Sam Parnia

Background: Antivirals remain an important treatment strategy for persons who experience severe and life-threatening COVID-19. Ensitrelvir is an oral 3CL protease inhibitor with potent antiviral activity. Methods: We conducted an international randomized, placebo-controlled trial of ensitrelvir with standard of care (SOC) among adults hospitalized for COVID-19. The primary outcome was clinical recovery assessed by the days to recovery scale through day 60 (DRS-60), analyzed using a Van Elteren test. Results: From 2023 to 2025, 589 participants received blinded study treatment (293 ensitrelvir and 296 placebo). Median age was 69 years, 49% were female, 68% were White, and SOC commonly included corticosteroids (61% and 54%) and remdesivir (62% and 60%) in ensitrelvir and placebo groups, respectively. Median DRS-60 category was 6 (IQR: 3-15) in the ensitrelvir and 5.5 (IQR: 3-12) in the placebo group (P = .19), and the OR was 0.82 (95% CI: 0.62-1.09) for a better DRS-60 category with ensitrelvir. Ensitrelvir participants had lower detectable viral antigen in plasma at Day 5 (13.4% vs 25.1%; P < .001). There was no difference in secondary clinical outcomes or prespecified safety outcomes, though the mortality rate was 6.1% vs 4.4% and the frequency of hemorrhagic events was 3.4% vs 0.3% among ensitrelvir and placebo groups, respectively. Conclusions: Ensitrelvir treatment did not improve clinical recovery in addition to SOC for adults hospitalized for COVID-19. The lower illness severity in the Omicron era compared with earlier periods in the COVID-19 pandemic and high use of remdesivir and corticosteroids, may have contributed to the lack of clinical benefit.

Background: Current cardiopulmonary resuscitation (CPR) guidelines recommend a ventilation rate of 10 breaths/min in adult cardiac arrest patients with an advanced airway in place; however, this guideline is based almost exclusively on animal model studies. The objective of this study was to examine the association between mean ventilation rates during in-hospital cardiac arrest with return of spontaneous circulation (ROSC). Methods: This was a secondary analysis of a cohort undergoing CPR for in-hospital cardiac arrest with an advanced airway in place had that ventilation rate and end-tidal CO ₂ (ETCO ₂ ) continuously recorded. Subjects were enrolled at 25 tertiary care centers in the United States and United Kingdom. A subset of subjects also had intra-cardiac arrest arterial blood gases collected as part of routine clinical care. Results: Ventilation rate and ETCO ₂ measurements were collected for 222 subjects and arterial blood gas data for 127 subjects. We observed 84.7% of subjects were ventilated > 10 breaths/min. When dichotomized to subjects receiving close to current guidelines (6-12 breaths/min) and those with higher ventilation rates >12 breaths/min, subjects with higher ventilation rates had greater rate of ROSC (45% vs. 24% p = 0.009). Ventilation rate had a significant impact on ROSC even after adjusting for age, sex, shockable initial rhythm, pre-cardiac arrest severity of critical illness, and mechanical chest compression device usage, with an adjusted odds ratio of 1.15 per two breaths/min increase (95% CI 1.04-1.28; p = 0.006). Regression analysis suggested increasing ventilation rates may start to have a negative association with ROSC when beyond 26 breaths/min. Patients ventilated > 12 breaths/min demonstrated increased mean ETCO ₂ levels (median 25 mm Hg vs. 17 mm Hg for those with mean ventilation rates within 6-12 breaths/min; p < 0.001). PaO ₂ and PaCO ₂ levels did not differ between ventilation groups, suggesting that the observed effects may relate to hemodynamic rather than ventilatory effects. Conclusions: Ventilation in excess of guideline-recommended rates is common. Higher ventilation rates above 6-12 breaths and below 26 breaths/min were associated with increased odds of ROSC. This may be due to improved hemodynamics. Guidelines on ventilation during CPR may require further examination.

Rationale: There are limited therapeutic options for patients with coronavirus disease (COVID-19)-related acute respiratory distress syndrome with inflammation-mediated lung injury. Mesenchymal stromal cells offer promise as immunomodulatory agents. Objectives: Evaluation of efficacy and safety of allogeneic mesenchymal cells in mechanically-ventilated patients with moderate or severe COVID-19–induced respiratory failure. Methods: Patients were randomized to two infusions of 2 million cells/kg or sham infusions, in addition to the standard of care. We hypothesized that cell therapy would be superior to sham control for the primary endpoint of 30-day mortality. The key secondary endpoint was ventilator-free survival within 60 days, accounting for deaths and withdrawals in a ranked analysis. Measurements and Main Results: At the third interim analysis, the data and safety monitoring board recommended that the trial halt enrollment as the prespecified mortality reduction from 40% to 23% was unlikely to be achieved (n = 222 out of planned 300). Thirty-day mortality was 37.5% (42/112) in cell recipients versus 42.7% (47/110) in control patients (relative risk [RR], 0.88; 95% confidence interval, 0.64–1.21; P = 0.43). There were no significant differences in days alive off ventilation within 60 days (median rank, 117.3 [interquartile range, 60.0–169.5] in cell patients and 102.0 [interquartile range, 54.0–162.5] in control subjects; higher is better). Resolution or improvement of acute respiratory distress syndrome at 30 days was observed in 51/104 (49.0%) cell recipients and 46/106 (43.4%) control patients (odds ratio, 1.36; 95% confidence interval, 0.57–3.21). There were no infusion-related toxicities and overall serious adverse events over 30 days were similar. Conclusions: Mesenchymal cells, while safe, did not improve 30-day survival or 60-day ventilator-free days in patients with moderate and/or severe COVID-19–related acute respiratory distress syndrome.

An inadvertent consequence of advances in stem cell research, neuroscience, and resuscitation science has been to enable scientific insights regarding what happens to the human brain in relation to death. The scientific exploration of death is in large part possible due to the recognition that brain cells are more resilient to the effects of anoxia than assumed. Hence, brain cells become irreversibly damaged and “die” over hours to days postmortem. Resuscitation science has enabled life to be restored to millions of people after their hearts had stopped. These survivors have described a unique set of recollections in relation to death that appear universal. We review the literature, with a focus on death, the recalled experiences in relation to cardiac arrest, post–intensive care syndrome, and related phenomena that provide insights into potential mechanisms, ethical implications, and methodologic considerations for systematic investigation. We also identify issues and controversies related to the study of consciousness and the recalled experience of cardiac arrest and death in subjects who have been in a coma, with a view to standardize and facilitate future research.