intensive care unit (ICU) patients over time. Methods: We reviewed all epidemiological data, including comorbidities, types and severity of organ failure, interventions, lengths of stay and outcome, for patients from the Sepsis Occurrence in Acutely ill Patients (SOAP) study, an observational study conducted in European intensive care units in 2002, and the Intensive Care Over Nations (ICON) audit, a survey of intensive care unit patients conducted in 2012. Results: We compared the 3147 patients from the SOAP study with the 4852 patients from the ICON audit admitted to intensive care units in the same countries as those in the SOAP study. The ICON patients were older (62.5 Â± 17.0 vs. 60.6 Â± 17.4 years) and had higher severity scores than the SOAP patients. The proportion of patients with sepsis at any time during the intensive care unit stay was slightly higher in the ICON study (31.9 vs. 29.6%, p = 0.03). In multilevel analysis, the adjusted odds of ICU mortality were significantly lower for ICON patients than for SOAP patients, particularly in patients with sepsis [OR 0.45 (0.35â0.59), p < 0.001]. Conclusions: Over the 10-year period between 2002 and 2012, the proportion of patients with sepsis admitted to European ICUs remained relatively stable, but the severity of disease increased. In multilevel analysis, the odds of ICU mortality were lower in our 2012 cohort compared to our 2002 cohort, particularly in patients with sepsis.

2018 - Epidemiology of intensive care unit-acquired sepsis in Italy: results of the SPIN-UTI network [Articolo su rivista]
Agodi, A; Barchitta, M; Auxilia, F; Brusaferro, S; D'Errico, M M; Montagna, M T; Pasquarella, C; Tardivo, S; Arrigoni, C; Fabiani, L; Laurenti, P; Mattaliano, A R; Orsi, G B; Squeri, R; Torregrossa, M V; Mura, ; I and 123 collaborators: Aiello, Mr; Alliani, C; Amatucci, Mr; Antoci, M; Antonelli, M; Astuto, M; Arnoldo, L; Arru, B; Baccari, G; Barbadoro, P; Barbara, A; Barilaro, C; Battaglia, P; Bellocchi, P; Bernasconi, Mo; Bianco, A; Bissolo, E; Bocchi, A; Bruno, A; Brusaferro, M; Buccheri, M; Campanella, F; Canino, R; Cannistrà, A; Carini, Sa; Catalano, S; Castellani, P; Castiglione, G; Coniglio, S; Consolante, C; Conte, C; Contrisciani, R; Corallini, R; Crollari, P; Damiani, G; Denaro, C; De Remigis, S; Diana, F; Di Bartolo, R; Di Benedetto, A; Di Fabio, G; Di Falco, C; Digeronimo, V; Di Gregorio, P; Distefano, R; Egitto, G; Falciani, E; Farruggia, P; Fenaroli, S; Ferlazzo, G; Garofalo, G; Girardis, M; Giovanelli, L; Giubbini, G; Graceffa, A; Guadagna, A; Gregu, G; Ingala, F; Innocenzi, L; La Camera, G; La Rosa, Mc; Lesa, L; Longhitano, Am; Luppino, G; Maida, Cm; Manta, G; Marino, G; Masia, Md; Maviglia, R; Mazzetti, M; Maugeri, A; Megna, Mt; Mella, Lm; Milazzo, M; Milia, M; Minari, C; Minerva, M; Mordacci, M; Murgia, P; Oliveri, P; Olori, Mp; Pagliarulo, R; Palermo, R; Pandiani, I; Pappalardo, F; Papetti, C; Partenza, A; Pascu, D; Pasculli, M; Pavia, M; Pavone, Ml; Pellegrino, Mg; Pelligra, F; Pillon, D; Pintaudi, S; Pitzoi, L; Pinto, A; Piotti, P; Pupo, S; Quattrocchi, R; Righi, E; Rigo, A; Rigo, A; Romeo, A; Rosa, E; Rutigliano, S; Sarchi, P; Scimonello, G; Seminerio, A; Stefanini, P; Sticca, G; Taddei, S; Tessari, L; Tetamo, R; Ticca, M; Tribastoni, S; Vallorani, S; Venturoni, F; Vitagliano, E; Vitali, P; Zappone, A; Zei, E; Zeoli, Mp.
abstract

Sepsis is the major cause of mortality from any infectious disease worldwide. Sepsis may be the result of a healthcare associated infection (HAI): the most frequent adverse events during care delivery especially in Intensive Care Units (ICUs). The main aim of the present study was to describe the epidemiology of ICU-acquired sepsis and related outcomes among patients enrolled in the framework of the Italian Nosocomial Infections Surveillance in ICUs - SPIN-UTI project.

2018 - Erratum to: The Intensive Care Global Study on Severe Acute Respiratory Infection (ICâGLOSSARI): a multicenter, multinational, 14-day inception cohort study (Intensive Care Medicine, (2016), 42, 5, (953), 10.1007/s00134-016-4317-4) [Articolo su rivista]
Sakr, Yasser; Ferrer, Ricard; Reinhart, Konrad; Beale, Richard; Rhodes, Andrew; Moreno, Rui; Timsit, Jean Francois; Brochard, Laurent; Thompson, B. Taylor; Rezende, Ederlon; Chiche, Jean Daniel; Auer, J.; Schatzl, G.; Mach, K.; Gruber, H.; Schreurs, E.; Vander Laenen, M.; Ceunen, H.; Wauters, J.; Francois, G.; Deschamps, P.; Castanares, D.; Debels, D.; Pierrakos, C.; Vincent, J. L.; Taccone, F.; Vymazal, T.; Gornik, I.; Vujiaklija Brajkovic, A.; Medici, R.; Nielsen, J.; Bendtsen, A.; Siegel, H.; Suonsyrjä, T.; Hraech, S.; Daviaux, F.; Guillot, M.; Castelain, V.; Losser, R. -R.; Novy, E.; Bouadma, L.; Misset, B.; Philippart, F.; Mallat, J.; Zogheib, E.; Miclo, M.; Teboul, J. -L.; Anguel, N.; Darmon, M.; Pham, T.; Barberet, G.; Plantefeve, G.; Floccard, B.; Kheladze, Z.; Bloos, F.; Faltlhauser, A.; Helmes, T.; Zacharowski, K.; Meybohm, P.; Schwarzkopf, K.; Christ, M.; Baumgaertel, M.; John, S.; Nentwich, J.; Deja, M.; Goldmann, A.; Gottschalk, A.; Honig, F.; Siepe, B.; Goebel, U.; Lehmke, J.; Behrens, S.; Fiedler, K.; Sagoschen, I.; Riessen, R.; Haap, M.; Simon, Ph.; Kaisers, U.; Behrens, S.; Niesen, M.; Jaschinski, U.; Hoersch, S.; Jung, A.; Allgaeuer, S.; Haake, H.; Lange, A.; Papanikolaou, M.; Balla, M.; Giannakou, M.; Soultati, I.; Nikos, G.; Koulouras, V.; Kyriazopoulos, G.; Gkika, D.; Vlachogianni, G.; Psaroulis, K.; Mouloudi, E.; Massa, E.; Nichol, A.; Meany, E.; Motherway, C.; Bellani, G.; Pota, V.; Schiavone, V.; Girardis, M.; Busani, S.; Petrucci, N.; Di Pasquale, R.; Mazzini, P.; Molin, A.; Pellerano, G.; Volta, C.; Spadaro, S.; Guarracino, F.; Savioli, M.; Pellis, T.; Chinellato, N.; Gatta, A.; Cecchini, F.; Raineri, S. M.; Cortegiani, A.; Kekstas, G.; Karosas, V.; Anguseva, T.; Mitrev, Z.; Beck, O.; Cimic, N.; Janssen, G.; Bormans, L.; Kuiper, M.; Koopmans, K.; Den Boer, S.; de Groot, M.; Dennesen, P.; van den Bosch, J.; Kluge, G.; Mikaszewska-Sokolewicz, M.; Lazowski, T.; Chruscikowski, M.; Machon, J.; Adamik, B.; Kübler, A.; Wieczorek, A.; Afonso, S.; Matos, R.; Catorze, N.; Araujo, A.; Costa, Z.; Pais-de-Lacerda, A.; Martins, I.; Cardiga, R.; Fernandes, L.; Serra, I.; Martinho, A.; Tomescu, D.; Popescu, M.; Scarlatescu, E.; Stoica, R.; Macri, A.; Filipescu, D.; Rupnik, E.; Tomic, V.; Sifrer, F.; Sole Violan, J.; Ferrer Agüero, J. M.; Izura, J.; Monedero, P.; de Cabo, C. Muños; Aguilar, G.; Belda, F. J.; Blanquer, J.; Nives Carbonell, E.; Lopez-Delgado, J. -C.; Aragon, C.; Joya, C.; Ortiz-Leyba, C.; Fernandez Gonzalez, C. J.; de la Torre-Prados, M. -V.; Puerto-Morlan, A.; Araujo Aguilar, P.; Tomás Marsilla, J. I.; Vera Aratcoz, P.; Olmo, A.; Ferrer Roca, R.; Catalan, R. M.; Garcia Olivares, P.; Albis, A.; Alvarez, M.; Corcoles Gonzalez, V.; Gutierrez Rubio, J. M.; Montoiro Allue, R.; Rubio Mateo-Sidron, J.; Hobrok, M.; Cecconi, M.; Di Tomasso, N.; Raj, A.; Szakmany, T.; Srinivasa, L.; Mathew, S.; Ferguson, A.; Blahut-Zugaj, M.; Watters, M.; Henderson, S.; Sim, M.; Csabi, P.; O’Neill, O.; Nutt, C.; Humphreys, S.; Bhowmick, K.; Donnelly, A.; O’Kane, S.; Garfield, M.; Jha, R.; Unni, N.; Gordon, A.; Rubulotta, F.; Ravi, K.; Lunch, G.; Franco, F.; Higgs, D.; Strandvik, G.; Jonas, A.; Hopkins, Ph.; Hurst, T.; Bellini, A.; Balogun, O.; Srinivasan, R.; Ostermann, M.; Alexander, P.; Mccalman, K.; Bedford, J.; Fulop, M.; Brescia, G.; Strachan, J.; Meyer, J.; Stotz, M.; Brett, S.; Zand, F.; Nikandish, R.; Hashemian, S.; Jamaati, H.; Alsheikhly, A. S.; Almekhlafi, G.; Albarrak, M.; Maghrabi, A.; Salahuddin, N.; Aisa, T.; Atalan, H. K.; Sungur, M.; Hegazi, M.; Bauer, P.; Mukkera, S.; Fried, J.; Barger, M.; Gueret, R.; Gonzalez, C.; Lovesio, C.; Dellera, Ch.; Barrios, D.; Leite Mendes, C.; Gottardo, P.; Caser, E.; Santos, C.; Carvalho, A.; Teixeira, C.; Samaniego, W.; Whittle, S.; Molano, D.; Rojas, A.; Guerra, K.; Villamagua, B.; Salgado-Yepez, E.; Morocho, D.; Remache-Vargas, N.; Ñamendys-Silva, S.; Rodriguez, D.; Dominguez, G.; Barraza, G.; Bermudez-Aceves, E.; Sanchez-Hurtad
abstract

In both the original publication (DOI 10.1007/s00134-015-4206-2) and the first erratum (DOI 10.1007/s00134-016-4317-4), the members of the IC-GLOSSARI Investigators and the ESICM Trials Group were provided in such a way that they could not be indexed as collaborators on PubMed. The publisher apologizes for these errors and is pleased to list the members of the groups here: (Table presented.).

2018 - Experienced Use of Dexmedetomidine in the Intensive Care Unit: A Report of a Structured Consensus [Articolo su rivista]
Pasero, Daniela; Sangalli, Fabio; Baiocchi, Massimo; Blangetti, Ilaria; Cattaneo, Sergio; Paternoster, Gianluca; Moltrasio, Marco; Auci, Elisabetta; Murrino, Patrizia; Forfori, Francesco; Forastiere, Ester; De Cristofaro, Maria Giovanna; Deste, Giorgio; Feltracco, Paolo; Petrini, Flavia; Tritapepe, Luigi; Girardis, Massimo
abstract

OBJECTIVE: Management of pain, agitation and delirium (PAD) remains to be a true challenge in critically ill patients. The pharmacological proprieties of dexmedetomidine (DEX) make it an ideal candidate drug for light and cooperative sedation, but many practical questions remain unanswered. This structured consensus from 17 intensivists well experienced on PAD management and DEX use provides indications for the appropriate use of DEX in clinical practice. METHODS: A modified RAND/UCLA appropriateness method was used. In four predefined patient populations, the clinical scenarios do not properly cope by the current recommended pharmacological strategies (except DEX), and the possible advantages of DEX use were identified and voted for agreement, after reviewing literature data. RESULTS: Three scenarios in medical patients, five scenarios in patients with acute respiratory failure undergoing non-invasive ventilation, three scenarios in patients with cardiac surgery in the early postoperative period and three scenarios in patients with overt delirium were identified as challenging with the current PAD strategies. In these scenarios, the use of DEX was voted as potentially useful by most of the panellists owing to its specific pharmacological characteristics, such as conservation of cognitive function, lack of effects on the respiratory drive, low induction of delirium and analgesia effects. CONCLUSION: DEX might be considered as a first-line sedative in different scenarios even though conclusive data on its benefits are still lacking.

2018 - Landiolol in patients with septic shock resident in an intensive care unit (LANDI-SEP): study protocol for a randomized controlled trial [Articolo su rivista]
Unger, Martin; Morelli, Andrea; Singer, Mervyn; Radermacher, Peter; Rehberg, Sebastian; Trimmel, Helmut; Joannidis, Michael; Heinz, Gottfried; Cerny, Vladimír; Dostál, Pavel; Siebers, Christian; Guarracino, Fabio; Pratesi, Francesca; Biancofiore, Gianni; Girardis, Massimo; Kadlecova, Pavla; Bouvet, Olivier; Zörer, Michael; Grohmann-Izay, Barbara; Krejcy, Kurt; Klade, Christoph; Krumpl, Günther
abstract

BACKGROUND: In patients with septic shock, the presence of an elevated heart rate (HR) after fluid resuscitation marks a subgroup of patients with a particularly poor prognosis. Several studies have shown that HR control in this population is safe and can potentially improve outcomes. However, all were conducted in a single-center setting. The aim of this multicenter study is to demonstrate that administration of the highly beta1-selective and ultrashort-acting beta blocker landiolol in patients with septic shock and persistent tachycardia (HR ≥ 95 beats per minute [bpm]) is effective in reducing and maintaining HR without increasing vasopressor requirements. METHODS: A phase IV, multicenter, prospective, randomized, open-label, controlled study is being conducted. The study will enroll a total of 200 patients with septic shock as defined by The Third International Consensus Definitions for Sepsis and Septic Shock criteria and tachycardia (HR ≥ 95 bpm) despite a hemodynamic optimization period of 24-36 h. Patients are randomized (1:1) to receive either standard treatment (according to the Surviving Sepsis Campaign Guidelines 2016) and continuous landiolol infusion to reach a target HR of 80-94 bpm or standard treatment alone. The primary endpoint is HR response (HR 80-94 bpm), the maintenance thereof, and the absence of increased vasopressor requirements during the first 24 h after initiating treatment. DISCUSSION: Despite recent studies, the role of beta blockers in the treatment of patients with septic shock remains unclear. This study will investigate whether HR control using landiolol is safe, feasible, and effective, and further enhance the understanding of beta blockade in patients with septic shock. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2017-002138-22 . Registered on 8 August 2017.

2018 - MESSA A PUNTO DI UN SISTEMA INNOVATIVO PER MONITORARE IN TEMPO REALE LA FORMAZIONE DI BIOFILM DI PSEUDOMONAS AERUGINOSA SU TUBI ENDOTRACHEALI [Poster]
Sala, A.; Pericolini, E.; Colombari, B.; Ferretti, G.; Iseppi, R.; Ardizzoni, A.; Girardis, M.; Castagnoli, A.; Peppoloni, S.; Blasi, E.
abstract

INTRODUZIONE La maggior parte delle infezioni associate all’assistenza sono dovute alla capacità che molti patogeni hanno di produrre biofilm sui diversi dispositivi medici utilizzati. Ad esempio, i pazienti sottoposti a ventilazione assistita sono particolarmente a rischio di sviluppare infezioni respiratorie legate alla formazione di biofilm da parte di Pseudomonas aeruginosa su tubi endotracheali (TE), che evolvono spesso in polmoniti severe. La maggior parte delle attuali conoscenze relative alla formazione di tali biofilm sui dispositivi medici derivano da studi in vitro su micropiastre in polistirene o su materiali plastici. Tuttavia, i risultati che derivano da questi studi non rispecchiano pienamente ciò che accade a livello clinico, poiché la formazione del biofilm è fortemente influenzata da parametri quali la forma e la composizione dei materiali usati per produrre i TE, oltre che da fattori di virulenza microbici. In questo studio abbiamo messo a punto un sistema innovativo in vitro per monitorare in tempo reale la formazione di biofilm di P. aeruginosa su TE. METODI Tramite l’utilizzo di un ceppo batterico geneticamente modificato bioluminescente, è stato possibile monitorare in tempo reale la formazione di biofilm direttamente sui TE, attraverso la valutazione della bioluminescenza (BL). La validità di tale metodo innovativo è stata comparata a metodiche standard (cristal violetto e microscopia confocale). E’ stata inoltre valutata la percentuale di cellule vive/morte nel del biofilm formato sui TE, la produzione di pioverdina e la presenza di DNA extracellulare (in fluorescenza). RISULTATI Dimostriamo che: 1) P. aeruginosa è in grado di produrre biofilm su TE 2) il segnale di BL, emesso solo da cellule vitali, è proporzionale al numero di batteri rilevabili mediante conta delle unità formanti colonia, 3) la quantificazione del segnale consente di misurare il biofilm prodotto tenendo conto non solo del contributo dei fattori microbici ma anche della forma e del materiale di cui sono fatti i TE, 4) è possibile studiare la produzione di fattori di virulenza e l’attività metabolica dei batteri incorporati nel biofilm sui TE. CONCLUSIONI Il modello descritto è ad oggi il sistema in vitro che mima più da vicino quello che può accadere nei pazienti con infezioni TE-associate. Per tale motivo potrà avere un’immediata applicazione per lo screening e la valutazione dell’attività anti- biofilm di nuovi farmaci come anche di nuovi materiali per la produzione di dispositivi medici.

2018 - Oxygen in the critically ill: friend or foe? [Articolo su rivista]
Damiani, Elisa; Donati, Abele; Girardis, Massimo
abstract

To examine the potential harmful effects of hyperoxia and summarize the results of most recent clinical studies evaluating oxygen therapy in critically ill patients.

2018 - Procalcitonin-guided antibiotic therapy: an expert consensus [Articolo su rivista]
Bartoletti, Michele; Antonelli, Massimo; Bruno Blasi, Francesco Arturo; Casagranda, Ivo; Chieregato, Arturo; Fumagalli, Roberto; Girardis, Massimo; Pieralli, Filippo; Plebani, Mario; Rossolini, Gian Maria; Sartelli, Massimo; Viaggi, Bruno; Viale, Pierluigi; Viscoli, Claudio; Pea, Federico
abstract

BACKGROUND: Procalcitonin (PCT) is a useful biomarker of bacterial infection and its use is associated to reduced duration of antibiotic therapy in the setting of intensive care medicine. To address the need of practical guidance for the use of PCT in various clinical settings, a group of experts was invited to participate at a consensus process with the aims of defining the rationale for appropriate use of PCT and for improving the management of critically ill patients with sepsis. METHODS: A group of 14 experts from anesthesiology and critical care, infectious diseases, internal medicine, pulmonology, clinical microbiology, laboratory medicine, clinical pharmacology and methodology provided expert opinion through a modified Delphi process, after a comprehensive literature review. RESULTS: The appropriateness of use of PCT in terms of diagnosis, prognosis and antimicrobial stewardship was assessed for different scenarios or settings such us management of infection in the emergency department, regular wards, surgical wards or in the intensive care unit. Similarly, appropriateness and timing of PCT measurement were evaluated. All the process consisted in three Delphi rounds. CONCLUSIONS: PCT use is appropriate in algorithms for antibiotic de-escalation and discontinuation. In this case, reproducible, high sensitive assays should be used. However, initiation or escalation of antibiotic therapy in specific scenarios, including acute respiratory infections, should not be based solely on PCT serum levels. Clinical and radiological findings, evaluation of severity of illness and of patient's characteristics should be taken into proper account in order to correctly interpret PCT results.

2018 - Purpura Fulminans and Septic Shock due to Capnocytophaga Canimorsus after Dog Bite: A Case Report and Review of the Literature [Articolo su rivista]
Mantovani, Elena; Busani, Stefano; Biagioni, Emanuela; Venturelli, Claudia; Serio, Lucia; Girardis, Massimo
abstract

Primary infection by Capnocytophaga canimorsus after dog bite is rare but may be difficult to identify and rapidly lethal. We describe a case of fatal septic shock with fulminant purpura occurred in a patient without specific risk factor two days after an irrelevant dog bite. The patient was brought to hospital because of altered mental status, fever, and abdominal pain. In a few hours patient became hypoxic and cyanotic. The patient became extremely hypotensive with shock refractory to an aggressive fluid resuscitation (40 ml/kg crystalloids). She received vasoactive drugs, antibiotic therapy, and blood purification treatment, but cardiac arrest unresponsive to resuscitation maneuvers occurred. Case description and literature review demonstrated that, also in patients without specific risk factors, signs of infection after dog bite should be never underestimated and should be treated with a prompt antibiotic therapy initiation even before occurrence of organ dysfunction.

2018 - Real-time monitoring of Pseudomonas aeruginosa biofilm formation on endotracheal tubes in vitro [Articolo su rivista]
Pericolini, E.; Colombari, B.; Ferretti, Gianmarco; Iseppi, R.; Ardizzoni, A.; Girardis, M.; Sala, Arianna; Peppoloni, S.; Blasi, Elisabetta
abstract

BACKGROUND: Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for both acute and chronic infections in humans. In particular, its ability to form biofilm, on biotic and abiotic surfaces, makes it particularly resistant to host's immune defenses and current antibiotic therapies as well. Innovative antimicrobial materials, like hydrogel, silver salts or nanoparticles have been used to cover new generation catheters with promising results. Nevertheless, biofilm remains a major health problem. For instance, biofilm produced onto endotracheal tubes (ETT) of ventilated patients plays a relevant role in the onset of ventilation-associated pneumonia. Most of our knowledge on Pseudomonas aeruginosa biofilm derives from in vitro studies carried out on abiotic surfaces, such as polystyrene microplates or plastic materials used for ETT manufacturing. However, these approaches often provide underestimated results since other parameters, in addition to bacterial features (i.e. shape and material composition of ETT) might strongly influence biofilm formation. RESULTS: We used an already established biofilm development assay on medically-relevant foreign devices (CVC catheters) by a stably transformed bioluminescent (BLI)-Pseudomonas aeruginosa strain, in order to follow up biofilm formation on ETT by bioluminescence detection. Our results demonstrated that it is possible: i) to monitor BLI-Pseudomonas aeruginosa biofilm development on ETT pieces in real-time, ii) to evaluate the three-dimensional structure of biofilm directly on ETT, iii) to assess metabolic behavior and the production of microbial virulence traits of bacteria embedded on ETT-biofilm. CONCLUSIONS: Overall, we were able to standardize a rapid and easy-to-perform in vitro model for real-time monitoring Pseudomonas aeruginosa biofilm formation directly onto ETT pieces, taking into account not only microbial factors, but also ETT shape and material. Our study provides a rapid method for future screening and validation of novel antimicrobial drugs as well as for the evaluation of novel biomaterials employed in the production of new classes of ETT.

2017 - A Global Declaration on Appropriate Use of Antimicrobial Agents across the Surgical Pathway [Articolo su rivista]
Sartelli, Massimo; Kluger, Yoram; Ansaloni, Luca; Carlet, Jean; Brink, Adrian; Hardcastle, Timothy C.; Khanna, Ashish; Chicom-Mefire, Alain; Rodríguez-Baño, Jesús; Nathwani, Dilip; Mendelson, Marc; Watkins, Richard R.; Pulcini, Celine; Beović, Bojana; May, Addison K.; Itani, Kamal M. F.; Mazuski, John E.; Fry, Donald E.; Coccolini, Federico; Rasxa, Kemal; Montravers, Philippe; Eckmann, Christian; Abbo, Lilian M.; Abubakar, Salisu; Abu-Zidan, Fikri M.; Adesunkanmi, Abdulrashid Kayode; Al-Hasan, Majdi N.; Althani, Asma A.; Ticas, Jorge Eduardo Alvarenga; Ansari, Shamshul; Ansumana, Rashid; Da Silva, André Ricardo Araujo; Augustin, Goran; Bala, Miklosh; Balogh, Zsolt J.; Baraket, Oussema; Bassetti, Matteo; Bellanova, Giovanni; Beltran, Marcelo A.; Ben-Ishay, Ofir; Biffl, Walter L.; Boermeester, Marja A.; Brecher, Stephen M.; Bueno, Juan; Cainzos, Miguel A.; Cairns, Kelly; Camacho-Ortiz, Adrian; Ceresoli, Marco; Chandy, Sujith J.; Cherry-Bukowiec, Jill R.; Cirocchi, Roberto; Colak, Elif; Corcione, Antonio; Cornely, Oliver A.; Cortese, Francesco; Cui, Yunfeng; Curcio, Daniel; Damaskos, Dimitris; Dasx, Koray; Delibegovic, Samir; Demetrashvili, Zaza; De Simone, Belinda; De Souza, Hamilton Petry; De Waele, Jan; Dhingra, Sameer; Diaz, Jose J.; Di Carlo, Isidoro; Di Marzo, Francesco; Di Saverio, Salomone; Dogjani, Agron; Dorj, Gereltuya; Dortet, Laurent; Duane, Therese M.; Dupont, Herve; Egiev, Valery N.; Eid, Hani O.; Elmangory, Mutasim; El-Sayed Marei, Hany; Enani, Mushira Abdulaziz; Escandón-Vargas, Kevin; Faro, Mario P.; Ferrada, Paula; Foghetti, Domitilla; Foianini, Esteban; Fraga, Gustavo P.; Frattima, Sabrina; Gandhi, Chinmay; Gattuso, Gianni; Giamarellou, Eleni; Ghnnam, Wagih; Gkiokas, George; Girardis, Massimo; Goff, Debbie A.; Gomes, Carlos Augusto; Gomi, Harumi; Gronerth, Rosio Isabel Guerra; Guirao, Xavier; Guzman-Blanco, Manuel; Haque, Mainul; Hecker, Andreas; Hell, Markus; Herzog, Torsten; Hicks, Lauri; Kafka-Ritsch, Reinhold; Kao, Lillian S.; Kanj, Souha S.; Kaplan, Lewis J.; Kapoor, Garima; Karamarkovic, Aleksandar; Kashuk, Jeffry; Kenig, Jakub; Khamis, Faryal; Khokha, Vladimir; Kiguba, Ronald; Kirkpatrick, Andrew W.; Kørner, Hartwig; Koike, Kaoru; Kok, Kenneth Y. Y.; Kon, Kateryna; Kong, Victor; Inaba, Kenji; Ioannidis, Orestis; Isik, Arda; Iskandar, Katia; Labbate, Maurizio; Labricciosa, Francesco M.; Lagrou, Katrien; Lagunes, Leonel; Latifi, Rifat; Lasithiotakis, Kostas; Laxminarayan, Ramanan; Lee, Jae Gil; Leone, Marc; Leppäniemi, Ari; Li, Yousheng; Liang, Stephen Y.; Liau, Kui-Hin; Litvin, Andrey; Loho, Tonny; Lowman, Warren; Machain, Gustavo M.; Maier, Ronald V.; Manzano-Nunez, Ramiro; Marinis, Athanasios; Marmorale, Cristina; Martin-Loeches, Ignacio; Marwah, Sanjay; Maseda, Emilio; Mcfarlane, Michael; De Melo, Renato Bessa; Melotti, Maria Rita; Memish, Ziad; Mertz, Dominik; Mesina, Cristian; Menichetti, Francesco; Mishra, Shyam Kumar; Montori, Giulia; Moore, Ernest E.; Moore, Frederick A.; Naidoo, Noel; Napolitano, Lena; Negoi, Ionut; Nicolau, David P.; Nikolopoulos, Ioannis; Nord, Carl Erik; Ofori-Asenso, Richard; Olaoye, Iyiade; Omari, Abdelkarim H.; Ordoñez, Carlos A.; Ouadii, Mouaqit; Ouedraogo, Abdoul-Salam; Pagani, Leonardo; Paiva, José Artur; Parreira, Jose Gustavo; Pata, Francesco; Pereira, Jorge; Pereira, Nuno R.; Petrosillo, Nicola; Picetti, Edoardo; Pintar, Tadeja; Ponce-De-Leon, Alfredo; Popovski, Zagorka; Poulakou, Garyphallia; Preller, Jacobus; Guerrero, Adrián Puello; Pupelis, Guntars; Quiodettis, Martha; Rawson, Timothy M.; Reichert, Martin; Reinhart, Konrad; Rems, Miran; Rello, Jordi; Rizoli, Sandro; Roberts, Jason; Rubio-Perez, Ines; Ruppé, Etienne; Sakakushev, Boris; Sall, Ibrahima; Kafil, Hossein Samadi; Sanders, James; Sato, Norio; Sawyer, Robert G.; Scalea, Thomas; Scibé, Rodolfo; Scudeller, Luigia; Lohse, Helmut Segovia; Sganga, Gabriele; Shafiq, Nusrat; Shah, Jay N.; Spigaglia, Patrizia; Suroowan, Shanoo; Tsioutis, Constantinos; Sifri, Costi
abstract

This declaration, signed by an interdisciplinary task force of 234 experts from 83 different countries with different backgrounds, highlights the threat posed by antimicrobial resistance and the need for appropriate use of antibiotic agents and antifungal agents in hospitals worldwide especially focusing on surgical infections. As such, it is our intent to raise awareness among healthcare workers and improve antimicrobial prescribing. To facilitate its dissemination, the declaration was translated in different languages.

2017 - Effects of short-term hyperoxia on erythropoietin levels and microcirculation in critically Ill patients: a prospective observational pilot study [Articolo su rivista]
Donati, Abele; Damiani, Elisa; Zuccari, Samuele; Domizi, Roberta; Scorcella, Claudia; Girardis, Massimo; Giulietti, Alessia; Vignini, Arianna; Adrario, Erica; Romano, Rocco; Mazzanti, Laura; Pelaia, Paolo; Singer, Mervyn
abstract

BACKGROUND: The normobaric oxygen paradox states that a short exposure to normobaric hyperoxia followed by rapid return to normoxia creates a condition of 'relative hypoxia' which stimulates erythropoietin (EPO) production. Alterations in glutathione and reactive oxygen species (ROS) may be involved in this process. We tested the effects of short-term hyperoxia on EPO levels and the microcirculation in critically ill patients.METHODS: In this prospective, observational study, 20 hemodynamically stable, mechanically ventilated patients with inspired oxygen concentration (FiO2) â¤0.5 and PaO2/FiO2ââ¥â200Â mmHg underwent a 2-hour exposure to hyperoxia (FiO2 1.0). A further 20 patients acted as controls. Serum EPO was measured at baseline, 24Â h and 48Â h. Serum glutathione (antioxidant) and ROS levels were assessed at baseline (t0), after 2Â h of hyperoxia (t1) and 2Â h after returning to their baseline FiO2 (t2). The microvascular response to hyperoxia was assessed using sublingual sidestream dark field videomicroscopy and thenar near-infrared spectroscopy with a vascular occlusion test.RESULTS: EPO increased within 48Â h in patients exposed to hyperoxia from 16.1 [7.4-20.2] to 22.9 [14.1-37.2] IU/L (pâ=â0.022). Serum ROS transiently increased at t1, and glutathione increased at t2. Early reductions in microvascular density and perfusion were seen during hyperoxia (perfused small vessel density: 85% [95% confidence interval 79-90] of baseline). The response after 2Â h of hyperoxia exposure was heterogeneous. Microvascular perfusion/density normalized upon returning to baseline FiO2.CONCLUSIONS: A two-hour exposure to hyperoxia in critically ill patients was associated with a slight increase in EPO levels within 48Â h. Adequately controlled studies are needed to confirm the effect of short-term hyperoxia on erythropoiesis.TRIAL REGISTRATION: ClinicalTrials.gov ( www.clinicaltrials.gov ), NCT02481843 , registered 15th June 2015, retrospectively registered.

2017 - Impact of Pre-Analytical Time on the Recovery of Pathogens from Blood Cultures: Results from a Large Retrospective Survey [Articolo su rivista]
Venturelli, Claudia; Righi, Elena; Borsari, Lucia; Aggazzotti, Gabriella; Busani, Stefano; Mussini, Cristina; Rumpianesi, Fabio; Rossolini, Gian Maria; Girardis, Massimo
abstract

Prompt identification of bloodstream pathogens is essential for optimal management of patients. Significant changes in analytical methods have improved the turnaround time for laboratory diagnosis. Less attention has been paid to the time elapsing from blood collection to incubation and to its potential effect on recovery of pathogens. We evaluated the performance of blood cultures collected under typical hospital conditions in relation to the length of their pre-analytical time. We carried out a large retrospective study including 50,955 blood cultures collected, over a 30-month period, from 7,035 adult septic patients. Cultures were accepted by the laboratory only during opening time (Mon-Fri: 8am±4pm; Sat: 8am±2pm). Samples collected outside laboratory hours were stored at room temperature at clinical wards. All cultures were processed by automated culture systems. Day and time of blood collection and of culture incubation were known for all samples. A maximum pre-analytical interval of 2 hours is recommended by guidelines. When the laboratory was open, 57% of cultures were processed within 2 h. When the laboratory was closed, 4.9% of cultures were processed within 2 h (P<0.001). Samples collected when the laboratory was closed showed pre-analytical times significantly longer than those collected when laboratory was open (median time: 13 h and 1 h, respectively, P<0.001). The prevalence of positive cultures was significantly lower for samples collected when the laboratory was closed compared to open (11% vs 13%, P<0.001). The probability of a positive result decreased of 16% when the laboratory was closed (OR:0.84; 95%CI:0.80±0.89, P<0.001). Further, each hour elapsed from blood collection to incubation resulted associated with a decrease of 0.3% (OR:0.997; 95%CI:0.994±0.999, P<0.001) in the probability of a positive result. Delayed insertions of cultures into automated systems was associated with lower detection rates, with potentially important consequences for patients. In each hospital setting the logistic factors able to shorten pre-analytical time should be carefully investigated and specifically targeted.

2017 - Injury-induced immunosuppression: we are finally on the right track? [Articolo su rivista]
Busani, Stefano; Cossarizza, Andrea; Girardis, Massimo
abstract

Non abstract

2017 - JLB: a flexible and effective device in critical patients. Review of clinical cases [Articolo su rivista]
Brugioni, L.; Tazzioli, G.; Elisabetta, Bertellini; Girardis, M.; Nicolini, M.; Barchetti, M.; Pinelli, G.; Barozzi, M.; Schepis, F.; Bianchini, M.; Martella, P.; Borsatti, A.; de NIederhausern, F.; Mori, F.; Scarabottini, S.; Ravazzini, M.; Piani, Federica; Righetti, A.; Buda, Marina; Carella, Elena; Campanale, Sergio
abstract

JLB catheter (Deltamed Inc) is an alternative way to manage difficult venous access; it is placed under US-guidance in large bore veins, with an easy-sterile approach. Internal jugular vein (IJV) is the first choice for cannulation, followed by subclavian or deep upper-arm veins. The catheter is available in different lengths and gauges, it allows high flow rates and can be left in place up to 30 days. From June 2015 to March 2017, JLB has been positioned in 409 patients: in 354 as primary access in IJV, brachial or subclavian vein; in 55 cases JLB became an introducing line for the Seldinger guidewire and further CVC positioning. All clinical cases were reviewed selecting those with greater clinical relevance. We report 8 cases in which JLB resulted determinant for the patient treatment: a 16 years old obese girl born with perinatal distress, a 78 years old obese woman with hemorrhagic shock caused by gastrointestinal bleeding, a 40 years old man with severe hypokalemia, a 30 years old man with severe sepsis, a 40 years old man with Becker’s muscular dystrophy and severe sepsis, a 40 years old man with multiple myeloma who had to carry out cycles of chemotherapy, a 76 years old man with CMV pancolitis and myelofibrosis who needed parenteral nutrition, antiviral therapy and frequent blood and platelets transfusion. Moreover, it has been useful in elderly patients who needed to carry out palliative care for seniority or cancer lasting up to 30 days . In our experience the JLB catheter is safe, easy to place, quick and cost –effective. It is a valid solution either in unstable patients requiring an immediate access in emergency and stable patients with difficult venous access, in which invasive devices can be considered an over-treatment.

2017 - Management of intra-abdominal infections: Recommendations by the WSES 2016 consensus conference [Articolo su rivista]
Sartelli, Massimo; Catena, Fausto; Abu-Zidan, Fikri M.; Ansaloni, Luca; Biffl, Walter L.; Boermeester, Marja A.; Ceresoli, Marco; Chiara, Osvaldo; Coccolini, Federico; De Waele, Jan J.; Di Saverio, Salomone; Eckmann, Christian; Fraga, Gustavo P.; Giannella, Maddalena; Girardis, Massimo; Griffiths, Ewen A.; Kashuk, Jeffry; Kirkpatrick, Andrew W.; Khokha, Vladimir; Kluger, Yoram; Labricciosa, Francesco M.; Leppaniemi, Ari; Maier, Ronald V.; May, Addison K.; Malangoni, Mark; Martin-Loeches, Ignacio; Mazuski, John; Montravers, Philippe; Peitzman, Andrew; Pereira, Bruno M.; Reis, Tarcisio; Sakakushev, Boris; Sganga, Gabriele; Soreide, Kjetil; Sugrue, Michael; Ulrych, Jan; Vincent, Jean-Louis; Viale, Pierluigi; Moore, Ernest E.
abstract

This paper reports on the consensus conference on the management of intra-abdominal infections (IAIs) which was held on July 23, 2016, in Dublin, Ireland, as a part of the annual World Society of Emergency Surgery (WSES) meeting. This document covers all aspects of the management of IAIs. The Grading of Recommendations Assessment, Development and Evaluation recommendation is used, and this document represents the executive summary of the consensus conference findings.

2017 - Oxygen Supplementation Among Patients in the Intensive Care Unit Reply [Articolo su rivista]
Girardis, M; Busani, S
abstract

2017 - Randomized, multicenter trial of lateral Trendelenburg versus semirecumbent body position for the prevention of ventilator-associated pneumonia [Articolo su rivista]
Li Bassi, Gianluigi; Panigada, Mauro; Ranzani, Otavio T.; Zanella, Alberto; Berra, Lorenzo; Cressoni, Massimo; Parrini, Vieri; Kandil, Hassan; Salati, Giovanni; Selvaggi, Paola; Amatu, Alessandro; Sanz-Moncosi, Miquel; Biagioni, Emanuela; Tagliaferri, Fernanda; Furia, Mirella; Mercurio, Giovanna; Costa, Antonietta; Manca, Tullio; Lindau, Simone; Babel, Jaksa; Cavana, Marco; Chiurazzi, Chiara; Marti, Joan-Daniel; Consonni, Dario; Gattinoni, Luciano; Pesenti, Antonio; Wiener-Kronish, Janine; Bruschi, Cecilia; Ballotta, Andrea; Salsi, Pierpaolo; Livigni, Sergio; Iotti, Giorgio; Fernandez, Javier; Girardis, Massimo; Barbagallo, Maria; Moise, Gabriella; Antonelli, Massimo; Caspani, Maria Luisa; Vezzani, Antonella; Meybohm, Patrick; Gasparovic, Vladimir; Geat, Edoardo; Amato, Marcelo; Niederman, Michael; Kolobow, Theodor; Torres, Antoni
abstract

Purpose: The lateral Trendelenburg position (LTP) may hinder the primary pathophysiologic mechanism of ventilator-associated pneumonia (VAP). We investigated whether placing patients in the LTP would reduce the incidence of VAP in comparison with the semirecumbent position (SRP). Methods: This was a randomized, multicenter, controlled study in invasively ventilated critically ill patients. Two preplanned interim analyses were performed. Patients were randomized to be placed in the LTP or the SRP. The primary outcome, assessed by intention-to-treat analysis, was incidence of microbiologically confirmed VAP. Major secondary outcomes included mortality, duration of mechanical ventilation, and intensive care unit length of stay. Results: At the second interim analysis, the trial was stopped because of low incidence of VAP, lack of benefit in secondary outcomes, and occurrence of adverse events. A total of 194 patients in the LTP group and 201 in the SRP group were included in the final intention-to-treat analysis. The incidence of microbiologically confirmed VAP was 0.5% (1/194) and 4.0% (8/201) in LTP and SRP patients, respectively (relative risk 0.13, 95% CI 0.02â1.03, pÂ =Â 0.04). The 28-day mortality was 30.9% (60/194) and 26.4% (53/201) in LTP and SRP patients, respectively (relative risk 1.17, 95% CI 0.86â1.60, pÂ =Â 0.32). Likewise, no differences were found in other secondary outcomes. Six serious adverse events were described in LTP patients (pÂ =Â 0.01 vs. SRP). Conclusions: The LTP slightly decreased the incidence of microbiologically confirmed VAP. Nevertheless, given the early termination of the trial, the low incidence of VAP, and the adverse events associated with the LTP, the study failed to prove any significant benefit. Further clinical investigation is strongly warranted; however, at this time,Â the LTP cannot be recommended as a VAP preventive measure. ClinicalTrials.gov identifier: NCT01138540.

2017 - The Role of Adjunctive Therapies in Septic Shock by Gram Negative MDR/XDR Infections [Articolo su rivista]
Busani, Stefano; Roat, Erika; Serafini, Giulia; Mantovani, Elena; Biagioni, Emanuela; Girardis, Massimo
abstract

Patients with septic shock by multidrug resistant microorganisms (MDR) are a specific sepsis population with a high mortality risk. The exposure to an initial inappropriate empiric antibiotic therapy has been considered responsible for the increased mortality, although other factors such as immune-paralysis seem to play a pivotal role. Therefore, beyond conventional early antibiotic therapy and fluid resuscitation, this population may benefit from the use of alternative strategies aimed at supporting the immune system. In this review we present an overview of the relationship between MDR infections and immune response and focus on the rationale and the clinical data available on the possible adjunctive immunotherapies, including blood purification techniques and different pharmacological approaches.

2017 - The prognostic importance of chronic end-stage diseases in geriatric patients admitted to 163 Italian ICUs [Articolo su rivista]
Poole, D.; Finazzi, S.; Nattino, G.; Radrizzani, D.; Gristina, G.; Malacarne, P.; Livigni, S.; Bertolini, G.; Sorgato, C.; Mannoni, R.; Agnelli, V.; Chiani, C.; Lanza, G.; Venturini, E.; Gianni, M.; Olivieri, M. C.; Guerriero, B.; Della Mora, E.; Palmer, M.; Blasetti, A.; Coletta, R.; Covani Frigieri, F.; Guarducci, M. D.; Caracciolo, A.; Lain, G.; Bernard, M.; DE Blasio, E.; Zanni, V.; Marchesi, G.; Madeira, S. M.; Spagarino, E.; Potalivo, A.; Mengoli, F.; Parrini, V.; Sagliaschi, U.; Prandini, A.; Rosano, A.; Natalini, G.; Piccioni, G.; Schiavuzzi, M.; Bronzini, N.; Piva, S.; Besozzi, A.; Napoleone, A.; Patrignani, L.; Pisu, M.; Mancosu, S.; Chiarello, M.; Pastorini, S.; Bassi, G.; Negro, G.; Orsini, I.; Marifoglou, D.; Pota, V.; Pegoraro, M.; Sucre, M. J.; DI Masi, P.; Castiglione, G.; Morello, G.; Garofalo, G.; Caroleo, S.; Visconti, M. G.; Gamberini, E.; Mastroianni, A.; Liccardi, M. M.; Anelati, D.; Martinelli, S.; Bonato, A.; Adorni, A.; Colombo, D.; Dal Cero, P.; Crema, L.; Petrucci, N.; Beck, E.; Alleva, S.; Giuntini, R.; DA Re, D.; Casalini, P.; Fabi, M. C.; Galeotti, E.; Bagalini, G.; Bellonzi, A.; Zoppellari, R.; Lamborghini, S.; Pera, L.; Doni, L.; Bonizzoli, M.; Librenti, M.; Barattini, M.; Mangani, V.; Terzitta, M.; Guagliardi, C.; Bruzzone, C.; Arditi, E.; Cerana, M.; Tavola, M.; Falini, S.; Vespignani, M. G.; Salvi, G.; Ramello, P. L.; Molesi, A.; Ceradelli, M.; Buonanno, R.; Righini, E.; DI Cocco, A.; DI Martino, R.; Cinque, E.; Bonfiglio, M.; Ciceri, R.; Colombo, L.; Nardini, M.; Rossi, G.; Boccalatte-Rosa, D. L.; Babini, M.; Zompanti, V.; Negri, G.; Antonini, B.; Baratta, A.; Zuccaro, F.; Rossi, M.; Pedeferri, M.; Bellin, M.; Sicignano, A.; Pezzi, A.; Leggieri, C.; Fontana, G.; Faraldi, L.; Cigada, M. G.; Magenta, P.; Colombo, R.; Colombo, S.; Gonzi, S.; Pizzali, M.; Girardis, M.; Piccinini, P.; Bignone, P.; Padovan, L.; Bianchin, A.; Caria, F. C.; Randellini, R.; Roticiani, V.; Grassi, M.; Belluomo Anello, C.; Decristofaro, M.; Postiglione, M.; Giacomello, S.; Olivieri, C.; Vaccari, C.; Dal Ferro, M.; Messina, M.; Belgiorno, N.; Odetto, L.; Pasetti, G. S.; Balicco, B.; Pizzaballa, M. L.; Muraro, L.; Pignataro, A.; Guadagna, A.; Fabbri, P. G.; Tetamo, R.; Bottazzi, A.; Mediani, T. S.; Gorietti, A.; Breschi, C.; Ciani, A.; Segalini, P.; Codeluppi, V.; Berruto, F.; Pastorelli, M.; Comite, C.; Pelati, E.; Bertolini, R.; Lefons, U.; DI Pasquale, D. A.; Mannolini, G.; Vlassich, F.; Becarelli, S.; Garelli, A.; Salsi, P.; Rossi, S.; Facondini, F.; Alampi, D.; Cingolani, E.; Molino, F. M.; Nardi, G.; Casula, M.; DE Blasi, R. A.; Vulcano, G. A.; Azzolini, M.; Bernasconi, M. O.; Bellato, V.; Calicchio, G.; Righetti, F.; Turati, M.; Dei Poli, M.; Zaro, G.; Brizio, E.; Coaloa, M.; Falzetti, G.; Mamprin, F.; Liverani, C. M.; Clementi, S.; Bonucci, P.; Varesio, V.; Pannacci, R.; Fiore, G.; Gallo, M.; Torta, M.; Selvaggi, P.; Bert, P. P.; Segala, V.; Pettazzi, G.; Bensi, M.; Bocchi, A.; Cima, M.; Morbelli, M.; Peta, M.; Colombo, R.; DI Stella, R.; Maggiolo, C.; Lembo, R.; Pero, A.; Marafon, S.; Carnevale, L.; Vanzino, R.; Vecchiarelli, P.; Marino, G.
abstract

BACKGROUND: The number of elderly patients undergoing major surgical interventions and then needing admission to intensive care unit (ICU) grows steadily. We investigated this issue in a cohort of 232,278 patients admitted in five years (2011-2015) to 163 Italian general ICUs. METHODS: Surgical patients older than 75 registered in the GiViTI MargheritaPROSAFE project were analyzed. The impact on hospital mortality of important chronic conditions (severe COPD, NYHA class IV, dementia, end-stage renal disease, cirrhosis with portal hypertension) was investigated with two prognostic models developed yearly on patients staying in the ICU less or more than 24 hours. RESULTS: 44,551 elderly patients (19.2%) underwent emergency (47.3%) or elective surgery (52.7%). At least one severe comorbidity was present in 14.6% of them, yielding a higher hospital mortality (32.4%, vs. 21.1% without severe comorbidity). In the models for patients staying in the ICU 24 hours or more, cirrhosis, NYHA class IV, and severe COPD were constant independent predictors of death (adjusted odds ratios [ORs] range 1.67-1.97, 1.54-1.91, and 1.34-1.50, respectively), while dementia was statistically significant in four out of five models (adjusted ORs 1.23-1.28). End-stage renal disease, instead, never resulted to be an independent prognostic factor. For patients staying in the ICU less than 24 hours, chronic comorbidities were only occasionally independent predictors of death. CONCLUSIONS: Our study confirms that elderly surgical patients represent a relevant part of all ICUs admissions. About one of seven bear at least one severe chronic comorbidity, that, excluding end-stage renal disease, are all strong independent predictors of hospital death.

2016 - A critical appraisal of the quality of analgosedation guidelines in critically ill patients [Articolo su rivista]
Girardis, Massimo; Cantaroni, Cosetta; Savoia, Gennaro; Melotti, Rita; Conti, Giorgio
abstract

The management of analgesia and sedation in critically ill patients is still a challenge due to the shortage of evidence-based treatments. The main objectives of the present study were to critically evaluate the quality of current clinical practice guidelines (CPGL) published on this matter and to identify the contrasting positions and unsolved questions.

2016 - Dexmedetomidine for agitated delirium in intensive care unit intubated patients [Articolo su rivista]
Busani, Stefano; Cantaroni, Cosetta; Girardis, Massimo
abstract

No abstract

2016 - Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial [Articolo su rivista]
Girardis, Massimo; Busani, Stefano; Damiani, Elisa; Donati, Abele; Rinaldi, Laura; Marudi, Andrea; Morelli, Andrea; Antonelli, Massimo; Singer, Mervyn
abstract

Despite suggestions of potential harm from unnecessary oxygen therapy, critically ill patients spend substantial periods in a hyperoxemic state. A strategy of controlled arterial oxygenation is thus rational but has not been validated in clinical practice.

2016 - Evaluation of serum (1 → 3)-β-D-glucan clinical performance: kinetic assessment, comparison with galactomannan and evaluation of confounding factors [Articolo su rivista]
Pini, Pietro; Bettua, C; Orsi, Carlotta Francesca; Venturelli, C; Forghieri, F; Bigliardi, S; Faglioni, L; Luppi, Fabrizio; Serio, L; Codeluppi, M; Luppi, Mario; Mussini, Cristina; Girardis, Massimo; Blasi, Elisabetta
abstract

Purpose We investigated the clinical performance of (1 → 3)-β-d-glucan (BG), as an early marker of invasive fungal infections (IFI), in different clinical settings. Methods BG serum levels were assessed by Fungitell (Associates of Cape Cod, Inc), in parallel with galactomannan (GM) when requested by clinicians. By a prospective monocentric study, 270 episodes at risk or with suspect of IFI were enrolled, namely 58 proven-probable invasive aspergillosis (IA), 27 proven invasive candidiasis (IC), 11 possible IC, 16 P.jirovecii pneumonia (PJP), 4 episodes of other IFI and 154 non-IFI controls. Results We found that (a) the BG overall sensitivity, specificity, positive predictive value and negative predictive value (NPV) were 87.9, 80.5, 76.7 and 89.9 %, respectively; (b) the highest sensitivity was found in the IC groups, followed by PJP, IA and other IFI groups; (c) an association was observed between BG kinetics and patients outcome; (d) in the IA episodes, the combination of BG or GM vs GM alone increased sensitivity from 60.0 to 83.3 % in the haematological patients; (e) false-positive BG results were related to Gram-negative infections or infusion of polyclonal IgM-enriched immunoglobulins, where high levels of BG were indeed detected. Conclusion Besides strengthening its overall good clinical performance, we provide evidence that serum BG correlates with clinical outcome and that, once used in combination with GM, BG allows to enhance IFI diagnosis rate. The high sensitivity and NPV, observed in the Intensive Care Unit setting, open to BG validation as a marker for assessment of antifungal treatment.

2016 - Intravenous immunoglobulin in septic shock: review of the mechanisms of action and meta-analysis of the clinical effectiveness [Articolo su rivista]
Busani, Stefano; Damiani, Elisa; Cavazzuti, Ilaria; Donati, Abele; Girardis, Massimo
abstract

Sepsis is characterized by a complex immune response. In this study we aimed to provide a review of the mechanisms of action of immunoglobulin (Ig) related to sepsis and an updated meta-analysis of the clinical effectiveness of the Ig use in septic patients.

2015 - A challenging case of pregnancy with placenta accreta and very rare irregular antibodies versus Cromer blood group system: a case report [Articolo su rivista]
Busani, Stefano; VOLPI GHIRARDINI, Annamaria; Petrella, Elisabetta; Neri, Isabella; Casari, Federico; Venturelli, Donatella; De Santis, Mario; Montagnani, Giuliano; Facchinetti, Fabio; Girardis, Massimo
abstract

ntroduction: This report describes the challenges of treating a pregnant woman who had a rare case of critical placenta accreta with concurrent Cromer system anti-Tc(a) and anti-Kidd A alloantibodies. No previous case of such alloimmunization in a patient with placenta accreta has been reported. Case presentation: A 28-year-old African woman with anti-Cromer Tc(a) antibodies, anti-Kidd A antibodies and placenta accreta was admitted to the obstetric emergency department at our university hospital with persistent vaginal bleeding. Her rare Cromer blood group system antibodies had been diagnosed 1 month earlier; no compatible blood had been found despite a worldwide search. We performed a cesarean section after placement of Fogarty balloons in her uterine arteries with preoperative endovascular interventional radiology. Other therapeutic interventions included preoperative iron administration to raise hemoglobin and the scheduled predeposit of autologous blood. Intraoperative therapeutic management was aimed at preventing coagulopathy and massive bleeding. With the use of alternative medical techniques determined during perioperative planning, her intraoperative blood loss was only 1000mL, despite the placenta accreta. She was discharged from the hospital 4 days after cesarean section. Conclusions: To the best of our knowledge, this is the first report of an alloimmunized patient with two different alloantibodies and concurrent high risk of bleeding because of placenta accreta. The close collaboration among obstetricians, anesthesiologists, interventional radiologists, blood bank pathologists and intensive care doctors prevented serious consequences in this patient. The exceptional feature of this case is the patient's double risk: the placenta accreta and the inability to transfuse compatible blood. These two extreme situations challenged the multidisciplinary medical team.

2015 - A one-year prospective study of refractory status epilepticus in Modena, Italy [Articolo su rivista]
Giovannini, Giada; Monti, Giulia; Polisi, Michela M; Mirandola, Laura; Marudi, Andrea; Pinelli, Giovanni; Valzania, Franco; Girardis, Massimo; Nichelli, Paolo Frigio; Meletti, Stefano
abstract

Refractory status epilepticus (RSE) is a particular critical condition characterized by seizures that continue despite the use of first- and second-line therapies and by high mortality. To date, only one prospective study investigated clinical features and prognostic factors in RSE. In this study, we performed a one-year prospective survey to identify clinical features, outcomes, and variables associated with the development of RSE in the adolescent and adult population of Modena, northern Italy. We observed 83 episodes of SE in 83 patients. In 31% of the cases, third-line therapy (anesthetic drug) was needed. Among this group, 14% resolved and were classified as RSE, while, in 17%, seizures recurred at withdrawal of anesthetics and were classified as super-RSE. The development of RSE/super-RSE was associated with a stuporous/comatose state at presentation and with the absence of a previous history of epilepsy. Refractory status epilepticus/super-refractory status epilepticus showed a worse outcome compared with responsive SE: 54% versus 21% for 30-day mortality; 19% versus 56% for a return to baseline condition. This prospective study confirms stupor/coma at onset as a relevant clinical factor associated with SE refractoriness. We observed a rate of RSE comparable with previous reports, with high mortality and morbidity. Mortality in the observed RSE was higher than in previous studies; this result is probably related to the low rate of a previous epilepsy history in our population that reflects a high incidence of acute symptomatic etiologies, especially the inclusion of patients with postanoxic SE who have a bad prognosis per se. This article is part of a Special Issue entitled "Status Epilepticus".

2015 - Detection of Pneumocystis jirovecii and Aspergillus spp. DNa in bronchoalveolar lavage fluids by commercial real-time PCr assays: comparison with conventional diagnostic tests [Articolo su rivista]
Orsi, Carlotta Francesca; Bettua, Clotilde; Pini, Pietro; Venturelli, Claudia; La Regina, Annunziata; Morace, Giulia; Luppi, Mario; Forghieri, Fabio; Bigliardi, Sara; Luppi, Fabrizio; Codeluppi, Mauro; Girardis, Massimo; Blasi, Elisabetta
abstract

The present study employed two commercial real-time PCR kits, MycAssay™ Pneumocystis (PJ-PCR) and MycAssay™ Aspergillus (ASP-PCR), for the search of fungal DNA on 44 bronchoalveolar lavage (BAL) fluids from patients at risk of invasive fungal disease. Operationally, on the basis of clinical diagnosis and according to the European Organization for Research and Treatment Cancer/Mycoses Study Group (EORTC/MSG) criteria, patients were clustered in 3 groups: a P. jirovecii pneumonia (PCP) group, an invasive aspergillosis (IA) group and a control (CTRL) group, consisting of 8, 10 and 24 patients, respectively. The results were compared to those obtained with conventional diagnostic assays, including BAL culture, galactomannan-ELISA (GM) and immunofluorescence (IF). The PJ-PCR assay returned a sensitivity and specificity of 100% and 94.4%, respectively. The ASP-PCR assay showed a sensitivity and specificity of 80% and 97.1%. When compared to the culture assay, the ASP-PCR showed enhanced sensitivity, and a good level of agreement (kappa = 0.63) was observed between ASP-PCR and GM assays. Overall, our data emphasize the diagnostic usefulness of the two commercial real-time PCR assays, especially in high-risk patients where timing is critical and a low fungal burden may hamper correct and prompt diagnosis by conventional tests.

2015 - Effect of performance improvement programs on compliance with sepsis bundles and mortality: A systematic review and meta-analysis of observational studies [Articolo su rivista]
Damiani, Elisa; Donati, Abele; Serafini, Giulia; Rinaldi, Laura; Adrario, Erica; Pelaia, Paolo; Busani, Stefano; Girardis, Massimo
abstract

Background: Several reports suggest that implementation of the Surviving Sepsis Campaign (SSC) guidelines is associated with mortality reduction in sepsis. However, adherence to the guideline-based resuscitation and management sepsis bundles is still poor. Objective: To perform a systematic review of studies evaluating the impact of performance improvement programs on compliance with Surviving Sepsis Campaign (SSC) guideline-based bundles and/or mortality. Data Sources: Medline (PubMed), Scopus and Intercollegiate Studies Institute Web of Knowledge databases from 2004 (first publication of the SSC guidelines) to October 2014. Study Selection: Studies on adult patients with sepsis, severe sepsis or septic shock that evaluated changes in compliance to individual/combined bundle targets and/or mortality following the implementation of performance improvement programs. Interventions may consist of educational programs, process changes or both. Data Extraction: Data from the included studies were extracted independently by two authors. Unadjusted binary data were collected in order to calculate odds ratios (OR) for compliance to individual/combined bundle targets. Adjusted (if available) or unadjusted data of mortality were collected. Random-effects models were used for the data synthesis. Results: Fifty observational studies were selected. Despite high inconsistency across studies, performance improvement programs were associated with increased compliance with the complete 6-hour bundle (OR = 4.12 [95% confidence interval 2.95-5.76], I2 = 87.72%, k = 25, N = 50,081) and the complete 24-hour bundle (OR = 2.57 [1.74-3.77], I2 = 85.22%, k = 11, N = 45,846) and with a reduction in mortality (OR = 0.66 [0.61-0.72], I2 = 87.93%, k = 48, N = 434,447). Funnel plots showed asymmetry. Conclusions: Performance improvement programs are associated with increased adherence to resuscitation and management sepsis bundles and with reduced mortality in patients with sepsis, severe sepsis or septic shock.

2015 - Immune System Dysfunction and Multidrug-resistant Bacteria in Critically Ill Patients: Inflammasones and Future Perspectives [Capitolo/Saggio]
Girardis, Massimo; Busani, Stefano; DE BIASI, Sara
abstract

Despite the significant improvements in knowledge, technology and pharmacology obtained in the last few decades, we are not yet ready to provide individualized therapy for critically ill patients with sepsis. Clinicians tend to manage patients according to evidence-based guidelines that are derived from large randomized trials in which single patient characteristics and types of infection are rarely considered. But, as is well known, different types of infection in patients with different characteristics may cause different consequences and may need different treatments. One of the aspects that remains rather unexplored in clinical practice is the immune response of the patient in the intensive care unit (ICU). On a day-to-day basis in the ICU we are dealing with patients who have a higher susceptibility to nosocomial infections with multidrug-resistant (MDR) bacteria without really understanding the cause. Antibiotic therapy alone in these patients is frequently insufficient, so it is necessary to study an alternative way to make sure that the immune response can actively participate in the elimination of the pathogens [1]. Infection with MDR bacteria frequently occurs in debilitated patients, such as those with shock, surgical complications, prolonged antibiotic therapies and immunosuppressive therapy [2]. The association between MDR infection and immunoparalysis is likely due to a disorder of innate and adaptive immune responses in critically ill patients.

2015 - The Surviving Sepsis Campaign bundles and outcome: results from the International Multicentre Prevalence Study on Sepsis (the IMPreSS study) [Articolo su rivista]
Rhodes, Andrew; Phillips, Gary; Beale, Richard; Cecconi, Maurizio; Chiche, Jean Daniel; De Backer, Daniel; Divatia, Jigeeshu; Du, Bin; Evans, Laura; Ferrer, Ricard; Girardis, Massimo; Koulenti, Despoina; Machado, Flavia; Simpson, Steven Q; Tan, Cheng Cheng; Wittebole, Xavier; Levy, Mitchell
abstract

Despite evidence demonstrating the value of performance initiatives, marked differences remain between hospitals in the delivery of care for patients with sepsis. The aims of this study were to improve our understanding of how compliance with the 3-h and 6-h Surviving Sepsis Campaign (SSC) bundles are used in different geographic areas, and how this relates to outcome.

2014 - Albumin replacement in patients with severe sepsis or septic shock [Articolo su rivista]
Pietro, Caironi; Gianni, Tognoni; Serge, Masson; Roberto, Fumagalli; Antonio, Pesenti; Marilena, Romero; Caterina, Fanizza; M., Stat; Luisa, Caspani; Stefano, Faenza; Giacomo, Grasselli; Gaetano, Iapichino; Massimo, Antonelli; Vieri, Parrini; Gilberto, Fiore; Roberto, Latini; Luciano, Gattinoni; for the ALBIOS Study, Investigators; Girardis, Massimo
abstract

Although previous studies have suggested the potential advantages of albumin administration in patients with severe sepsis, its efficacy has not been fully established.

2014 - Arterial hyperoxia and mortality in critically ill patients: a systematic review and meta-analysis [Articolo su rivista]
Damiani, Elisa; Adrario, Erica; Girardis, Massimo; Romano, Rocco; Pelaia, Paolo; Singer, Mervyn; Donati, Abele
abstract

IntroductionThe safety of arterial hyperoxia is under increasing scrutiny. We performed a systematic review of the literature to determine whether any association exists between arterial hyperoxia and mortality in critically ill patient subsets.MethodsMedline, Thomson Reuters Web of Science and Scopus databases were searched from inception to June 2014. Observational or interventional studies evaluating the relationship between hyperoxia (defined as a supranormal arterial O2 tension) and mortality in adult intensive care unit (ICU) patients were included. Studies primarily involving patients with exacerbations of chronic pulmonary disease, acute lung injury and perioperative administration were excluded. Adjusted odds ratio (OR) of patients exposed versus those non-exposed to hyperoxia were extracted, if available. Alternatively, unadjusted outcome data were recorded. Data on patients, study characteristics and the criteria used for defining hyperoxia exposure were also extracted. Random-effects models were used for quantitative synthesis of the data, with a primary outcome of hospital mortality.ResultsIn total 17 studies (16 observational, 1 prospective before-after) were identified in different patient categories: mechanically ventilated ICU (number of studies (k)¿=¿4, number of participants (n)¿=¿189,143), post-cardiac arrest (k¿=¿6, n¿=¿19,144), stroke (k¿=¿2, n¿=¿5,537), and traumatic brain injury (k¿=¿5, n¿=¿7,488). Different criteria were used to define hyperoxia in terms of PaO2 value (first, highest, worst, mean), time of assessment and pre-determined cut-offs. Data from studies on ICU patients were not pooled because of extreme heterogeneity (Inconsistency (I2) 96.73%). Hyperoxia was associated with increased mortality in post-cardiac arrest patients (OR¿=¿1.42 (1.04 to 1.92) I2 67.73%) stroke (OR¿=¿1.23 (1.06 to 1.43) I2 0%) and traumatic brain injury (OR¿=¿1.41 (1.03 to 1.94) I2 64.54%). However, these results are limited by significant heterogeneity between studies.ConclusionsHyperoxia may be associated with increased mortality in patients with stroke, traumatic brain injury and those resuscitated from cardiac arrest. However, these results are limited by the high heterogeneity of the included studies.

2014 - Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit [Articolo su rivista]
Vincent, Jl; Marshall, Jc; Namendys Silva, Sa; François, B; Martin Loeches, I; Lipman, J; Reinhart, K; Antonelli, M; Pickkers, P; Njimi, H; Jimenez, E; Sakr, Y; Study Investigators, ICON i. n. v. e. s. t. i. g. a. t. o. r. s.; Girardis, Massimo
abstract

Global epidemiological data regarding outcomes for patients in intensive care units (ICUs) are scarce, but are important in understanding the worldwide burden of critical illness. We, therefore, did an international audit of ICU patients worldwide and assessed variations between hospitals and countries in terms of ICU mortality.

2014 - Checklist for anesthesiological process: analysis of risks [Articolo su rivista]
Ghirardini, A. M; Guerra, Emmanuele; Serio, L; Girardis, Massimo; Pasetto, Alberto; Busani, Stefano
abstract

Several methods are reported in the literature to analyze medically undesirable events during hospital care. Each method has several limitations, so no one has been defined as the standard tool to be able to detect failure during a medical process. The aim of this study was to compare an anesthesiological perioperative checklist with traditional Regional Incident Reporting (RIR) form in detecting and describing failures.

2014 - Clinical performance of a commercial real-time PCR assay for Aspergillus DNA detection in serum samples from high-risk patients: comparison with a galactomannan enzyme immunoassay [Articolo su rivista]
Pini, Pietro; Orsi, Carlotta Francesca; Luppi, Fabrizio; Girardis, Massimo; Blasi, Elisabetta
abstract

We investigated the clinical performance of a polymerase chain reaction (PCR)-based commercial platform, the Myconostica MycAssay™ Aspergillus (MAP), for fungal DNA detection in the serum of patients at risk of invasive aspergillosis (IA). Sixty-four hospitalized patients were prospectively enrolled and a total of 71 different episodes were investigated (30 episodes were clinically/microbiologically classified as IA and 41 as control episodes). When MAP was compared to the galactomannan (GM) assay, no significant differences were found in terms of sensitivity (46.7 % vs. 50.0 %), specificity (97.6 % vs. 95.1 %), positive predictive value (PPV) (93.3 % vs. 88.2 %), and negative predictive value (NPV) (71.4 % vs. 72.2 %). The corresponding areas under the curve (AUC) of the receiver operating characteristic (ROC) curves were also superimposable. Overall, because of the good agreement between the two assays and considering the high specificity and PPV of the MAP, we suggest the use of this PCR-based platform as a second-level examination for the evaluation of clinically undefined cases where culture or GM have provided positive results.

2014 - Early therapy with IgM-enriched polyclonal immunoglobulin in patients with septic shock [Articolo su rivista]
Cavazzuti, Ilaria; Serafini, Giulia; Busani, Stefano; Rinaldi, Laura; Biagioni, Emanuela; Buoncristiano, Marta; Girardis, Massimo
abstract

To determine whether there was an association between adjunctive therapy with IgM-enriched immunoglobulin (IgM) and the 30-day mortality rate in patients with septic shock.

2014 - Error in An Italian consensus for invasive candidiasis management (ITALIC) [Articolo su rivista]
Scudeller, L; Viscoli, C.; Menichetti, F.; Del Bono, V.; Cristini, F.; Tascini, C.; Bassetti, M.; Viale, P.; Italic Group: Chiara, Adembri; Massimo, Antonelli; Giacomo, Borgonovo; Francesco, Bruno; Ercole, Concia; Francesco Giuseppe De, Rosa; Vincenzo, Emmi; Silvano, Esposito; Roberto, Fumagalli; Girardis, Massimo
abstract

Introduction: Invasive candidiasis (IC) has primarily been studied in intensive care unit (ICU) patients, although, in reality, a vast majority of these infections occur outside of the ICU. The recent publication of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines also deal with the non-ICU population, but many uncertainties remain on the management of IC, particularly in non-critically ill patients. Methods: The Italian Society of Antimicrobial Therapy, Società Italiana di Terapia Antimicrobica (SITA), produced practical, hospital-wide recommendations on the management of Candida infection in non-immunocompromised patients in the hospital ward. Results and discussion: Our focus is on patient stratification in terms of risk factors for IC and of clinical severity, emphasising a high index of suspicion to ensure early diagnosis, early treatment and de-escalation when a patient is clinically stable, in order to optimise resource allocation. © 2013 Springer-Verlag.

2014 - Indagini multidirezionali nella diagnosi di infezione fungina invasiva: ricerca di beta-glucano e rilevazione di profili anticorpali specifici [Abstract in Atti di Convegno]
Pini, P; Ardizzoni, A; Orsi, Cf; Bettua, C; Venturelli, C; Girardis, M; Luppi, M; Codeluppi, M; Peppoloni, S; Posteraro, B; Sanguinetti, M; Saez-Roson, A; Moragues, Md; Blasi, E
abstract

2014 - Loss of self-regulation in interstitial fluid dynamics of septic patients, and oedema development patterns [Capitolo/Saggio]
Biagioni, Emanuela; Girardis, Massimo
abstract

Attempts to effectively intervene on sepsis mechanisms by correcting the dysfunction and the pathological activation of microcirculation-and, therefore, of the endothelium-represent the most fascinating challenge for physicians and researchers dealing with these patients. However, to date there is no evidence that specific therapeutic strategies aimed at controlling micro-vascular endothelium may, in patients suffering septic shock, provide clinical benefits and increased survival probability. As for oedema and sepsis, the news is even worse: We know that the formation of oedema is a constant in patients with sepsis, we know that the development of oedema can cause the deterioration of organ functioning due to deficient perfusion and cellular oxygenation and we know that, unfortunately, today there is no effective drug nor winning strategy.

2014 - Oxygen saturation in central venous blood: does the site of measurement matter? [Articolo su rivista]
Girardis, Massimo; Biagioni, Emanuela
abstract

2014 - Trends in ventilator-associated pneumonia: Impact of a ventilator care bundle in an Italian tertiary care hospital intensive care unit [Articolo su rivista]
Righi, Elena; Aggazzotti, Gabriella; Elena, Ferrari; Chiara, Giovanardi; Stefano, Busani; Laura, Rinaldi; Girardis, Massimo
abstract

Background: The impact on ventilator-associated pneumonia (VAP) occurrence of a multifaceted program, including progressive strategies for VAP prevention, implemented in an Italian intensive care unit (ICU) is reported. Methods: All adults admitted to the ICU in 2004-2010 with a length of stay 72 hours and mechanical ventilation time 48 hours were included in the study. Demographics, clinical information, and data on VAP were extracted from the ICU-acquired infection surveillance dataset. A standardized bundle for VAP prevention was implemented in 2004. In 2008, selective digestive tract decontamination (SDD) was added to the protocol. Changes in VAP incidence were evaluated. Results: There were 1,372 subjects included in the study. Overall, 156 (11.4%) developed VAP. In the second part of the study VAP incidence decreased from 15.9% to 6.7% (P <.001). Reductions both in early-onset VAP (6.6% to 1.9%; P < .001) and late-onset VAP (9.3% to 4.7%; P < .001) incidence were observed. Multivariate analysis showed a significant reduction in the risk of developing VAP from multidrug resistant pathogens in the bundle plus SDD period as well (odds ratio, .54; 95% confidence interval, .31-.91). Conclusion: The implementation of a standardized approach to patient care, including a number of key reduction interventions, was associated with a significant reduction in the risk of developing VAP.

2014 - Wernicke's encephalopathy in a malnourished surgical patient: a difficult diagnosis [Articolo su rivista]
Busani, Stefano; Bonvecchio, Cinzia; Gaspari, Arianna; Malagoli, Marcella; Todeschini, Alessandra; Cautero, Nicola; Girardis, Massimo
abstract

Wernicke's encephalopathy is an acute neurological disorder resulting from thiamine deficiency mainly related to alcohol abuse. Severe thiamine deficiency is an emerging problem in non-alcoholic patients and it may develop in postoperative surgical patients with risk factors.

2014 - World Society of Emergency Surgery (WSES) guidelines for management of skin and soft tissue infections [Articolo su rivista]
Sartelli, Massimo; Malangoni, Mark A; May, Addison K; Viale, Pierluigi; Kao, Lillian S; Catena, Fausto; Ansaloni, Luca; Moore, Ernest E; Moore, Fred A; Peitzman, Andrew B; Coimbra, Raul; Leppaniemi, Ari; Kluger, Yoram; Biffl, Walter; Koike, Kaoru; Girardis, Massimo; Ordonez, Carlos A; Tavola, Mario; Cainzos, Miguel; Di Saverio, Salomone; Fraga, Gustavo P; Gerych, Igor; Kelly, Michael D; Taviloglu, Korhan; Wani, Imtiaz; Marwah, Sanjay; Bala, Miklosh; Ghnnam, Wagih; Shaikh, Nissar; Chiara, Osvaldo; Faro, Mario Paulo; Pereira, Gerson Alves; Gomes, Carlos Augusto; Coccolini, Federico; Tranà, Cristian; Corbella, Davide; Brambillasca, Pietro; Cui, Yunfeng; Segovia Lohse, Helmut A; Khokha, Vladimir; Kok, Kenneth Yy; Hong, Suk Kyung; Yuan, Kuo Ching
abstract

Skin and soft tissue infections (SSTIs) encompass a variety of pathological conditions ranging from simple superficial infections to severe necrotizing soft tissue infections. Necrotizing soft tissue infections (NSTIs) are potentially life-threatening infections of any layer of the soft tissue compartment associated with widespread necrosis and systemic toxicity. Successful management of NSTIs involves prompt recognition, timely surgical debridement or drainage, resuscitation and appropriate antibiotic therapy. A worldwide international panel of experts developed evidence-based guidelines for management of soft tissue infections. The multifaceted nature of these infections has led to a collaboration among surgeons, intensive care and infectious diseases specialists, who have shared these guidelines, implementing clinical practice recommendations.

2013 - A Janus role for MerTK in the outcome of septic shock [Articolo su rivista]
Girardis, Massimo; Cossarizza, Andrea
abstract

2013 - Aggressive versus conservative initiation of antibiotics [Articolo su rivista]
Girardis, Massimo; Bassetti, Matteo; Lewis, Russel E; Viale, Pierluigi
abstract

2013 - Characteristics and outcome predictors of patients involved in an outbreak of Burkholderia cepacia complex [Articolo su rivista]
Righi, Elena; Girardis, Massimo; P., Marchegiano; C., Venturelli; S., Tagliazucchi; M., Pecorari; Borsari, Lucia; Carluccio, Eugenia; M., Codeluppi; Mussini, Cristina; Aggazzotti, Gabriella
abstract

A Burkholderia cepacia complex outbreak occurred among ventilated non-cystic fibrosis patients in an intensive care unit (ICU) in Italy: 33 colonized and 13 infected patients were included in a retrospective study aimed at investigating factors related to clinical infection and mortality. Demographic/clinical conditions and mortality did not vary significantly between colonized and infected patients, both groups showing high mortality rates compared with the overall ICU population and similar to that observed in patients with other infections. In multivariate regression analysis, disease severity (defined by the Simplified Acute Physiology Score II) and age were the only independent predictors of early mortality (odds ratio: 1.12; 95% confidence interval: 1.02-1.26; and 1.07; 1.01-1.15, respectively).

2013 - Characterization of Specific Immune Responses to Different Aspergillus Antigens during the Course of Invasive Aspergillosis in Hematologic Patients [Articolo su rivista]
Potenza, Leonardo; Vallerini, Daniela; Barozzi, Patrizia; Riva, Giovanni; Forghieri, Fabio; Beauvais, Anne; Beau, Remi; Candoni, Anna; Maertens, Johan; Rossi, Giulio; Morselli, Monica; Zanetti, Eleonora; Quadrelli, Chiara; Codeluppi, Mauro; Guaraldi, Giovanni; Pagano, Livio; Caira, Morena; DEL GIOVANE, Cinzia; Maccaferri, Monica; Stefani, Alessandro; Morandi, Uliano; Tazzioli, Giovanni; Girardis, Massimo; Delia, Mario; Specchia, Giorgina; Longo, Giuseppe; Marasca, Roberto; Narni, Franco; Merli, Francesco; Imovilli, Annalisa; Apolone, Giovanni; Carvalho, Agostinho; Comoli, Patrizia; Romani, Luigina; Latgè, Jean Paul; Luppi, Mario
abstract

Several studies in mouse model of invasive aspergillosis (IA) and in healthy donors have shown that different Aspergillus antigens may stimulate different adaptive immune responses. However, the occurrence of Aspergillus-specific T cells have not yet been reported in patients with the disease. In patients with IA, we have investigated during the infection: a) whether and how specific T-cell responses to different Aspergillus antigens occur and develop; b) which antigens elicit the highest frequencies of protective immune responses and, c) whether such protective T cells could be expanded ex-vivo. Forty hematologic patients have been studied, including 22 patients with IA and 18 controls. Specific T cells producing IL-10, IFN-γ, IL-4 and IL-17A have been characterized through enzyme linked immunospot and cytokine secretion assays on 88 peripheral blood (PB) samples, by using the following recombinant antigens: GEL1p, CRF1p, PEP1p, SOD1p, α1-3glucan, β1-3glucan, galactomannan. Specific T cells were expanded through short term culture. Aspergillus-specific T cells producing non-protective interleukin-10 (IL-10) and protective interferon-gamma (IFN-γ) have been detected to all the antigens only in IA patients. Lower numbers of specific T cells producing IL-4 and IL-17A have also been shown. Protective T cells targeted predominantly Aspergillus cell wall antigens, tended to increase during the IA course and to be associated with a better clinical outcome. Aspergillus-specific T cells could be successfully generated from the PB of 8 out of 8 patients with IA and included cytotoxic subsets able to lyse Aspergillus hyphae. Aspergillus specific T-cell responses contribute to the clearance of the pathogen in immunosuppressed patients with IA and Aspergillus cell wall antigens are those mainly targeted by protective immune responses. Cytotoxic specific T cells can be expanded from immunosuppressed patients even during the infection by using the above mentioned antigens. These findings may be exploited for immunotherapeutic purposes in patients with IA. © 2013 Potenza et al.

2013 - Early alterations of B cells in patients with septic shock: another piece in the complex puzzle of the immune response in sepsis [Articolo su rivista]
Girardis, Massimo; Cossarizza, Andrea
abstract

Impairment of the inflammatory-immune response is currently accepted as a hallmark of severe sepsis even in the early stages of the disease. In this context, the alterations of the circulating B-lymphocytes have never been described in detail. The study by Monserrat and colleagues in the previous issue of Critical Care indicated that, in patients with septic shock, the B-cell compartment is early and deeply altered with different patterns in subset distribution and activation between survivors and non-survivors.

2013 - Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial [Articolo su rivista]
Morelli, Andrea; Ertmer, Christian; Westphal, Martin; Rehberg, Sebastian; Kampmeier, Tim; Ligges, Sandra; Orecchioni, Alessandra; D'Egidio, Annalia; D'Ippoliti, Fiorella; Raffone, Cristina; Venditti, Mario; Guarracino, Fabio; Girardis, Massimo; Tritapepe, Luigi; Pietropaoli, Paolo; Mebazaa, Alexander; Singer, Mervyn
abstract

β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation in septic shock. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects.

2013 - Effectiveness of sepsis bundle application in cirrhotic patients with septic shock: A single-center experience [Articolo su rivista]
Rinaldi, Laura; Ferrari, Elena; Marietta, Marco; Donno, Lara; Trevisan, Davide; Codeluppi, Mauro; Busani, Stefano; Girardis, Massimo
abstract

Purpose: To evaluate the effect of adherence to evidence-based guidelines of the Surviving Sepsis Campaign (SSC) on the outcome of cirrhotic patients with septic shock admitted to the intensive care unit. Methods: This prospective observational cohort study included 38 patients with documented liver cirrhosis and septic shock admitted to a multidisciplinary intensive care unit at a University Hospital from January 2005 to June 2009. In each patient, the compliance to 4 resuscitation (ie, 6-hour bundle) and to 3 management (i.e. 24-hour bundle) interventions recommended by the SSC guidelines and the 30-day mortality were measured. Results: The 6-hour, 24-hour, and all bundles were completed in 50 %, 52%, and 39% of the patients, respectively. The characteristics at admission and the 30-day mortality of patients with all-bundle compliance (n = 15; mortality 86.6%) were similar to those of patients without bundle compliance (n = 23; mortality 78.2%), except for central venous O 2 saturation. Unadjusted and adjusted regression analysis showed that none of the single sepsis interventions and bundles were independently associated with 30-day mortality. Conclusions: In our observational study, the adherence to the interventions recommended by the SSC evidence-based guidelines did not provide an improvement in the survival rate of cirrhotic patients with septic shock. © 2012 Elsevier Inc. All rights reserved.

2013 - Endotoxin activity levels as a prediction tool for risk of deterioration in patients with sepsis not admitted to the intensive care unit: a pilot observational study [Articolo su rivista]
Biagioni, Emanuela; Venturelli, Claudia; Klein, David J; Buoncristiano, Marta; Rumpianesi, Fabio; Busani, Stefano; Rinaldi, Laura; Donati, Abele; Girardis, Massimo
abstract

The aim of this prospective observational study was to evaluate in patients with sepsis not requiring intensive care unit admission the relationship between the levels of endotoxin activity assay (EAA) early after sepsis recognition and the risk of development of organ dysfunction (OD).

2013 - Hemostasis in acute liver and kidney failure: nothing is as it seems [Articolo su rivista]
Girardis, Massimo; Marietta, Marco
abstract

Very little is known about the behavior of the hemostatic system in patients with acute kidney injury (AKI) associated with acute liver failure (ALF). Agarwal and colleagues show that patients who suffer from both ALF and AKI exhibit a higher degree of hemostasis impairment than those with normal renal function. Both anticoagulant and procoagulant factors were impaired. The development of AKI appears to displace the hemostatic equilibrium toward a more prothrombotic pattern.

2013 - RICERCA DI MARCATORI PER LA DIAGNOSI DI INFEZIONE FUNGINA INVASIVAE (IFI) MEDIANTE APPROCCIO DIAGNOSTICO COMBINATO [Poster]
Bettua, Clotilde; Ardizzoni, Andrea; Orsi, Carlotta Francesca; Pini, Pietro; Venturelli, Claudia; Girardis, Massimo; Peppoloni, Samuele; Posteraro, Brunella; Sanguinetti, Maurizio; Moragues, Maria Dolores; Blasi, Elisabetta
abstract

Introduzione L'incidenza di IFI ed in particolare delle candidiasi nei pazienti ricoverati in terapia intensiva è in costante aumento ed è associata ad un’elevata mortalità. Evidenze recenti sottolineano l’importanza di indagini multidirezionali e multi-parametriche ai fini di una diagnosi più rapida e precoce possibile. Scopo del presente studio è valutare l’efficacia di un approccio combinato che prevede la ricerca dell’antigene beta-glucano e di anticorpi specifici verso antigeni selezionati di Candida. Metodi 18 pazienti (Reparto di Terapia Intensiva, AOU-Policlinico Modena) sono stati arruolati e suddivisi in due gruppi: gruppo IFI (pazienti con aspergillosi o candidiasi invasiva proven/probable o con diagnosi clinica di pneumocistosi polmonare) e gruppo non-IFI (soggetti ospedalizzati con diagnosi diversa da IFI). In totale, sono stati saggiati 42 sieri con il saggio panfungino (1-3)-β-D-glucano (BG, Fungitell ®) e mediante un saggio sierologico “home-made” basato su microarray proteico per la determinazione quantitativa della risposta anticorpale nei confronti di 11 antigeni di Candida albicans. Risultati Il saggio BG ha mostrato sensibilità, specificità, valore predittivo positivo e negativo di 100%, 85,7%, 88,9 % e 100% rispettivamente; l’analisi delle curve ROC ha restituito una AUC di 0.857 (95% CI: 0.577-1). Il saggio sierologico ha rilevato nei pazienti con emocoltura positiva, una risposta anticorpale nei confronti di 3 antigeni (Bgl2, Pgk1 e Grp2), recentemente descritti come marker diagnostici di candidasi invasiva (Ardizzoni et al., 2013 – submitted). Nessuna risposta anticorpale significativa è invece emersa dall’analisi del siero di pazienti con probabile/possibile IFI e di pazienti non-IFI. Conclusioni La combinazione dei risultati del BG assay e del saggio sierologico in microarray, condotti parallelamente all’emocoltura, può fornire indicazioni diagnostiche e prognostiche aggiuntive in pazienti con provata o sospetta candidiasi invasiva. Riteniamo che questo approccio diagnostico combinato possa rivelarsi particolarmente utile soprattutto nei pazienti con emocoltura negativa.

2013 - Successful liver transplantation in a patient with splanchnic vein thrombosis and pulmonary embolism due to polycythemia vera with Jak2v617f mutation and heparin-induced thrombocytopenia. [Articolo su rivista]
Biagioni, E; Pedrazzi, Paola; Marietta, M; DI BENEDETTO, Fabrizio; Villa, Erica; Luppi, Mario; Girardis, Massimo
abstract

Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatment resulting in a severe acquired thrombophilic condition with an associated mortality of about 10 %. We report the first case of successful urgent liver transplantation (LT) in a patient with end-stage liver disease due to a Budd-Chiari syndrome, portal vein thrombosis and pulmonary embolism due to acquired thrombophilia associated to polycythemia vera carrying JAK2V617F gene mutation and HIT in the acute phase. Lepirudin was used to provide anticoagulation in the LT perioperative period that was performed without haemorrhagic and thrombotic complications despite the donor received heparin during liver explantation.

2013 - The aPC treatment improves microcirculation in severe sepsis/septic shock syndrome [Articolo su rivista]
Donati, Abele; Damiani, Elisa; Botticelli, Laura; Adrario, Erica; Lombrano, Maria R.; Domizi, Roberta; Marini, Benedetto; Van Teeffelen, Jurgen W. G. E.; Carletti, Paola; Girardis, Massimo; Pelaia, Paolo; Ince, Can
abstract

Background: The role of recombinant activated protein C (aPC) during sepsis is still controversial. It showed anti-inflammatory effect and improved the microvascular perfusion in experimental models of septic shock. The present study was aimed at testing the hypothesis that recombinant aPC therapy improves the microcirculation during severe sepsis.Methods: Prospective observational study on patients admitted in a 12-beds intensive care unit of a university hospital from July 2010 to December 2011, with severe sepsis and at least two sepsis-induced organ failures occurring within 48 hours from the onset of sepsis, who received an infusion of aPC (24 mcg/kg/h for 96 hours) (aPC group). Patients with contraindications to aPC administration were also monitored (no-aPC group).At baseline (before starting aPC infusion, T0), after 24 hours (T1a), 48 hours (T1b), 72 hours (T1c) and 6 hours after the end of aPC infusion (T2), general clinical and hemodynamic parameters were collected and the sublingual microcirculation was evaluated with sidestream dark-field imaging. Total vessel density (TVD), perfused vessel density (PVD), De Backer score, microvascular flow index (MFIs), the proportion of perfused vessels (PPV) and the flow heterogeneity index (HI) were calculated for small vessels. The perfused boundary region (PBR) was measured as an index of glycocalyx damage. Variables were compared between time points and groups using non parametric or parametric statistical tests, as appropriate. Results: In the 13 aPC patients mean arterial pressure (MAP), base excess, lactate, PaO2/FiO2 and the Sequential Organ Failure Assessment (SOFA) score significantly improved over time, while CI and ITBVI did not change. MFIs, TVD, PVD, PPV significantly increased over time and the HI decreased (p < 0.05 in all cases), while the PBR did not change. No-aPC patients (n = 9) did not show any change in the microcirculation over time. A positive correlation was found between MFIs and MAP. TVD, PVD and De Backer score negatively correlated with norepinephrine dose, and the SOFA score negatively correlated with MFIs, TVD and PVD. Conclusions: aPC significantly improves the microcirculation in patients with severe sepsis/septic shock. Trial registration: NCT01806428. © 2013 Donati et al.; licensee BioMed Central Ltd.

2013 - The need for networking in sepsis research: a must to move forward [Articolo su rivista]
Caironi, P; Girardis, Massimo
abstract

2012 - A new technique for percutaneous dilatational tracheostomy (G-Trach): Preliminary experience in pigs [Articolo su rivista]
R., Guerra; A. D., Monte; Girardis, Massimo
abstract

Tracheostomies are currently used for airway management in patients requiring long-term respiratory assistance. The dilatational percutaneous technique of forming tracheostomies is a valuable alternative to traditional surgical 'open' techniques. In this study, we tested a new dilatational percutaneous tracheostomy device using a balloon dilator with a particular innovative shape (G-Trach). At the Autonomous University of Barcelona Veterinary Institute, eight pigs (weighing 20-40 kg) were anaesthetised and underwent tracheostomy using the novel G-Trach technique. The mean (SD) procedure time was 2.63 (0.64) min from tracheal puncture to ventilation through the tracheostomy tube, and the mean (SD) time from positioning the dilator balloon to introducing the cannula was 0.71 (0.38) min. Vital functions and oxygen saturation remained constant throughout the procedures. Postmortem examinations did not reveal any tracheal injury. The G-Trach seems to be a safe and easy new dilatational percutaneous technique for forming tracheostomies. The minimal subcutaneous tissue dissection could potentially decrease complications when compared with standard dilatational percutaneous tracheostomy methods. To confirm this hypothesis a human trial is ongoing. © Anaesthesia © 2012 The Association of Anaesthetists of Great Britain and Ireland.

2012 - Abdominal compartment syndrome and fluid replacement: a dog that bites its own tail? [Capitolo/Saggio]
Girardis, Massimo; E., Biagioni
abstract

2012 - Acute renal failure and liver necrosis associated to allopurinol therapy. [Articolo su rivista]
Biagioni, E.; Busani, S.; Rinaldi, L.; Marietta, M.; Girardis, Massimo
abstract

2012 - Erratum: Acute renal failure and renal replacement therapy in the postoperative period of orthotopic liver transplant patients versus nonelective abdominal surgery patients (Transplantation Proceedings (2011) 43:4 (1145-1147)) [Articolo su rivista]
Biagioni, E.; Cavazzuti, I.; Busani, S.; Trevisan, D.; Zavatti, L.; Ferrari, E.; Girardis, M.
abstract

2012 - Exogenous surfactant, a role in the adult respiratory distress syndrome? [Articolo su rivista]
Busani, S.; Girardis, Massimo; Pasetto, A.
abstract

2012 - Hospital staff education on severe sepsis/septic shock and hospital mortality: an original hypothesis [Articolo su rivista]
Capuzzo, Maurizia; Rambaldi, Marco; Pinelli, Giovanni; Campesato, Manuela; Pigna, Antonia; Zanello, Marco; Barbagallo, Maria; Girardis, Massimo; Toschi, Elena
abstract

BACKGROUND: Signs of serious clinical events overlap with those of sepsis. We hypothesised that any education on severe sepsis/septic shock may affect the outcome of all hospital patients. We designed this study to assess the trend of the mortality rate of adults admitted to hospital for at least one night in relationship with a hospital staff educational program dedicated to severe sepsis/septic shock. METHODS: This study was performed in six Italian hospitals in the same region. Multidisciplinary Sepsis Teams members were selected by each hospital management among senior staff. The education included the following steps: i) the Teams were taught about adult learning, problem based learning, and Surviving Sepsis guidelines, and provided with educational material (literature, electronic presentations, scenarios of clinical cases for training and booklets); ii) they started delivering courses and seminars each to their own hospital staff in the last quarter of 2007.To analyse mortality, we selected adult patients, admitted for at least one night to the wards or units present in all the study hospitals and responsible for 80% of hospital deaths. We fitted a Poisson model with monthly hospital mortality rates from December 2003 to August 2009 as dependent variable. The effect of the educational program on hospital mortality was measured as two dummy variables identifying a first (November 2007 to December 2008) and a second (January to August 2009) education period. The analysis was adjusted for a linear time trend, seasonality and monthly average values of age, Charlson score, length of stay in hospital and urgent/non-urgent admission. RESULTS: The hospital staff educated reached 30.6% at the end of June 2009. In comparison with the pre-education period, the Relative Risk of death of the patient population considered was 0.93 (95% confidence interval [CI] 0.87-0.99; p 0.025) for in-patients in the first, and 0.89 (95% CI 0.81-0.98; p 0.012) for those in the second period after education. CONCLUSION: Our hypothesis that a program educating hospital staff to early detection and treatment of severe sepsis/septic shock may affect the outcome of all hospital patients is original, but it has to be corroborated by other experiences.

2012 - Levosimendan in a case of severe peri-myocarditis associated with influenza A/H1N1 virus. [Articolo su rivista]
S., Busani; A., Pasetto; Ligabue, Guido; V., Malavasi; R., Lugli; Girardis, Massimo
abstract

2012 - PSP/reg: a new stone in sepsis biomarkers? [Articolo su rivista]
S., Busani; Girardis, Massimo
abstract

ABSTRACT: Rapid diagnosis, appropriate management, and time are the key factors for improving survival rate in many emergency clinical scenarios such as acute myocardial infarction, pulmonary embolism, cerebral stroke, and severe sepsis. Clinical signs and electrocardiographic, radiological, and echographic investigations associated with biomarkers usually allow a quick diagnosis in all of the above situations, except severe sepsis, in which the diagnosis in the early phases is often only presumptive. In sepsis, microbiological cultures are still considered the 'gold standard' for diagnosis, whereas the numerous biomarkers investigated are actually valuable only for patient stratification and evaluation of clinical course. In this issue of Critical Care, Que and colleagues describe the prognostic value of pancreatic stone protein/regenerating protein (PSP/reg) concentration in patients with severe infections. The data reported are interesting, but several questions about this biomarker arise, and further studies are needed to understand its role in sepsis and clinical practice.

2012 - Relationship between polyclonal immunoglobulin therapy and colonization by Candida spp. [Abstract in Rivista]
Serafini, G.; Cavazzuti, I; Venturelli, C.; Girardis, Massimo
abstract

2012 - Sepsis Stewardship Programs: Methods and Results [Capitolo/Saggio]
Girardis, Massimo; Busani, S.; Pan, A.
abstract

2012 - Sorveglianza epidemiologica delle infezioni ospedaliere condotta all’interno di una convenzione tra il Dipartimento di Scienze di Sanità Pubblica dell’Università Modena e Reggio Emilia e l’Azienda Ospedaliero-Universitaria Policlinico di Modena. [Abstract in Rivista]
Righi, Elena; Aggazzotti, Gabriella; Cattani, S; Girardis, Massimo; Vecchi, E; Marchegiano, P; Cencetti, S.
abstract

A partire da settembre 2007 il Dipartimento di Scienze di Sanità Pubblica dell’Università di Modena e Reggio-Emilia e la Direzione Generale dell’Azienda Ospedaliero-Universitaria Policlinico di Modena hanno attivato una convenzione con l’obiettivo di effettuare una mappatura dei sistemi di sorveglianza già in atto, valutarne i risultati, identificare e implementare gli eventuali interventi migliorativi e rafforzativi.L’attività, svolta grazie ad una stretta collaborazione con il CIO, ha seguito diversi step metodologici: – individuazione delle infezioni prioritarie da includere nella sorveglianza e delle popolazioni target; – individuazione delle definizioni di caso e degli indicatori già riconosciuti ed utilizzati da protocolli regionali nazionali o internazionali; – censimento dei sistemi di sorveglianza già in essere; – raccolta e analisi dei dati disponibili con particolare attenzione agli indicatori selezionati; – confronto dei dati delle IOS specifiche per tipologia o per reparto con dati regionali, nazionali o internazionali; – individuazionedelle criticità emerse da confronti interni ed esterni; – messa a punto di interventi di miglioramento della sorveglianza e delle misure di controllo basate su linee guida internazionali o nazionali. La mappatura dei sistemi di sorveglianza delle IOS presso l’Azienda ha evidenziato la presenza di sistemi già attivi da alcuni anni nella Terapia Intensiva Neonatale, nelle terapie intensive per gli adulti e nelle Chirurgie. I tassi di incidenza delle IOS sono risultati in linea con i dati dei sistemi di sorveglianza regionali (SIChER), nazionali (SPINUTI, GiViTI) ed internazionali (NNIS e VON). La collaborazione attivata in questi anni ha permesso, inoltre, di ampliare e rinforzare i sistemi di sorveglianza già in essere, con l’obiettivo di aumentare il numero e la tipologia di IOS sorvegliate, di estendere la sorveglianza anche ad altre unità, di migliorare la completezza e l’accuratezza della raccolta dati, con particolare attenzione ai patogeni emergenti e alle ntibioticoresistenze.

2011 - Acute renal failure and renal replacement therapy in the postoperative period of orthotopic liver transplant patients versus nonelective abdominal surgery patients [Articolo su rivista]
Biagioni, Emanuela; Cavazzuti, Ilaria; Busani, Stefano; Trevisan, Davide; Zavatti, Laura; Ferrari, Elena; Girardis, Massimo
abstract

Acute renal failure (ARF) often complicates the postoperative period of patients undergoing orthotopic liver transplantation (OLT); it is habitually associated with high mortality rates. Similarly, patients undergoing major nonelective abdominal surgery are prone to ARF because of their frequent preexistent morbidities, abdominal sepsis, and needed for extended surgical procedures. The aim of this study was to evaluate the incidence of ARF and use of renal replacement therapy (RRT) among OLT versus nonelective abdominal surgery patients and associations with clinical outcomes. We studied all the patients admitted to a surgical intensive care unit (ICU) from January 2008 to December 2009 after OLT or nonelective abdominal surgery. The inclusion criteria were an ICU stay of at least 48 hours and without prior end-stage renal failure. OLT patients (n = 84) were younger and less severly ill than surgery patients (n = 60). ARF occurrence was lower among the OLT (29%) than the surgery group (47%) requiring RRT in 71% and 53% of patients due to ARF, respectively. The ICU mortality of ARF patients in both groups (29% OLT and 51% surgery) were greater than among subjects without ARF (2% and 6%). The occurrence of ARF is common among these two patient groups, and associated with increased risk of death among in surgery (+45%) versus in OLT (+27%) patients. © 2011 Elsevier Inc. All rights reserved.

2011 - Early serum endotoxin level and organ failure in septic patients [Abstract in Rivista]
Biagioni, E; Bertazzoni, G; Braccini, S; Boni, E; Trevisan, D; Venturelli, C; Girardis, Massimo
abstract

2011 - Early use of immunoglobulin in septic shock [Abstract in Atti di Convegno]
Cavazzuti, I; Girardis, Massimo
abstract

2011 - Emorragia massiva: dalle linee guida ai bundles di trattamento [Relazione in Atti di Convegno]
Girardis, Massimo; Pedrazzi, P; Braccini, Ms; Busani, S; Marietta, M; Pasetto, A.
abstract

2011 - Il monitoraggio perioperatorio del paziente settico [Capitolo/Saggio]
Girardis, Massimo; E., Biagioni
abstract

2011 - Il politraumatizzato [Capitolo/Saggio]
Rambaldi, M.; Busani, S.; Baranzoni, M. T.; Girardis, Massimo
abstract

2011 - Long Term Effects of an in-Hospital Program on Sepsis Management in ICU [Abstract in Rivista]
Ferrari, E.; Serafini, G.; Trevisan, D.; Donno, L.; Rinaldi, L.; Girardis, Massimo
abstract

2011 - Massive bleeding: Are we doing our best? [Articolo su rivista]
Marietta, M; Pedrazzi, P; Girardis, Massimo; Luppi, Mario
abstract

Massive bleeding accounts for more than 50% of all trauma-related deaths within the first 48. h following hospital admission and it can significantly raise the mortality rate of any kind of surgery. Despite this great clinical relevance, evidence on the management of massive bleeding is surprisingly scarce, and its treatment is often based on empirical grounds. Successful treatment of massive haemorrhage depends on better understanding of the associated physiological changes as well as on good team work among the different specialists involved in the management of such a complex condition.

2011 - Outbreak of Burkholderia cepacia in an intensive care unit: temporal trend, clinical characteristics and outcomes of patients [Abstract in Rivista]
Righi, Elena; Aggazzotti, Gabriella; Borsari, Lucia; Fantuzzi, A.; Ferrari, E.; Vecchi, E.; Venturelli, C.; Marchegiano, P.; Girardis, Massimo; Centetti, S.
abstract

Burkholderia cepacia, an environmental microorganism which can be an opportunistic pathogen in patients with cystic fibrosis, is emerging as a causative agent of nosocomial outbreaks involving bloodstream,respiratory tract, and urinary tract infections in intensive care unit (ICU) settings. An outbreak of B.cepacia has recently occurred in ICU at the teaching hospital in Modena (northern Italy). A sudden increaseof B. cepacia positive cultures has been highlighted thank to the alert organisms laboratory surveillance activities routinely performed at the structure. The outbreak lasted 18 months and involved 46 patients(25 males and 21 females, mean age 63±18years): 63% of the subjects were colonized and 37% developed an infection (respiratory tract infection). The analysis of spatial and temporal trends of cases together with different environmental investigations and the genotyping of the isolated microorganisms allowed to identify and to remove the source of the outbreak, a contaminated mouthwash for oral hygiene of patients, determining the rapid resolution of the outbreak. A descriptive epidemiological survey of cases has been performed as well, in order to investigate the relationship between host, pathogen and environment and to identify potential predictors to clinical response. Characteristics of infected and colonized patients were compared: no significant differences were found as thetwo groups showed very really similar demographic and clinical conditions and outcomes (mortality rate: 50% in both groups). Severity of the underlying disease resulted the main factor influencing mortality risk, however it did not appear to be related to thecolonized or infected status of patients.

2011 - Polmonite associata alla ventilazione: esperienza di sette anni in una terapia intensiva polivalente [Relazione in Atti di Convegno]
Ferrari, E; Giovanardi, C; Girardis, Massimo
abstract

2011 - Progetto “lotta alla sepsi" in emilia-romagna [Relazione in Atti di Convegno]
Girardis, Massimo; Cavazzuti, I; Baricchi, R; Caramelli, F; D’Errico, A; Giordani, S; Giovannitti, A; Melotti, R; Peghetti, A; Pinelli, G; Resi, D; Sangiorgi, G; Tumietto, F; Zanello, M; Moro, Ml
abstract

2011 - Sindrome Compartimentale addominale e rianimazione fluidica: un cane che si magia la coda? [Capitolo/Saggio]
Girardis, Massimo; E., Biagioni
abstract

2011 - The clinical significance of cardiac output measurement in patients with persistent shock: preliminary result of a randomized trial [Abstract in Rivista]
Trevisan, D; Zavatti, L; Andreotti, A; Giovannini, S; Busani, S; Girardis, Massimo
abstract

2011 - Troponin in high risk surgical patients admitted to ICU: a 3 years experience [Abstract in Rivista]
Andreotti, A; Rinaldi, L; Casolari, Mc; Tagliazucchi, M; Girardis, Massimo; Pasetto, A.
abstract

2011 - Use of early corticosteroid therapy on ICU admission in patients affected by severe pandemic (H1N1)v influenza A infection [Articolo su rivista]
I. a., Martin Loeches; T. b., Am; A. p., Dl; R., Moreno; E. u., Silva; C., Sprung; J. a., Chiche; D. s., Eg; M. q., Dv; C. r., Dy; R. d., Pearse; R. n., Ck; J. a., Rello; A. a., Rodriguez; M. d., Capuzzo; R. e., Reina; B. e., Marsh; H., Flaaten; G., Sigurdsson; Z., Ivana; V., Cerny; M., Quintel; T., Welte; M., Mayorga; G., Offenstadt; B., Guidet; P., Levin; H., Rothen; C. g., Gomersall; S. g., Hashemian; C., Katsanoulas; H., Mouloudi; F., Kapadia; A., Valentin; G., Hedenstierna; A., Perner; G. h., Bugedo; E., Ruokonen; A., Arandes; J., Montejo; R., Peñíscola; C., Hermosa; F., Gordo; J., Latour; L., Vidaur; M., Alvarez Gonzalez; L., Alvarez Rocha; A. D., Pablo; C., Ferri; L. D., Arbina; C., Cânones; J., Insausti; J., Cambronero; B., Galvan; J., Luna; R., Blancas; C., Garcia; R., Sierra; F., Dorado; P., Monedero; J., Llagunes; P., Cobo; A., Socias; R., Leon Lopez; E., Esteban; M., Lacueva; M., Magret; F. D., Nogal; A., Dinis; A., Bártolo; A., Ramos; C., Franca; C., Estevens; C., Granja; C., Fidalgo; E., Almeida; E., Lafuente; F., Rua; F., Esteves; J. h., Clemente; J., Nóbrega; J., Pereira; J., Moura; L. T., E; L., Telo; L., Santos; M., Pedrosa; M., Oliveira; M., Resende; N., Catorze; P., Coutinho; R., Ribeiro; R., Moreno; I., Miranda; T., Cardoso; V., Branco; G., Bellani; R., Urbino; A., Peris; A., Amatu; G., Berlot; F., Marzani; U., Corbanese; A., David; P., Chiarandini; F., Corte; M., Caspani; C., Alessandra; V., Mangani; R., Tetamo; A., Wolfler; G., Tappatà; V., Nicoletta; G., Bertolini; L., Pelagalli; A., Molin; Girardis, Massimo; G., Gristin; A., Lam; I., Crabb; R., Cusack; R., Jackson; C., Veerappan; C., Whiteley; T., Ware; S., Krueper; C., Mckinstry; A., Ferguson; F., Rubulotta; E., Valencia; S., Gonzalez; V., Cevallos; A., Zazu; J., Fresco; G., Galindez; C., Barrios; C., Lovesio; B., Villamagua; M., Cadena; E., Salgado; M., García; G., Paredes; M., Donnelly; D., O'Croinin; J., Bates; N., Kavanagh; B., O'Brien; R., Plant; M., Scully; R., Farragher; L., Oliveira; S., Mataloun; V., Dantas; L., Simvoulidis; P., Duarte; C., Grion; A., Germano; J., Laake; E., Helset; D., Klausen; H., Flaatten; K., Bruheim; B., Kristinsson; S., Sigurdsson; J., Hrubý; R., Valkova; R., Janda; I., Zykova; A., Kernchen; F., Bloos; S., Rosseau; J., Krassler; F., Fischer; A., Arroyo Sanchez; A., Poquet; I., Palomino; F., Rafael; J., Salasfoch; G., Dubar; J., Tonnelier; S., Barbar; M., Dobrzynski; A., Mignon; D., Jakobson; M., Klein; E., Segal; Y., Barlavie; M., Hersch; Z., Salomón; H., Zender; H., Rothen; K., Chan; T., Buckley; U., Batranovic; I., Schaffer; J., Sretkovic; D., Koulenti; E., Mouloudi; P., Clouva Molyvdas; M., Gurjar; D., Vijayan; G., Hinterholzer; A., Kulier; C., Verlaat; D., Ebel; J., Persson; S., Walther; P., Petersen; W., Swinnen; V., Collin; H., Olsen; P., Gutierrez; G., Thiery; H., Laine; A., Rumba; S., Maiyalagan; T., Bui
abstract

Introduction: Early use of corticosteroids in patients affected by pandemic (H1N1)v influenza A infection, although relatively common, remains controversial. Methods: Prospective, observational, multicenter study from 23 June 2009 through 11 February 2010, reported in the European Society of Intensive Care Medicine (ESICM) H1N1 registry. Results: Two hundred twenty patients admitted to an intensive care unit (ICU) with completed outcome data were analyzed. Invasive mechanical ventilation was used in 155 (70.5%). Sixty-seven (30.5%) of the patients died in ICU and 75 (34.1%) whilst in hospital. One hundred twenty-six (57.3%) patients received corticosteroid therapy on admission to ICU. Patients who received corticosteroids were significantly older and were more likely to have coexisting asthma, chronic obstructive pulmonary disease (COPD), and chronic steroid use. These patients receiving corticosteroids had increased likelihood of developing hospital-acquired pneumonia (HAP) [26.2% versus 13.8%, p < 0.05; odds ratio (OR) 2.2, confidence interval (CI) 1.1-4.5]. Patients who received corticosteroids had significantly higher ICU mortality than patients who did not (46.0% versus 18.1%, p < 0.01; OR 3.8, CI 2.1-7.2). Cox regression analysis adjusted for severity and potential confounding factors identified that early use of corticosteroids was not significantly associated with mortality [hazard ratio (HR) 1.3, 95% CI 0.7-2.4, p = 0.4] but was still associated with an increased rate of HAP (OR 2.2, 95% CI 1.0-4.8, p < 0.05). When only patients developing acute respiratory distress syndrome (ARDS) were analyzed, similar results were observed. Conclusions: Early use of corticosteroids in patients affected by pandemic (H1N1)v influenza A infection did not result in better outcomes and was associated with increased risk of superinfections. associated with mortality [hazard ratio (HR) 1.3, 95% CI 0.7-2.4, p = 0.4] but was still associated with an increased rate of HAP (OR 2.2, 95% CI 1.0-4.8, p < 0.05). When only patients developing acute respiratory distress syndrome (ARDS) were analyzed, similar results were observed. Conclusions: Early use of corticosteroids in patients affected by pandemic (H1N1)v influenza A infection did not result in better outcomes and was associated with increased risk of superinfections. © Copyright jointly held by Springer and ESICM 2010.

2010 - Controllo della glicemia nel paziente critico post-chirurgico e non [Relazione in Atti di Convegno]
Trevisan, D; Girardis, Massimo
abstract

2010 - EPIDEMIA DA INFEZIONE DI BURKHOLDERIA CEPACIA IN TERAPIA INTENSIVA: SORVEGLIANZA E CONTROLLO [Abstract in Rivista]
Borsari, Lucia; Righi, Elena; Aggazzotti, Gabriella; Fantuzzi, A; Ferrari, Elena; Vecchi, E; Venturelli, C; Marchigiano, P; Girardis, Massimo
abstract

Obiettivo: Burkholdera cepacia, microrganismo conosciuto soprattutto per la sua patogenicità in soggetti con fibrosi cistica, negli ultimi anni sta sempre più emergendo come causa di importanti epidemie in ambito ospedaliero. In questo studio viene descritto un caso di epidemia da B. cepacia verificatosi nell’unità di terapia intensiva dell’Azienda Ospedaliero Universitaria Policlinico di Modena e vengono prese in analisi le misure adottate per il controllo dell’epidemia stessa.Metodi: Tutti i pazienti ricoverati in terapia intensiva da gennaio 2005 ad aprile 2006 con almeno un riscontro positivo per B. cepacia sono stati inclusi nell’analisi descrittiva. Le misure di controllo adottate e le indagini di laboratorio e ambientali eseguite al fine di identificare la fonte d’infezione sono state poi esaminate e descritte.Risultati: Grazie al sistema di segnalazione di eventi sentinella attivo nella struttura all’inizio del 2005 è stato evidenziato un improvviso aumento degli isolamenti di B. cepacia in terapia intensiva. Tra il 2005 e il 2006 sono stati identificati in totale 46 casi, di cui 63% colonizzazioni e 37% infezioni, soprattutto polmonari. I microrganismi isolati in diversi materiali biologici sono risultati sensibili a piperacillina e sulfametoxazolo/trimetropin. Per contenere la diffusione sono state adottate immediatamente diverse misure di controllo quali l’isolamento dei casi e la stretta osservanza delle misure di asepsi e del lavaggio delle mani. Le indagini ambientali sono state numerose e hanno permesso di evidenziare la presenza di B. cepacia in acqua deionizzata utilizzata dalla farmacia ospedaliera per la preparazione di un collutorio impiegato di routine per le procedure di igiene orale. Rimossa la fonte di trasmissione e grazie alle misure specifiche di controllo messe in atto, l’epidemia è stata risolta completamente.Conclusioni: L’inclusione di B. cepacia tra i patogeni ‘sentinella’ monitorati routinariamente presso il Policlinico di Modena ha permesso di identificare rapidamente un’epidemia dovuta a un patogeno che nella maggior parte dei casi non da sintomi d’infezione. E’ stato quindi possibile adottare rapidamente misure di controllo appropriate, identificare la fonte di trasmissione e ridurre in modo significativo l’impatto dell’infezione. Questo microrganismo, solitamente non presente in modo endemico nei reparti, viene considerato un tracciante dell’andamento generale del rischio infettivo nosocomiale: la sua identificazione ha permesso di riconoscere e modificare pratiche assistenziali non completamente corrette al fine di migliorare sempre più la qualità dell’assistenza erogata.

2010 - Early use of immunoglobulin in septic shock [Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Donno, L; Braccini, Ms; Busani, S; Girardis, Massimo
abstract

2010 - Effects of selective decontamination of the digestive tract on Acinetobacter baumanii related ventilation acquired pneumonia: preliminary data [Abstract in Rivista]
Ferrari, E; Serio, L; Venturelli, C; Codeluppi, M; Righi, Elena; Mussini, Cristina; Marchegiano, P; Bosi, I; Girardis, Massimo
abstract

2010 - Effects of sepsis resuscitation bundle in cirrhotic patients with septic shock [Abstract in Rivista]
Rinaldi, L; Ferrari, E; Trevisan, D; Donno, L; Girardis, Massimo
abstract

2010 - Immunoglobulin usage in severe infections and sepsis [Relazione in Atti di Convegno]
Girardis, Massimo; Cavazzuti, I.
abstract

2010 - Levosimendan in cardiac failure after subarachnoid hemorrhage. [Articolo su rivista]
Busani, S; Rinaldi, L; Severino, C; Cobelli, M; Pasetto, Alberto; Girardis, Massimo
abstract

The aim of this study is to report the development of cardiac failure after subarachnoid hemorrhage (SAH) with recovery of heart and cerebral function. This is a case report of a 38-year-old woman who was admitted to the intensive care unit (ICU) at Policlinico di Modena, Italy. This woman developed a deep state of coma because of severe SAH. After cerebral hemorrhage, patient showed a cardiogenic shock, which needed invasive monitoring. Cerebral perfusion pressure had to be restored, so fluids, dopamine, norepinephrine, and dobutamine were in administered sequentially. Despite these supportive treatments, hemodynamic parameters further worsened and echocardiography showed a global depressed left ventricular (LV) contraction with poor ejection fraction (EF) and restrictive type of LV relaxation pattern. Twenty-four hours after ICU admission, levosimendan was started with the aim to improve cardiac function because of the refractoriness of all other treatments. Eight hours after levosimendan infusion, cardiac function improved and, within the after 24 hours, EF and LV relaxation pattern recovered. Neurologic state and computed tomography images improved day by day, and after 9 days from the ICU admission, we transferred the patient to the neurosurgical ward with very good neurologic conditions and no deficits in motility. The conventional management of post-SAH cardiovascular failure is based on the use of norepinephrine, dobutamine, and high amount of fluids. This strategy did not provide any improvement, so we decided for levosimendan infusion to counteract myocardial stunning. The improvement in cardiac EF, LV wall motion, and filling pressure observed in our patient could be explained due to the antistunning triple-mechanism action of levosimendan. Data available on the levosimendan effectiveness in patients with SAH and its effect on intracranial pressure are still lacking, but we think that neurogenic cardiac failure can be treated at first with levosimendan. © 2010 Lippincott Williams & Wilkins.

2010 - Modified Early Warning Score and identification of patients with severe sepsis [Abstract in Rivista]
Zavatti, L; Barbieri, E; Amateis, E; Girardis, Massimo
abstract

2010 - Posttraumatic massive bleeding: a challenging multidisciplinary task. [Articolo su rivista]
Marietta, M; Pedrazzi, P; Girardis, Massimo; Busani, S; Torelli, G.
abstract

Massive bleeding is a key issue in the treatment of trauma and surgery. It does in fact account for more than 50% of all trauma-related deaths within the first 48 h following hospital admission, and it can significantly raise the mortality rate of any kind of surgery. Despite this great clinical relevance, evidence on the management of massive bleeding is surprisingly scarce, and its treatment is often based on empirical grounds. Successful treatment of massive haemorrhage depends on better understanding of the associated physiological changes as well as on good team work between the different specialists involved in the management of such a complex condition. The aim of this article is to provide an overview of the pathophysiology as well as of current treatment options of such a condition, including the new concept of "damage control resuscitation", which integrates permissive hypotension, haemostatic resuscitation and damage control surgery.

2010 - Surfactant therapy and intravenous zanamivir in severe respiratory failure due to persistent influenza A/H1N1 2009 virus infection. [Articolo su rivista]
Busani, S; Girardis, Massimo; Biagioni, E; Pasetto, A; Sambri, V.
abstract

2010 - Two-stage liver transplantation: an effective procedure in urgent conditions. [Articolo su rivista]
Montalti, R.; Busani, S.; Masetti, M.; Girardis, Massimo; Benedetto, F. D.; Begliomini, B.; Rompianesi, G.; Rinaldi, L.; Ballarin, R.; Pasetto, A.; Gerunda, Giorgio Enrico
abstract

Temporary portocaval shunt and total hepatectomy is a technique used in the presence of toxic liver syndrome because of fulminant hepatic failure, hepatic trauma, primary non-function (PNF), and eclampsia. We performed this technique on four patients. An indication for anhepatic state was severe hemodynamic instability in three of them. Etiologies of these three patients were as follows: PNF after liver transplantation, ischemic hepatitis after right hepatic artery embolization, and massive reperfusion syndrome during a liver transplantation. In the fourth patient, during the liver transplantation when hepatic artery was ligated, a kidney carcinoma in the donor graft was discovered. We decided to complete the hepatectomy and to construct a temporary portocaval shunt. Mean anhepatic phases were 19 h and 15 min. All patients survived the two-stage liver transplantation procedure without major complications. Our cases demonstrated that temporary portocaval shunt while awaiting urgent liver transplantation could be an effective "bridge" in selected patients who develop toxic liver syndrome; however, a short time between portocaval shunt and transplantation and careful intensive care managements are mandatory.

2010 - Venous-arterial PCO2 difference as an early predictor of organ dysfunction in the ICU [Abstract in Rivista]
Biagioni, E; Boni, E; Girardis, Massimo
abstract

2009 - Bronchoalveolar lavage (BAL) and supplementation with exogenous surfactant in adults with acute respiratory distress syndrome (ARDS) [Abstract in Rivista]
Busani, S; Cavazzuti, I; Fabbri, L; Lumachi, L; Lo Pardo, D; Michielan, F; Vassalli, Pa; Pacini, D; D’Este, G; Girardis, Massimo; Pasetto, Alberto
abstract

2009 - Effects of a correct use of recombinant human activated C protein in patients with septic shock [Abstract in Rivista]
Ferrari, E; Girardis, Massimo; Donno, L; Rinaldi, L; Iacomini, E.
abstract

2009 - Effects of intravenous IGM-enriched immunoglobulins on muscle tissue microcirculation in septic shock: a preliminary report [Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Braccini, Ms; Bertolotti, V; Andreotti, A; Busani, S; Girardis, Massimo
abstract

2009 - Effects on management and outcome of severe sepsis and septic shock patients admitted to the intensive care unit after implementation of a sepsis program: a pilot study. [Articolo su rivista]
Girardis, Massimo; Rinaldi, L; Donno, L; Marietta, M; Codeluppi, M; Marchegiano, P; Venturelli, C; Sopravvivere alla Sepsi Group of the Modena University, Hospital
abstract

INTRODUCTION: The application in clinical practice of evidence-based guidelines for the management of patients with severe sepsis/septic shock is still poor in the emergency department, while little data are available for patients admitted to the intensive care unit (ICU). The aim of this study was to evaluate the effect of an in-hospital sepsis program on the adherence to evidence-based guidelines and outcome of patients with severe sepsis/septic shock admitted to the ICU.METHODS: This prospective observational cohort study included 67 patients with severe sepsis/septic shock admitted to a multidisciplinary ICU at a University Hospital from January 2005 to June 2007. Compliance to 5 resuscitation and 4 management sepsis interventions and in-hospital mortality were measured following an educational program on sepsis for physician and nurses of all hospital departments and hospital implementation of a specific protocol for recognition and management of patients with severe sepsis/septic shock, including an early consultation by a skilled 'sepsis team'.RESULTS: During the study period, the compliance to all 9 interventions increased from 8% to 35% of the patients (P < 0.01). The implementation of resuscitation and management interventions was associated with a lower risk of in-hospital mortality (23% vs 68% and 27% vs 68%, P < 0.01). In the latter 2 semesters, after activation of the 'sepsis team', in-hospital mortality of ICU septic shock patients decreased by about 40% compared with the previous period (32% vs 79%, P < 0.01).CONCLUSIONS: In our experience, an in-hospital sepsis program, including education of health-care personnel and process-changes, improved the adherence to guidelines and the survival rate of patients with severe sepsis/septic shock admitted to the ICU.

2009 - Il paziente itterico grave [Abstract in Rivista]
Rinaldi, L; Girardis, Massimo
abstract

2009 - Perioperative red blood cell transfusion and outcome in stable patients after elective major vascular surgery. [Articolo su rivista]
Bursi, F; Barbieri, A; Politi, L; Di Girolamo, A; Malagoli, A; Grimaldi, T; Rumolo, A; Busani, S; Girardis, Massimo; Jaffe, As; Modena, Maria Grazia
abstract

OBJECTIVES:Definitive evidence that red blood cell transfusion improves outcome after vascular surgery is lacking. The aims of the study were to determine, among stable consecutive patients who underwent elective major vascular surgery, (1) the association between postoperative transfusion and 30-day death, myocardial infarction, and both, and (2) and if this association differs according to the presence of postoperative anaemia (haemoglobin value less than 9.0 g/dL within 7 days after surgery).METHODS:A retrospective observational study was conducted on 359 patients prospectively screened according to the ACC/AHA guidelines for preoperative risk in non-cardiac surgery. Main outcome was 30-day death; secondary outcomes 30-day myocardial infarction, and composite of 30-day myocardial infarction or death.RESULTS:Of the patients included, 95 (26.5%) received at least one unit of red blood cells. Patients who received transfusion had a significantly increased hazard of 30-day death (hazard ratio [HR] 11.72, 95% confidence interval [CI] 3.92-35.10; p<0.0001), myocardial infarction (HR 3.3, 95% CI 1.7-6.1; p=0.0003), and both (HR 4.0 95% CI 2.2-7.3; p<0.0001). Such associations held even after adjusting for baseline characteristics, surgical risk, bleeding, and propensity to receive transfusion. There was a significant interaction between transfusion and postoperative anaemia (p=0.012). In patients without anaemia, transfusion was associated with higher risk of 30-day death (HR 19.20, 95% CI 3.99-92.45; p=0.007), myocardial infarction (HR 5.05, 95% CI 2.23-11.44; p=0.0001), and both. Conversely, in patients with anaemia this association was not significant.CONCLUSIONS:In patients who underwent elective major vascular surgery, perioperative transfusion was associated with a significantly increased risk of 30-day events which was more attributable to patients with lesser degree of anaemia. Our data caution against the use of liberal transfusion in

2009 - Preliminary report on 30 months experience of in-hospital sepsis team [Abstract in Rivista]
Zavatti, L; Donno, L; Barbieri, E; Amateis, E; Rinaldi, L; Codeluppi, M; Girardis, Massimo
abstract

2009 - The use of blood products in massive bleeding: a preliminary report [Abstract in Rivista]
Giuliani, Enrico; Braccini, Ms; Cantaroni, C; Semeraro, G; Bertellini, E; De Palma, M; Marietta, M; Pinelli, G; Rambaldi, M; Girardis, Massimo
abstract

2009 - Usutu virus infection in a patient who underwent orthotropic liver transplantation, Italy, August-September 2009. [Articolo su rivista]
Cavrini, F; Gaibani, P; Longo, Fulvio Giovanni; Pierro, Am; Rossini, Gian Paolo; Bonilauri, P; Gerunda, Giorgio Enrico; DI BENEDETTO, Fabrizio; Pasetto, Alberto; Girardis, Massimo; Dottori, M; Landini, Mp; Sambri, V.
abstract

We report a case of Usutu virus (USUV)-related illness in a patient that underwent an orthotropic liver transplant (OLT). Post transplant, the patient developed clinical signs of a possible neuroinvasive disease with a significant loss of cerebral functions. USUV was isolated in Vero E6 cells from a plasma sample obtained immediately before the surgery, and USUV RNA was demonstrated by RT-PCR and sequencing. This report enlarges the panel of emerging mosquito-borne flavivirus-related disease in humans.

2008 - Applicazione delle linee guida nella pratica clinica: tre anni di esperienza nel policlinico di Modena [Relazione in Atti di Convegno]
Girardis, Massimo; Rinaldi, L; Donno, L; Codeluppi, M; Marietta, M; Venturelli, C; Marchegiano, P.
abstract

2008 - Effetto sul microcircolo della terapia con proteina C attivata ricombinante umana in pazienti con shock settico [Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Busani, S; Donno, L; Iacomini, E; Girardis, Massimo
abstract

2008 - Incidence and clinical outcomes of ventilator-associated pneumonia in liver transplant and non-liver transplant surgical patients. [Articolo su rivista]
C. M., Pellegrino; M., Codeluppi; S., Assenza; S., Cocchi; DI BENEDETTO, Fabrizio; Girardis, Massimo
abstract

The aim of this study was to compare the incidence of ventilator-associated pneumonia (VAP) and clinical outcome among patients undergoing orthotopic liver transplantation (OLT) admitted to our surgical intensive care unit (ICU). Patients with an ICU stay longer than 4 days who had undergone surgery within 48 hours of admission were included in the study. Patients were subdivided into a liver transplant group (OLT) and no-liver transplant group (noLT). Diagnosis of VAP was based on microbiological data with a positive culture from a sample collected >or=48 hours after admission. VAP was defined as early if the positive culture occurred within the 4th day of admission, and late if after the 4th day. Three hundred seventy-three noLT and 71 OLT patients showed no differences in sex, mean severity score on admission (SAPS II), length of stay, and outcomes. The incidence of VAP was also similar in the 2 groups (27.3\% in the noLT group vs 25.3\% in the OLT group). Both in the OLT and noLT groups, the VAP patients showed higher (P< .05) SAPS II scores on admission, length of ICU stay, and mortality rates than the non-VAP patients, without any difference between the 2 groups. VAP is a frequent complication in ICU surgical patients, particularly those with high severity scores on admission. In an ICU surgical population, liver transplantation per se does not seem to increase the patients' risk either for VAP acquisition or for bad outcomes.

2008 - La lotta alle infezioni in Terapia Intensiva [Articolo su rivista]
Girardis, Massimo; C., Venturelli; Aggazzotti, Gabriella; Righi, Elena
abstract

In questo articolo vengono presentati i risultati relativi alla sorveglianza delle infezioni nosocomiali condotta nella Unità Operativa di Terapia Intensiva Post-Operatoria (TIPO) dell'Azienda Ospedaliera Universitaria Policlinico di Modena

2008 - Recombinant activated factor VII in critical bleeding after orthotopic liver transplantation. [Articolo su rivista]
Busani, S; Semeraro, G; Cantaroni, C; Masetti, M; Marietta, M; Girardis, Massimo
abstract

Critical bleeding throughout the intraoperative phase of orthotopic liver transplantation (OLT) strongly increases patient mortality and intensive care unit (ICU) stay. The aim of this study was to report our experience on the use of recombinant activated factor VII (rFVIIa) in postoperative critical bleeding after OLT. In 7 patients with persistent severe bleeding after application of a standard transfusion protocol, we administered a 90 microg/kg bolus of rFVIIa and if necessary eventually repeated it after 3 hours. We recorded the blood loss and the need for transfusions before and after the rFVIIa therapy. Blood losses and need for platelets significantly decreased after rFVIIa administration; a nonsignificant decrease in red blood cells and fresh frozen plasma transfusions also occurred. In 6 patients treatment with rFVIIa was effective; only 1 patient died because of hemorrhagic shock and no thromboses were detected among the treated patients. Awaiting stronger evidence from randomized controlled trials, we suggest that in some challenging cases of massive bleeding rFVIIa should be considered a useful option to control bleeding.

2008 - Sorveglianza delle infezioni in terapia intensiva postoperatoria dell’Azienda Ospedaliera-Universitaria Policlinico di Modena [Abstract in Rivista]
Righi, Elena; Girardis, Massimo; Assenza, Silvia; Donno, Lara; Morandi, Matteo; Zambelli, Ilaria; Aggazzotti, Gabriella
abstract

La Terapia Intensiva Post Operatoria (TIPO) dell’Azienda Policlinico di Modena aderisce al Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva (GiViTI), e partecipa al Petalo “Sorveglianza Infezioni” con l’obiettivo di descrivere l'epidemiologia delle infezioni nei reparti di terapia Intensiva (TI) in Italia, di individuare e descrivere i principali fattori di rischio e fattori prognostici delle infezioni e di confrontare i diversi reparti in termini di incidenza di infezioni e loro gravità, di flora batterica prevalente, di incidenza di infezioni sostenute da germi multiresistenti.Nell’anno 2006 sono stati sorvegliati 767 soggetti; al momento dell’ammissione in TIPO 43 di essi presentavano infezioni (incidenza cumulativa di infezione all’ammissione: 5,6%). Durante la degenza 45 soggetti hanno poi acquisito una o più infezioni (incidenza cumulativa di infezione acquisita durante la degenza: 5,9%). Trenta polmoniti sono insorte durante la degenza; tra quelle manifestate dopo 48 h di ventilazione artificiale, 8 sono risultate sicuramente associate a ventilazione meccanica invasiva (VAP) (incidenza cumulativa 1.0%). Tra le batteriemie acquisite dai soggetti durante la degenza 3 sono risultate sicuramente associate all’utilizzo di catetere venoso centrale (CVC) evidenziando una incidenza cumulativa pari a 0.4%.Almeno la metà degli episodi infettivi insorge entro la terza giornata di degenza (mediana 3 giorni; media 4.3 ±5 giorni). Infezioni multiple sono state osservate in 15 soggetti (62.5% degli infetti). I microrganismi più frequentemente associati ad infezioni appartengono al genere stafilococco (43.9% degli isolamenti) ed in particolare molto diffuso è risultato Staphylococcus aureus (16 isolamenti). Anche Enterococchi (10 isolamenti) e Candide (10 isolamenti), in particolare Candida albicans, risultano diffusi. Microrganismi resistenti (appartenenti ai generi Pseudomonas e Stenotrophomonas) sono stati isolati in 6 episodi infettivi (14.6%). I dati rilevati risultano in linea con quanto osservato nelle altre TI aderenti Petalo “Sorveglianza Infezioni” del GiViTI.

2008 - Strategies to control massive abdominal bleeding. [Articolo su rivista]
Busani, S; Cavazzuti, I; Marietta, M; Pasetto, A; Girardis, Massimo
abstract

Abdominal trauma is divided into blunt and penetrating causes. Massive intraabdominal hemorrhage after injury represents the most dangerous precipitating factor that can affect survival if not promptly managed. The first target to achieve management of bleeding patients is control of the source, and then adequate resuscitation and optimization of hemostasis. New procoagulant drugs as recombinant activated factor VII (rFVIIa) seem to play an interesting role in bleeding control after trauma. Our experience with rFVIIa in six patients who were refractory to standard treatments demonstrated a good survival rate after massive abdominal bleeding. Regardless of new drugs and new technologies, a multidisciplinary approach is the cornerstone of the primary care of the these patients.

2008 - Studio del microcircolo in pazienti con patologia epatica e/o shock settico [Abstract in Rivista]
Rinaldi, L; Donno, L; Cavazzuti, I; Ferrari, E; Amateis, E; Girardis, Massimo
abstract

2008 - Team sepsi intraospedaliero: esperienza preliminare [Abstract in Rivista]
Donno, L; Amateis, E; Rinaldi, L; Codeluppi, M; Girardis, Massimo
abstract

2008 - Use of activated protein C in liver transplantation patients with septic shock. [Articolo su rivista]
Rinaldi, L; Marietta, M; Mignini, Ma; Donno, L; Busani, S; Codeluppi, M; Masetti, M; Girardis, Massimo
abstract

Recombinant human activated protein C (rhAPC) has been approved for use in patients with severe sepsis at high risk of death. Because of the high risk of bleeding, liver transplantation (LT) patients have been excluded from the randomized control trials that evaluated efficacy and safety of rhAPC and, thus, few data are available on the use of this drug in LT patients with severe sepsis. We describe our experience with 5 LT recipients treated for septic shock with the best conventional therapy and rhAPC. Before rhAPC therapy, all the patients showed septic shock, with ≥3 organ dysfunctions and thrombocytopenia with impairment of coagulation. rhAPC therapy started within 30 hours after septic shock onset in all the patients who recovered from sepsis-induced circulatory failure, improved organ dysfunction, and completed the 96 hours of rhAPC therapy. During rhAPC infusion, 4 patients received fresh'frozen plasma and/or platelet concentrates because of thrombocytopenia and severe hemostasis dysfunction. No major bleeding occurred and only 1 patient presented with minor bleeding events. © 2008 AASLD.

2008 - ∆PCO2 arteriosa e venosa e troponina come markers biologici in terapia intensiva [Relazione in Atti di Convegno]
Girardis, Massimo; Biagioni, E; Boni, E; Andreotti, A; Scarinci, N; Busani, S; Rinaldi, L.
abstract

2007 - Anestesia e coagulazione quale monitoraggio [Relazione in Atti di Convegno]
Cantaroni, C; Semeraro, G; Braccini, S; Busani, S; Marietta, M; Girardis, Massimo; Pasetto, A.
abstract

2007 - Comment on [A modified goal-directed protocol improves clinical outcome in intensive care unit patients with septic shock patients: a randomized controlled trial.] [Articolo su rivista]
L., Rinaldi; Girardis, Massimo
abstract

2007 - Differenza di CO2 nel sangue venoso centrale e nel sangue arterioso come indice precoce di insufficienza d’organo [Abstract in Rivista]
Biagioni, E; Boni, E; Busani, S; Girardis, Massimo; Pasetto, A.
abstract

2007 - Differenze microcircolatorie tra sepsi severa e shock settico rilevate con spettroscopia nel vicino infrarosso [Abstract in Rivista]
Cavazzuti, I; Rinaldi, L; Busani, S; Donno, L; Girardis, Massimo
abstract

2007 - Gram-positive bloodstream infections in liver transplant recipients: incidence, risk factors, and impact on survival. [Articolo su rivista]
A., Bedini; M., Codeluppi; S., Cocchi; Guaraldi, Giovanni; DI BENEDETTO, Fabrizio; C., Venturelli; Masetti, Michele; F., Prati; Mussini, Cristina; V., Borghi; Girardis, Massimo; Gerunda, Giorgio Enrico; F., Rumpianesi; Esposito, Roberto
abstract

The objective of the study was to assess the incidence, risk factors, and survival of gram-positive bloodstream infections (GP-BSIs) among liver transplant recipients during the first year after transplantation. Between October 2000 and September 2006, 42 episodes of GP-BSIs occurred in 205 patients with an overall incidence of 0.20 episodes/patient. Coagulase-negative staphylococci were detected in 45.2% of cases, Enterococcus species in 42.9% (E faecalis, eight; E faecium, seven; E avium, two; E gallinarum, one) and Staphylococcus aureus in 11.9%. Retransplantation was the only independent risk factor for GP-BSI (odds ratio [OR], 0.253; 95% confidence interval (CI), 0.089 to 0.715; P = .009). Thirty-day mortality rate was 28.5% and S aureus infections were related to a poorer outcome. It is noteworthy that all the isolates of S aureus were methicillin-resistant. Ampicillin was inactive against all the strains of E faecium and 50% of E avium isolates, but active against all E faecalis and E gallinarum strains. All the isolates were glycopeptide-susceptible. No significant differences in mortality rate were observed in relation to sex, etiologies of end-stage liver disease, cytomegalovirus infection/reinfection, type of donor, rejection, or retransplantation. GP-BSI, the only independent risk factor for death (OR, 0.262; 95% CI, 0.106 to 0.643; P = .003), reduced the survival rate by 26% in the first year posttransplant. In conclusion, GP-BSIs impact significantly on morbidity and mortality posttransplant, particularly among retransplantations. Control measures are required to reduce the incidence of GP-BSIs in liver transplant recipients. These findings must be considered when empirical antimicrobial therapy is indicated while awaiting blood-culture results.

2007 - Il ruolo della programmazione regionale: l’esperienza dell’Emilia Romagna nella lotta alla sepsi [Relazione in Atti di Convegno]
Girardis, Massimo; L., Donno; L., Rinaldi; M., Marietta; M., Codeluppi; Pmarchegiano, ; R., Baricchi; F., Caramelli; A., D’Errico; A., Giovannitti; R., Melotti; A., Peghetti; G., Pinelli; D., Resi; G., Sangiorgi; F., Tumietto; M., Zanello; Ml, Moro
abstract

2007 - Intracerebral haemorrhage in anticoagulated patients [Relazione in Atti di Convegno]
Marietta, M; Pedrazzi, P; Busani, S; Girardis, Massimo; Cantaroni, C; Torelli, G.
abstract

2007 - Intracerebral haemorrhage: an often neglected medical emergency. [Articolo su rivista]
Marietta, M; Pedrazzi, P; Girardis, Massimo; Torelli, G.
abstract

Intracerebral haemorrhage (ICH) is the deadliest form of stroke, carrying a mortality rate between 30% and 55%, increasing to 67% in patients on oral anticoagulant therapy (OAT). Despite its relevant incidence, the treatment of ICH has been until recently a largely neglected item, addressed by only a few trials. Early treatment of ICH in non-anticoagulated patients with recombinant activated factor VII (rFVII) has been demonstrated to be able to limit the growth of the haematoma, but such a promising result requires further confirmations. In ICH patients receiving OAT a prompt reversal of the anticoagulant effect should be warranted in order to reduce the consequences of this dreadful adverse event. In clinical practice, however, just a small proportion of anticoagulated patients receive this treatment, probably because of the fear of thromboembolic complications. It is now time to check our way of thinking about ICH, regarding and treating it as a compelling medical emergency. © Springer-Verlag Italia 2007.

2007 - Liver transplantation in HIV patients [Abstract in Rivista]
Masetti, M.; Cocchi, S.; Montalti, R.; Guaraldi, Giovanni; Romano, A.; Codeluppi, M.; Girardis, Massimo; De Ruvo, N.; Busani, S.; Ballarin, R.; DI BENEDETTO, Fabrizio; Guerrini, G. P.; Iemmolo, R. M.; Rompianesi, G.; Gerunda, Giorgio Enrico
abstract

not available

2007 - Peri-operative respiratory failure in a cirrhotic patient: a misleading diagnosis. [Articolo su rivista]
Busani, S.; Rinaldi, L.; Barbieri, E.; Drago, A.; Barbieri, A.; Girardis, Massimo
abstract

Patients with chronic liver disease may present with different degrees of respiratory dysfunction whose differential diagnosis is important before elective surgery. We report the case of a misleading diagnosis of peri-operative respiratory failure in a cirrhotic patient who underwent mastectomy. Intra-operative respiratory failure was ascribed by the anaesthetic team to pulmonary embolism and after the operation this diagnosis was still suspected. Despite postoperative heparin treatment, pulmonary gas exchange remained severely impaired. On the hypothesis of a right to left shunt, we performed transoesophageal echocardiography with a bubble test and confirmed hepatopulmonary syndrome. We administered anticoagulant therapy to the patient following surgery, increasing the risk of haemorrhage. We also continued orotracheal intubation and mechanical ventilation longer than was needed. Respiratory symptoms in a patient with liver disease should not be underestimated and up to 20\% of these patients may have hepatopulmonary syndrome.

2007 - Pratica Trasfusionale in pazienti con emorragia critica: esperienza del Policlinico di Modena [Abstract in Rivista]
Cantaroni, C; Semeraro, G; Braccini, S; Busani, S; Marietta, M; De Palma, M; Girardis, Massimo
abstract

2007 - Programma educazionale: effetti su gestione e outcome in pazienti con sepsis severa/shock settico ricoverati in TI [Abstract in Rivista]
Donno, L; Rinaldi, L; Marchegiano, P; Barbieri, E; Kameni, H; Amateis, E; Assenza, S; Ferrari, E; Ferrari, G; Girardis, Massimo
abstract

2006 - Anestesia e disordini vasculo-polmonari nel paziente epatopatico: iter diagnostico e ruolo dello screening precoce [Relazione in Atti di Convegno]
Busani, S; Rinaldi, L; Girardis, Massimo
abstract

2006 - Applicazione dei “sepsis care bundles” nei pazienti con shock settico [Abstract in Rivista]
Donno, L; Rinaldi, L; Marchegiano, P; Kameni, H; Amateis, E; Girardis, Massimo
abstract

2006 - Continuous quality improvement in intensive care medicine. The GiViTI Margherita project - Report 2005 [Articolo su rivista]
Ffelli, S. a; Rossi, C. a; Anghileri, A. a; Giardino, M. a; Carnevale, L. b; Messina, M. c; Neri, M. d; Langer, M. e; Bertolini, G. a.; Abastanotti, M. f; Alberti, A. g; Alborghetti, A. h; Angiolini, P. i; Anticoli, B. S. j; Archi, D. k; Arditi, E. l; Badii, F. m; Balata, A. n; Barattini, M. i; Barbagli, R. i; Bartoccini, A. o; Bartoli, T. p; Bassi, F. q; Beck, E. r; Belloni, U. G. s; Berardino, M. t; Bernasconi, M. O. u; Bianchin, A. v; Blasetti, A. w; Boccalatte, Rosa; D. x, Bonaccorso; G. y, Bonfà; A. z, Bonfiglio; M., Aa; Bonizzoli, M. i; Bottari, ; V., Ab; Breschi, ; C., Ac; Bressan, S. t; Brunori, ; E., Ad; Burgio, ; G., Ae; Buzzetti, ; V., Af; Cabano, ; G. V., Ag; Calicchio, ; G., Ah; Caracciolo, ; M., Ai; Casagli, ; S., Aj; Casagrande, ; L., Ak; Casciani, M. j; Castiglione, ; G., Al; Cavallo, R. t; Chiarello, ; M., Am; Chieregato, ; A., An; Chinelli, ; E., Ao; Chini, ; G., Ap; Clemente, ; S., Aq; Coaloa, ; M., Ar; Colombo, ; R., As; Colonna, ; S. S., At; Cominotti, ; S., Au; Corsini, ; W., Av; Constanzo, ; E., Aw; Crema, ; L., Ax; Crestan, ; E., Ay; Dal, Cero; P., Az; Dal, Ferro; M., Ba; Dal, Poggetto; L., Bb; Dal, Pos; L., Bc; David, ; A., Bd; De, Blasi; R. A., J; De, Luca; A., I; De, Negri; P., Be; Dei, Poli; M., Bf; Del, Sarto; P., Bg; Di, Masi; P., Bh; Di, Pasquale; D., Bi; Elvio, ; D. B., Bj; Fabbri, ; E., Bk; Fabbri, L. i; Fabbri, ; P. G., Ae; Fabi, ; M. C., Bl; Faccio, L. t; Falconio, ; A., Bm; Fasiolo, ; S., Bn; Febbrari, ; P., Bo; Ferrante, ; M., Bo; Ferraro, ; F., Bp; Fiore, ; G., Bq; Fontaneto, ; C., Br; Gabini, ; R., Bs; Galeotti, ; E., Bt; Gamberini, ; E., An; Garelli, ; A., Bu; Garofalo, ; G., Al; Giacopuzzi, ; L., Bv; Gianni, ; M., Bw; Giannoni, ; S., Bx; Girardis, Massimo; Giudici, ; D., As; Giugiaro, ; P. M., Bz; Gorietti, ; A., Ca; Grassi, ; P., Cb
abstract

Aim. The assessment of the quality of intensive care medicine is mandatory in the modern healthcare system. In Italy, the GiViTI (Gruppo Italiano per la Valutazione degli Interventi in Terapia Intensiva) network is working in this field since 1991 and it now involves 295 out of the about 450 Italian intensive care units (ICU). In 2002 GiViTI launched a project for the continuous quality assessment and improvement that is now joined by 180 ICUs. Data collected in 2005 are analyzed and presented. Methods. All admitted patients were entered in a validated software, which performs a multitude of validity checks during the data entry. Data were further reviewed by the co-ordinating center; patients admitted in months with more than 10% of incomplete or inconsistent records in each ICU were excluded from the analysis. Each year, a multivariate logistic regression model is fitted to identify predictors of hospital mortality. Starting from the SAPS 2 and the 2004 GiViTI model predictions of hospital mortality, two calibration tables and curves are presented. Results. In 2005, 180 Italian ICUs collected data on 55 246 patients. After excluding those admitted in months with an unjustified lower recruitment rate or with less than 90% of complete and consistent data, we had 52 816 (95.6%) valid cases. Although the rough hospital mortality in 2005 was 1% higher than in 2004 (22.6% vs 21.5%), the adjusted mortality shows a statistically significant 4% reduction (obser-ved-to-expected ratio: 0.96; 95% CI: 0.94-0.97). Conclusion. Italian ICUs in 2005 performed better than in 2004, at a parity of patient severity.

2006 - Definizione di protocolli condivisi Trattamento fine vita in terapia intensiva [Abstract in Rivista]
Dall’Oglio, D; Mirri, P; Chierego, G; Leonelli, V; Girardis, Massimo; Pasetto, A.
abstract

2006 - Definizione di protocolli condivisi nell’emorragia critica [Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S; Cantaroni, C.
abstract

2006 - Emorragia critica: clinica, diagnosi e trattamento [Abstract in Atti di Convegno]
Cantaroni, C; Chierego, G; Busani, S; Marietta, M; Girardis, Massimo
abstract

2006 - Intra-abdominal hypertension in nonelective surgery: A preliminary report [Articolo su rivista]
Busani, S; Soccorsi, Mc; Poma, C; Girardis, Massimo
abstract

Intra-abdominal hypertension (IAH) is recognized to be associated with adverse outcomes in critically ill patients. Etiologic factors for IAH can be divided into three categories: medical, posttraumatic, and surgical/postoperative. No studies have been performed on patients who underwent nonelective surgery, so our aim was to determine prospectively the incidence of IAH among these patients during their intensive care stay to correlate intra-abdominal pressure (IAP) and other parameters. Abdominal pressure was recorded twice daily with the standard method. The study group enrolled 22 patients who underwent an abdominal operation that met urgency criteria and with a postoperative intensive care unit (ICU) stay of at least 48 hours. Several serum and clinical parameters were studied for the first 5 postoperative days as well as during ICU and hospital stay as well as monitored hospital mortality. Our results demonstrated that mortality was definitely higher among patients who developed IAH compared with non-IAH patients. Our results highlighted that a strong correlation existed between increasing values of IAP and worsening serum creatinine and PaO2/FiO(2) quotient among patients who underwent nonelective surgery.

2006 - Living donor liver transplantation and management of portal venous pressure. [Articolo su rivista]
Busani, S; Marconi, G; Schiavon, L; Rinaldi, L; Del Buono, M; Masetti, Michele; Girardis, Massimo
abstract

Small-for-size syndrome occurs in the presence of a reduced mass of liver that is insufficient to maintain normal liver function. It has been speculated that this dysfunction is principally associated with graft exposure to excessive portal perfusion. The aim of these cases was to evaluate the efficacy of octreotide, a splanchnic vasoconstrictor, and esmolol, a selective beta-blocker, to modify the portal perfusion in the postoperative phase after left living related liver transplantation (LRLT). Four patients who underwent left LRLT with graft-to-recipient weight ratios of 0.60 +/- 0.24 were studied with a catheter placed in a jejunal vein. We observed high basal values of hepatic venous pressure gradient (HVPG) and portal vein flow (PVF). Octreotide infusion decreased HVPG, an effect that was more pronounced when it was combined with esmolol. The administration of both drugs was also associated with an improvement in portal vein oxygen saturation. Despite variation in PVF, the plasma disappearance rate of indocyanin green did not change during the infusion of the two drugs. In conclusion, octreotide and esmolol infusion allowed a manipulation of portal vein pressure that should be measured in left LRLT using a small-for-size graft.

2006 - More on: Platelet count and the Use of Recombinant Factor VIIa for the treatment of Bleeding Complications after Hematopoietic Stem Cell Transplantation [Articolo su rivista]
Marietta, M; Facchini, L; Girardis, Massimo; Luppi, Mario; Torelli, Giuseppe
abstract

n.d.

2006 - Muscle oxygenation in septic patients treated with activated protein C [Abstract in Rivista]
Rinaldi, L; Busani, S; Girardis, Massimo
abstract

2006 - New frontiers in critical bleeding [Relazione in Atti di Convegno]
Busani, S; Donno, L; Girardis, Massimo
abstract

2006 - Posttransplant cerebral hemorrhage in a patient with familial amyloidotic polyneuropathy [Articolo su rivista]
L., Rinaldi; S., Busani; Pasetto, Alberto; Girardis, Massimo
abstract

2006 - Rectal amputation sparing by haemostatic therapy with recombinant factor Vlla in a patient with cytomegalovirus-related colitis [Articolo su rivista]
Girardis, Massimo; Marietta, M; Busani, S; Codeluppi, M; Villa, Erica; Pasetto, A.
abstract

The use of rFVIIa allowed to rescue the integrity of intestinal tract

2006 - Sepsis bundles in non intensive care patients [Abstract in Rivista]
Donno, L; Finelli, M; Rinaldi, L; Marchegiano, P; Cappi, C; Codeluppi, M; Busani, S; Girardis, Massimo
abstract

2006 - Thymoglobulin-induced severe cardiovascular reaction and acute renal failure in a patient scheduled for orthotopic liver transplantation [Articolo su rivista]
Busani, S.; Rinaldi, L.; Begliomini, Bruno; Pasetto, Alberto; Girardis, Massimo
abstract

Antithymocyte globulin (ATG) has been shown to be effective as a pretreatment immunosuppressive agent in liver transplantation because of the ability to wean tacrolimus monotherapy after 4 months in pretreated recipients. However, the use of ATG can be complicated by serious side effects. Reported side effects include severe cardiopulmonary reactions, adult respiratory distress syndrome and hematological disorders. We report a case of a patient with a medical history of cirrhosis scheduled for orthotopic liver transplantation that, during the operation, showed swelling, hyperthermia, tachycardia and hypotension after the administration of ATG. Acute renal failure (ARF) was another serious side effect that our patient developed during ICU star, we ascribed the occurrence of ARF to the serum sickness disease triggered by the ATG administration. only one case has been reported of ARF after ATG-therapy before our experience. Therefore, severe hyperthermia and signs of cardiovascular dysfunction early after the beginning of ATG administration should be carefully evaluated and may need to consider the immediate ATG therapy withdrawal to prevent ARF.

2006 - Utilizzo del RFVII nell’emorragia post-partum: caso clinico [Abstract in Rivista]
Chierego, G; Cantaroni, C; Severino, C; Marietta, M; Marudi, A; Girardis, Massimo
abstract

2005 - Ineffectiveness of a new therapeutical strategy in preventing ventilator associated pneumonia [Abstract in Atti di Convegno]
Cm, Pellegrino; F., Stagni; Girardis, Massimo
abstract

2005 - Inefficacia nella prevenzione delle polmoniti di una strategia di miglioramento nella gestione del paziente ventilato [Abstract in Rivista]
F., Stagni; Cm, Pellegrino; Girardis, Massimo
abstract

2005 - Muscle PO2 during rhAPC administration in septic shock: a preliminary report [Abstract in Rivista]
Rinaldi, L.; Busani, S.; Girardis, Massimo
abstract

2005 - Nuove Tecnologie nello studio dell’ossigenazione tissutale [Relazione in Atti di Convegno]
L., Rinaldi; Girardis, Massimo
abstract

2005 - Nuove strategie di approccio al sanguinamento critico. Ruolo del critical bleeding network [Relazione in Atti di Convegno]
Girardis, Massimo
abstract

2005 - Severe bleeding in critical care [Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Marietta, M.
abstract

2005 - Use of recombinant factor VIIa in thrombocytopenic patient with spontaneous intracerebral haemorrhage. [Articolo su rivista]
Busani, S.; Marietta, M.; Pasetto, A.; Girardis, Massimo
abstract

In this report, we describe the use of rFVIIa in a thrombocytopenicpatient with ICH undergoing emergency craniotomy forhematoma evacuation.

2005 - [Outcome of isolated small bowel transplantation in adults: experience from a single Italian center] [Articolo su rivista]
DI BENEDETTO, Fabrizio; A., Lauro; M., Masetti; Cautero, Nicola; N. D., Ruvo; Quintini, Cristiano; S., Sassi; F. D., Francesco; T. D., Usò; A., Romano; A., Dazzi; G., Molteni; Begliomini, Bruno; A., Siniscalchi; L. D., Pietri; Bagni, Alessandra; A., Merighi; M., Codeluppi; Girardis, Massimo; G., Ramacciato; A. D., Pinna
abstract

AIM: Isolated small bowel transplantation is becoming the treatment of choice for adult patients with serious parenteral nutrition (PN) related complications: we report our three-year experience (December 2000-December 2003) from a single Italian center (Modena-Italy), with one of the larger European series. METHODS: We transplanted 14 patients, with a previous mean PN course of 27 months and a mean 21-month post-transplantation follow-up (range 3-36 months), obtaining a one-year actuarial survival rate of 92.3% with no intraoperative deaths. RESULTS: We lost 1 patient (7.2%), died for post-transplantation overwhelming sepsis following Cytomegalovirus (CMV) enteritis. Thirteen patients are alive, with one-year actuarial graft survival rate of 85.1%: 1 patient underwent graft removal (7.2%) for intractable severe acute rejection. Our immunosuppressive regimen was based on tacrolimus and 3 induction protocols: daclizumab (8 patients) with steroids, alemtuzumab (4 patients) and thymoglobulin (2 patients) without steroids. In 9 cases, we added sirolimus. Nine recipients experienced 22 episodes of acute cellular rejection (ACR), treated successfully in all cases but one. One patient (7.2%) was treated successfully for Post Transplant Lymphoproliferative Disease (PTLD) and is disease-free after 8 months. CONCLUSIONS: Small bowel transplantation can achieve optimal results depending on appropriate immunosuppressive management and candidate selection, added to shorter ischemia time and careful donor and graft selection.

2004 - Activated factor VII in major abdominal surgery and liver transplantattion [Relazione in Atti di Convegno]
M., Marietta; Girardis, Massimo; Pasetto, Alberto; G., Torelli
abstract

2004 - Biochemical markers of sepsis [Relazione in Atti di Convegno]
Liva, S.; Busani, S.; Rinaldi, L.; Girardis, Massimo
abstract

2004 - Comment on: "Hemodynamic response to coupled plasmafiltration-adsorption in human septic shock" by Formica et al. [Articolo su rivista]
Girardis, Massimo
abstract

2004 - Intraoperative and post-operative management of living donor liver transplanted patients [Relazione in Atti di Convegno]
Pasetto, Alberto; Busani, S.; Donno, L.; Fanigliulo, Ma; De Pietri, L.; Siniscalchi, A.; Begliomini, Bruno; Girardis, Massimo
abstract

2004 - Non invasive monitoring of dead space and pulmonary capillary blood flow to optimise mechanical ventilation [Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Rinaldi, L.
abstract

2004 - Renal complications after liver transplantation: orthotopic versus living related [Abstract in Atti di Convegno]
Bondi, F.; Busani, S.; Serio, L.; Girardis, Massimo; Pasetto, Alberto
abstract

2004 - The effects of prostaglandin E1 on indocyanine green clearance after liver transplantation [Abstract in Atti di Convegno]
L., Donno; Ma, Fanigliulo; Girardis, Massimo
abstract

2004 - Thymoglobulin-induced severe cardiovascular reaction and acute renal failure in a patient scheduled for orthotopic liver transplantation [Abstract in Atti di Convegno]
Busani, S.; Rinaldi, L.; Serio, L.; Bondi, F.; Begliomini, Bruno; Pasetto, Alberto; Girardis, Massimo
abstract

2004 - Use of a new hemostatic drug in the management of severe bleeding in surgical patients [Relazione in Atti di Convegno]
Girardis, Massimo; Marietta, M.; Busani, S.; Pasetto, Alberto
abstract

2004 - Utilizzo di emostatici: approccio corrente e nuove prospettive [Relazione in Atti di Convegno]
Marietta, M.; Busani, S.; Girardis, Massimo
abstract

2004 - rVIIa nelle emorragie incontrollabili: protocolli clinici e sorveglianza uso clinico [Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Marietta, M.
abstract

2003 - Bioartificial liver support with human hepatocytes and MARS in fulminant hepatic failure: comparison with standard therapy [Abstract in Atti di Convegno]
R., Balugani; H., Bertani; M., del Buono; R., Iemmolo; Gelmini, Roberta; Girardis, Massimo; Villa, Erica
abstract

2003 - Muscle perfusion and oxygen consumption by near-infrared spectroscopy in septic-shock and non-septic-shock patients [Articolo su rivista]
Girardis, Massimo; Rinaldi, L.; Busani, S.; Flore, I.; Mauro, S.; Pasetto, Alberto
abstract

Objective. To measure muscle blood flow (Qtis) and oxygen consumption (VO(2)tis) in septic and non-septic critically ill patients by near-infrared spectroscopy (NIRS). Setting. Surgical intensive care unit of a university hospital. Patients and participants. Four patients with septic shock, eight post-surgical critically ill patients and ten healthy volunteers. Measurements and results. Oxyhaemoglobin (HbO(2)) and deoxyhaemoglobin (HbH) variations after venous occlusion were measured by NIRS in the brachioradialis muscle. We calculated Qtis by the rate of HbO(2) and HbH increase in the first 30 s of venous occlusion divided by haemoglobin blood concentration. VO(2)tis was calculated by subtraction of the arterial HbH from the initial increase of HbH after venous occlusion extrapolated to 1 min. Tissue oxygenation index [TOI = HbO(2)/(HbO(2)+HbH)] was also measured before venous occlusion. Two measurements in patients with septic shock, and one measurement in non-septic-shock patients and healthy subjects, were obtained. Of the measurements, 35% were repeated because of low-quality NIRS signal. VO(2)tis and Qtis were two times larger (P<0.05) in patients with septic shock than in patients without and in healthy subjects. The TOI was very similar among the three groups. Conclusion. In septic-shock patients the increase in VO(2)tis was associated with an equivalent increase in Qtis. Therefore, tissue O-2 supply does not seem to be a limiting factor for muscle O-2 consumption. NIRS combined with venous occlusion allows a rapid, non-invasive and simultaneous assessment of regional perfusion and oxygen consumption. In case of microcirculatory shunt occurrence, the TOI should be cautiously used to assess tissue oxygenation state.

2003 - Post-transplant cerebral haemorrhage in patient with TTR-FAP [Abstract in Atti di Convegno]
Rinaldi, L.; Busani, S.; Girardis, Massimo; Serio, L.; Pasetto, A.
abstract

2003 - Prostaglandin E1 and indocyanine green disappearance rate after liver surgery [Abstract in Atti di Convegno]
L., Donno; M., Fratini; V., Braglia; L., Rinaldi; Girardis, Massimo
abstract

2003 - Recipient proinflammatory state and graft dysfunction in liver transplantation: preliminary report. [Abstract in Atti di Convegno]
S., Liva; Girardis, Massimo; G., Chierego; C., Tetta; A., Siniscalchi; Begliomini, Bruno; Pasetto, Alberto
abstract

2003 - Splanchnic vasoconstrictors and vasodilators in a case of left lobe liver transplantation. [Abstract in Atti di Convegno]
Busani, S.; Girardis, Massimo; Donno, L.; Rinaldi, L.; Serio, L.; Miller, C.; Pinna, Ad
abstract

2003 - Tissue oxygenation by near infrared spectroscopy [Relazione in Atti di Convegno]
Girardis, Massimo; Rinaldi, L.; Busani, S.
abstract

2003 - Venous-arteriolar reflex in human gastrocnemius studied by NIRS. [Relazione in Atti di Convegno]
Binzoni, T; Ngo, L; Girardis, Massimo; Springett, R; Terrier, F; Delpy, D.
abstract

Heat-up tilting manoeuvre from 0 to 60 degrees induces oxygenated and deoxygenated haemoglobin concentration changes in the human gastrocnemius. These changes, measured by NIRS, can only be partially explained by the blood volume displacement due to the gravitational force. In the present study it is demonstrated, by a dye dilution technique (indocyanine green), that a reduction in blood flow (venous-arteriolar and/or spinal reflex) is responsible of the limited oxyhaemoglobin concentration increase observed when going from 0 (2.54 +/- 0.48 blood flow in arbitrary units, a.u.) to 60 (1.46 +/- 0.55 a.u.) degrees. The proposed technique is potentially applicable to the detection of specific pathological aspects of microcirculation, such as arterial occlusion in the leg, diabetes mellitus, and congestive heart failure, where the venous-arteriolar reflex may be affected.

2003 - [Living donor liver transplantation, adult to adult]. [Articolo su rivista]
A., Pinna; M., Masetti; C., Miller; A., Dazzi; B., Begliomini; A., Siniscalchi; N., Cautero; F. D., Benedetto; A., Lauro; Girardis, Massimo; Villa, Erica; G., Ramacciato
abstract

Since living donor liver transplantation (LDLT) can offer a viable response to the lack of transplantable cadaveric organs, our center instituted an LDLT program in 2001.The authors report their experience with the first 35 LDLT procedures successfully completed at the Liver and Multiorgan Transplant Center of the University of Modena between 9 May 2001 and 21 May 2003. The case series comprised 35 patients, 7 of which received a left-half liver and 1 a left lobe.The global survival rate was 77.2\% (27 out of 35 patients), with a mean follow-up period of 295 days; the survival rate at 1 year was 81\%. In 4 cases (11\%) retransplantation was performed. The donor demographics are described; all donors returned to their normal activities before transplantation, after a mean follow-up period of 373 days. No intraoperative complications were experienced by the donors, whereas during the postoperative period, 2 donors (5.7\%) developed major complications (1 biliary fistula on the cut surface, 1 stenosis of the main bile duct).Our study shows that LDLT can be safely completed in the donor, with good results achieved in the recipient as well. Underlying these results is the accurate pretransplant assessment that continued into the operation itself. Even more important was the demonstrated ability and experience of the surgical team to attain results in the donor which we believe are necessary for carrying forth a LDLT program.

2002 - Comparative analysis of intraoperative data in living donor and cadaveric liver transplantation [Abstract in Atti di Convegno]
L., De Pietri; A., Roberti; M., Degoli; M., Gazzi; L., Rinaldi; A., Siniscalchi; B., Begliomini; Girardis, Massimo; Pasetto, Alberto
abstract

2002 - Does any medical intervention modify outcome in patients with hepatic failure [Relazione in Atti di Convegno]
C., Bassi; A., Borghi; N., De Maria; Girardis, Massimo; A., Liberati; V., Solfrini; Villa, Erica
abstract

2002 - Early experiences with a porcine hepatocyte-based bioartificial liver in acute hepatic failure patients [Articolo su rivista]
E., Morsiani; P., Pazzi; A. C., Puviani; M., Brogli; L., Valieri; P., Gorini; P., Scoletta; E., Marangoni; R., Ragazzi; G., Azzena; E., Frazzoli; D. D., Luca; E., Cassai; G., Lombardi; A., Cavallari; S., Faenza; A., Pasetto; Girardis, Massimo; E., Jovine; A. D., Pinna
abstract

Orthotopic liver transplantation (OLT) is the only effective therapeutic modality in severe acute hepatic failure (AHF). The scarcity of organs for transplantation leads to an urgent necessity for temporary liver support treatments in AHF patients. A hepatocyte-based bioartificial liver (BAL) is under investigation with the main purpose to serve as bridging treatment until a liver becomes available for OLT, or to promote spontaneous liver regeneration. We developed a novel radial-flow bioreactor (RFB) for three-dimensional, high-density hepatocyte culture and an integrated pumping apparatus in which, after plasmapheresis, the patient's plasma is recirculated through the hepatocyte-filled RFB. Two hundred thirty grams of freshly isolated porcine hepatocytes were loaded into the RFB for clinical liver support treatment. The BAL system was used 8 times in supporting 7 AHF patients in grade III-IV coma, all waiting for an urgent OLT Three patients with no history of previous liver diseases were affected by fulminant hepatic failure (FHF) due to hepatitis B virus, 3 by primary non-function (PNF) of the transplanted liver, and one by AHF due to previous abdominal trauma and liver surgery. Six out of 7 patients underwent OLT following BAL treatment(s), which lasted 6-24 hours. All patients tolerated the procedures well, as shown by an improvement in the level of encephalopathy, a decrease in serum ammonia, transaminases and an amelioration of the prothrombin time, with full neurological recovery after OLT Our initial clinical experience confirms the safety of this BAL configuration and suggests its clinical efficacy as a temporary liver support system in AHF patients.

2002 - Extravascular lung water and intravascular volume monitoring. [Articolo su rivista]
A., Roberti; Girardis, Massimo
abstract

2002 - Flusso capillare polmonare e spazio morto alveolare con metodiche combinate di capnografia volumetrica e CO2 partial rebreathing [Relazione in Atti di Convegno]
Girardis, Massimo; Busani, S.; Rinaldi, L.; Pasetto, A.
abstract

2002 - Hemodynamic effects of different surgical techniques in orthotopic liver transplantation. [Abstract in Atti di Convegno]
Busani, S.; Roberti, A.; Rinaldi, L.; Siniscalchi, A.; Girardis, Massimo; Pasetto, A.
abstract

2002 - Literature overview on artificial liver support in fulminant hepatic failure: A methodological approach [Articolo su rivista]
H., Bertani; Gelmini, Roberta; MG Del, Buono; N., De Maria; Girardis, Massimo; Villa, Erica; V., Solfrini
abstract

Artificial liver support is a therapeutic option for subjects with fulminant hepatic failure. Results of these studies suggest a possible favourable effect on this condition. The aim of the present review is to evaluate not the results of the different artificial systems available but the methodology used to achieve these results. A computer and manual search of the literature was performed, 832 pertinent references were retrieved. Seventy-seven were full papers reporting the application of artificial liver support in animals or humans (15 RCTs (3 in humans, 12 in animals), 53 uncontrolled phase I trials, 9 case reports)., The results of this review indicate that, although the rationale of artificial liver support as shown by animal studies is acceptable, the widespread use in clinical practice is not justified and a controlled design for the studies on artificial liver support systems is mandatory.

2002 - Non invasive assessment of liver function by indocyanine green: preliminary report. [Relazione in Atti di Convegno]
V., Braglia; A., Roberti; S., Ivagnes; L., Serio; G., Chierego; Girardis, Massimo; Pasetto, Alberto
abstract

2002 - Ossido nitrico per via inalatoria nel paziente con insufficienza respiratoria acuta. [Abstract in Atti di Convegno]
Lombardini, C; Davolio, L; Girardis, Massimo
abstract

2002 - Pain management after small bowel/multivisceral transplantation [Articolo su rivista]
A., Siniscalchi; Begliomini, Bruno; L., De Pietri; Si, Petracca; V., Braglia; Girardis, Massimo; Pasetto, Alberto; Masetti, Michele; Cautero, Nicola; Jovine, Elio; Ad, Pinna
abstract

2002 - Pathophysiology of body fluids in anesthesia and intensive care [Abstract in Atti di Convegno]
Girardis, Massimo; L., Rinaldi; F., Bondi; P., Pantazopulos; G., Chierego
abstract

2002 - Perioperative hemodynamic profile in patients with early allograft dysfunction after liver transplantation [Relazione in Atti di Convegno]
Roberti, ; Busani, S.; Rinaldi, L.; Baraoni, S.; Girardis, Massimo; Pasetto, A.
abstract

2002 - Post-operative respiratory dysfunction after liver transplantation [Relazione in Atti di Convegno]
Crimi, E.; Donato, P.; Rinaldi, L.; Busani, S.; Girardis, Massimo
abstract

2002 - Profilassi delle complicanze micotiche nel trapianto di intestino e multiviscerale con amfotericina B liposomiale (Ambisome). [Abstract in Atti di Convegno]
Codeluppi, M.; Guaraldi, Giovanni; Bedini, A.; Cocchi, S.; Jovine, Elio; Pinna, A. D.; Ivagnez Petracca, S.; Girardis, Massimo
abstract

Il trapianto di intestino è gravato da una elevata incidenza di complicanze micotiche, prevalentemente causate da Candida spp. e Aspergillus spp. L'alto grado di immunosoppressione necessario in questo genere di trapianto, la massiccia translocazione batterica intestinale che accompagna l'atto operatorio ed episodi di rigetto ne costituiscono i principali fattori patogenetici. Per tali motivi è indicata una profilassi universale con antimicotici sistemici.

2002 - Relationship between infections and organ dysfunction after orthotopic liver transpalantation. [Relazione in Atti di Convegno]
L., Rinaldi; Girardis, Massimo; E., Becchi; Paladini, M. E.; G., Chierego; L., Serio; Pasetto, Alberto
abstract

2002 - Studio caso-controllo sui fattori di rischio delle infezioni micotiche nei pazienti sottoposti a trapianto ortotopico di fegato (OLT) da donatore cadavere e da donatore vivente. [Abstract in Atti di Convegno]
Guaraldi, Giovanni; Bedini, A.; Borghi, R.; Pomelli, I.; Venturelli, C.; Codeluppi, M.; Orlando, G.; Seghetto, B.; Cardini, G.; Girardis, Massimo; Gelmini, Roberta; Masetti, Michele; Pinna, A. D.; Esposito, Roberto
abstract

La sopravvivenza e la qualità della vita dei pazienti sottoposti a trapianto di organo solido è notevolmente migliorata grazie a innovative tecniche chirurgiche, a nuove terapie immunosoppressive e a un miglior controllo delle complicanze infettive. Nonostante ciò l'incidenza delle infezioni micotiche profonde nei pazienti sottoposti a OLT, rimane più alta rispetto ad altri tipi di trapianto di organo solido, e determina una mortalità ad esse correlata tutt'ora rilevante. Non è noto se i pazienti sottoposti a trapianto da donatore vivente abbiano un'incidenza minore di infezioni micotiche rispetto a quelli sottoposti da donatore cadavere.

2002 - The importance of information on volaemia during the perioperative period: new versus old technique [Relazione in Atti di Convegno]
Girardis, Massimo; A., Roberti; A., Pasetto
abstract

2002 - Valutazione della volemia e nuovi plasma expanders [Relazione in Atti di Convegno]
Pasetto, Alberto; A., Roberti; F., Bondi; G., Chierego; Girardis, Massimo
abstract

2001 - Evaluation of tissue blood flow and oxygenation by near infrared spectroscopy in septic patient [Abstract in Rivista]
Girardis, Massimo; Rinaldi, L.; Busani, S.; Flore, I.; Mauro, S.; Pasetto, Alberto
abstract

2001 - Extracorporeal liver support with plasma adsorbent system. A case report. [Relazione in Atti di Convegno]
M., D’Astuto; G., Chierego; S., Ivagnes; Girardis, Massimo; Pasetto, Alberto
abstract

2001 - Hemodynamic and metabolic evaluations by rebreathing method [Relazione in Atti di Convegno]
Girardis, Massimo; C., Lombardini; A., Pasetto
abstract

2001 - Non invasive mechanical ventilation vs invasive mechanical ventilation in COPD patients with comatose acute respiratory failure [Abstract in Rivista]
M., Moretti; Girardis, Massimo; A., Marchioni; M., De Guglielmo; C., Lombardini; L., Rinaldi; A., Pasetto; Lm, Fabbri
abstract

2001 - Relationship between oxygen uptake and cardiac output during vascular surgery [Abstract in Rivista]
Roberti, ; Busani, S.; Rinaldi, L.; Girardis, Massimo; Pasetto, Alberto
abstract

2001 - Tissue perfusion and oxygenation in septic patients [Abstract in Atti di Convegno]
Rinaldi, L.; Busani, S.; Flore, I.; Spampinato, A.; Raffaelli, M.; Girardis, Massimo
abstract

2001 - [Life threatening asthma associated to severe pneumonia and acute myopathy]. [Articolo su rivista]
Girardis, Massimo; Raffaelli, M; Flore, I; Pressacco, C; Pasetto, A.
abstract

A young male was transferred to our intensive care unit (ICU) from the intensive care unit of a local hospital where he was admitted for life-threatening asthma ten days before. As severe hypoxemia, we immediately started inhaled nitric oxide (iNO) that improved significantly pulmonary gas exchange. The first day after admission in our ICU, a chest computed tomography showed a three-lobar pneumonia and, therefore, a broad-spectrum antibiotic therapy was decided. iNO therapy was withdrawn 96 hours after the beginning because of a stable improvement of pulmonary gas exchange and a relative loss of efficacy. Five days after arrival in our ICU, sedative and neuromuscular blocking drugs initiated 15 days before were stopped and, after the awakening, the patient presented tetra-paresis. Muscle biopsy and electromyography indicated an acute myopathy that was probably caused by the association between large doses of steroids and neuromuscular blocking agents. In spite of an intensive physiotherapy program, the patient was extubated only 15 days after admission and he underwent non-invasive mechanical ventilation for further 7 days. The patient was discharged from our ICU 10 days after extubation with a good restore of muscle functioning which was complete two months later.

2000 - Delayed upper airway obstruction following a retropharyngeal haematoma after minor head trauma. [Articolo su rivista]
F., Kette; P., Mergoni; Girardis, Massimo; D., Sabbadini; M., Zauli; L., Sussi; Pasetto, Alberto
abstract

The development of a retropharyngeal haematoma may occur rarely after major head, face or cervical spine injuries, and it is even less frequent following minor trauma. As these patients are commonly not intubated, a life-threatening upper airway obstruction may occur. We report the case of a man who experienced a late retropharyngeal haematoma with delayed, progressive upper airway obstruction after a minor frontal wound. After an emergency intubation a nuclear magnetic resonance highlighted the magnitude of the bleeding into the retropharynx accounting for the slow onset of the symptoms. Predisposing factors such as antithrombotic therapies and vascular lesions may enhance the risk of occurrence even after minor trauma. Hypotheses on how to identify this potentially fatal complication earlier are reported.

2000 - Oxygen cascade in liver surgery [Relazione in Atti di Convegno]
Girardis, Massimo; F., Colò; C., Gonano; R., Pace; A., Pasqualucci; A., Pasetto
abstract

2000 - Prevention of post-herpetic neuralgia: Acyclovir and prednisolone versus epidural local anesthetic and methylprednisolone [Articolo su rivista]
A., Pasqualucci; V., Pasqualucci; F., Galla; V. D., Angelis; V., Marzocchi; R., Colussi; F., Paoletti; Girardis, Massimo; M., Lugano; F. D., Sindaco
abstract

Treatment of herpes zoster (HZ) includes the use of acyclovir with or without steroids. An alternative therapy is the epidural administration of local anesthetics with or without steroids. This trial compared the efficacy of these two treatment regimens in the prevention of post-herpetic neuralgia (PHN).Six hundred adults over 55 years of age with a rash of less than 7 days duration, and severe pain due to HZ, were enrolled and randomized to receive either intravenous acyclovir (10 mg/kg three times daily) for 9 days+prednisolone (60 mg per day with progressive reduction) for 21 days, or 6-12 ml bupivacaine (0.25\%) every 6-8 or 12 h+methylprednisolone 40 mg every 3-4 days by epidural catheter during a period ranging from 7 to 21 days. Efficacy was evaluated at 1, 3, 6 and 12 months. PHN was assessed as pain and/or allodynia, and "abnormal sensations" (hypoesthesia, burning, itching, etc.). Statistical analysis was performed based on the intent-to-treat population.In the 485 patients who completed the study, the incidence of pain after 1 year was 22.2\% (51 patients of 230) after acyclovir+steroids, and 1.6\% (4 patients of 255) after epidural analgesia+steroids. The incidence of abnormal sensations was 12.2\% (28 patients) after acyclovir+steroids, and 4.3\% (11 patients) in group B.Epidural administration of local anesthetic and methylprednisolone is significantly more effective in preventing PHN at 12 months compared to intravenous acyclovir and prednisolone.

2000 - The effects of clonidine on cardiovascular system during gynecologic surgery [Abstract in Atti di Convegno]
G., Chierego; Girardis, Massimo; Varutti, A. M.; S., Donato; S., Ivagnes; Pasetto, Alberto
abstract

2000 - The hemodynamic and metabolic effects of tourniquet application during knee surgery. [Articolo su rivista]
Girardis, Massimo; S., Milesi; S., Donato; M., Raffaelli; A., Spasiano; G., Antonutto; A., Pasqualucci; A., Pasetto
abstract

We evaluated the effects of tourniquet application on the cardiovascular system and metabolism in 10 young men undergoing knee surgery with general anesthesia. The duration of inflation was from 75 to 108 min. Heart rate, mean arterial pressure, cardiac index (CI) by pulse contour method, and systemic vascular resistance were measured before, during, and after tourniquet inflation. pH, PaO(2), PaCO(2), and lactate blood concentrations were also measured. VO(2) and VCO(2) were assessed every minute from tracheal intubation up to 15 min after tourniquet deflation and VO(2) in excess of the basal value over the 15 min after deflation (VO(2)exc) was calculated. Mean arterial pressure increased 26\% (P: < 0.05) during inflation and returned to basal values after deflation. CI did not change immediately after inflation; although, thereafter, it increased 18\% (P: < 0.05). Five minutes after deflation, CI further increased to a value 40\% higher than the basal value. Therefore, systemic vascular resistance increased 20\% suddenly after inflation (P: < 0.05) and decreased 18\% after deflation (P: < 0.05). VO(2) and VCO(2) remained stable during inflation and increased (P: < 0.05) after deflation. VO(2)exc depended on duration of tourniquet inflation time (Tisch) (P: < 0.05). After deflation, PaCO(2) and lactate increased (P: < 0.05) while Tisch increased. We conclude that tourniquet application induces modifications of the cardiovascular system and metabolism, which depend on tourniquet phase and on Tisch. Whether these modifications could be relevant in patients with poor physical conditions is not known. Implications: The clinical effects of tourniquet application were evaluated in 10 young men undergoing knee surgery. Our data indicate that tourniquet application causes hemodynamic and metabolic changes which may become clinically relevant after a long period of tourniquet inflation, particularly in patients with concomitant cardiovascular diseases.

2000 - Variazioni degli scambi gassosi polmonari dopo broncoscopia ripetuta in pazienti intubati [Abstract in Rivista]
D., Gattari; R., Carlon; G., Maringelli; A., Spampinato; L., Rinaldi; Girardis, Massimo
abstract

1999 - Effects of microgravity on maximal power of lower limbs during very short efforts in humans. [Articolo su rivista]
Antonutto, G; Capelli, C; Girardis, Massimo; Zamparo, P; di Prampero, Pe
abstract

The maximal power of the lower limbs was determined in four astronauts (age 37-53 yr) 1) during maximal pushes of approximately 250 ms on force platforms ["maximal explosive power" (MEP)] or 2) during all-out bouts of 6-7 s on an isokinetic cycloergometer [pedal frequency 1 Hz: maximal cycling power (MCP)]. The measurements were done before and immediately after spaceflights of 31-180 days. Before flight, peak and mean values were 3.18 +/- 0.38 and 1.5 +/- 0. 13 (SD) kW for MEP and 1.17 +/- 0.12 and 0.68 +/- 0.08 kW for MCP, respectively. After reentry, MEP was reduced to 67% after 31 days and to 45% after 180 days. MCP decreased less, attaining approximately 75% of preflight level, regardless of the flight duration. The recovery of MCP was essentially complete 2 wk after reentry, whereas that of MEP was slower, a complete recovery occurring after an estimated time close to that spent in flight. In the same subjects, the muscle mass of the lower limbs, as assessed by NMR, decreased by 9-13%, irrespective of flight duration (J. Zange, K. Müller, M. Schuber, H. Wackerhage, U. Hoffmann, R. W. G unther, G. Adam, J. M. Neuerburg, V. E. Sinitsyn, A. O. Bacharev, and O. I. Belichenko. Int. J. Sports Med. 18, Suppl. 4: S308-S309, 1997). The larger fall in maximal power, compared with that in muscle mass, suggests that a fraction of the former (especially relevant for MEP) is due to the effects of weightlessness on the motor unit recruitment pattern.

1999 - Monitoraggio in anestesia d’urgenza [Capitolo/Saggio]
M., Raffaelli; Girardis, Massimo
abstract

1999 - Oxygen conductance equation in septic patient: a preliminary report [Abstract in Rivista]
GIRARDIS, Massimo; S., Mauro; A., Spampinato; S., Milesi; A., Pasetto
abstract

xA model of the metabolic internal power ((E) over dot(int)) during cycling, which includes the gravity acceleration (a(g)) as a variable, is presented. This model predicts that (E) over dot(int) is minimal in microgravity (0 g; g = 9.81 m s(-2)), and increases linearly with a(g), whence the hypothesis that the oxygen uptake ((V) over dot O-2) during cycling depends on a(g). Repeated (V) over dot O-2 measurements during steady-state exercise at 50, 75 and 100 W on the cycle ergometer, performed in space (0 g) and on Earth (1 g) on two subjects. validated the model. (V) over dot O-2, was determined from the time course of decreasing O-2 fraction during rebreathing. The gas volume during rebreathing was determined by the dilution principle. using an insoluble inert gas (SF6). Average (V) over dot O-2 for subject 1 at each power was 0.99, 1.22 and 1.52 L min(-1) at 1 g (n = 3) and 0.91, 1.13 and 1.32 L min(-1) at 0 g (n = 5). For subject 2 it was 0.90. 1.12 and 1.42 L min(-1) at 1 g, and 0.76, 0.98 and 1.21 L min(-1) at 0 g. These values corresponded to those predicted from the model. Although resting (V) over dot O-2 was lower at 0 g than at 1 g, the net (total minus resting) exercise (V) over dot O-2 was still smaller at 0 g than at 1 g. This difference reflects the lower (E) over dot(int) at 0 g.

1999 - Oxygen cost of dynamic leg exercise on a cycle ergometer: effects of gravity acceleration. [Articolo su rivista]
Girardis, Massimo; Linnarsson, D; Moia, C; Pendergast, Dr; Ferretti, G.
abstract

A model of the metabolic internal power (Ė(int)) during cycling, which includes the gravity acceleration (a(g)) as a variable, is presented. This model predicts that Ė(int) is minimal in microgravity (0 g; g = 9.81 m s-2), and increases linearly with a(g), whence the hypothesis that the oxygen uptake (V̇O2) during cycling depends on a(g). Repeated V̇O2 measurements during steady-state exercise at 50, 75 and 100 W on the cycle ergometer, performed in space (0 g) and on Earth (1 g) on two subjects, validated the model. V̇O2 was determined from the time course of decreasing O2 fraction during rebreathing. The gas volume during rebreathing was determined by the dilution principle, using an insoluble inert gas (SF6). Average V̇O2 for subject 1 at each power was 0.99, 1.21 and 1.52 L min-1 at 1 g (n = 3) and 0.91, 1.13 and 1.32 L min-1 at 0 g (n = 5). For subject 2 it was 0.90, 1.12 and 1.42 L min-1 at 1 g, and 0.76, 0.98 and 1.21 L min-1 at 0 g. These values corresponded to those predicted from the model. Although resting V̇O2 was lower at 0 g than at 1 g, the net (total minus resting) exercise V̇O2 was still smaller at 0 g than at 1 g. This difference reflects the lower Ė(int) at 0 g.

1999 - Severe hypoxemia and pulmonary hypertension during orthotopic liver transplantation: a successful use of inhaled nitric oxide. [Articolo su rivista]
Girardis, Massimo; Pasqualotto, A; Colò, F; Dal Pos, L; Sabbadini, D; Pasqualucci, A; Pasetto, A.
abstract

1999 - Valutazioni delle condizioni idro-elettrolitiche del paziente [Capitolo/Saggio]
D., Tomasello; Girardis, Massimo
abstract

1998 - Applicazione dell’equazione di conduttanza dell’O2 nella pratica clinica [Abstract in Rivista]
PE di, Prampero; Girardis, Massimo; Pasetto, Alberto
abstract

1998 - Applicazione di un algoritmo per il controllo della ventilazione polmonare durante colecistectomia laparoscopica [Abstract in Rivista]
M., Raffaelli; C., Levato; S., Milesi; E., Crimi; Girardis, Massimo
abstract

1998 - Cascata dell’O2 durante trapianto ortotopico di fegato [Abstract in Rivista]
Girardis, Massimo; G., Como; F., Colò; L., Dal Pos; A., Pasqualotto; D., Sabbadini
abstract

1998 - Effects of prolonged bed rest on cardiovascular oxygen transport during submaximal exercise in humans. [Articolo su rivista]
Ferretti, G; Girardis, Massimo; Moia, C; Antonutto, G.
abstract

he hypothesis was tested that prolonged bed rest impairs O2 transport during exercise, which implies a lowering of cardiac output Qc and O2 delivery (QaO2). The following parameters were determined in five males at rest and at the steady-state of the 100-W exercise before (B) and after (A) 42-day bed rest with head-down tilt at -6 degrees: O2 consumption (VO2), by a standard open-circuit method; Qc, by the pressure pulse contour method, heart rate (fc), stroke volume (Qh), arterial O2 saturation, blood haemoglobin concentration ([Hb]), arterial O2 concentration (CaO2), and QaO2. The VO2 was the same in A and in B, as was the resting fc. The fc at 100 W was higher in A than in B (+17.5%). The Qh was markedly reduced (-27.7% and -22.2% at rest and 100 W, respectively). The Qc was lower in A than in B [-27.6% and -7.8% (NS) at rest and 100 W, respectively]. The CaO2 was lower in A than in B because of the reduction in [Hb]. Thus also QaO2 was lower in A than in B (-32.0% and -11.9% at rest and at 100 W, respectively). The present results would suggest a down-regulation of the O2 transport system after bed rest.

1998 - Low flow Anesthesia: an overview [Relazione in Atti di Convegno]
P., Chiarandini; Girardis, Massimo; A., Pasqualucci; L., Miceli; Pasetto, Alberto
abstract

1998 - Ostruzione tardiva delle vie aeree da ematoma retrofaringeo secondario a trauma cranico lieve [Abstract in Rivista]
P., Mergoni; F., Kette; D., Sabbadini; Girardis, Massimo; M., Zauli; L., Sussi; A., Pasetto
abstract

1998 - Pulmonary ventilation by an algorithm during laparoscopic cholecystectomy [Relazione in Atti di Convegno]
S., Milesi; E., Crimi; C., Levato; M., Raffaelli; Girardis, Massimo; Pasetto, Alberto
abstract

1998 - Utilizzo del tourniquet in chirurgia ortopedica: variazioni emodinamiche e metaboliche [Abstract in Rivista]
S., Milesi; Girardis, Massimo; M., Raffaelli; A., Spasiano; S., Donato; A., Pasetto
abstract

1998 - [Non-invasive evaluation of cardic output by analysis of peripheral pressure profile in patients recovering in intensive care]. [Articolo su rivista]
Girardis, Massimo; Antonutto, G; Vecellio, A; Dal Pos, L; Pasetto, A.
abstract

BACKGROUND: The analysis of the arterial pulse contour obtained by means of a non-invasive device (Finapres) seems to be an ideal method to measure cardiac output (CO). An individual calibration factor (Z) dimensionally equal to aortic impedence is the necessary pre-requisite to calculate CO by pulse contour analysis. To verify the reliability of non-invasive pulse contour method, we compared the COs measured from Finapres tracings with those measured from thermodilution method in Intensive Care patients. METHODS: In 9 patients undergoing cardiac and general surgery, CO was measured from thermodilution (COTD) within 24 hours of postoperative period (total of 67 measurements). During COTD measurements, Finapres tracings were recorded and then analysed to calculate CO by two different procedures. In the former (COA), Z was calculated from an algorithm which takes into account heart rate, mean arterial pressure and age of the patient. In the latter procedure (COB), Z was experimentally determined from the initial COTD measure and then updated for the hemodynamic conditions of the patient. RESULTS: COTD ranged between 3.5 and 9.5 L.min-1 (mean value 5.53 +/- 1.29 L.min-1). The mean difference between COTD e COA was 0.485 +/- 1.537 L.min-1 and the mean percentage error was 25.1 +/- 14.5%. The experimental determination of Z reduced the mean difference and the mean percentage error between thermodilution and Finapres method to--0.002 +/- 1.056 L.min-1 and 15.5 +/- 11.0%, respectively. The regression line between COTD and COB turned out to be: COB = 0.68 + 0.88.COTD (r = 0.73). CONCLUSIONS: The pulse contour analysis applied to Finapres tracing allows to calculate CO with reasonable accuracy in the intensive care patients. An initial experimental determination of Z is recommended to improve the accuracy of Finapres method.

1997 - A low invasive method to evaluate the cardiovascular effects of PEEP [Abstract in Atti di Convegno]
P., Chiarandini; M., Raffaelli; Girardis, Massimo; A., Spasiano; A., Pasetto
abstract

1997 - An algorithm to calculate pulmonary ventilation during laparoscopic cholecystectomy [Relazione in Atti di Convegno]
M., Raffaelli; Girardis, Massimo; E., Crimi; C., Levato; Pasetto, Alberto
abstract

1997 - Effects of elastic recoil on maximal explosive power of the lower limbs. [Articolo su rivista]
Zamparo, P; Antonutto, G; Capelli, C; Girardis, Massimo; Sepulcri, L; di Prampero, Pe
abstract

he maximal explosive power during a two legs jump was measured on four competitive athletes [mean age 24(SD 4.3) years; height 1.79 (SD 0.09) m; body mass 68.7 (SD 12.8) kg] at different starting knee angles (70, 90, 110, 130 and 150 degrees). The experiments were performed on a newly developed instrument with which both force and speed could be measured using a force platform and a wire tachometer, respectively, and on a conventional force platform. At the smallest knee angle (70 degrees) the mean power output (W in watts per kilogram) developed during the jump was found not to differ significantly between the two methods (P > 0.1). At the larger knee angles W was 18.4% (90 degrees), 34.5% (110 degrees), 47.4% (130 degrees) and 19.4% (150 degrees) higher using the conventional force platform (P < 0.05 throughout). The difference of W between the two methods was attributed to the recovery of elastic energy due to the counter movement which immediately preceded the jump on the conventional platform, but not on the newly developed instrument. Indeed because of a mechanical arrangement which prevented the subject from moving towards the platforms, eccentric work (W-) could not be performed on the newly developed instrument; whereas W- on the conventional force platform was almost negligible at 70 degrees knee angle [mean 1.7 (SD 2.3 J)] reached a maximum of 13.1 (SD 7.9) J at 130 degrees and decreased again to a mean 4.7 (SD 3.6) J for the largest angle (150 degrees). Furthermore, on the conventional force platform, the force at the onset of the positive speed phase (Fi) was an increasing function of W- (r2 = 0.519, P < 0.001); and the difference of W between the conventional and new instruments was larger the larger the difference of Fi (r2 = 0.391, P < 0.01).

1997 - Il monitoraggio degli scambi gassosi in anestesia: ossimetria e capnometria [Relazione in Atti di Convegno]
F., Colò; Girardis, Massimo; Pasetto, Alberto
abstract

1997 - O2 pathway during abdominal aortic cross-clamping [Abstract in Atti di Convegno]
Girardis, Massimo; F., Fontana; Mg, Platini; B., Allaria; Pasetto, Alberto
abstract

1997 - Tourniquet application during knee surgery: hemodynamic and metabolic effects. [Relazione in Atti di Convegno]
S., Milesi; S., Donato; Girardis, Massimo; M., Raffaelli; A., Spasiano; Pasetto, Alberto
abstract

1996 - Does minimal flow anesthesia impair pulmonary gas exchange? [Relazione in Atti di Convegno]
S., Donato; Girardis, Massimo; P., Chiarandini; C., Pressacco; C., Chiesena; A., Pasetto
abstract

1996 - Effects of body size, body density, gender and growth on underwater torque. [Articolo su rivista]
Zamparo, P; Antonutto, G; Capelli, C; Francescato, Mp; Girardis, Massimo; Sangoi, R; Soule, Rg; Pendergast, Dr
abstract

wo forces act on a human body motionless in water: weight (W) and buoyancy (B). They are applied to the center of mass (CM) and to the center of volume (CV) of the subject, respectively. CM and CV do not coincide; this generates a torque that is a measure of the tendency of the upper part of the body to rise, rotating around its center of mass. To quantify this tendency, Pendergast & Craig defined 'underwater torque' (T') as the product of the net force with which the feet of a subject lying horizontally in water tend to sink, times the distance between the feet and the center of volume of the lungs. In this paper we have investigated: (a) the relationships between T' and body weight (BW), height (H), body surface area (BS), body density (BD) and leg density (LD) in a group of 30 subjects (group A, 14 females and 16 males, age range 16-50 years); and (b) the effect of gender and growth on T' in a group of 110 subjects (group B, 67 girls and 43 boys, age range 12-17 years). In group A, T' was found to be linearly related with BW (r=0.833, P<0.001), H (r=0.803, P<0.001), BS (r=0.866, P<0.001), BD (r=0.617, P<0.001) and LD (r=0.549, P<0.005). A multiple linear regression analysis showed that BS and BD explained about 85% of the variability of T' (r2=0.85). In group B, T' was found to increase linearly with age (r=0.47, P<0.01), the increasing rate being three times higher in boys compared with girls. As a consequence, the T' ratio between boys and girls increased with age, from 1.69 at 13 years to 2.04 at 16 years.

1996 - The effect of laparoscopic cholecystectomy on cardiovascular function and pulmonary gas exchange. [Articolo su rivista]
Girardis, Massimo; U. D., Broi; G., Antonutto; Pasetto, Alberto
abstract

Hemodynamic changes, pulmonary CO2 elimination (VECO2) and gas exchange were evaluated during laparoscopic cholecystectomy. An algorithm to calculate inspired ventilation (VI) needed to maintain constant PaCO2 was also developed. In 12 ASA physical status I patients undergoing laparoscopic cholecystectomy, heart rate (HR), mean arterial pressure (MAP), cardiac index (CI), and systemic vascular resistance index (SVRI) were measured by the analysis of a radial artery pressure profile before, during, and after CO2 insufflation. Alveolar-arterial oxygen pressure gradient (P(A-a)O2), physiological and alveolar ventilatory dead space fractions (VDphys/VT; VDalv/VT), and PaCO2 were measured as well. VECO2 was assessed every minute in the patients maintained in the head-up position. HR did not significantly change during pneumoperitoneum, whereas MAP showed a transient increase (24.9\%; P < 0.05) after CO2 insufflation. CI remained stable during pneumoperitoneum, but increased (25.0\%; P < 0.05) after deflation. As a consequence, SVRI transiently increased after CO2 insufflation and decreased by 15.8\% (P < 0.05) 5 min after deflation. P(A-a)O2 increased slightly (P < 0.05) with increased anesthesia time. VDphys/VT and VDalv/VT did not change after pneumoperitoneum onset, but VDalv/VT decreased after CO2 deflation (13.4\%; P < 0.05). VECO2 increased (decreased) after a monoexponential time course during (after) CO2 insufflation in 8 of 12 patients. The mean time constants (t) of the monoexponential functions were 26.3 and 15.4 min during and after pneumoperitoneum. A monoexponential time course was shown also by PaCO2 during CO2 insufflation (tau = 27.8 min). Finally, the VI needed to maintain PaCO2 at a selected value could be calculated by the following algorithm: VI = [0.448.(1-e(-t/tau) + 2.52].(VA.PaCO2.713)-1, where VA corresponds to alveolar ventilation and t must be chosen according to the pneumoperitoneum phase. We conclude that CO2 insufflation in the abdominal cavity does not induce significant changes in cardiopulmonary function in ASA physical status I patients. The algorithm proposed seems to be a useful tool for the anesthesiologists to maintain constant PaCO2 during all surgical procedures.

1995 - Effects of microgravity on muscular explosive power of the lower limbs in humans [Abstract in Rivista]
G., Antonutto; C., Capelli; Girardis, Massimo; P., Zamparo; PE di, Prampero
abstract

1995 - Noninvasive assessment of cardiac output from arterial pressure profiles during exercise. [Articolo su rivista]
Antonutto, G; Girardis, Massimo; Tuniz, D; di Prampero, Pe
abstract

he stroke volume of the left ventricle (SV) was assessed in nine young men (mean age 22.2, ranging from 20 to 25 years) during cycle ergometer upright exercise at exercise intensities from 60 to 150 W (about 20% to 80% of individual maximal aerobic power). The SV was calculated from noninvasive tracings of the arterial blood pressure, determined from photoplethysmograph records and compared to the SV determined simultaneously by pulsed Doppler echocardiography (PDE). Given the relationship SV = As.Z-1 in which A(s) is the area underneath the systolic pressure profile (in millimetres of mercury and second), and Z (in millimetres of mercury and second per millilitre) is the apparent hydraulic impedance of the circulatory system, a prerequisite for the assessment of SV from the photoplethysmograph tracings is a knowledge of Z. The experimental value of Z (hereafter defined Z*) was calculated by dividing A(s) (from the finger photoplethysmograph) by SV as obtained by PDE. When the whole group of subjects was considered, Z* was not greatly affected by the exercise intensity: it amounted to 0.089 (SD 0.028; n = 36). The Z was also estimated independently of any parameter other than heart rate (HR), mean (MAP) and pulse (PP) arterial blood pressure obtained from the photoplethysmograph. A computerized statistical method allowed us to interpolate the experimental values of Z*, HR, PP and MAP by the equation Zm = a.(b + c.HR + d.PP + e.MAP)-1, thus obtaining the coefficients a to e. The mean percentage error between Zm (calculated from the coefficients obtained and Z* was 21.8 (SD 14.3)%. However, it was observed that, in a given subject, Z* was significantly affected by the exercise intensity. Therefore, to improve the estimate of Z a second algorithm was developed to update the experimental value of Z determined initially at rest (Zin). This updated value (Zcor) of Z was calculated as Zcor = Zin. [(f/(i + g.(HR/HRin) + h.(PP/PPin) + 1.(MAP/MAPin)], where HRin, PPin, MAPin, HR, PP, MAP are the above parameters at rest and during exercise, respectively. Also in this case, the coefficients f to 1 were determined by a computerized statistical method using Z* as the experimental reference. The values of Zcor so obtained allowed us to calculate SV from arterial pulse contour analysis as SVF = As.Z-1cor. The mean percentage error between the SVF obtained and the values simultaneously determined by PDE, was 10.0 (SD 8.7)%. It is concluded that the SV of the left ventricle, and hence cardiac output, can be determined during exercise from photoplethysmograph tracings with reasonable accuracy, provided that an initial estimate of SV at rest is made by means an independent high quality reference method.

1995 - Oxygen cost of internal work during cycling. [Articolo su rivista]
M. P., Francescato; Girardis, Massimo; P. E., Di
abstract

The energy cost of internal work and its relationships with lower limb mass and pedalling frequency were studied in four male subjects [age 22.2 (SD 1.5) years, body mass 81.0 (SD 5.1) kg, maximal O2 uptake (VO2max) above resting 3.06 (SD 0.4) l.min-1]. The subjects cycled at 40, 60, 80 and 100 rpm and at five different exercise intensities for every pedalling frequency (unloaded condition, UL); the same exercises were repeated after having increased the lower limbs' masses by 40\% (loaded condition, L). The exercise intensities were chosen so that the oxygen consumption (VO2) did not exceed 75\% of VO2max. For all the subjects and all the conditions, the rate of VO2 above resting increased linearly with the mechanical power (W). The y-intercepts of the linear regressions of VO2 on W, normalised per kilogram of overall lower limbs mass were the same in both UL and L and increased with the 4.165 power of pedalling frequency (fp). These intercepts were taken to represent the metabolic counterpart of the internal power dissipation in cycling; they amounted to 0.78, 0.34, 3.29 and 10.30 W.kg-1 for pedalling frequencies of 40, 60, 80 and 100 rpm respectively. The slope of the regression lines (delta W/delta VO2) represents the delta efficiency of cycle ergometer exercise; this was also affected by fp, ranging, on average, from 22.9\% to 32.0\%. These data allowed us to obtain a comprehensive description of the effects of fp (per minute), exercise intensity (W, watts) and lower limbs' mass with or without added loads (mL, kg), on VO2 (ml.min-1) during cycling: VO2 = [mL.(4.3.10(-8).fp4.165/0.35)] + (1/[(3.594.10(-5).fp2 - 0.003.fp + 0.326).0.35]).W. The mean percentage error between the VO2 predicted from this equation and the actual value was 12.6\%. This equation showed that the fraction of the overall VO2 due to internal work, for a normal 70-kg subject pedalling at 60 rpm and 100 W was of the order of 0.2.

1995 - Rapporto ventilo-perfusorio durante anestesia a bassi flussi [Relazione in Atti di Convegno]
Pasetto, Alberto; Girardis, Massimo; P., Chiarandini; S., Donato; Am, Varutti
abstract

1994 - Assessment of cardiac output from noninvasive determination of arterial pressure profile in subjects at rest. [Articolo su rivista]
Antonutto, G; Girardis, Massimo; Tuniz, D; Petri, E; Capelli, C.
abstract

he stroke volume of the left ventricle (SV) was calculated from noninvasive recordings of the arterial pressure using a finger photoplethysmograph and compared to the values obtained by pulsed Doppler echocardiography (PDE). A group of 19 healthy men and 12 women [mean ages: 20.8 (SD 1.6) and 22.2 (SD 1.6) years respectively] were studied at rest in the supine position. The ratio of the area below the ejection phase of the arterial pressure wave (A(s)) to SV, as obtained by PDE, yielded a "calibration factor" dimensionally equal to the hydraulic impedance of the system (Zao = A(s).SV-1). The Zao amounted on average to 0.062 (SD 0.018) mmHg.s.cm-3 for the men and to 0.104 (SD 0.024) mmHg.s.cm-3 for the women. The Zao was also estimated from the equation: Zao = a.(d + b.HR + c.PP + e.MAP)-1, where HR was the heart rate, PP the pulse pressure, MAP the mean arterial pressure and the coefficients of the equation were obtained by an iterating statistical package. The value of Zao thus obtained allowed the calculation of SV from measurements derived from the photoplethysmograph only. The mean percentage error between the SV thus obtained and those experimentally determined by PDE amounted to 14.8 and 15.6 for the men and the women, respectively. The error of the estimate was reduced to 12.3 and to 11.1, respectively, if the factor Zao, experimentally obtained from a given heart beat, was subsequently applied to other beats to obtain SV from the A(s) measurement in the same subject.

1994 - Dolore neoplastico: fattori predittivi nei trattamenti neurolesivi [Relazione in Atti di Convegno]
Pasetto, Alberto; A., Pasqualucci; F., Colò; Girardis, Massimo
abstract

1994 - [Effects of age, body weight, and ventilatory pattern on the difference between arterial and end-tidal PCO2]. [Articolo su rivista]
F., Colò; Girardis, Massimo; A., Pasqualucci; U. D., Broi; A., Pasetto
abstract

To evaluate the effects of physiological ventilatory patterns on P(a-ET)CO2 gradient and on the alveolar dead space production during controlled mechanical ventilation.Prospective and experimental comparison among three different ventilatory settings in three different groups of subjects.General surgery's operating-theatre in university hospital.Twenty-eight patients subdivided randomly in 3 groups differing for ventilatory setting. I group: constant tidal volume (VC = 8 ml.kg-1) and 3 different respiratory frequencies (f = 10, 12 and 14 breaths.min-1); II group: constant ventilation (112 ml.kg-1) but VC and f modified in three different ways; III group: inspiratory volume was set to give an end-tidal PCO2 (PETCO2) of about 35 mmHg. The cases were subdivided, on the basis of P(a-ET)CO2 distribution, in three groups: group with values larger than mean plus 1 standard deviation, group with values between +/- 1 standard deviation and group with values lower than mean minus 1 standard deviation. Moreover in two homogeneous groups for age.General surgery but not important because measures were performed before surgical manoeuvres.Anthropometrical data (age and body weight), PaCO2, PETCO2, heart rate, invasive arterial pressure, ventilatory parameters and airway pressure were collected for every subject and ventilatory setting; arterial to end-tidal difference P(a-ET)CO2 and P(a-ET)CO2.PaCO2(-1) were calculated during data analysis. The P(a-ETFCO2 and P(a-ET)CO2.PaCO2(-1) values were not significantly different among the three different ventilatory patterns both in the first and in the second group. P(a-ET)CO2 values were significantly correlated with age, body weight and airway pressure. These parameters were correlated significantly also with P(a-ET)CO2.PaCO2(-1) values.Ventilatory setting, used in a normal physiological range, don't affect P(a-ET)CO2 difference during mechanical ventilation. Age, body weight and airway pressure of the patient must be considered to obtain a correct value of PaCO2 by the measure of PETCO2.

1993 - Artificial gravity as a tool to prevent cardiovascular deconditioning in Space. Cardio-circulatory responses to short-radius rotation and exercise in human centrifuge [Relazione in Atti di Convegno]
G., Antonutto; Girardis, Massimo; PE di, Prampero; D., Linnarsson
abstract

1993 - Control of post-operative pain by a PCA throwaway device [Relazione in Atti di Convegno]
A., Pasetto; F., Colò; A., Pasqualucci; Girardis, Massimo; F., Savron; M., Baldassarre
abstract

1993 - Effects of prolonged cycle ergometer exercise on maximal muscle power and oxygen uptake in humans. [Articolo su rivista]
Capelli, C; Antonutto, G; Zamparo, P; Girardis, Massimo; di Prampero, Pe
abstract

he mechanical power (Wtot, W.kg-1) developed during ten revolutions of all-out periods of cycle ergometer exercise (4-9 s) was measured every 5-6 min in six subjects from rest or from a baseline of constant aerobic exercise [50%-80% of maximal oxygen uptake (VO2max)] of 20-40 min duration. The oxygen uptake [VO2 (W.kg-1, 1 ml O2 = 20.9 J)] and venous blood lactate concentration ([la]b, mM) were also measured every 15 s and 2 min, respectively. During the first all-out period, Wtot decreased linearly with the intensity of the priming exercise (Wtot = 11.9-0.25.VO2). After the first all-out period (t greater than 5-6 min), and if the exercise intensity was less than 60% VO2max, Wtot, VO2 and [la]b remained constant until the end of the exercise. For exercise intensities greater than 60% VO2max, VO2 and [la]b showed continuous upward drifts and Wtot continued decreasing. Under these conditions, the rate of decrease of Wtot was linearly related to the rate of increase of VO2 [(dWtot/dt) (W.kg-1 x s-1) = 5.0 x 10(-5) -0.20.(VO2/dt) (W.kg-1 x s-1)] and this was linearly related to the rate of increase of [la]b [(dVO2/dt) (W.kg-1 x s-1) = 2.3 x 10(-4) + 5.9 x 10(-5).(d[la]b/dt) (mM.s-1)].(ABSTRACT TRUNCATED AT 250 WORDS)

1993 - Effects of respiratory pattern on the arterial to end-tidal CO2 difference during general anaesthesia: preliminary report [Poster]
F., Colò; Girardis, Massimo; Pasetto, Alberto
abstract

1993 - Energetics of best performances in middle-distance running. [Articolo su rivista]
Di Prampero, Pe; Capelli, C; Pagliaro, P; Antonutto, G; Girardis, Massimo; Zamparo, P; Soule, Rg
abstract

Oxygen consumption (VO2) and blood lactate concentration were determined during constant-speed track running on 16 runners of intermediate level competing in middle distances (0.8-5.0 km). The energy cost of track running per unit distance (Cr) was then obtained from the ratio of steady-state VO2, corrected for lactate production, to speed; it was found to be independent of speed, its overall mean being 3.72 +/- 0.24 J.kg-1 x m-1 (n = 58; 1 ml O2 = 20.9 J). Maximal VO2 (VO2max) was also measured on the same subjects. Theoretical record times were then calculated for each distance and subject and compared with actual seasonal best performances as follows. The maximal metabolic power (Er max) a subject can maintain in running is a known function of VO2max and maximal anaerobic capacity and of the effort duration to exhaustion (te). Er max was then calculated as a function of te from VO2max, assuming a standard value for maximal anaerobic capacity. The metabolic power requirement (Er) necessary to cover a given distance (d) was calculated as a function of performance time (t) from the product Crdt-1 = Er. The time values that solve the equality Er max(te) = Er(t), assumed to yield the theoretical best t, were obtained by an iterative procedure for any given subject and distance and compared with actual records

1989 - Work performance efficiency during all out efforts [Abstract in Atti di Convegno]
C., Capelli; G., Antonutto; P., Zamparo; Girardis, Massimo; PE di, Prampero
abstract

Università degli studi di Modena e Reggio Emilia

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