Comparison between Propofol and Total Inhalational Anaesthesia on Cardiovascular Outcomes Following On-pump Cardiac Surgery in Higher-Risk Patients A Randomised Controlled Pilot and Feasibility Study (preprint)

Abstract Objectives: Myocardial revascularisation and cardiopulmonary bypass (CPB) can cause ischemia-reperfusion injury, leading to myocardial and other end-organ damage. Volatile anaesthetics protect the myocardium in experimental studies, however there is uncertainty as whether this translates into clinical benefits. Methods: In this single blinded parallel group randomised controlled feasibility trial higher-risk patients undergoing elective coronary artery bypass graft surgery with an additive European System for Cardiac Operative Risk Evaluation (EuroScore) > 5 were randomised to receive either propofol or total inhalational anaesthesia for maintenance of anaesthesia. The primary outcome was the feasibility to recruit and randomise 50 patients across two cardiac surgical centres and secondary outcomes included the feasibility of collecting the planned perioperative data and clinically relevant outcomes and assessments of effective patient identification, screening and recruitment. Results: All 50 patients were recruited within 11 months in two centres allowing for a 13-month hiatus in recruitment due to the COVID-19 pandemic. Overall, 50/108 (46%) of eligible patients were recruited. One patient withdrew before surgery and one patient did not undergo surgery. All but one completed in-hospital and 30-day follow-up. Conclusions: It is feasible to recruit and randomise higher-risk patients undergoing CABG surgery to a study comparing total inhalational and propofol anaesthesia in a timely manner and with high acceptance and completion rates.

Effect of Heparin and Tocilizumab in Patients with Severe COVID-19: The HEPMAB Randomized Clinical Trial (preprint)

BackgroundClinical presentation of severe Coronavirus disease 2019 (COVID-19) is associated to an intense inflammatory response and thrombogenesis. The benefits of the association of interleukin-6 receptor blockade (tocilizumab) and therapeutic-dose anticoagulation remains unclear. We aimed to assess whether heparin and tocilizumab could effectively reduce inflammation and thrombogenesis in severe COVID-19 patients. MethodsThis is an open-label, multicenter, randomized, clinical trial, involving patients with severe COVID-19 infection. Eligible patients were randomly assigned in a 1:1:1:1 ratio to receive either therapeutic or prophylactic anticoagulation with heparin, with or without an intravenous single dose of tocilizumab. The participants in the study were assigned to one of the four distinct arms: 1) therapeutic anticoagulation; 2) prophylactic anticoagulation; 3) therapeutic anticoagulation plus a single intravenous dose of tocilizumab; and 4) prophylactic anticoagulation plus a single intravenous dose of tocilizumab. The primary outcome was clinical improvement at day 30, defined as a composite of hospital discharge and/or a reduction of at least 2 points of the modified ordinal scale of 7 points recommended by the World Health Organization. ResultsWe enrolled 308 patients. Patients randomized to receive therapeutic anticoagulation more frequently had clinical improvement at day 30 when compared to the prophylactic anticoagulation patients [64/75 (85%) versus 51/80 (64%), odds ratio, 3.31; 95% confidence interval, 1.51; 7.26 P=0.003]. Major bleeding was more frequent in the therapeutic anticoagulation group (6.7%) and in the therapeutic anticoagulation plus tocilizumab group (5.0%), compared to the prophylactic anticoagulation group (P=0.02). All-cause mortality at day 30 was significantly lower in therapeutic anticoagulation group (9.3%), when compared to prophylactic anticoagulation group (28.7%), therapeutic anticoagulation plus tocilizumab group (21.5%) and prophylactic anticoagulation plus tocilizumab group (25.7%), P=0.02. ConclusionsIn this randomized clinical trial involving severe COVID-19 patients, therapeutic anticoagulation resulted in clinical improvement at 30 days. Even if therapeutic anticoagulation increased bleeding, it was associated with a reduced overall mortality. Tocilizumab did not provide additional benefits to heparin in COVID-19 patients. Trial registrationClinicaltrials.gov NCT04600141. Registered October 22, 2020. https://www.clinicaltrials.gov/study/NCT04600141?term=NCT04600141&rank=1

Preexisting and new-onset diabetes in patients with COVID-19 pneumonia (preprint)

Objective. The aim of the current study was to compare clinical characteristics, laboratory findings and major outcomes of patients hospitalized for COVID-19 pneumonia with new-onset or preexisting diabetes. Design. A cohort of 176 adult patients with a diagnosis of pre-existing (n=112) or new-onset diabetes (n=55) and confirmed COVID-19 pneumonia was studied. Clinical outcomes and laboratory findings were analysed according to the presence of preexisting or new-onset diabetes. The time to viral clearance and the persistence of hyperglycemia were assessed during the follow-up after hospital discharge. Results. Patients with new-onset diabetes had lower BMI, significantly less comorbidities and higher levels of inflammatory markers and indicators of multi-organ injury than those with preexisting diabetes. No differences between preexisting and new onset diabetes were evident for symptoms at admission, humoral response against SARS-CoV-2 or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. New-onset diabetes was independently associated with the risk of adverse clinical outcome defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p=0.001), even after adjustment for age, sex and other selected variables associated with COVID-19 severity. Furthermore, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p=0.063) between new-onset diabetes and the time to swab negativization. During follow-up we observed that in 30% of the patients with new-onset diabetes hyperglycemia reversed when the viral infection resolved. Conclusions. The recognition of new-onset diabetes as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.

Thromboembolism risk among patients with diabetes/stress hyperglycemia and COVID-19 (preprint)

A bstract Purpose Individuals with diabetes/stress hyperglycemia carry an increased risk for adverse clinical outcome in case of SARS-CoV-2 infection. The purpose of this study was to evaluate whether this risk is, at least in part, modulated by an increase of thromboembolic complications. Methods We prospectively followed 180 hospitalized patients with confirmed COVID-19 pneumonia admitted to the Internal Medicine Units of San Raffaele Hospital. Data from 11 out of 180 patients were considered incomplete and excluded from the analysis. We analysed inflammation, tissue damage biomarkers, hemostatic parameters, thrombotic events (TEs) and clinical outcome according to the presence of diabetes/stress hyperglycemia. Results Among 169 patients, 51 (30.2%) had diabetes/stress hyperglycemia. Diabetes/stress hyperglycemia and fasting blood glucose (FBG) were associated with increased inflammation and tissue damage circulating markers, higher D-dimer levels, increased prothrombin time and lower antithrombin III activity. Forty-eight venous and 10 arterial TEs were identified in 49 (29%) patients. Diabetes/stress hyperglycemia (HR 2.71, p=0.001), fasting blood glucose (HR 4.32, p<0.001) and glucose variability (HR 1.6, p < 0.009) were all associated with an increased risk of thromboembolic complication. TEs significantly increased the risk for an adverse clinical outcome only in the presence of diabetes/stress hyperglycemia (HR 3.05, p=0.01) or fasting blood glucose ≥ 7 mmol/l (HR 3.07, p=0.015). Conclusions Thromboembolism risk is higher among patients with diabetes/stress hyperglycemia and COVID-19 pneumonia and is associated to poor clinical outcome. In case of SARS-Cov-2 infection patients with diabetes/stress hyperglycemia could be considered for a more intensive prophylactic anticoagulation regimen.

Outcomes of COVID-19 Patients Intubated After Failure of Non-Invasive Ventilation: A Multicenter Observational Study. (preprint)

IntroductionThe efficacy of non-invasive ventilation (NIV) in acute respiratory failure secondary to SARS-CoV-2 infection remains controversial. Current literature mainly examined efficacy, safety and potential predictors of NIV failure provided out of the Intensive Care Unit (ICU). On the contrary, the outcomes of ICU patients, intubated after NIV failure, remain to be explored. The aims of the present study are: 1) investigating in-hospital mortality in coronavirus disease 2019 (COVID-19) ICU patients receiving endotracheal intubation after NIV failure and 2) assessing whether the length of NIV application affects patient survival. MethodsThis observational multicenter study included all consecutive COVID-19 adult patients, admitted into the twenty-five ICUs of the COVID-19 VENETO ICU network (February-April 2020), who underwent endotracheal intubation after NIV failure. ResultsAmong the 704 patients admitted to ICU during the study period, 280 (40%) presented the inclusion criteria and were enrolled. The median age was 69 [60-76] years; 219 patients (78%) were male. In-hospital mortality was 43%. Only the length of NIV application before ICU admission (OR 2.03 (95% CI 1.06 - 4.98), p = 0.03) and age (OR 1.18 (95% CI 1.04 - 1.33), p < 0.01) were identified as independent risk factors of in-hospital mortality; whilst the length of NIV after ICU admission did not affect patient outcome. ConclusionsIn-hospital mortality of ICU patients intubated after NIV failure was 43%. Days on NIV before ICU admission and age were assessed to be potential risk factors of greater in-hospital mortality. 

Efficacy and Safety of IL-6 Inhibitors in Patients with COVID-19 Pneumonia: A Systematic Review and Meta-Analysis of Multicentre, Randomised Trials (preprint)

Introduction: The novel coronavirus disease 2019 (COVID-19) is frequently characterized by dysregulated host immune response with hyperinflammation and self-induced host inflammatory damage that results in severe respiratory failure and frequently death. Interleukin-6 (IL-6) appeared among the key cytokines involved in COVID-19 associated cytokine storm. Therefore, several trials investigated whether IL-6 inhibition with tocilizumab or sarilumab could improve symptoms and outcome of COVID-19 patients. We performed a meta-analysis of randomized trials to test this hypothesis.Methods: PubMed, Scopus, Cochrane central register and medRxiv were searched by two independent investigators up to February 23rd, 2021. Inclusion criteria were: administration of tocilizumab or sarilumab, COVID-19 pneumonia, randomized controlled trials. Studies in setting other than adult human COVID-19 were excluded. The primary outcome was mortality at the longest follow-up available. Secondary outcomes included need for intubation and incidence of adverse events. Two independent investigators examined and extracted data from eligible trials.Results: A total of 371 studies were assessed, with a total of 10 studies (6,465 patients) finally included in the meta-analysis. All the trials were multicentre and the majority were open-label vs standard treatment. IL-6 inhibitors use was associated with reduced all-cause mortality at the longest follow-up available (823/3,310 [24·9%] in the IL-6 inhibitors group versus 902/3,038 [29·7%] in the control group, RR = 0·89; 95% CI 0·82 to 0·96; p for effect = 0·003, I2 = 6%, with eight studies included). Use of IL-6 inhibitors was associated with a significant reduction in need for intubation, while we found no difference in rate of adverse events and secondary infections.Conclusion: Administration of IL-6 inhibitors may reduce all-cause longest follow-up mortality and need for intubation in COVID-19 patients, without increasing risk of adverse events. However, these findings need to be confirmed in high-quality randomized controlled trials.Funding Statement: None.Declaration of Interests: None.

Low Diaphragm Muscle Mass Predicts Adverse Outcome in Patients Hospitalized for Covid-19 Pneumonia (preprint)

Purpose: The aim of this study was to evaluate whether measurement of diaphragm thickness by ultrasonography may be a clinically useful noninvasive method for identifying patients at risk of adverse outcomes defined as need of invasive mechanical ventilation or death. Methods: We retrospectively reviewed the records of consecutive of 77 patients with laboratory-confirmed Covid-19 infection admitted to our intermediate care unit in Pisa between March 5 and March 30, 2020, with follow up until hospital discharge or death. Logistic regression was used identify variables potentially associated with adverse outcomes and those P<0.10 were entered into a multivariate logistic regression model. Cumulative probability for lack of adverse outcomes in patients with or without low baseline diaphragm muscle mass was calculated with the Kaplan–Meier product-limit estimator.Results: The main findings of this study are that 1) patients who developed adverse outcomes had thinner diaphragm than those who did not (2.0 vs 2.2 mm, p:0.001), 2) DT and lymphocyte count were independent significant predictors of adverse outcomes, with end-expiratory DT being the strongest (-708, OR: 0.492, p: 0.018).Conclusion: Diaphragmatic ultrasound may be a valid tool to evaluate the risk of respiratory failure. Evaluating the need of mechanical ventilation treatment should be based not only on PaO2/FiO2, but on a more comprehensive assessment including DT because if the lungs become less compliant a thinner diaphragm, albeit free of intrinsic abnormality, may become exhausted, thus contributing to severe respiratory failure. 

The Effect of Angiotensin II Infusion on Markers of Organ Function in Invasively Ventilated COVID-19 Patients (preprint)

Background: The use of angiotensin II (ANGII) in invasively ventilated COVID-19 patients is controversial. Its effect on markers of organ function is unknown.Methods: We used ANGII either as rescue vasopressor agent or as low dose vasopressor support. Patients treated before ANGII availability or in an adjacent COVID-19 ICU served as controls. For data analysis, we applied Bayesian modelling as appropriate. We assessed the effects of ANG on markers of organ function.Results: We compared 46 ANGII patients with 53 controls. Compared with controls, ANGII increased MAP (median difference, 9.05 mmHg [95% confidence interval, 1.87 to 16.22]; p = 0.013) and PaO2/FiO2 ratio (median difference, 23.17 [95% confidence interval, 3.46 to 42.88]; p = 0.021). ANGII had no effect on lactate, urinary output, serum creatinine, C-Reactive protein, platelet count, or thromboembolic complications. However, it significantly decreased the odd ratio of liver dysfunction (odds ratio: 0.32; 0.09 to 0.94) and, on Bayesian modelling, in patients with abnormal baseline serum creatinine, ANGII carried a 95.7% probability of decreasing renal replacement therapy use. Conclusions: In ventilated COVID-19 patients, ANGII therapy was associated with increased blood pressure and PaO2/FiO2 ratios, decreased odds ratio of liver dysfunction, and a high probability of decreasing renal replacement therapy use in patients with abnormal baseline serum creatinine.