Adit A. Ginde

IMPORTANCE: Emergency tracheal intubation in critically ill adults is a high-risk procedure. OBJECTIVES: To evaluate associations of ketamine vs. etomidate with cardiovascular collapse and other peri-intubation outcomes. DESIGN, SETTING, AND PARTICIPANTS: Secondary analysis of individual-participant data from the DEVICE and PREOXI trials, treating induction medication as an observational exposure. The cohort included 2357 adults intubated in emergency departments or ICUs; 1822 received etomidate, 312 ketamine, and 223 other induction regimens. MAIN OUTCOMES AND MEASURES: The primary outcome was cardiovascular collapse, defined as new or increased vasopressor use, nadir systolic blood pressure below 65 mm Hg, or cardiac arrest between induction and 2 minutes after intubation. Secondary outcomes included severe hypoxemia (oxygen saturation < 80%) and procedural outcomes. RESULTS: In weighted analyses, cardiovascular collapse occurred in 14.0% of etomidate recipients and 20.4% of ketamine recipients. In weighted, covariate-adjusted models, ketamine was associated with higher odds of cardiovascular collapse (adjusted odds ratio [aOR], 1.80; 95% CI, 1.24–2.62) and new or increased vasopressor use (aOR, 1.51; 95% CI, 1.02–2.23), nominally lower odds of severe hypoxemia (aOR, 0.50; 95% CI, 0.28–0.88), and shorter modeled time to successful intubation (hazard ratio, 1.16; 95% CI, 1.02–1.33). The latter two associations were not significant after multiplicity adjustment. Estimates for systolic blood pressure below 65 mm Hg and cardiac arrest were too imprecise for reliable inference. Successful intubation on the first attempt and 28-day in-hospital mortality did not clearly differ between ketamine and etomidate. CONCLUSIONS AND RELEVANCE: Compared with etomidate, ketamine was associated with higher odds of cardiovascular collapse, primarily reflecting new or increased vasopressor use. Associations with severe hypoxemia and intubation time did not remain significant after multiplicity adjustment. Because induction medication was not randomized and residual confounding remains possible, these associations should not be interpreted as causal.

Background: Antiviral treatment options for hospitalized COVID-19 patients are limited. Methods: We conducted a phase 2/3, randomized, placebo-controlled clinical trial of PF-07304814, an intravenous SARS-CoV-2 protease inhibitor. From September-December 2021, adults hospitalized for COVID-19 were randomized to continuous intravenous infusion of PF-07304814 (250 mg/24 hours) or placebo for 120-hours (or hospital discharge). The primary outcome was time to sustained recovery through day 90. The primary safety outcome through day 28 was a composite of death, serious adverse events, organ failure, thromboembolic events (pre-specified as events of special interest), serious infections, and grade 3/4 adverse events. Results: We randomized 58 participants (32 PF-07304814; 26 placebo). After three participants experienced serious adverse events (SAEs), two related to thromboembolic events and one to acute abdominal pain, the trial was put on hold by regulators and thereafter administratively closed. The composite safety outcome through day 28 occurred in 17/32 (53%) participants assigned PF-07304814 and 11/26 (42%) participants assigned placebo (hazard ratio (HR) 1.20, 95% CI 0.56–2.57; p = 0.64). The estimated cumulative incidence of sustained recovery at day 90 was 75% for PF-07304814 and 50% for placebo participants (sHR 1.41; 95% CI: 0.71–2.80). In the PF-07304814 arm, 4 (12.5%) experienced a thromboembolic event; all died by day 90. In the placebo arm, 2 (7.7%) experienced a thromboembolic event (HR 1.46, 95% CI 0.27–7.95); both survived to the end of follow-up. Conclusion: The risk/benefit of PF-07304814 could not be established due to early termination of enrollment. Rates of thromboembolic events with PF-07304814 were not statistically different than placebo. Trial Registration: TICO ClinicalTrials.gov number, NCT04501978, Registration date: August 6, 2020. Keypoints: The safety and efficacy of an intravenous SARS-CoV-2 protease inhibitor PF-07304814 could not be established in this randomized controlled trial of 58 participants. These results provide preliminary data for testing other protease inhibitors and antiviral medications in hospitalized COVID-19 patients.

Background: SARS-CoV-2 has evolved through a combination of gradual accumulation of spike protein mutations and infrequent evolutionary jumps, such as the transition from Omicron XBB to JN.1 lineages. The latter has been associated with decreased COVID-19 vaccine effectiveness (VE) but less is known about the impact of gradual spike protein evolution on VE.Methods: This multicenter test-negative, case-control VE analysis was conducted using data collected over two seasons (September 13, 2023–April 30, 2025) from 26 hospitals in 20 U.S. states in the IVY Network. Case-patients were hospitalized adults with COVID-19–like illness and a positive SARS-CoV-2 test with sequencing of nasal swab specimens; controls had COVID-19–like illness but tested negative. Counts of S31 deletions and nonsynonymous mutations in the S1 spike protein domain relative to each season’s vaccine strain were tabulated for each case. Multinomial logistic regression was used to estimate VE stratified by S1 mutation count categories after adjusting for demographics, clinical characteristics, and region.Results: 2,727 COVID-19 cases with sequencing and 14,870 controls were enrolled during September 2023–April 2025 (median age = 66 years; 51% female; 58% non-Hispanic White). Circulating SARS-CoV-2 viruses diverged from the vaccine strain at an average rate of one S1 mutation every 81 days. VE against COVID-19–associated hospitalizations was 48% (95% CI, 34%–60%) for SARS-CoV-2 viruses with 0–10 mutations 7–89 days after vaccination and 48% (95% CI, 24%–64%) at 90–179 days. VE was 43% (95% CI, 17%–61%) for divergent SARS-CoV-2 lineages 7–89 days after vaccination and 2% (95% CI, -26%–24%) at 90–179 days. Overall VE was 68% (95% CI, 22%–87%) for viruses with 0–2 mutations, 49% (23%–67%) for 3 mutations, 45% (23%–60%) for 4 mutations, 44% (13%–64%) for 5 mutations, and 38% (1%–62%) for 6–10 mutations.Conclusions: During 2023–2025, COVID-19 mRNA vaccines provided some protection against COVID-19–associated hospitalization irrespective of genetic divergence from the vaccine strain, but effectiveness against high divergence strains was not sustained at longer intervals from vaccination.

Human metapneumovirus (HMPV) is a significant cause of acute respiratory illness in both children and adults, yet its genomic epidemiology remains understudied compared to other respiratory viruses. Here, we report an expanded genomic surveillance of HMPV in the United States, utilizing 325 newly sequenced samples from two cohorts: the household-based HIVE study (2010–2022) in Michigan and the multicenter IVY network (2022–2025) of hospitalized adults. Our analyses revealed the continued predominance of the A2.2.2 clade and little geographic structure in the US. Genomic diversity is highest in the glycoprotein (G); we identified a shift from variants bearing the 180nt duplication to ones with a 111nt duplication. Phylogenetic analyses supported the duplication-deletion model for the origin of the duplications. The conserved fusion (F) protein shows limited antigenic variation and low rates of nonsynonymous substitutions, suggesting stability in epitopes targeted by vaccine candidates. These findings underscore the utility of enhanced genomic surveillance for understanding HMPV evolution and informing vaccine development. Summary: Genomic surveillance of HMPV in the United States over a 15 year period reveals extensive genetic diversity and more rapid evolution in the G protein compared to the F protein, which is targeted by vaccines under development.

Preoxygenation is a critical step in airway management aimed at reducing the risk of hypoxemia, a potentially life-threatening complication, during emergency tracheal intubation in critically ill patients. Challenges with ventilation and intubation are unpredictable, making it essential to optimize oxygenation prior to induction to improve patient safety. During the preoxygenation phase of intubation, a patient receives 100% fraction of inspired oxygen (FiO2) to replace alveolar nitrogen, increasing oxygen reserves, and arterial oxygen partial pressure (PaO2) to prolong safe apnea time. Preoxygenation strategies primarily rely on two categories of oxygen delivery systems: noninvasive ventilation (NIV) and oxygen masks. Each has unique advantages and limitations, and both have been studied in various clinical trials. When used effectively, these techniques optimize oxygenation, enhance first-pass intubation success, and reduce peri-intubation complications. This article reviews the physiological basis and technical application of oxygen masks and NIV-based preoxygenation strategies, discusses their comparative efficacy, and provides practical guidance on selecting and implementing the optimal approach based on patient condition and resource availability. By integrating best practices, clinicians can reduce complications and improve outcomes during emergency airway management in critically ill patients.

Preoxygenation is a critical step in airway management aimed at reducing the risk of hypoxemia, a potentially life-threatening complication, during emergency tracheal intubation in critically ill patients. Challenges with ventilation and intubation are unpredictable, making it essential to optimize oxygenation prior to induction to improve patient safety. During the preoxygenation phase of intubation, a patient receives 100% fraction of inspired oxygen (FiO2) to replace alveolar nitrogen, increasing oxygen reserves, and arterial oxygen partial pressure (PaO2) to prolong safe apnea time. Preoxygenation strategies primarily rely on two categories of oxygen delivery systems: noninvasive ventilation (NIV) and oxygen masks. Each has unique advantages and limitations, and both have been studied in various clinical trials. When used effectively, these techniques optimize oxygenation, enhance first-pass intubation success, and reduce peri-intubation complications. This article reviews the physiological basis and technical application of oxygen masks and NIV-based preoxygenation strategies, discusses their comparative efficacy, and provides practical guidance on selecting and implementing the optimal approach based on patient condition and resource availability. By integrating best practices, clinicians can reduce complications and improve outcomes during emergency airway management in critically ill patients.

BACKGROUND: Active vitamin D metabolites, including 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), have potent immunomodulatory effects that attenuate acute kidney injury (AKI) in animal models. METHODS: We conducted a phase 2, randomized, double-blind, multiple-dose, 3-arm clinical trial comparing oral calcifediol (25D), calcitriol (1,25D), and placebo among 150 critically ill adult patients at high risk of moderate to severe acute kidney injury (AKI). The primary endpoint was a hierarchical composite of death, kidney replacement therapy (KRT), and kidney injury (baseline-adjusted mean change in serum creatinine), each assessed within 7 days following enrollment using a rank-based procedure. Secondary endpoints included new or progressive AKI and a composite of KRT or death. Hypercalcemia was the key safety endpoint. We also performed RNA-Seq on circulating CD14 ⁺ monocytes collected immediately prior to randomization and 2 days later. RESULTS: The global rank score for the primary endpoint was similar among calcifediol- ( n = 51) versus placebo- ( n = 49) treated patients ( P = 0.85) and for calcitriol ( n = 50) versus placebo-treated patients ( P = 0.58). Secondary endpoints also occurred at similar rates across groups. Hypercalcemia occurred in 1 patient in the calcifediol group (1.7%), 1 patient in the calcitriol group (2.0%), and no patients in the placebo group. Compared with placebo, calcitriol upregulated more individual genes and pathways in circulating monocytes than did calcifediol, including pathways involving IFN-α, IFN-γ, oxidative phosphorylation, DNA repair, and heme metabolism. CONCLUSION: Treatment with calcifediol or calcitriol in critically ill adults upregulated multiple genes and pathways involving immunomodulation, DNA repair, and heme metabolism, but it did not attenuate AKI. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02962102) FUNDING: NIH/NIDDK grant K23DK106448 (to DEL) and NIH/NHLBI grant R01HL16687 (to EYK).

BACKGROUND: Supplemental oxygen is essential in caring for adults with acute thermal burns but can expose patients to excess inspired oxygen. We sought to determine the safety and effectiveness of targeting normoxemia (peripheral oxygen saturation [SpO₂] 90–96%) in adults with acute thermal burns admitted to a specialized burn unit. We hypothesized that targeting normoxemia would increase the number of supplemental oxygen-free days (SOFDs) and safely reduce exposure to hyperoxemia. METHODS: In this multicenter cluster-randomized, stepped-wedge trial, we randomized six US burn centers to cross over from usual care to targeted normoxemia at three-month intervals between January 15, 2021, and October 15, 2022. In usual care, supplemental oxygen was determined by treating clinicians. In targeted normoxemia, we specified decreasing administered supplemental oxygen whenever SpO₂ was >96%. The primary outcome was SOFD, defined as the number of days alive and not receiving supplemental oxygen through Day 28. Safety outcomes included hypoxemia (SpO₂ < 88%), in-hospital mortality, and adverse events. RESULTS: The 1,437 enrolled patients were mean age 48 years, 26% female, 38% with full-thickness burns, and 11% mean total body surface area burned. The proportion of time spent in normoxemia increased from 77% in the usual care group to 81% in the targeted normoxemia group. Time spent with hyperoxemia (SpO₂ > 96%) decreased from 22% to 17%, and hypoxemia was similar between groups (0.7% vs. 0.8%). The raw mean number of SOFD was 18.8 days for targeted normoxemia and 17.2 days for usual care (adjusted mean difference [aMD], 0.90 days; 95% confidence interval [CI], −0.77 to 2.57; p = 0.29). Hospital-free days through Day 90 were greater among the targeted normoxemia group (71 days) than the usual care group (70 days) (aMD, 3.47 days; 95% CI, 0.19–6.76). In-hospital mortality to Day 90 occurred in 36 (5.7%) targeted normoxemia patients and 65 (8.1%) usual care patients (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.31–1.42). CONCLUSION: Targeting normoxemia did not increase supplemental oxygen-free days among adults with acute thermal burns, but safely maintained clinical outcomes. LEVEL OF EVIDENCE: Therapeutic Care/Management; Level I. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT 04534972

Background: COVID-19 patients have experienced worry, altered provider-patient interactions, and options to use novel treatments, initially with neutralizing monoclonal antibodies (mAbs). Limited research has been performed on these aspects of the COVID-19 outpatient experience. Objective: This study aimed to evaluate the experiences of outpatients recently diagnosed with COVID-19, who were eligible for use of mAbs, during the diagnosis and treatment process based on sociodemographic and clinical factors. Methods: This was a self-reported cohort study performed via telephone surveys. Participants included COVID-19 outpatients who met at least one emergency use criterion for mAbs during the first 120 days after a SARS-CoV-2 positive test. We analyzed survey results using multivariable logistic regression for non-scale outcomes and adjusted proportional odds logistic regression for scaled outcomes. Results: Greater worry about their COVID-19 diagnosis was reported by younger, female, and Hispanic patients and those with Medicaid insurance, two or more comorbid conditions, BMI > 25, and at least 2 COVID-19 vaccinations. Greater provider trust was reported by patients with ≥ 2 years of college education, one or more comorbid conditions, and one or more COVID-19 vaccinations; whereas less provider trust was reported by patients ages 45–64 years, with usual place of care in a walk-in clinic, and those without Commercial, Medicare, or Medicaid insurance. In patients who did not receive mAbs, patients with Medicaid and those without Commercial/Medicare insurance were among the factors that were less likely be offered mAbs by a provider. Discussion: This report describes factors associated with multiple aspects of outpatients’ experience of COVID-19. This study demonstrated that there are important differences in the experience of outpatient COVID-19 patients based on sociodemographic factors and clinical factors, as well as where additional strategies are needed to improve this experience and associated outcomes.

Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We, therefore, tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF stabilizer vadadustat. Subsequent studies in genetic models implicated alveolus-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase II trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO ₂ ≤ 94%). Patients ( n = 448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the 2 groups. Vadadustat treatment induced surrogate HIF target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline fraction of inspired oxygen of 80% or higher ( n = 106), the estimated probability of the primary outcome was 12.1% (vadadustat) versus 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2–associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.