Publications by authors named "Giacomo Grasselli"

146 Publications

Reply: Can We Reliably Predict the Failure of Non-invasive Ventilation in COVID‑19‑associated Acute Hypoxemic Respiratory Failure?

Ann Am Thorac Soc 2021 Apr 12. Epub 2021 Apr 12.

University of Milan, Department of Pathophysiology and Transplantation, Milano, Italy.

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http://dx.doi.org/10.1513/AnnalsATS.202103-398LEDOI Listing
April 2021

Prone position in intubated, mechanically ventilated patients with COVID-19: a multi-centric study of more than 1000 patients.

Crit Care 2021 04 6;25(1):128. Epub 2021 Apr 6.

Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20122, Milan, Italy.

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 PaO/FiO 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 PaO/FiO 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.
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http://dx.doi.org/10.1186/s13054-021-03552-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8022297PMC
April 2021

Quantification of Recirculation During Veno-Venous Extracorporeal Membrane Oxygenation: In Vitro Evaluation of a Thermodilution Technique.

ASAIO J 2021 Mar 29. Epub 2021 Mar 29.

From the School of Medicine and Surgery, University of Milan-Bicocca, Monza, Italy Center for Preclinical Research, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy Department of Anesthesia and Critical Care, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy Department of Anesthesia and Critical Care, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Veno-venous extracorporeal membrane oxygenation (vv-ECMO) represents one of the most advanced respiratory support for patients suffering from severe acute respiratory distress syndrome. During vv-ECMO a certain amount of extracorporeal oxygenated blood can flow back from the reinfusion into the drainage cannula without delivering oxygen to the patient. Detection and quantification of this dynamic phenomenon, defined recirculation, are critical to optimize the ECMO efficiency. Our study aimed to measure the recirculation fraction (RF) using a thermodilution technique. We built an in vitro circuit to simulate patients undergoing vv-ECMO (ECMO flow: 1.5, 3, and 4.5 L/min) with different cardiac output, using a recirculation bridge to achieve several known RFs (from 0% to 50%). The RF, computed as the ratio of the area under temperature-time curves (AUC) of the drainage and reinfusion, was significantly related to the set RF (AUC ratio (%) = 0.979 × RF (%) + 0.277%, p < 0.0001), but it was not dependent on tested ECMO and cardiac output values. A Bland-Altman analysis showed an AUC ratio bias (precision) of -0.21% for the overall data. Test-retest reliability showed an intraclass correlation coefficient of 0.993. This study proved the technical feasibility and computation validity of the applied thermodilution technique in computing vv-ECMO RF.
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http://dx.doi.org/10.1097/MAT.0000000000001428DOI Listing
March 2021

Mechanical ventilation parameters in critically ill COVID-19 patients: a scoping review.

Crit Care 2021 03 20;25(1):115. Epub 2021 Mar 20.

General Intensive Care Unit, Shaare Zedek Medical Center, Jerusalem, Israel.

Background: The mortality of critically ill patients with COVID-19 is high, particularly among those receiving mechanical ventilation (MV). Despite the high number of patients treated worldwide, data on respiratory mechanics are currently scarce and the optimal setting of MV remains to be defined. This scoping review aims to provide an overview of available data about respiratory mechanics, gas exchange and MV settings in patients admitted to intensive care units (ICUs) for COVID-19-associated acute respiratory failure, and to identify knowledge gaps.

Main Text: PubMed, EMBASE, and MEDLINE databases were searched from inception to October 30, 2020 for studies providing at least one ventilatory parameter collected within 24 h from the ICU admission. The quality of the studies was independently assessed using the Newcastle-Ottawa Quality Assessment Form for Cohort Studies. A total of 26 studies were included for a total of 14,075 patients. At ICU admission, positive end expiratory pressure (PEEP) values ranged from 9 to 16.5 cm of water (cmHO), suggesting that high levels of PEEP were commonly used for setting MV for these patients. Patients with COVID-19 are severely hypoxemic at ICU admission and show a median ratio of partial pressure of arterial oxygen to fraction of inspired oxygen (PaO/FiO) ranging from 102 to 198 mmHg. Static respiratory system compliance (Crs) values at ICU admission were highly heterogenous, ranging between 24 and 49 ml/cmHO. Prone positioning and neuromuscular blocking agents were widely used, ranging from 17 to 81 and 22 to 88%, respectively; both rates were higher than previously reported in patients with "classical" acute respiratory distress syndrome (ARDS).

Conclusions: Available data show that, in mechanically ventilated patients with COVID-19, respiratory mechanics and MV settings within 24 h from ICU admission are heterogeneous but similar to those reported for "classical" ARDS. However, to date, complete data regarding mechanical properties of respiratory system, optimal setting of MV and the role of rescue treatments for refractory hypoxemia are still lacking in the medical literature.
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http://dx.doi.org/10.1186/s13054-021-03536-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980724PMC
March 2021

Endothelial damage in septic shock patients as evidenced by circulating syndecan-1, sphingosine-1-phosphate and soluble VE-cadherin: a substudy of ALBIOS.

Crit Care 2021 03 19;25(1):113. Epub 2021 Mar 19.

Department of Cardiovascular Medicine, Mario Negri Institute for Pharmacological Research IRCCS, Via Mario Negri 2, 20156, Milan, Italy.

Background: Septic shock is characterized by breakdown of the endothelial glycocalyx and endothelial damage, contributing to fluid extravasation, organ failure and death. Albumin has shown benefit in septic shock patients. Our aims were: (1) to identify the relations between circulating levels of syndecan-1 (SYN-1), sphingosine-1-phosphate (S1P) (endothelial glycocalyx), and VE-cadherin (endothelial cell junctions), severity of the disease, and survival; (2) to evaluate the effects of albumin supplementation on endothelial dysfunction in patients with septic shock.

Methods: This was a retrospective analysis of a multicenter randomized clinical trial on albumin replacement in severe sepsis or septic shock (the Albumin Italian Outcome Sepsis Trial, ALBIOS). Concentrations of SYN-1, S1P, soluble VE-cadherin and other biomarkers were measured on days 1, 2 and 7 in 375 patients with septic shock surviving up to 7 days after randomization.

Results: Plasma concentrations of SYN-1 and VE-cadherin rose significantly over 7 days. SYN-1 and VE-cadherin were elevated in patients with organ failure, and S1P levels were lower. SYN-1 and VE-cadherin were independently associated with renal replacement therapy requirement during ICU stay, but only SYN-1 predicted its new occurrence. Both SYN-1 and S1P, but not VE-cadherin, predicted incident coagulation failure. Only SYN-1 independently predicted 90-day mortality. Albumin significantly reduced VE-cadherin, by 9.5% (p = 0.003) at all three time points.

Conclusion: Circulating components of the endothelial glycocalyx and of the endothelial cell junctions provide insights into severity and progression of septic shock, with special focus on incident coagulation and renal failure. Albumin supplementation lowered circulating VE-cadherin consistently over time.

Clinical Trial Registration: ALBIOS ClinicalTrials.gov number NCT00707122.
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http://dx.doi.org/10.1186/s13054-021-03545-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980645PMC
March 2021

Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

Cochrane Database Syst Rev 2021 03 18;3:CD013881. Epub 2021 Mar 18.

Cochrane France, Paris, France.

Background: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance.

Objectives: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly.

Search Methods: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021.

Selection Criteria: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity.

Data Collection And Analysis: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events.

Main Results: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes.

Authors' Conclusions: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).
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http://dx.doi.org/10.1002/14651858.CD013881DOI Listing
March 2021

Personal protective equipment use by healthcare workers in intensive care unit during the early phase of COVID-19 pandemic in Italy: a secondary analysis of the PPE-SAFE survey.

Ther Adv Infect Dis 2021 Jan-Dec;8:2049936121998562. Epub 2021 Feb 25.

Department of Surgical, Oncological and Oral Science (Di.Chir.On.S.), University of Palermo, Italy. Departement of Anaesthesia, Intensive Care and Emergency, Policlinico Paolo Giaccone, Via del Vespro 129, 90127, Palermo, Italy.

Background: Italy was the first Western country to be heavily affected by COVID-19. Healthcare workers (HCWs) were exposed to a high risk of occupational infection, partially due to insufficient personal protective equipment (PPE) supplies. This study aimed to describe the practices, availability, training, confidence in PPE use and the adverse effects due to extended PPE use, as reported by HCWs in Italy. We also aimed to provide a comparison between Italian data and those from other countries.

Methods: This study was a secondary analysis of a previously published international study, the PPE-SAFE Survey, conducted in April 2020. Data were analysed from the original study database.

Results: We analysed the responses from 380 healthcare workers based in Italy, out of the 2711 respondents to the international survey. Among the Italian respondents, FFP2 and FFP3 respirators or equivalent were the most used masks for routine tasks (respectively 188/380, 50%; and 163/380, 43%). The median time of wearing PPE without taking a break was 5 h [interquartile range (IQR) 4-6], with statistically significant difference from other countries [median 4 h (IQR 2-5)  < 0.0001]. In Italy, 249 out of 380 (65%) HCWs had never performed a formal fit test for a N95 mask or equivalent and 91/380 (24%) never had a partner for donning and doffing procedures. Most of the respondents (299/380, 79%) had received formal training in PPE use at any time.

Conclusion: Most of the surveyed Italian HCWs reported working at above usual capacity, long shifts with PPE without breaks and routine use in intensive care unit of aerosol protection (e.g. FFP2/FFP3), hazmat suits and face shields/visors. The correct adherence to safety procedures (e.g. donning/doffing in pairs, performing fit test) has substantial scope for improvement in the future.
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http://dx.doi.org/10.1177/2049936121998562DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922607PMC
February 2021

Albumin replacement therapy in immunocompromised patients with sepsis - Secondary analysis of the ALBIOS trial.

J Crit Care 2021 Feb 9;63:83-91. Epub 2021 Feb 9.

Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy; Department of Anesthesia and Critical Care, Azienda-Ospedaliero Universitaria S. Luigi Gonzaga, Orbassano, Italy.

Background: The best fluid replacement strategy and the role of albumin in immunocompromised patients with sepsis is unclear.

Methods: We performed a secondary analysis of immunocompromised patients enrolled in the ALBIOS trial which randomized patients with severe sepsis or septic shock to receive either 20% albumin (target 30 g per liter or more) and crystalloid or crystalloid alone during ICU stay.

Results: Of 1818 patients originally enrolled, 304 (16.4%) were immunocompromised. One-hundred-thirty-nine (45.7%) patients were randomized in the albumin while 165 (54.2%) in the crystalloid group. At 90 days, 69 (49.6%) in the albumin group and 89 (53.9%) in the crystalloids group died (hazard ratio - HR - 0.94; 95% CI 0.69-1.29). No differences were observed with regards to 28-day mortality, SOFA score (and sub-scores), length of stay in the ICU and in the hospital, proportion of patients who had developed acute kidney injury or received renal replacement therapy, duration of mechanical ventilation. Albumin was not independently associated with a higher or lower 90-day mortality (HR 0.979, 95% CI 0.709-1.352) as compared to crystalloid.

Conclusion: Albumin replacement during the ICU stay, as compared with crystalloids alone, did not affect clinical outcomes in a cohort of immunocompromised patients with sepsis.
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http://dx.doi.org/10.1016/j.jcrc.2021.01.016DOI Listing
February 2021

Viscoelastic Coagulation Monitor as a Novel Device to Assess Coagulation at the Bedside. A Single-Center Experience During the COVID-19 Pandemic.

ASAIO J 2021 03;67(3):254-262

From the Department of Anaesthesia and Critical Care, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.

Viscoelastic coagulation monitor (VCM) is a portable device developed to evaluate the viscoelastic properties of whole blood activated by contact with glass. In this study, VCM was employed to analyze the viscoelastic profiles of 36 COVID-19 intensive care patients. Full anticoagulant dose heparin (unfractionated [UFH]; low molecular weight [LMWH]) was administrated to all patients. The association between VCM and laboratory parameters was retrospectively analyzed. The administration of UFH-influenced VCM parameters prolonging clotting time (CT) and clot formation time (CFT) and reducing angle (alpha) and amplitudes of the VCM tracings (A10, A20, and maximum clot firmness [MCF]) compared with LMWH therapy. A tendency toward hypercoagulation was observed by short CT and CFT in patients receiving LMWH. Clotting time was correlated with UFH dose (Spearman's rho = 0.48, p ≤ 0.001), and no correlation was found between CT and LMWH. All VCM tracings failed to show lysis at 30 and 45 minutes, indicating the absence of fibrinolysis. A10, A20, and MCF exhibited very-good to good diagnostic accuracy for detecting platelet count and fibrinogen above the upper reference limit of the laboratory. In conclusion, VCM provided reliable results in COVID-19 patients and was easy to perform with minimal training at the bedside.
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http://dx.doi.org/10.1097/MAT.0000000000001380DOI Listing
March 2021

SARS-CoV-2 RNA in plasma samples of COVID-19 affected individuals: a cross-sectional proof-of-concept study.

BMC Infect Dis 2021 Feb 17;21(1):184. Epub 2021 Feb 17.

Department of Laboratories, Unit of Diagnostic Microbiology and Immunology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Recent studies showed that plasma SARS-CoV-2 RNA seems to be associated with worse COVID-19 outcome. However, whether specific population can be at higher risk of viremia are to date unexplored.

Methods: This cross-sectional proof-of-concept study included 41 SARS-CoV-2-positive adult individuals (six affected by haematological malignancies) hospitalized at two major hospital in Milan, for those demographic, clinical and laboratory data were available. SARS-CoV-2 load was quantified by ddPCR in paired plasma and respiratory samples. To assess significant differences between patients with and patients without viremia, Fisher exact test and Wilcoxon test were used for categorical and continuous variables, respectively.

Results: Plasma SARS-CoV-2 RNA was found in 8 patients (19.5%), with a median (IQR) value of 694 (209-1023) copies/mL. Viremic patients were characterized by an higher mortality rate (50.0% vs 9.1%; p = 0.018) respect to patients without viremia. Viremic patients were more frequently affected by haematological malignancies (62.5% vs. 3.0%; p < 0.001), and had higher viral load in respiratory samples (9,404,000 [586,060-10,000,000] vs 1560 [312-25,160] copies/mL; p = 0.002).

Conclusions: Even if based on a small sample population, this proof-of-concept study poses the basis for an early identification of patients at higher risk of SARS-CoV-2 viremia, and therefore likely to develop severe COVID-19, and supports the need of a quantitative viral load determination in blood and respiratory samples of haematologic patients with COVID-19 in order to predict prognosis and consequently to help their further management.
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http://dx.doi.org/10.1186/s12879-021-05886-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7887543PMC
February 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).

BMJ Open 2021 Feb 11;11(2):e036616. Epub 2021 Feb 11.

Anesthesia and Intensive Care, University Hospital Modena, Modena, Emilia-Romagna, Italy

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.
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http://dx.doi.org/10.1136/bmjopen-2019-036616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880103PMC
February 2021

Assessment of Platelet Thrombus Formation under Flow Conditions in Adult Patients with COVID-19: An Observational Study.

Thromb Haemost 2021 Feb 5. Epub 2021 Feb 5.

Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background:  Coronavirus disease 2019 (COVID-19) is associated with systemic inflammation, which may dysregulate platelet function. Total Thrombus-Formation Analysis System (T-TAS) is a flow-chamber device that analyses platelet-mediated thrombus formation in capillary channels through the following parameters: (1) the area under the flow-pressure curve (AUC), (2) occlusion start time (OST), time needed to reach OST, and (3) occlusion time (OT), time needed to reach the occlusion pressure.

Methods And Findings:  Sixty-one COVID-19 patients admitted to intensive, subintensive, and low intensive care were prospectively enrolled according to the time of admission: group A (up to 8 days) ( = 18); group B (from 9 to 21 days) ( = 19), and group C ( > 21 days) ( = 24). T-TAS measurements were performed at enrolment and after 7 days. Median OST was similar among groups. AUC was lower in group A compared to B ( = 0.001) and C ( = 0.033). OT was longer in group A compared to B ( = 0.001) and C ( = 0.028). Platelet count (PC) was higher in group B compared to A ( = 0.024). The linear regression showed that OT and AUC were independent from PC in group A (OT: 0.149 [95% confidence interval [CI]: -0.326 to 0.624],  = 0.513 and AUC: 0.005 [95% CI: -0.008 to 0.017],  = 0,447). In contrast, in group B, PC was associated with OT (-0.019 [-0.028 to 0.008],  = 0.023) and AUC (0.749 [0.358-1.139],  = 0,015), similarly to group C. Conversely, patients with different illness severity had similar T-TAS parameters.

Conclusion:  COVID-19 patients display an impaired platelet thrombus formation in the early phase of the disease compared to later stages and controls, independently from illness severity.
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http://dx.doi.org/10.1055/s-0041-1722919DOI Listing
February 2021

Heparin-Free Lung Transplantation on Venovenous Extracorporeal Membrane Oxygenation Bridge.

ASAIO J 2021 Jan 28. Epub 2021 Jan 28.

From the Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy Department of Thoracic Surgery and Lung Transplant, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Milan, Italy Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Extracorporeal membrane oxygenation (ECMO) bridge to lung transplantation (LuTX) exposes the patients to a high risk of perioperative bleeding secondary to systemic anticoagulation and coagulation factors deficiency. With this case series, we propose innovative "no-heparin" management of ECMO-bridge support during LuTX, based upon 1) control heparin resistance with antithrombin III in the preoperative period; 2) relying upon a fully functional, brand new heparinized ECMO circuit; 3) completely avoiding perioperative heparin; 4) hampering fibrinolysis with tranexamic acid; and 5) limiting venoarterial (VA) ECMO escalation, and the following need for full anticoagulation. Following the application of this new approach, we carried out three challenging clinical cases of bilateral ECMO-bridged LuTX effectively, with limited intraoperative blood requirement and no major postoperative bleeding or thromboembolic events. Of note, two of them had an extremely high risk for hemorrhage due to complete right lung anatomic derangement in case number 2 and surgical adhesion following first LuTX in case number 3, while for the case number 1, no blood products were administered during surgery. Despite the limited patient population, such an approach relies on a strong rationale and may be beneficial for managing ECMO bridging to LuTX. Prospective studies are necessary to confirm the validity of our strategy.
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http://dx.doi.org/10.1097/MAT.0000000000001371DOI Listing
January 2021

Overcoming the Limits of Reconditioning: Seventeen Hours of Ex-Vivo Lung Perfusion (EVLP) with Successful Transplantation from Uncontrolled Circulatory Death Donor.

Transplantation 2021 Jan 25. Epub 2021 Jan 25.

Thoracic Surgery and Lung Transplantation Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. University of Milan, Milan, Italy. Anesthesia, Intensive Care and Emergency, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. Pathology Unit, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. Internal Medicine Department, Respiratory Unit and Adult Cystic Fibrosis Center, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico of Milan, Milan, Italy. San Gerardo Hospital, ASST-Monza, Monza, Italy. University of Milano-Bicocca, Milan, Italy.

Background: Uncontrolled donors after circulatory death (DCD) are an extraordinary resource to increase the number of lungs available for transplantation. However, the risk of the warm ischemia resulting from cardiac arrest to irreversibly damage the organs is considerable. Moreover, graft preservation issues and organizational problems often worsen the dangerous effects of warm ischemia. Ex-Vivo Lung Perfusion (EVLP) enables to evaluate and recondition lungs whose functionality is doubtful, as well as to overcome the difficulties related to time and logistics.

Methods: We report the case of uncontrolled DCD lungs successfully treated with an exceptionally prolonged EVLP. Since the donor's blood count and liver biopsy showed signs of a possible leukaemia, EVLP was protracted up to seventeen hours while waiting for immunohistochemical analyses to rule out this diagnosis; eventually, the results came back negative and lungs were judged suitable for transplantation.

Results: The recipient was a 32-year old male with cystic fibrosis, colonized by Pandoraea pnomenusa. Bilateral transplantation required central extracorporeal membrane oxygenation. The patient was extubated after 36 hours and was discharged 21 days after the operation. Despite early re-colonization by Pandoraea pnomenusa and airway complications requiring pneumatic dilatation, he is alive and has a satisfactory respiratory function 15 months after transplantation.

Conclusions: Uncontrolled DCD represents a challenge due to both logistical issues and the complexity of grafts evaluation before procurement: EVLP with cellular perfusate could be a valuable tool to overcome these limits. Nonetheless, caution should be exercised when interpreting the effects of this technique on airway healing.
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http://dx.doi.org/10.1097/TP.0000000000003646DOI Listing
January 2021

Volatile Sedation for Acute Respiratory Distress Syndrome Patients on Venovenous Extracorporeal Membrane Oxygenation and Ultraprotective Ventilation.

Crit Care Explor 2021 Jan 8;3(1):e0310. Epub 2021 Jan 8.

Dipartimento di Medicina e Chirurgia, Università degli Studi di Milano-Bicocca, Monza, Italy.

Patients on extracorporeal support for severe acute respiratory distress syndrome may require a prolonged period of deep sedation. In these patients, volatile sedation may represent a valid alternative to IV drugs. The aim of our study was to describe the feasibility of volatile sedation in a large cohort of acute respiratory distress syndrome patients undergoing venovenous extracorporeal membrane oxygenation and ultraprotective ventilation.

Design: Retrospective monocentric study.

Setting: Adult ICU, ASST Monza, Italy.

Patients: Adult patients who underwent volatile sedation with isoflurane during venovenous extracorporeal membrane oxygenation between 2009 and 2019.

Interventions: Isoflurane was delivered via the AnaConDa system. The sedation level, hemodynamics, and laboratory tests were compared between the volatile sedation phase and the IV sedation phases before and after the isoflurane sedation period.

Measurements And Main Results: About 74 patients (50 yr [43-56 yr]) were included. Median duration of venovenous extracorporeal membrane oxygenation support was 22 days (14-51 d). Volatile sedation started on day 3 (2-6) of extracorporeal membrane oxygenation support, and its median duration was 7 days (4-13 d), ranging from 1 to 38 days. A total of 970 venovenous extracorporeal membrane oxygenation days were analyzed. During the volatile phase, the sedation level was slightly deeper (bispectral index 39 ± 6) compared with the IV phase before and after isoflurane (42 ± 8 and 43 ± 9, respectively, < 0.001). Requirements of fentanyl and remifentanyl were reduced during the volatile phase. Minor differences in hemodynamics were observed during volatile sedation: mean arterial pressure was lower (75 ± 13 vs 79 ± 14 and 80 ± 15; < 0.001), whereas cardiac output was higher (8.5 ± 1.9 vs 7.9 ± 1.8 and 8.0 ± 1.8; = 0.003). Aspartate aminotransferase levels were lower during the volatile sedation phases ( < 0.001), whereas alanine aminotransferase, triglycerides, and creatine phosphokinase were more altered during the IV sedation phase before isoflurane ( < 0.001).

Conclusions: Volatile sedation represents an alternative to IV agents to achieve long-term deep sedation in critically ill patients on extracorporeal membrane oxygenation undergoing ultraprotective ventilation.
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http://dx.doi.org/10.1097/CCE.0000000000000310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7803679PMC
January 2021

Good clinical practice for the use of vasopressor and inotropic drugs in critically ill patients: state-of-the-science and expert consensus.

Minerva Anestesiol 2021 01 12. Epub 2021 Jan 12.

Department of Anesthesia and Intensive Care, University Hospital of Modena, Modena, Italy.

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 evidences 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.
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http://dx.doi.org/10.23736/S0375-9393.20.14866-1DOI Listing
January 2021

Noninvasive Ventilatory Support of COVID-19 Patients Outside the Intensive Care Units (WARd-COVID).

Ann Am Thorac Soc 2021 Jan 4. Epub 2021 Jan 4.

University of Milano-Bicocca, Milan, Italy , Department of Medicine and Surgery, Milano, Italy.

Rationale: Treatment with non-invasive ventilation (NIV) in COVID-19 is frequent. Shortage of Intensive care unit (ICU) beds led clinicians to deliver NIV also outside intensive care units (ICUs). Data about the use of NIV in COVID-19 is limited.

Objective: To describe the prevalence and clinical characteristics of patients with COVID-19 treated with NIV outside the ICUs. To investigate the factors associated with NIV failure (need for intubation or death).

Methods: In this prospective single day observational study, we enrolled adult COVID-19 patients, treated with NIV outside the ICU from thirty-one hospitals in Lombardy, Italy.

Results: We collected data on demographic, clinical characteristics, ventilatory management and patients' outcome. Of 8753 COVID-19 patients present in the hospitals on the study day, 909 (10%) were receiving NIV outside the ICU. 778/909 (85%) patients were treated with Continuous Positive Airway Pressure (CPAP), delivered by helmet in 617 (68%). NIV failed in 300 patients (37.6%), while 498 (62.4%) were discharged alive without intubation. Overall mortality was 25%. NIV failure occurred in 152/284 (53%) patients with a PaO2/FiO2 ratio < 150 mmHg. Higher C-reactive protein, lower PaO2/FiO2, and platelet counts were independently associated with increased risk of NIV failure.

Conclusions: The use of NIV outside the ICUs, in COVID-19 was common, with a predominant use of helmet CPAP, with a rate of success greater than 60% and close to 75% in full treatment patients. C-reactive protein, PaO2/FiO2, platelet counts were independently associated with increased risk of NIV failure. Clinical trial registered with ClinicalTrials.gov (NCT04382235).
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http://dx.doi.org/10.1513/AnnalsATS.202008-1080OCDOI Listing
January 2021

Increasing dosages of low-molecular-weight heparin in hospitalized patients with Covid-19.

Intern Emerg Med 2021 Jan 3. Epub 2021 Jan 3.

A. Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca' Granda-Ospedale Maggiore Policlinico, Via Pace 9, 20122, Milan, Italy.

We conducted an observational cohort study in adult patients consecutively admitted for the respiratory illness Covid-19 to our hub hospital from March 9 to April 7, 2020. The high observed rate of venous thromboembolism prompted us to increase the prophylactic doses of enoxaparin from 40 mg daily up to 1 mg/kg twice daily in patients admitted to intensive care units (ICU), 0.7 mg/kg twice daily in high-intensity of care wards and 1 mg/kg daily in low-intensity of care wards. Patients on high enoxaparin doses were compared to those who received prophylaxis with the standard dosage. Efficacy endpoints were mortality, clinical deterioration, and the occurrence of venous thromboembolism, safety endpoint was the occurrence of major bleeding. Of 278 patients with Covid-19, 127 received prophylaxis with high enoxaparin doses and 151 with standard dosage. At 21 days, the incidence rate of death and clinical deterioration were lower in patients on higher doses than in those on the standard dosage (hazard ratio 0.39, 95% confidence interval 0.23-0.62), and the incidence of venous thromboembolism was also lower (hazard ratio 0.52, 95% confidence interval 0.26-1.05). Major bleeding occurred in four of 127 patients (3.1%) on the high enoxaparin dosage. In conclusion, in the cohort of patients with Covid-19 treated with high enoxaparin dosages we observed a 60% reduction of mortality and clinical deterioration and a 50% reduction of venous thromboembolism compared to standard dosage prophylaxis. However, 3% of patients on high enoxaparin dosages had non-fatal major bleeding.
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http://dx.doi.org/10.1007/s11739-020-02585-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778858PMC
January 2021

Early Phases of COVID-19 Are Characterized by a Reduction in Lymphocyte Populations and the Presence of Atypical Monocytes.

Front Immunol 2020 9;11:560330. Epub 2020 Dec 9.

Infectious Diseases Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy.

Background: Severe acute respiratory syndrome coronavirus 2 is a recently discovered pathogen responsible of coronavirus disease 2019 (COVID-19). The immunological changes associated with this infection are largely unknown.

Methods: We evaluated the peripheral blood mononuclear cells profile of 63 patients with COVID-19 at diagnosis. We also assessed the presence of association with inflammatory biomarkers and the 28-day mortality.

Results: Lymphocytopenia was present in 51 of 63 (80.9%) patients, with a median value of 720 lymphocytes/µl (IQR 520-1,135). This reduction was mirrored also on CD8+ (128 cells/µl, IQR 55-215), natural killer (67 cells/µl, IQR 35-158) and natural killer T (31 cells/µl, IQR 11-78) cells. Monocytes were preserved in total number but displayed among them a subpopulation with a higher forward and side scatter properties, composed mainly of cells with a reduced expression of both CD14 and HLA-DR. Patients who died in the 28 days from admission (N=10, 15.9%), when compared to those who did not, displayed lower mean values of CD3+ (337.4 cells/µl vs 585.9 cells/µl; p=0.028) and CD4+ cells (232.2 cells/µl vs 381.1 cells/µl; p=0.042) and an higher percentage of CD8+/CD38+/HLA-DR+ lymphocytes (13.5% vs 7.6%; p=0.026).

Discussion: The early phases of COVID-19 are characterized by lymphocytopenia, predominance of Th2-like lymphocytes and monocytes with altered immune profile, which include atypical mononuclear cells.
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http://dx.doi.org/10.3389/fimmu.2020.560330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756112PMC
January 2021

Barotrauma in mechanically ventilated patients with Coronavirus disease 2019: a survey of 38 hospitals in Lombardy, Italy.

Minerva Anestesiol 2021 02 16;87(2):193-198. Epub 2020 Dec 16.

Department of Anesthesiology and Intensive Care Units, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy.

Background: The aim was to describe the incidence and risk factors of barotrauma in patients with the Coronavirus disease 2019 (COVID-19) on invasive mechanical ventilation, during the outbreak in our region (Lombardy, Italy).

Methods: The study was an electronic survey open from March 27 to May 2, 2020. Patients with COVID-19 who developed barotrauma while on invasive mechanical ventilation from 61 hospitals of the COVID-19 Lombardy Intensive Care Unit network were involved.

Results: The response rate was 38/61 (62%). The incidence of barotrauma was 145/2041 (7.1%; 95%-CI: 6.1-8.3%). Only a few cases occurred with ventilatory settings that may be considered non-protective such as a plateau airway pressure >35 cmH2O (2/113 [2%]), a driving airway pressure >15 cmH2O (30/113 [27%]), or a tidal volume >8 mL/kg of ideal body weight and a plateau airway pressure >30 cmH2O (12/134 [9%]).

Conclusions: Within the limits of a survey, patients with COVID-19 might be at high risk for barotrauma during invasive (and allegedly lung-protective) mechanical ventilation.
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http://dx.doi.org/10.23736/S0375-9393.20.15002-8DOI Listing
February 2021

Ventilation of coronavirus disease 2019 patients.

Curr Opin Crit Care 2021 02;27(1):6-12

Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy.

Purpose Of Review: To summarize the current knowledge of pathophysiology and ventilatory management of acute respiratory failure in COVID-19.

Recent Findings: Early reports suggested that COVID-19 is an 'atypical ARDS' with profound hypoxemia with normal respiratory system compliance (Crs). Contrarily, several more populated analyses showed that COVID-19 ARDS has pathophysiological features similar to non-COVID-19 ARDS, with reduced Crs, and high heterogeneity of respiratory mechanics, hypoxemia severity, and lung recruitability. There is no evidence supporting COVID-19-specific ventilatory settings, and the vast amount of available literature suggests that evidence-based, lung-protective ventilation (i.e. tidal volume ≤6 ml/kg, plateau pressure ≤30 cmH2O) should be enforced in all mechanically ventilated patients with COVID-19 ARDS. Mild and moderate COVID-19 can be managed outside of ICUs by noninvasive ventilation in dedicated respiratory units, and no evidence support an early vs. late intubation strategy. Despite widely employed, there is no evidence supporting the efficacy of rescue therapies, such as pronation, inhaled vasodilators, or extracorporeal membrane oxygenation.

Summary: Given the lack of evidence-based specific ventilatory strategies and a large amount of literature showing pathophysiological features similar to non-COVID-19 ARDS, evidence-based lung-protective ventilatory strategies should be pursued in all patients with COVID-19 ARDS.
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http://dx.doi.org/10.1097/MCC.0000000000000793DOI Listing
February 2021

Right Ventricle Dysfunction in Patients With Adult Cystic Fibrosis Enlisted for Lung Transplant.

Transplant Proc 2021 Jan-Feb;53(1):260-264. Epub 2020 Nov 27.

Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy.

Knowledge of preoperative right heart function of adult patients with cystic fibrosis (CF) awaiting lung transplant (LUTX) is limited. The echocardiography of adult patients with CF enlisted for LUTX was retrospectively analyzed and compared with standards and invasive analyses (right heart catheterization, multigated radionuclide ventriculography). We included 49 patients (reported as mean ± standard deviation; 29 ± 9 years of age; forced expiratory volume in first second of expiration, 31% ± 11% predicted; lung allocation score, 36 ± 5; invasive mean pulmonary artery pressure, 17 ± 5 mm Hg; multigated radionuclide ventriculography right ventricle [RV] ejection fraction, 50% ± 9%). Patients had increased RV end-diastolic area, RV wall thickness, and increased pulmonary artery acceleration time with subnormal tricuspid annular plane systolic excursion, tissue Doppler positive peak systolic velocity, and fraction area change. Subnormal tricuspid annular plane systolic excursion (< 23 mm), tissue Doppler positive peak systolic velocity (< 14 cm/s), and fraction area change (< 49%) had high sensitivity and negative predictive value in predicting impaired RV. EJECTION FRACTION: A good correlation between echocardiographic estimated and invasively measured systolic pulmonary artery pressure was observed (R = 0.554, P < .001). Adults with CF awaiting LUTX have morphologic alterations of the right heart, with subclinical impairment of RV systolic function. Echocardiography may be used as a bedside, repeatable, and reliable noninvasive test to screen further deterioration in RV function while on the waiting list for LUTX. More prospective follow-up echocardiographic studies are necessary to confirm such a hypothesis.
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http://dx.doi.org/10.1016/j.transproceed.2020.09.020DOI Listing
November 2020

The ADAMTS13-von Willebrand factor axis in COVID-19 patients.

J Thromb Haemost 2021 02 18;19(2):513-521. Epub 2020 Dec 18.

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.

Background: Severe coronavirus disease 2019 (COVID-19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients.

Objectives: To investigate the mechanism of microthrombosis in COVID-19 progression.

Patients/methods: We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin-cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross-sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high-flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19).

Results: Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID-19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high-to-low molecular-weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care.

Conclusions: We found a significant alteration of the VWF-ADAMTS13 axis in COVID-19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID-19 patients and their risk of microthrombosis.
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http://dx.doi.org/10.1111/jth.15191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753796PMC
February 2021

Management of critically ill patients with COVID-19: suggestions and instructions from the coordination of intensive care units of Lombardy.

Minerva Anestesiol 2020 11;86(11):1234-1245

School of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.

With 63,098 confirmed cases on 17 April 2020 and 11,384 deaths, Lombardy has been the most affected region in Italy by coronavirus disease 2019 (COVID-19). To cope with this emergency, the COVID-19 Lombardy intensive care units (ICU) network was created. The network identified the need of defining a list of clinical recommendations to standardize treatment of patients with COVID-19 admitted to Intensive Care Unit (ICU). Three core topics were identified: 1) rational use of intensive care resources; 2) ventilation strategies; 3) non-ventilatory interventions. Identification of patients who may benefit from ICU treatment is challenging. Clinicians should consider baseline performance and frailty status and they should adopt disease-specific staging tools. Continuous positive airway pressure, mainly delivered through a helmet as elective method, should be considered as initial treatment for all patients with respiratory failure associated with COVID-19. In case of persisting dyspnea and/or desaturation despite 4-6 hours of noninvasive ventilation, endotracheal intubation and invasive mechanical ventilation should be considered. In the early phase, muscle relaxant use and volume-controlled ventilation is recommended. Prone position should be performed in patients with PaO2/FiO2≤100 mmHg. For patients admitted to ICU with COVID-19 interstitial pneumonia, we do not recommend empiric antibiotic therapy for community-acquired pneumonia. Consultation of an infectious disease specialist is suggested before start of any antiviral therapy. In conclusion, the COVID-19 Lombardy ICU Network identified a list of best practice statements supported by the available evidence and clinical experience or identified as panel members expert opinions for the management of critically ill patients with COVID-19.
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http://dx.doi.org/10.23736/S0375-9393.20.14762-XDOI Listing
November 2020

Nasal high flow higher than 60 L/min in patients with acute hypoxemic respiratory failure: a physiological study.

Crit Care 2020 11 23;24(1):654. Epub 2020 Nov 23.

Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Background: Nasal high flow delivered at flow rates higher than 60 L/min in patients with acute hypoxemic respiratory failure might be associated with improved physiological effects. However, poor comfort might limit feasibility of its clinical use.

Methods: We performed a prospective randomized cross-over physiological study on 12 ICU patients with acute hypoxemic respiratory failure. Patients underwent three steps at the following gas flow: 0.5 L/kg PBW/min, 1 L/kg PBW/min, and 1.5 L/kg PBW/min in random order for 20 min. Temperature and FiO remained unchanged. Toward the end of each phase, we collected arterial blood gases, lung volumes, and regional distribution of ventilation assessed by electrical impedance tomography (EIT), and comfort.

Results: In five patients, the etiology was pulmonary; infective disease characterized seven patients; median PaO/FiO at enrollment was 213 [IQR 136-232]. The range of flow rate during NHF 1.5 was 75-120 L/min. PaO/FiO increased with flow, albeit non significantly (p = 0.064), PaCO and arterial pH remained stable (p = 0.108 and p = 0.105). Respiratory rate decreased at higher flow rates (p = 0.014). Inhomogeneity of ventilation decreased significantly at higher flows (p = 0.004) and lung volume at end-expiration significantly increased (p = 0.007), but mostly in the non-dependent regions. Comfort was significantly poorer during the step performed at the highest flow (p < 0.001).

Conclusions: NHF delivered at rates higher than 60 L/min in critically ill patients with acute hypoxemic respiratory failure is associated with reduced respiratory rate, increased lung homogeneity, and additional positive pressure effect, but also with worse comfort.
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http://dx.doi.org/10.1186/s13054-020-03344-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682052PMC
November 2020

Anakinra combined with methylprednisolone in patients with severe COVID-19 pneumonia and hyperinflammation: An observational cohort study.

J Allergy Clin Immunol 2021 Feb 19;147(2):561-566.e4. Epub 2020 Nov 19.

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Infectious Disease Unit, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy; Centre for Multidisciplinary Research in Health Science, University of Milan, Milan, Italy.

Background: Immunomodulants have been proposed to mitigate severe acute respiratory syndrome coronavirus 2-induced cytokine storm, which drives acute respiratory distress syndrome in coronavirus disease 2019 (COVID-19).

Objective: We sought to determine efficacy and safety of the association of IL-1 receptor antagonist anakinra plus methylprednisolone in severe COVID-19 pneumonia with hyperinflammation.

Methods: A secondary analysis of prospective observational cohort studies was carried out at an Italian tertiary health care facility. COVID-19 patients consecutively hospitalized (February 25, 2020, to March 30, 2020) with hyperinflammation (ferritin ≥1000 ng/mL and/or C-reactive protein >10 mg/dL) and respiratory failure (oxygen therapy from 0.4 FiO Venturi mask to invasive mechanical ventilation) were evaluated to investigate the effect of high-dose anakinra plus methylprednisolone on survival. Patients were followed from study inclusion to day 28 or death. Crude and adjusted (sex, age, baseline PaO:FiO ratio, Charlson index, baseline mechanical ventilation, hospitalization to inclusion lapse) risks were calculated (Cox proportional regression model).

Results: A total of 120 COVID-19 patients with hyperinflammation (median age, 62 years; 80.0% males; median PaO:FiO ratio, 151; 32.5% on mechanical ventilation) were evaluated. Of these, 65 were treated with anakinra and methylprednisolone and 55 were untreated historical controls. At 28 days, mortality was 13.9% in treated patients and 35.6% in controls (Kaplan-Meier plots, P = .005). Unadjusted and adjusted risk of death was significantly lower for treated patients compared with controls (hazard ratio, 0.33, 95% CI, 0.15-0.74, P = .007, and HR, 0.18, 95% CI, 0.07-0.50, P = .001, respectively). No significant differences in bloodstream infections or laboratory alterations were registered.

Conclusions: Treatment with anakinra plus methylprednisolone may be a valid therapeutic option in COVID-19 patients with hyperinflammation and respiratory failure, also on mechanical ventilation. Randomized controlled trials including the use of either agent alone are needed to confirm these results.
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http://dx.doi.org/10.1016/j.jaci.2020.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674131PMC
February 2021

Chest X-ray findings in a large cohort of 1117 patients with SARS-CoV-2 infection: a multicenter study during COVID-19 outbreak in Italy.

Intern Emerg Med 2020 Nov 20. Epub 2020 Nov 20.

Department of Radiology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy.

To describe radiographic key patterns on Chest X-ray (CXR) in patients with SARS-CoV-2 infection, assessing the prevalence of radiographic signs of interstitial pneumonia. To evaluate pattern variation between a baseline and a follow-up CXR. 1117 patients tested positive for SARS-CoV-2 infection were retrospectively enrolled from four centers in Lombardy region. All patients underwent a CXR at presentation. Follow-up CXR was performed when clinically indicated. Two radiologists in each center reviewed images and classified them as suggestive or not for interstitial pneumonia, recording the presence of ground-glass opacity (GGO), reticular pattern or consolidation and their distribution. Pearson's χ test for categorical variables and McNemar test (χ for paired data) were performed. Patients mean age 63.3 years, 767 were males (65.5%). The main result is the large proportion of positive CXR in COVID-19 patients. Baseline CXR was positive in 940 patients (80.3%), with significant differences in age and sex distribution between patients with positive and negative CXR. 382 patients underwent a follow-up CXR. The most frequent pattern on baseline CXR was the GGO (66.1%), on follow-up was consolidation (53.4%). The most common distributions were peripheral and middle-lower lung zone. We described key-patterns and their distribution on CXR in a large cohort of COVID-19 patients: GGO was the most frequent finding on baseline CXR, while we found an increase in the proportion of lung consolidation on follow-up CXR. CXR proved to be a reliable tool in our cohort obtaining positive results in 80.3% of the baseline cases.
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http://dx.doi.org/10.1007/s11739-020-02561-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7677441PMC
November 2020

The role for high flow nasal cannula as a respiratory support strategy in adults: a clinical practice guideline.

Intensive Care Med 2020 Dec 17;46(12):2226-2237. Epub 2020 Nov 17.

Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, ON, Canada.

Purpose: High flow nasal cannula (HFNC) is a relatively recent respiratory support technique which delivers high flow, heated and humidified controlled concentration of oxygen via the nasal route. Recently, its use has increased for a variety of clinical indications. To guide clinical practice, we developed evidence-based recommendations regarding use of HFNC in various clinical settings.

Methods: We formed a guideline panel composed of clinicians, methodologists and experts in respiratory medicine. Using GRADE, the panel developed recommendations for four actionable questions.

Results: The guideline panel made a strong recommendation for HFNC in hypoxemic respiratory failure compared to conventional oxygen therapy (COT) (moderate certainty), a conditional recommendation for HFNC following extubation (moderate certainty), no recommendation regarding HFNC in the peri-intubation period (moderate certainty), and a conditional recommendation for postoperative HFNC in high risk and/or obese patients following cardiac or thoracic surgery (moderate certainty).

Conclusions: This clinical practice guideline synthesizes current best-evidence into four recommendations for HFNC use in patients with hypoxemic respiratory failure, following extubation, in the peri-intubation period, and postoperatively for bedside clinicians.
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http://dx.doi.org/10.1007/s00134-020-06312-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670292PMC
December 2020