Ivor S. Douglas

Rationale: The impact of fluid resuscitation strategies on patient-centered outcomes of sepsis survivors is unknown. Objectives: To assess the effect of an early restrictive or liberal fluid resuscitation strategy on long-term functional outcomes in patients with sepsis-induced hypotension. Methods: SHAMROC (Sepsis-induced Hypotension: Assessing effect of Method of Resuscitation On patient-Centered outcomes) prospectively assessed the impact of random assignment to a restrictive or liberal fluid resuscitation strategy for sepsis-induced hypotension outcomes at 6 and 12 months after randomization in the NIH NHLBI PETAL Network’s CLOVERS trial (NCT03434028). The pre-specified analyses used trimmed means at 50% to prevent informative censoring of deceased patients. Measurements and Main Results: Of the 1563 participants included in the CLOVERS trial, 898 (57%) were included in the SHAMROC trial. As 196 were lost to follow-up, 702 participants were analyzed at 6 months (431 survivors and 271 non-survivors). Baseline characteristics were similar between the groups. At 6 months, no group differences were observed in cognitive function (restrictive versus liberal; trimmed mean difference in Montreal Cognitive Assessment-Blind Score, 0.11, 95% CI -1.44-1.70), executive function (trimmed mean difference in Hayling Sentence Completion Test, 0.38, 95% CI -0.97-1.76), disability status (trimmed mean difference in Activity of Daily Living Score, 0.03, 95% CI -0.84-0.90), mobility (trimmed mean difference in PROMIS Mobility Score, 0.72, 95% CI -2.20-3.64), and health-related quality of life (trimmed mean difference in EQ-5D-5L, -0.01, 95% CI -0.07-0.06). Outcomes also did not differ at 12 months. Conclusions: In this long-term follow-up of a randomized controlled trial of patients with sepsis-induced hypotension, the restrictive fluid strategy used in this study resulted in similar cognitive and physical function at 6 and 12 months, compared to a liberal fluid strategy.

Background: Heuristics are commonplace among novices and experts making clinical decisions, often guided by clinical intuition when there is diagnostic or therapeutic uncertainty. Compared with more experienced clinicians, trainees may lack the knowledge, insight, and intuition needed to appropriately select and apply heuristics and clinical decision rules. An improved understanding of the mental models and contextual factors that predispose trainees to misapplied heuristics, cognitive biases, and other decision-making errors is needed. Objectives: To test the use of cognitive task analysis for examining how trainees make high-risk decisions in complex, dynamic, and real-world practice environments. Methods: We conducted semistructured interviews between September 2019 and March 2020 using a cognitive task analysis technique called the critical decision method. Participants were third-year internal medicine resident physicians rotating in the medical intensive care unit at a major safety-net academic hospital. Interviews focused on fluid-resuscitation decisions for actual patients with septic shock. Data were coded and analyzed using a template approach with the Recognition-Primed Decision model as the guiding framework. Results: Eleven of 23 eligible residents completed a full interview. The median time from initial sepsis care to interview was 7 days (interquartile range, 6.5–11 d). Seven key domains related to fluid-resuscitation decisions were identified: cues, information, decision making, decision alternatives, analogs, expected outcomes, and goals. In addition to objective clinical data (e.g., serum lactate concentration), fluid-resuscitation decisions were most significantly influenced by clinical intuition, other nonphysiological contextual factors, and volume-based heuristics. For example, residents frequently prescribed fluid dependent on the total volume already administered. They assumed that patients receiving more than 3–5 L would not benefit from additional resuscitation, while using the same heuristic to disregard evidence-based predictors of fluid responsiveness. Evidence of related cognitive biases was also found, including premature closure, confirmation bias, and status quo (or default) bias. Conclusions: Cognitive task analysis is a promising tool for examining how trainees make high-risk clinical decisions. Better understanding the nature of trainees’ heuristics and cognitive biases has implications for designing educational and training strategies that improve their clinical reasoning.

CONTEXT: To evaluate and compare sublingual microscopy (SLM) to urinary glycosaminoglycan (GAG) assays, dimethylmethylene blue (DMMB) assay, and liquid chromatography tandem mass spectrometry (LC-MS/MS) quantification of GAGs as biomarkers of microvascular dysfunction in patients with sepsis and septic shock. HYPOTHESIS: Indicators of microvascular dysfunction and markers of endothelial glycocalyx (eGC) degradation would be associated with sepsis. METHODS AND MODELS: Prospective, observational case-control study. SETTING: Denver Health Medical Center, a safety-net hospital in Denver, CO. SUBJECTS: Forty-four adult patients with sepsis or septic shock and 24 healthy control patients undergoing elective orthopedic procedures. Exclusion criteria included pregnancy and incarceration. RESULTS: Sublingual microvascular parameters (De Backer Density, proportion of perfused vessels) were measured using darkfield sidestream microscopy, and urinary GAGs were measured via DMMB colorimetric assay and LC-MS/MS targeting heparan sulfate (HS), dermatan sulfate, and keratan sulfate. Validation of HS quantification was performed on a subset using hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS). LC-MS/MS HS was significantly higher in sepsis vs. controls (Area under the curve 0.85; 95% CI, 0.76–0.95), demonstrating higher diagnostic performance than SLM (De Backer Density AUC 0.71) and DMMB GAGs (AUC 0.62). LC-MS/MS and HILIC-MS HS levels were strongly correlated (R² = 0.97, p < 0.001). DMMB GAGs were associated with HS subtypes (p = 0.05) and SLM density (p = 0.03). No significant associations with in-hospital mortality or acute kidney injury were observed. INTERPRETATION AND CONCLUSIONS: Among the evaluated modalities, LC-MS/MS quantification of HS showed the greatest discriminative ability for identifying sepsis and correlated strongly with established mass spectrometric methods. SLM exhibited moderate diagnostic utility and significant associations with GAG levels, reinforcing its biologic relevance. However, its bedside application may be limited by challenges in image acquisition and analysis. The concordance across SLM, DMMB, and LC-MS/MS supports eGC degradation as a key feature of sepsis pathophysiology. These findings highlight the promise of LC-MS/MS as a scalable, rapid, and mechanistically informed platform for biomarker-driven enrichment in future sepsis trials and clinical care.

We measured circulating components of the renin-angiotensin system (RAS) longitudinally over 5 days among patients hospitalized with COVID-19 and new-onset hypoxemia. We found that higher serum angiotensin-converting enzyme (ACE)-2 protein and ACE2/ACE ratio, both at baseline and when analyzed as time-varying, repeated measures, were associated with lower 90-day mortality. Results suggest a role for circulating ACE2 as a biomarker of adverse outcomes and could inform treatment strategies targeting the RAS in severe COVID-19 illness.

OBJECTIVES: To assess whether initial fluid resuscitation with lactated Ringer’s solution compared with 0.9% saline is associated with improved clinical outcomes in patients with sepsis-induced hypotension. DESIGN: Secondary analysis of the randomized controlled Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial. SETTING: ICUs and emergency departments in 60 U.S. centers from March 2018 to January 2022. PATIENTS: Participants from the CLOVERS trial. Adult patients with a suspected or confirmed infection and hypotension caused by sepsis. INTERVENTIONS: Participants received 1–3 L of crystalloid fluid for initial fluid resuscitation before randomization. In this analysis, participants were categorized into a lactated Ringer’s group and a 0.9% saline group based on the fluid type predominantly used for the initial fluid resuscitation (i.e., ≥ 95% of pre-randomization fluid). MEASUREMENTS AND MAIN RESULTS: Of 1563 participants with sepsis-induced hypotension included in the CLOVERS trial, 622 (39.8%) received lactated Ringer’s solution and 690 (44.1%) received 0.9% saline as solution for the initial fluid bolus. Death before discharge home by day 90 occurred in 76 of 622 participants (12.2%) in the lactated Ringer’s group and in 110 of 690 participants (15.9%) in the 0.9% saline group, resulting in an adjusted hazard ratio of 0.71 (95% CI, 0.51–0.99; p = 0.043). Patients receiving lactated Ringer’s solution had more hospital-free days at 28 days than those receiving 0.9% saline (16.6 ± 10.8 vs. 15.4 ± 11.4, respectively; adjusted mean difference, 1.6 d [95% CI, 0.4–2.8 d; p = 0.009]). Treatment with 0.9% saline was associated with higher levels of serum chloride and decreased levels of serum bicarbonate. CONCLUSIONS: Initial fluid resuscitation with lactated Ringer’s solution, compared with 0.9% saline, might be associated with improved survival in patients with sepsis-induced hypotension.

Intensive care unit (ICU) strain, characterized by a discrepancy between perceived or actual intensive care resources and demand, significantly impacts patient outcomes and healthcare worker well-being. The coronavirus disease (COVID-19) pandemic exacerbated ICU strain, leading to increased mortality and extended hospital stays, affecting both critically ill patients with and without COVID-19. A systematic review identified 16 leading and lagging indicators of ICU capacity strain, including queuing, premature and after-hours ICU discharge, use of temporary space, length of stay, burnout, staffing and nurse-to-patient ratio, ICU census, acuity and turnover, standardized mortality ratio, readmissions, availability of critical supplies, ventilator use, and surgery cancellation. However, variability in operational definitions and limited evidence regarding the reliability, validity, usability, and feasibility limit the value of single indicators for informed strategic planning and policy guidance. Regional and national policies and programs are essential to enhance real-time monitoring for effective management of critical care resources, and they mitigate the impact of ICU strain, facilitating complex interhospital transfers to reduce strain and ensuring comprehensive strategies for enhancing ICU resilience. Proactive regional cooperation is advocated for policy formulation, knowledge exchange, and resource allocation to anticipate and mitigate ICU strain, ensuring equitable healthcare access during global health crises. The policy implications for future preparedness emphasize the importance of evidence-based triage and adaptable patient management strategies alongside ethical considerations in resource allocation and the role of behavioral economic insights in optimizing resource utilization and collaborative healthcare practices. This multifaceted approach for addressing ICU strain comprehensively and effectively during a pandemic would promote health equity and enhance healthcare system resilience under both routine operations and crisis conditions.

OBJECTIVES: Significant practice variation exists in the amount of resuscitative IV fluid given to patients with sepsis. Current research suggests equipoise between a tightly restrictive or more liberal strategy but data is lacking on a wider range of resuscitation practices. We sought to examine the relationship between a wide range of fluid resuscitation practices and sepsis mortality and then identify the primary driver of this practice variation. DESIGN: Retrospective analysis of the Premier Healthcare Database. SETTING: Six hundred twelve U.S. hospitals. PATIENTS: Patients with sepsis and septic shock admitted from the emergency department to the ICU from January 1, 2016, to December 31, 2019. INTERVENTIONS: The volume of resuscitative IV fluid administered before the end of hospital day- 1 and mortality. MEASUREMENTS AND MAIN RESULTS: In total, 190,682 patients with sepsis and septic shock were included in the analysis. Based upon patient characteristics and illness severity, we predicted that physicians should prescribe patients with sepsis a narrow mean range of IV fluid (95% range, 3.6–4.5 L). Instead, we observed wide variation in the mean IV fluids administered (95% range, 1.7–7.4 L). After splitting the patients into five groups based upon attending physician practice, we observed patients in the moderate group (4.0 L; interquartile range [IQR], 2.4–5.1 L) experienced a 2.5% reduction in risk-adjusted mortality compared with either the very low (1.6 L; IQR, 1.0–2.5 L) or very high (6.1 L; IQR, 4.0–9.0 L) fluid groups p < 0.01). An analysis of within- and between-hospital IV fluid resuscitation practices showed that physician variation within hospitals instead of practice differences between hospitals accounts for the observed variation. CONCLUSIONS: Individual physician practice drives excess variation in the amount of IV fluid given to patients with sepsis. A moderate approach to IV fluid resuscitation is associated with decreased sepsis mortality and should be tested in future randomized controlled trials.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates.Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo.Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation.Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days.Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL.Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, −1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, −6.3; 95% CI, −10.8 to −1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen.Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients.Trial Registration: ClinicalTrials.gov Identifier: NCT04291508