Our data reveal an association between toxic concentrations for a number of β-lactam agents and neurotoxic/nephrotoxic effects. We have defined threshold concentrations above which these toxicities become more likely. Clinicians should balance concerns for therapeutic efficacy with potential toxicity when considering aggressive therapy.

Writing Committee for the REMAP-CAP Investigators IMPORTANCE The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.OBJECTIVE To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19. DESIGN, SETTING, AND PARTICIPANTSThe ongoing Randomized, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomized 4763 adults with suspected or confirmed COVID-19 between March 9, 2020, and January 18, 2021, within at least 1 domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in 4 countries. Follow-up ended on April 19, 2021. INTERVENTIONSThe immunoglobulin domain randomized participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916). MAIN OUTCOMES AND MEASURESThe primary ordinal end point was organ support-free days (days alive and free of intensive care unit-based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned -1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support-free days, or both. The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support-free days; cardiovascular support-free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events. RESULTS Among the 2011 participants who were randomized (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support-free days was 0 (IQR, -1 to 16) in the convalescent plasma group and 3 (IQR, -1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11...

BackgroundVeno-arterial extracorporeal membrane oxygenation (VA ECMO) is an effective rescue therapy for severe cardiorespiratory failure, but morbidity and mortality are high. We hypothesised that survival decreases with longer VA ECMO treatment. We examined the Extracorporeal Life Support Organization (ELSO) registry for a relationship between VA ECMO duration and in-hospital mortality, and covariates including indication for support.MethodsAll VA runs from the ELSO database from 2002 to 2012 were extracted. Multiple runs and non-VA runs were excluded. Runs were categorized into diagnostic groups. Logistic regression for analysis of the effect of duration on outcome, and multivariate regression for diagnosis and other baseline factors were performed. Non-linear models including piecewise logistic models were fitted.ResultsThere were 2699 runs analysed over 14,747 days. Logistic regression analysis of the effect of duration on outcome, and multivariate regression analysis of diagnosis and other baseline factors were performed. In-hospital survival was 41.4% (95% CI 39.6–43.3). 75% of patients were supported for less than 1 week and 96% for less than 3 weeks. Median duration (4 days IQR 2.0–6.8) was greater in survivors (4.1 (IQR 2.5–6.7) vs 3.8 (IQR 1.7–7.0) p = 0.002). The final multivariate model demonstrated increasing survival to day 4 (OR 1.53 (95% CI 1.37–1.71) p < 0.001), decreasing from day 4 to 12 (OR 0.86 (95% CI 0.81–0.91), p < 0.001) with no significant change thereafter (OR 0.98 (95% CI 0.94–1.02), p = 0.400).ConclusionsECMO for 4 days or less is associated with higher mortality, likely reflecting early treatment failure. Survival is highest when patients are weaned on the fourth day of ECMO but likely decreases into the second week. While this does not suggest weaning at this point will produce better outcomes, it does reflect the likely time course of ECMO as a bridge in severe shock. Patients with some underlying conditions (like myocarditis and heart transplantation) achieve better outcomes despite longer support duration. These findings merit prospective study for the development of prognostic models and weaning strategies.