To understand how protein biomarkers in blood and urine that are aligned with host resistance to infection, disease tolerance, and damage are associated with clinical outcomes and sepsis subtypes in community-onset sepsis. Adults meeting Sepsis-3 criteria were prospectively enrolled within 6 h of emergency department arrival and assigned clinical subtypes (α, β, γ, δ), using the Sepsis ENdotyping in Emergency CAre (SENECA) approach. Using structured expert ranking with consensus adjudication, 16 plasma and urinary biomarkers obtained from remnant biospecimens were grouped into three mechanistic axes contributing to sepsis pathophysiology: host resistance to infection, disease tolerance, and damage to the host. Biomarkers for each concept were analyzed with principal component analysis as a signature, and multivariable logistic regression tested associations of each signature with 90-day mortality and sepsis subtype membership. Among 444 adults, the mean age was 60 years [SD: 16], the mean SOFA score was 4.3 [SD: 2.3], and 90-day mortality was 17

Importance:Sedatives, commonly administered in the clinical treatment of young children with critical illness, may be harmful to early brain development. Objective:To investigate whether sedative choice during critical illness in early childhood is associated with long-term neurocognitive function. Design, Setting, and Participants:This prospective cohort study was conducted among a subset of cognitively appropriate children with acute respiratory failure who were aged 8 years or younger when enrolled in the Randomized Evaluation of Sedation Titration for Respiratory Failure (RESTORE) cluster-randomized clinical trial conducted in 31 pediatric intensive care units (PICUs) comparing a nurse-implemented, goal-directed sedation protocol with usual care. Patients underwent neurocognitive testing 3 to 8 years after hospitalization at regional neuropsychology testing centers. Neurocognitive testing was conducted from February 16, 2015, to November 27, 2018. Assessors were blinded to the sedation provided. Data were analyzed from September 2022 to March 2026. Exposures:Critical illness and sedation. Main Outcomes and Measures:The primary outcome was IQ, estimated by the age-appropriate Vocabulary and Block Design subtests of the Wechsler Intelligence Scale. Drug- and dose-dependent associations between sedatives and neurocognitive function were assessed, adjusting for baseline factors and severity and course of critical illness. Results:Neurocognitive testing was performed among 256 children (median [IQR] age, 6.6 [5.4 to 9.0] years). Among 243 children with data, 228 children (93.8%) had age-appropriate global assessment of cognitive function (Pediatric Cognitive Performance Category = 1) at testing. Children were exposed to a median (IQR) of 8 (5 to 14) days of continuous sedation at a median (IQR) age of 1.0 (0.2 to 3.2) years. The mean (SD) estimated IQ was 100.3 (13.2), similar to the published test mean of 100. Mean (SD) estimated IQ at long-term follow-up was lowest in patients receiving an opioid- and benzodiazepine-only strategy (98.3 [11.8]), higher in patients receiving multiple sedative classes not including dexmedetomidine (100.6 [14.5]), and highest in patients receiving multiple sedative classes, including dexmedetomidine (101.9 [13.5]). Controlling for Hollingshead Socioeconomic Status score, severity of illness on PICU admission, and duration of mechanical ventilation, the adjusted mean difference in estimated IQ between the opioid- and benzodiazepine-only vs dexmedetomidine groups was -4.1 (95% CI, -7.3 to -0.9; P = .01). Conclusions and Relevance:In this study of young children who received more than a week of PICU sedation, the estimated IQ was similar to that of the general population. Children who received an opioid- and benzodiazepine-only strategy scored lower than those who received a strategy that included dexmedetomidine when controlling for socioeconomic status, illness severity, and duration of mechanical ventilation. Trial Registration:ClinicalTrials.gov Identifier: NCT02225041.

Government funding for biomedical research is the topic of this Healthy Dialogue conversation between JAMA Senior Editor Derek C. Angus, MD, MPH, and Jeremy Berg, PhD, former editor in chief of Science and former director of the National Institute of General Medical Sciences.

Importance:The Centers for Medicare & Medicaid Services reimburses remote monitoring to reduce hospital readmissions, yet its effectiveness remains uncertain. Objective:To evaluate effectiveness of remote monitoring in reducing readmissions following hospitalizations for serious infections overall and across prespecified subgroups. Design, Setting, and Participants:This randomized clinical trial was conducted from March 25, 2021, to December 9, 2024, using response adaptive randomization among postdischarge patients with sepsis or lower respiratory tract infection across 19 hospitals. Eligible patients were 21 years or older, lived in western Pennsylvania, were insured through the UPMC Health Plan or traditional fee-for-service Medicare, had a smartphone or other internet-connected device, had no cognitive impairment, and were at moderate or high risk for readmission at index hospitalization admission based on an internal predictive model. Analyses were based on intention to treat; data were analyzed from April to June 2025. Intervention:Four remote monitoring strategies combining questionnaire intensity (low vs high) and clinical response teams (standard vs enhanced) compared with usual care. Main Outcomes and Measures:The primary end point consisted of days at home at 90 days after discharge, assessed by posterior probability distribution for the cumulative odds ratios (CORs) in each study arm compared with usual care. Secondary end points included mortality, readmission, functional status, quality of life, and use of emergency department and hospice services. Results:Among the 1286 patients included in the analysis, the median age was 63 (IQR, 54-71) years; 665 patients (51.7%) were female. The median Charlson Comorbidity Index was 6 (IQR, 3-9), and 386 patients (32.6%) received intensive care. Patients were randomized to usual care (n = 399) or remote patient monitoring (RPM) with low- or high-intensity questionnaires and standard or enhanced clinical response team combinations: RPM-low standard response (n = 204), RPM-high standard response (n = 129), RPM-low enhanced response (n = 383), and RPM-high enhanced response (n = 171). Of 887 patients assigned to remote monitoring arms, 529 (59.6%) enrolled in the remote monitoring program. The median home days were similar across all study arms: 90 (IQR, 83-90) for usual care, 90 (IQR, 84-90) for RPM-low standard response, 90 (IQR, 85-90) for RPM-high standard response, 90 (IQR, 83-90) for RPM-low enhanced response, and 90 (IQR, 84-90) for RPM-high enhanced response. Compared with usual care, the CORs were 0.96 (credible interval [CrI], 0.70-1.32) for RPM-low standard response, 0.86 (95% CrI, 0.60-1.23) for RPM-high standard response, 1.01 (95% CrI, 0.76-1.33) for RPM-low enhanced response, and 0.96 (95% CrI, 0.69-1.36) for RPM-high enhanced response, and superiority probability was less than 55% for all comparisons. At least 1 readmission occurred in 151 of 399 patients (37.8%) in the usual care arm, 81 of 204 (39.7%) in the RPM-low standard response arm, 57 of 129 (44.2%) in the RPM-high standard response arm, 143 of 383 (37.3%) in the RPM-low enhanced response arm, and 62 of 171 (36.3%) in the RPM-high enhanced response arm. Among patients 65 years and older, standard and enhanced response arms had fewer home days compared with usual care (COR, 0.56 [95% CrI, 0.36-0.85] and 0.67 [95% CrI, 0.45-0.98], respectively; inferiority probability, 99.6% and 97.9%, respectively). Conclusions and Relevance:Among trial patients discharged after hospitalization for serious infections, remote monitoring did not increase time spent alive at home but reduced it in those 65 years and older. These findings support reevaluating and tailoring remote monitoring after acute care for sepsis and lower respiratory tract infection to support further alignment with patients' needs and desire for personalized monitoring. Trial Registration:ClinicalTrials.gov Identifier: NCT04829188.

Objective: To determine whether ivermectin improves outcomes for critically and noncritically ill hospitalized patients with COVID-19.Design: An ongoing international, multifactorial, adaptive platform, randomized, controlled trial.Setting: Hospitals in Pakistan, India, and Ireland between June 11, 2021, and September 9, 2022.Patients: Critically and noncritically ill patients.Interventions: Randomized to ivermectin or no ivermectin (control).Measurements and Main Results: The primary outcome was respiratory and cardiovascular organ support-free days, assessed on an ordinal scale combining in-hospital death (assigned a value of -1) and days free of organ support through day 21 in survivors. Analyses used a Bayesian cumulative logistic model. Enrollment was closed for operational futility, following external evidence suggesting no benefit with ivermectin in nonhospitalized patients with COVID-19. Among 61 critically ill patients, the median number of organ support-free days was -1, indicating death was the most common vital outcome (interquartile range [IQR], -1 to 17), for the ivermectin group and -1 (IQR, -1 to 17.25) for the control group (adjusted proportional odds ratio [OR], 0.94; 95% credible interval [CrI], 0.40-2.07) and the posterior probability of superiority to control was 44.2%. Among 89 noncritically ill patients, the median number of organ support-free days was 22 (IQR, 18.5-22) for ivermectin and 22 (IQR, 16-22) for control (adjusted proportional OR, 1.04; 95% CrI, 0.48-2.34) and the posterior probability of superiority was 53.7%. Among critically ill patients, hospital survival was 35.1% (13/37) for ivermectin and 37.5% (9/24) for control (adjusted OR, 1.00; 95% CrI, 0.39-2.32), posterior probability of superiority was 50.0%. Among noncritically ill patients, hospital survival was 84.1% (37/44) for ivermectin and 77.8% (35/45) for control (adjusted OR, 1.16; 95% CrI, 0.5-3.07), posterior probability of superiority was 63.3%.Conclusions: For critically and noncritically ill hospitalized patients with COVID-19, ivermectin was unlikely to improve the primary composite outcome of organ support-free days and hospital survival.

The rapid increase in use of ambient scribes and the potential implications for clinical practice are the focus of this installment of the Healthy Dialogue podcast, featuring JAMA Senior Editor Derek C. Angus, MD, MPH, and Vincent X. Liu, MD, MS, chief data officer of The Permanente Medical Group at Kaiser Permanente.

Intensive care is under increasing pressure due to demographic changes, availability of new complex therapies, and workforce shortages, resulting in a relative reduction in resources. Technological advances such as digitalization, wearable sensors, and artificial intelligence promise to improve care delivery, enabling providers to offer equal or higher-quality care at lower costs. However, no healthcare system has yet demonstrated large-scale gains in the efficiency of intensive care delivery. A central requirement is the capacity to translate ideas and concepts into value, providing changes that make services, products, and optimal care more accessible and affordable to a larger population, generating value. Innovation should thus be acknowledged as a fourth principal pillar of intensive care, alongside clinical excellence, research, and teaching. This paper presents the opinion of a multidisciplinary expert panel, proposing a framework to support the generation, implementation, and evaluation of innovation in intensive care. We identify and examine key areas and applications where innovation is urgently needed, including workforce development, technology adoption, environmental sustainability, and the transformation of medical education. We also highlight barriers and concerns that must be addressed when implementing innovation in ICUs. We integrate these into a comprehensive framework illustrated through concrete examples. Finally, we argue that innovation should not be driven solely by academia or industry, but strategically led by healthcare professionals and patients’ representatives, grounded in ethics and data, interdisciplinary, and centered on patients’ and society’s needs. This framework offers a pathway for innovation, supporting a more inclusive, effective, and sustainable future for intensive care.

QuestionDoes remote monitoring help individuals remain at home following hospitalization for serious infections?FindingsIn this randomized clinical trial of 1286 adults recovering at home after hospitalization for sepsis or lower respiratory tract infection, remote monitoring programs with high- or low-intensity question sets combined with a nurse response team or a nurse practitioner-led response team did not increase time spent at home. Conversely, the remote monitoring programs led to a reduction in time spent at home among Medicare-eligible patients 65 years or older.MeaningRemote monitoring, as implemented in this study, did not support Medicare's goals of reducing readmissions, particularly among older adults. This randomized clinical trial evaluates the effectiveness of remote monitoring programs led by nurses or nurse practitioners to reduce readmissions among patients after hospitalization for sepsis or lower respiratory tract infections. ImportanceThe Centers for Medicare & Medicaid Services reimburses remote monitoring to reduce hospital readmissions, yet its effectiveness remains uncertain.ObjectiveTo evaluate effectiveness of remote monitoring in reducing readmissions following hospitalizations for serious infections overall and across prespecified subgroups.Design, Setting, and ParticipantsThis randomized clinical trial was conducted from March 25, 2021, to December 9, 2024, using response adaptive randomization among postdischarge patients with sepsis or lower respiratory tract infection across 19 hospitals. Eligible patients were 21 years or older, lived in western Pennsylvania, were insured through the UPMC Health Plan or traditional fee-for-service Medicare, had a smartphone or other internet-connected device, had no cognitive impairment, and were at moderate or high risk for readmission at index hospitalization admission based on an internal predictive model. Analyses were based on intention to treat; data were analyzed from April to June 2025.InterventionFour remote monitoring strategies combining questionnaire intensity (low vs high) and clinical response teams (standard vs enhanced) compared with usual care.Main Outcomes and MeasuresThe primary end point consisted of days at home at 90 days after discharge, assessed by posterior probability distribution for the cumulative odds ratios (CORs) in each study arm compared with usual care. Secondary end points included mortality, readmission, functional status, quality of life, and use of emergency department and hospice services.ResultsAmong the 1286 patients included in the analysis, the median age was 63 (IQR, 54-71) years; 665 patients (51.7%) were female. The median Charlson Comorbidity Index was 6 (IQR, 3-9), and 386 patients (32.6%) received intensive care. Patients were randomized to usual care (n = 399) or remote patient monitoring (RPM) with low- or high-intensity questionnaires and standard or enhanced clinical response team combinations: RPM-low standard response (n = 204), RPM-high standard response (n = 129), RPM-low enhanced response (n = 383), and RPM-high enhanced response (n = 171). Of 887 patients assigned to remote monitoring arms, 529 (59.6%) enrolled in the remote monitoring program. The median home days were similar across all study arms: 90 (IQR, 83-90) for usual care, 90 (IQR, 84-90) for RPM-low standard response, 90 (IQR, 85-90) for RPM-high standard response, 90 (IQR, 83-90) for RPM-low enhanced response, and 90 (IQR, 84-90) for RPM-high enhanced response. Compared with usual care, the CORs were 0.96 (credible interval [CrI], 0.70-1.32) for RPM-low standard response, 0.86 (95% CrI, 0.60-1.23) for RPM-high standard response, 1.01 (95% CrI, 0.76-1.33) for RPM-low enhanced response, and 0.96 (95% CrI, 0.69-1.36) for RPM-high enhanced response, and superiority probability was less than 55% for all comparisons. At least 1 readmission occurred in 151 of 399 patients (37.8%) in the usual care arm, 81 of 204 (39.7%) in the RPM-low standard response arm, 57 of 129 (44.2%) in the RPM-high standard response arm, 143 of 383 (37.3%) in the RPM-low enhanced response arm, and 62 of 171 (36.3%) in the RPM-high enhanced response arm. Among patients 65 years and older, standard and enhanced response arms had fewer home days compared with usual care (COR, 0.56 [95% CrI, 0.36-0.85] and 0.67 [95% CrI, 0.45-0.98], respectively; inferiority probability, 99.6% and 97.9%, respectively). Conclusions and RelevanceAmong trial patients discharged after hospitalization for serious infections, remote monitoring did not increase time spent alive at home but reduced it in those 65 years and older. These findings support reevaluating and tailoring remote monitoring after acute care for sepsis and lower respiratory tract infection to support further alignment with patients' needs and desire for personalized monitoring.Trial RegistrationClinicalTrials.gov Identifier: NCT04829188

BACKGROUND:The optimal thromboprophylaxis among critically ill adults with COVID-19 is uncertain. OBJECTIVES:To determine the effectiveness and safety of intermediate-dose heparin compared with standard low-dose thromboprophylaxis. METHODS:In an ongoing adaptive platform trial (randomized embedded multifactorial adaptive platform for community-acquired pneumonia), critically ill patients with COVID-19 were randomized to intermediate-dose heparin or standard low-dose thromboprophylaxis. Interventions were continued in hospital for up to 14 days. The primary endpoint was organ support-free days (OSFDs), an ordinal outcome combining in-hospital survival and the number of days free of intensive care unit-based respiratory or cardiovascular organ support through 21 days. The primary analysis was an adjusted Bayesian hierarchical cumulative logistic model. An odds ratio (OR) > 1.0 represents an improved outcome with intermediate-dose heparin. RESULTS:Between April 27, 2021 and November 25, 2023, 1255 critically ill adults with COVID-19 were enrolled from 78 sites in 15 countries, of whom 1254 completed follow-up (n = 572 intermediate-dose, n = 682 low-dose). Enrollment was terminated prior to reaching a prespecified statistical trigger due to declining case numbers and slow recruitment. Median age was 59 years, and 36.7% were female (n = 461/1255). The probability that intermediate-dose heparin improved OSFDs was 73.5% (OR, 1.06; 95% credible interval, 0.87, 1.30), which did not meet the prespecified superiority threshold of 99%. Hospital survival was 77.1% (441/572) and 76.7% (523/682) in the intermediate- and low-dose heparin groups, respectively (median adjusted OR, 1.14; 95% credible interval, 0.86, 1.52). Major bleeding occurred in 10 of 572 (1.7%) and 14 of 682 (2.1%) patients receiving intermediate and standard low doses, respectively. CONCLUSION:Intermediate-dose heparin did not improve OSFDs or survival compared with standard thromboprophylaxis in critically ill patients with COVID-19. (ClinicalTrials.gov number: CT02735707).

In this JAMA film, Derek C. Angus, MD, MPH, of the University of Pittsburgh School of Medicine and a JAMA Senior Editor, discusses 5 areas of research that could benefit care for critically ill patients.

JAMA Senior Editor Derek C. Angus, MD, MPH, spoke with Gil Rabinovici, MD, a neurologist and director of the University of California San Francisco Alzheimer Disease Research Center, about the latest developments in dementia and Alzheimer disease research.

Twenty-five years of septic shock resuscitation trials have progressively transformed the physiological understanding of shock and the way bedside interventions are conceptualized. Early strategies focused on correcting isolated global hemodynamic or metabolic targets through protocolized interventions, whereas more recent approaches increasingly recognize septic shock as a heterogeneous, dynamic, and context-dependent condition requiring individualized physiological assessment. This perspective discusses how hemodynamic resuscitation trials during this quarter of a century have reshaped both the physiological understanding and methodological foundations of early shock management. Initial strategies, exemplified by early goal-directed therapy, aimed to correct global oxygen-derived variables through protocolized interventions designed to optimize oxygen delivery. However, the lack of reproducibility of this approach in subsequent multicenter trials, together with the recognition of the limitations of several other variables as potential resuscitation targets, revealed that septic shock cannot be adequately addressed through rigid algorithms based on isolated endpoints. Subsequent progress incorporated peripheral perfusion assessment, systematic evaluation of fluid responsiveness, critical care echocardiography, and hemodynamic phenotyping. Within this trajectory, ANDROMEDA-SHOCK shifted attention toward capillary refill time as a rapidly responsive clinical perfusion signal, contributing to improve some outcomes, and potentially limiting over-resuscitation. ANDROMEDA-SHOCK-2 further operationalized a personalized strategy based on capillary refill time, sequential phenotyping, reversible hemodynamic tests, and serial reassessment. A quarter of a century of septic shock resuscitation trials reveal a consistent pattern: strategies centered on fixed and isolated physiological targets have repeatedly failed to achieve reproducible improvements in patient-centered outcomes. Recent data support a shift from isolated hemodynamic or metabolic targets, toward a physiology-guided, phenotype-driven resuscitation strategy, in which interventions are applied as reversible tests within short decision cycles and guided by rapidly responsive perfusion signals. Trials such as ANDROMEDA-SHOCK-2 represent important steps in this ongoing transition, but further refinement, validation, and implementation across diverse settings remain necessary.