Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Patient and Health Care Provider Perspectives on Potential Preventability of Hospital Admission for Acute Exacerbation of Chronic Obstructive Pulmonary Disease: A Qualitative Study

Purpose: Chronic obstructive pulmonary disease (COPD) is a highly prevalent chronic disease partly characterised by the occurrence of acute exacerbations (AECOPD). The need for hospital admissions for COPD exacerbations could theoretically be decreased through timely and appropriate outpatient care or self-management. The aim of this study is to explore and compare patients’ and health care providers’ (HCP) perspectives on the potential preventability of COPD hospitalisations and to identify strategies to prevent unnecessary hospitalisations. Patients and Methods: Semi-structured interviews were conducted with patients admitted for an AECOPD (N = 11), HCPs on the respiratory ward (N = 11), and treating pulmonologists (N = 10). Interviews were transcribed verbatim and analysed using thematic content analysis. Results: Patient and HCP perspectives on the potential preventability of hospital admissions for AECOPD often conflict. The kappa coefficients were −0.18 [95% CI: −0.46–0.11] for patients and pulmonologists and −0.28 [95% CI: −0.80–0.21] for patients and HCPs, which indicates poor agreement. The kappa coefficient for pulmonologists and HCPs was 0.14 [95% CI: −0.13–0.41], which indicates slight agreement. Patient and HCP factors that could potentially prevent hospitalisation for AECOPD were identified, including timely calling for help, recognizing and acting on symptoms, and receiving instruction about COPD, including treatment and action plans. Conclusion: Patients and their HCPs have different beliefs about the potential preventability of AECOPD hospitalisations. Most patients and HCPs mentioned factors that potentially could have led to a different outcome for the current AECOPD or that could impact the patient’s health status and treatment of AECOPDs in the future. The factors identified in this study indicate that shared decision making is crucial to center the patient’s perspective and individual needs and to provide timely treatment or prevention of AECOPD, thereby potentially decreasing hospital admission rates

Uncoupled respiration, ROS production, acute lipotoxicity and oxidative damage in isolated skeletal muscle mitochondria from UCP3-ablated mice

AbstractThe function of uncoupling protein 3 (UCP3) is still not established. Mitochondrial uncoupling, control of ROS production, protection against lipotoxicity and protection against oxidative stress are functions classically discussed. To establish a role for UCP3 in these functions, we have here used UCP3 (−/−) mice, backcrossed for 10 generations on a C57Bl/6 background. In isolated skeletal muscle mitochondria, we examined uncoupled respiration, both unstimulated and in the presence of fatty acids. We did not observe any difference between mitochondria from wildtype and UCP3 (−/−) mice. We measured H2O2 production rate and respiration rate under reactive oxygen species-generating conditions (succinate without rotenone) but found no effect of UCP3. We tested two models of acute lipotoxicity—fatty acid-induced oxidative inhibition and fatty acid-induced swelling—but did not observe any protective effect of UCP3. We examined oxidative stress by quantifying 4-hydroxynonenal protein adducts and protein carbonyls in the mitochondria—but did not observe any protective effect of UCP3. We conclude that under the experimental conditions tested here, we find no evidence for the function of UCP3 being basal or induced uncoupling, regulation of ROS production, protection against acute lipotoxicity or protection against oxidative damage

Effect of Antiplatelet Therapy on Survival and Organ Support–Free Days in Critically Ill Patients With COVID-19

International audienc