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Objectives: To compare the safety and efficacy of ketamine and etomidate as induction agents to facilitate emergent endotracheal intubation., Data Sources: We searched MEDLINE, Embase, Cochrane Clinical Trials Register, and ClinicalTrials.gov from inception to April 3, 2024., Study Selection: We included randomized controlled trials (RCTs) that compared ketamine to etomidate to facilitate emergent endotracheal intubation in adults., Data Extraction: Reviewers screened abstracts, full texts, and extracted data independently and in duplicate. We pooled data using a random-effects model, assessed risk of bias using the modified Cochrane tool and certainty of evidence using the Grading Recommendations Assessment, Development, and Evaluation approach. We pre-registered the protocol on PROSPERO (CRD42023472450)., Data Synthesis: We included seven RCTs (n = 2384 patients). Based on pooled analysis, compared with etomidate, ketamine probably increases hemodynamic instability in the peri-intubation period (relative risk [RR], 1.29; 95% CI, 1.07-1.57; moderate certainty) but probably decreases the need for initiation of continuous infusion vasopressors (RR, 0.75; 95% CI, 0.57-1.00; moderate certainty) and results in less adrenal suppression (RR, 0.54; 95% CI, 0.45-0.66; moderate certainty). Ketamine probably has no effect on successful intubation on the first attempt (RR, 1.01; 95% CI, 0.97-1.05; moderate certainty) or organ dysfunction measured as the maximum Sequential Organ Failure Assessment (SOFA) score during the first 3 days in ICU (mean difference, 0.55 SOFA points lower; 95% CI, 1.12 lower to 0.03 higher; moderate certainty) and may have no effect on mortality (RR, 1.00; 95% CI, 0.83-1.21; low certainty) when compared with etomidate., Conclusions: Compared with etomidate, ketamine probably results in more hemodynamic instability during the peri-intubation period and appears to have no effect on successful intubation on the first attempt or mortality. However, ketamine results in decreased need for the initiation of vasopressor use and decreases adrenal suppression compared with etomidate., Competing Interests: Dr. Semler received support for article research from the National Institutes of Health. Dr. Sharif received funding from the McMaster University Department of Medicine Internal Career Research Award. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Plasma dipeptidyl peptidase-3 (DPP3) and renin levels are associated with organ dysfunction and mortality. However, whether these biomarkers are associated with the subsequent onset of shock in at-risk patients is unknown., Methods: Using plasma samples collected from participants enrolled in the fourth Accelerating COVID-19 Therapeutic Interventions and Vaccines Host Tissue platform trial, we measured DPP3 and renin in 184 subjects hospitalized with acute hypoxemia from COVID-19 without baseline vasopressor requirement. We calculated the odds ratio of development of shock (defined as the initiation of vasopressor therapy) by Day 28 based on Day 0 DPP3 and renin levels., Results: Subjects with DPP3 above the median had a significantly higher incidence of vasopressor initiation within 28 days (28.4 % vs. 16.7 %, p = 0.031) and higher 28-day mortality (25.0 % vs. 6.7 %, p < 0.001). After adjusting for covariables, DPP3 above the median was associated with shorter time to vasopressor initiation, greater 28-day mortality, fewer vasopressor-free days, and greater odds of a hypotensive event over 7 days. Significant associations were not observed for renin., Conclusions: In patients hospitalized with COVID-19 and hypoxemia without baseline hypotension, higher baseline plasma levels of DPP3 but not renin were associated with increased risk of subsequent shock and death., Competing Interests: Declaration of competing interest All authors completed and submitted the ICMJE form for disclosure of potential conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Peri-intubation complications are important sequelae of airway management in the emergency department (ED). Our objective was to quantify the increased risk of complications with multiple attempts at emergency airway intubation in the ED., Methods: This is a secondary analysis of a prospectively collected multicenter registry (National Emergency Airway Registry) consisting of attempted ED intubations among subjects aged >14 years. The primary exposure variable was the number of intubation attempts. The primary outcome measure was the occurrence of peri-intubation major complications within 15 min of intubation including hypotension, hypoxemia, vomiting, dysrhythmias, cardiac arrest, esophageal intubation, and failed airway with cricothyrotomy. We constructed multivariable logistic regression models to determine the associations between complications and the number of intubation attempts while controlling for measured pre-exposure variables., Results: There were 19,071 intubations in the NEAR database, of which 15,079 met inclusion for this analysis. Of these, 13,459 were successfully intubated on the first attempt, 1,268 on the second attempt, 269 on the third attempt, 61 on the fourth attempt, and 22 on the fifth or more attempt. A complication occurred in 2,137 encounters (14 %). Major complications accompanied 1,968 encounters (13 %) whereas minor complications affected 315 encounters (2 %). The most common major complication was hypoxia. In our multivariable logistic regression model, odds ratios with 95 % confidence intervals for the occurrence of major complications for multiple attempts compared to first-pass success were 4.4 (3.6-5.3), 7.4 (5.0-10.7), 13.9 (5.6-34.3), and 9.3 (2.1-41.7) for attempts 2-5+ (reference attempt 1), respectively., Conclusions: We found an independent association between the number of intubation attempts among ED patients undergoing emergency airway intubation and the risk of complications., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Published by Elsevier Inc.)

Rationale: For critically ill adults receiving invasive mechanical ventilation, the ventilator mode determines how breaths are delivered. Whether the choice of ventilator mode affects outcomes for critically ill patients is unknown. To compare the effects of three common ventilator modes (volume control, pressure control, and adaptive pressure control) on death and duration of mechanical ventilation., Methods: We conducted a pragmatic, cluster-randomized, crossover trial among adults receiving invasive mechanical ventilation in a medical ICU between November 1, 2022 and July 31, 2023. Each month, patients in the participating unit were assigned to receive volume control, pressure control, or adaptive pressure control during continuous mandatory ventilation. The primary outcome was ventilator-free days through 28 days., Results: Among 566 patients included in the primary analysis, the median number of ventilator-free days was 23 [IQR, 0-26] in the volume control group, 22 [0-26] in the pressure control group, and 24 [0-26] in the adaptive pressure control group (P=0.60). The median tidal volume was similar in the three groups, but the percentage of breaths larger than 8mL/kg of predicted body weight differed between volume control (median, 4.0%; IQR, 0.0-14.1), pressure control (10.6%; 0.0-31.5), and adaptive pressure control (4.7%; 0.0-19.2). Incidences of hypoxemia, acidemia, and barotrauma were similar in the three groups., Conclusions: Among critically ill adults receiving invasive mechanical ventilation, the use of volume control, pressure control, or adaptive pressure control did not affect the number of ventilator-free days, however, confidence intervals included differences that may be clinically meaningful.

Study Objective: To examine the association between the neuromuscular blocking agent received (succinylcholine versus rocuronium) and the incidences of successful intubation on the first attempt and severe complications during tracheal intubation of critically ill adults in an emergency department (ED) or ICU., Methods: We performed a secondary analysis of data from 2 multicenter randomized trials in critically ill adults undergoing tracheal intubation in an ED or ICU. Using a generalized linear mixed-effects model with prespecified baseline covariates, we examined the association between the neuromuscular blocking agent received (succinylcholine versus rocuronium) and the incidences of successful intubation on the first attempt (primary outcome) and severe complications during tracheal intubation (secondary outcome)., Results: Among the 2,440 patients in the trial data sets, 2,339 (95.9%) were included in the current analysis; 475 patients (20.3%) received succinylcholine and 1,864 patients (79.7%) received rocuronium. Successful intubation on the first attempt occurred in 375 patients (78.9%) who received succinylcholine and 1,510 patients (81.0%) who received rocuronium (an adjusted odds ratio of 0.87; 95% CI 0.65 to 1.15). Severe complications occurred in 67 patients (14.1%) who received succinylcholine and 456 patients (24.5%) who received rocuronium (adjusted odds ratio, 0.88; 95% CI 0.62 to 1.26)., Conclusion: Among critically ill adults undergoing tracheal intubation, the incidences of successful intubation on the first attempt and severe complications were not significantly different between patients who received succinylcholine and patients who received rocuronium., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Multi-Arm, Multi-Stage (MAMS) clinical trial designs allow for multiple therapies to be compared across a spectrum of clinical trial phases. MAMS designs fall under several overarching design groups, including adaptive designs (AD) and multi-arm (MA) designs. Factorial clinical trials designs represent a combination of factorial and MAMS trial designs and can provide increased efficiency relative to fixed, traditional designs. We explore design choices associated with Factorial Adaptive Multi-Arm Multi-Stage (FAST) designs, which represent the combination of factorial and MAMS designs., Methods: Simulation studies were conducted to assess the impact of the type of analyses, the timing of analyses, and the effect size observed across multiple outcomes on trial operating characteristics for a FAST design. Given multiple outcomes types assessed within the hypothetical trial, the primary analysis approach for each assessment varied depending on data type., Results: The simulation studies demonstrate that the proposed class of FAST trial designs can offer a framework to potentially provide improvements relative to other trial designs, such as a MAMS or factorial trial. Further, we note that the design implementation decisions, such as the timing and type of analyses conducted throughout trial, can have a great impact on trial operating characteristics., Conclusions: Motivated by a trial currently under design, our work shows that the FAST category of trial can potentially offer benefits similar to both MAMS and factorial designs; however, the chosen design aspects which can be included in a FAST trial need to be thoroughly explored during the planning phase., (© 2024. The Author(s).)

Importance: Intravenous fluids are an essential part of treatment in sepsis, but there remains clinical equipoise on which type of crystalloid fluids to use in sepsis. A previously reported sepsis subphenotype (ie, group D) has demonstrated a substantial mortality benefit from balanced crystalloids compared with normal saline., Objective: To test the hypothesis that targeting balanced crystalloids to patients with group D sepsis through an electronic health record (EHR) alert will reduce 30-day inpatient mortality., Design, Setting, and Participants: The Precision Resuscitation With Crystalloids in Sepsis (PRECISE) trial is a parallel-group, multihospital, single-blind, pragmatic randomized clinical trial to be conducted at 6 hospitals in the Emory Healthcare system. Patients with suspicion of group D infection in whom a clinician initiates an order for normal saline in the emergency department (ED) or intensive care unit (ICU) will be randomized to usual care and intervention arms., Intervention: An EHR alert that appears in the ED and ICUs to nudge clinicians to use balanced crystalloids instead of normal saline., Main Outcomes and Measures: The primary outcome is 30-day inpatient mortality. Secondary outcomes are ICU admission, in-hospital mortality, receipt of vasoactive drugs, receipt of new kidney replacement therapy, and receipt of mechanical ventilation (vasoactive drugs, kidney replacement therapy, and mechanical ventilation are counted if they occur after randomization and within the 30-day study period). Intention-to-treat analysis will be conducted., Discussion: The PRECISE trial may be one of the first precision medicine trials of crystalloid fluids in sepsis. Using routine vital signs (temperature, heart rate, respiratory rate, and blood pressure), available even in low-resource settings, a validated machine learning algorithm will prospectively identify and enroll patients with group D sepsis who may have a substantial mortality reduction from used of balanced crystalloids compared with normal saline., Results: On finalizing participant enrollment and analyzing the data, the study's findings will be shared with the public through publication in a peer-reviewed journal., Conclusions: With use of a validated machine learning algorithm, precision resuscitation in sepsis could fundamentally redefine international standards for intravenous fluid resuscitation., Trial Registration: ClinicalTrials.gov Identifier: NCT06253585.

Background: The best approaches to supplemental oxygen administration during surgery remain unclear, which may contribute to variation in practice. This study aimed to assess determinants of oxygen administration and its variability during surgery., Methods: Using multivariable linear mixed-effects regression, the study measured the associations between intraoperative fraction of inspired oxygen and patient, procedure, medical center, anesthesiologist, and in-room anesthesia provider factors in surgical cases of 120 min or longer in adult patients who received general anesthesia with tracheal intubation and were admitted to the hospital after surgery between January 2016 and January 2019 at 42 medical centers across the United States participating in the Multicenter Perioperative Outcomes Group data registry., Results: The sample included 367,841 cases (median [25th, 75th] age, 59 [47, 69] yr; 51.1% women; 26.1% treated with nitrous oxide) managed by 3,836 anesthesiologists and 15,381 in-room anesthesia providers. Median (25th, 75th) fraction of inspired oxygen was 0.55 (0.48, 0.61), with 6.9% of cases less than 0.40 and 8.7% greater than 0.90. Numerous patient and procedure factors were statistically associated with increased inspired oxygen, notably advanced American Society of Anesthesiologists classification, heart disease, emergency surgery, and cardiac surgery, but most factors had little clinical significance (less than 1% inspired oxygen change). Overall, patient factors only explained 3.5% (95% CI, 3.5 to 3.5%) of the variability in oxygen administration, and procedure factors 4.4% (95% CI, 4.2 to 4.6%). Anesthesiologist explained 7.7% (95% CI, 7.2 to 8.2%) of the variability in oxygen administration, in-room anesthesia provider 8.1% (95% CI, 7.8 to 8.4%), medical center 23.3% (95% CI, 22.4 to 24.2%), and 53.0% (95% CI, 52.4 to 53.6%) was unexplained., Conclusions: Among adults undergoing surgery with anesthesia and tracheal intubation, supplemental oxygen administration was variable and appeared arbitrary. Most patient and procedure factors had statistical but minor clinical associations with oxygen administration. Medical center and anesthesia provider explained significantly more variability in oxygen administration than patient or procedure factors., (Copyright © 2024 American Society of Anesthesiologists. All Rights Reserved.)

Objective: A trial comparing extended-release naltrexone and sublingual buprenorphine-naloxone demonstrated higher relapse rates in individuals randomized to extended-release naltrexone. The effectiveness of treatment might vary based on patient characteristics. We hypothesized that causal machine learning would identify individualized treatment effects for each medication., Methods: This is a secondary analysis of a multicenter randomized trial that compared the effectiveness of extended-release naltrexone versus buprenorphine-naloxone for preventing relapse of opioid misuse. Three machine learning models were derived using all trial participants with 50% randomly selected for training (n = 285) and the remaining 50% for validation. Individualized treatment effect was measured by the Qini value and c-for-benefit, with the absence of relapse denoting treatment success. Patients were grouped into quartiles by predicted individualized treatment effect to examine differences in characteristics and the observed treatment effects., Results: The best-performing model had a Qini value of 4.45 (95% confidence interval, 1.02-7.83) and a c-for-benefit of 0.63 (95% confidence interval, 0.53-0.68). The quartile most likely to benefit from buprenorphine-naloxone had a 35% absolute benefit from this treatment, and at study entry, they had a high median opioid withdrawal score ( P < 0.001), used cocaine on more days over the prior 30 days than other quartiles ( P < 0.001), and had highest proportions with alcohol and cocaine use disorder ( P ≤ 0.02). Quartile 4 individuals were predicted to be most likely to benefit from extended-release naltrexone, with the greatest proportion having heroin drug preference ( P = 0.02) and all experiencing homelessness ( P < 0.001)., Conclusions: Causal machine learning identified differing individualized treatment effects between medications based on characteristics associated with preventing relapse., Competing Interests: Conflicts of Interest: None., (Copyright © 2024 American Society of Addiction Medicine.)

Critical care trials evaluate the effect of interventions in patients with diverse personal histories and causes of illness, often under the umbrella of heterogeneous clinical syndromes, such as sepsis or acute respiratory distress syndrome. Given this variation, it is reasonable to expect that the effect of treatment on outcomes may differ for individuals with variable characteristics. However, in randomized controlled trials, efficacy is typically assessed by the average treatment effect (ATE), which quantifies the average effect of the intervention on the outcome in the study population. Importantly, the ATE may hide variations of the treatment's effect on a clinical outcome across levels of patient characteristics, which may erroneously lead to the conclusion that an intervention does not work overall when it may in fact benefit certain patients. In this review, we describe methodological approaches for assessing heterogeneity of treatment effect (HTE), including expert-derived subgrouping, data-driven subgrouping, baseline risk modeling, treatment effect modeling, and individual treatment rule estimation. Next, we outline how insights from HTE analyses can be incorporated into the design of clinical trials. Finally, we propose a research agenda for advancing the field and bringing HTE approaches to the bedside., Competing Interests: Dr. Graham Linck was supported, in part, by the National Institutes of Health (NIH)/the National Library of Medicine (NLM) training grant (T15LM007359). Dr. Goligher is supported by grants from the Canadian Institutes of Health Research and the National Sanitarium Association; he received consulting fees from Lungpacer Medical, Stimit LLC, and Bioage; honoraria for lectures from Vyaire, Draeger, and Getinge; advisory board participation for Getinge (current) and Lungpacer (previous); and receipt of equipment for research from Timpel and Lungpacer. Dr. Semler was supported, in part, by a grant from the NIH/National Center for Advancing Translational Sciences (5UL1TR002243), a grant from the NIH/National Heart, Lung, and Blood Institute (NHLBI) (K23HL143053), and a grant from the U.S. Department of Defense. Dr. Semler reports having received compensation from Baxter Healthcare Corporation for having delivered two virtual lectures at conferences; an honorarium from the University of Pittsburgh; compensation from Baxter Healthcare Corporation for having served on a medical advisory board; compensation for continuing medical education lectures from Northwest Anesthesia Seminars; and an honorarium from the Cleveland Clinic. Dr. Churpek was supported by a grant from NIH/NHLBI (R01HL157262) and NLM; he is a named inventor on a patent (No. 11,410,777) for electronic Cardiac Arrest Risk Triage score, a risk stratification tool for ward patients, and receives royalties from this IP from the University of Chicago. Dr. Semler has disclosed that he does not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

The optimal timing of intubation in acute hypoxaemic respiratory failure is uncertain and became a point of controversy during the COVID-19 pandemic. Invasive mechanical ventilation is a potentially life-saving intervention but carries substantial risks, including injury to the lungs and diaphragm, pneumonia, intensive care unit-acquired muscle weakness, and haemodynamic impairment. In deciding when to intubate, clinicians must balance premature exposure to the risks of ventilation with the potential harms of unassisted breathing, including disease progression and worsening multiorgan failure. Currently, the optimal timing of intubation is unclear. In this Personal View, we examine a range of parameters that could serve as triggers to initiate invasive mechanical ventilation. The utility of a parameter (eg, the ratio of arterial oxygen tension to fraction of inspired oxygen) to predict the likelihood of a patient undergoing intubation does not necessarily mean that basing the timing of intubation on that parameter will improve therapeutic outcomes. We examine options for clinical investigation to make progress on establishing the optimal timing of intubation., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Competing Interests: Dr. DeMasi received funding from the National Institutes of Health (grant 5T32GM108554). Dr. Qian received funding from Karl-Storz Endoscopy. Dr. Casey received funding from Fisher and Paykel. The remaining authors have disclosed that they do not have any potential conflicts of interest.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproved. The NHLBI of the NIH assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and well-being of ARDS survivors.

Background: Whether the use of fludrocortisone affects outcomes of patients with aneurysmal subarachnoid hemorrhage (aSAH)., Methods: We conducted a retrospective analysis of 78 consecutive patients with a ruptured aSAH at a single academic center in the United States. The primary outcome was the score on the modified Rankin scale (mRS, range, 0 [no symptoms] to 6 [death]) at 90 days. The primary outcome was adjusted for age, hypertension, aSAH grade, and time from aSAH onset to aneurysm treatment. Secondary outcomes were neurologic and cardiopulmonary dysfunction events., Results: Among 78 patients at a single center, the median age was 58 years [IQR, 49 to 64.5]; 64 % were female, and 41 (53 %) received fludrocortisone. The adjusted common odds ratio, aOR, of a proportional odds regression model of fludrocortisone use with mRS was 0.33 (95 % CI, 0.14-0.80; P = 0.02), with values <1.0 favoring fludrocortisone. Organ-specific dysfunction events were not statistically different: delayed cerebral ischemia (22 % vs. 39 %, P = 0.16); cardiac dysfunction (0 % vs. 11 %; P = 0.10); and pulmonary edema (15 % vs. 8 %; P = 0.59)., Conclusions: The risk of disability or death at 90 days was lower with the use of fludrocortisone in aSAH patients., Competing Interests: Declaration of competing interest Isaac Abecassis has the following disclosures: 1) Remedy Robotics: Consultant, Equity. 2) IschemaView Inc/Rapid AI: Clinical consultant. 3) Rapid Medical: Consultant. 4) Balt: Consultant. 5) CNS Foundation: Grant Research Support., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Importance: Among critically ill adults, randomized trials have not found oxygenation targets to affect outcomes overall. Whether the effects of oxygenation targets differ based on an individual's characteristics is unknown., Objective: To determine whether an individual's characteristics modify the effect of lower vs higher peripheral oxygenation-saturation (Spo2) targets on mortality., Design, Setting, and Participants: A machine learning model to predict the effect of treatment with a lower vs higher Spo2 target on mortality for individual patients was derived in the Pragmatic Investigation of Optimal Oxygen Targets (PILOT) trial and externally validated in the Intensive Care Unit Randomized Trial Comparing Two Approaches to Oxygen Therapy (ICU-ROX) trial. Critically ill adults received invasive mechanical ventilation in an intensive care unit (ICU) in the United States between July 2018 and August 2021 for PILOT (n = 1682) and in 21 ICUs in Australia and New Zealand between September 2015 and May 2018 for ICU-ROX (n = 965)., Exposures: Randomization to a lower vs higher Spo2 target group., Main Outcome and Measure: 28-Day mortality., Results: In the ICU-ROX validation cohort, the predicted effect of treatment with a lower vs higher Spo2 target for individual patients ranged from a 27.2% absolute reduction to a 34.4% absolute increase in 28-day mortality. For example, patients predicted to benefit from a lower Spo2 target had a higher prevalence of acute brain injury, whereas patients predicted to benefit from a higher Spo2 target had a higher prevalence of sepsis and abnormally elevated vital signs. Patients predicted to benefit from a lower Spo2 target experienced lower mortality when randomized to the lower Spo2 group, whereas patients predicted to benefit from a higher Spo2 target experienced lower mortality when randomized to the higher Spo2 group (likelihood ratio test for effect modification P = .02). The use of a Spo2 target predicted to be best for each patient, instead of the randomized Spo2 target, would have reduced the absolute overall mortality by 6.4% (95% CI, 1.9%-10.9%)., Conclusion and Relevance: Oxygenation targets that are individualized using machine learning analyses of randomized trials may reduce mortality for critically ill adults. A prospective trial evaluating the use of individualized oxygenation targets is needed.

Rationale: Among mechanically ventilated critically ill adults, the PILOT (Pragmatic Investigation of Optimal Oxygen Targets) trial demonstrated no difference in ventilator-free days among lower, intermediate, and higher oxygen-saturation targets. The effects on long-term cognition and related outcomes are unknown. Objectives: To compare the effects of lower (90% [range, 88-92%]), intermediate (94% [range, 92-96%]), and higher (98% [range, 96-100%]) oxygen-saturation targets on long-term outcomes. Methods: Twelve months after enrollment in the PILOT trial, blinded neuropsychological raters conducted assessments of cognition, disability, employment status, and quality of life. The primary outcome was global cognition as measured using the Telephone Montreal Cognitive Assessment. In a subset of patients, an expanded neuropsychological battery measured executive function, attention, immediate and delayed memory, verbal fluency, and abstraction. Measurements and Main Results: A total of 501 patients completed follow-up, including 142 in the lower, 186 in the intermediate, and 173 in the higher oxygen target groups. Median (interquartile range) peripheral oxygen saturation values in the lower, intermediate, and higher target groups were 94% (91-96%), 95% (93-97%), and 97% (95-99%), respectively. Telephone Montreal Cognitive Assessment score did not differ between lower and intermediate (adjusted odds ratio [OR], 1.36 [95% confidence interval (CI), 0.92-2.00]), intermediate and higher (adjusted OR, 0.90 [95% CI, 0.62-1.29]), or higher and lower (adjusted OR, 1.22 [95% CI, 0.83-1.79]) target groups. There was also no difference in individual cognitive domains, disability, employment, or quality of life. Conclusions: Among mechanically ventilated critically ill adults who completed follow-up at 12 months, oxygen-saturation targets were not associated with cognition or related outcomes.

Background: For every critically ill adult receiving invasive mechanical ventilation, clinicians must select a mode of ventilation. The mode of ventilation determines whether the ventilator directly controls the tidal volume or the inspiratory pressure. Newer hybrid modes allow clinicians to set a target tidal volume; the ventilator controls and adjusts the inspiratory pressure. A strategy of low tidal volumes and low plateau pressure improves outcomes, but the optimal mode to achieve these targets is not known., Research Question: Can a cluster-randomized trial design be used to assess whether the mode of mandatory ventilation affects the number of days alive and free of invasive mechanical ventilation among critically ill adults?, Study Design and Methods: The Mode of Ventilation During Critical Illness (MODE) trial is a cluster-randomized, multiple-crossover pilot trial being conducted in the medical ICU at an academic center. The MODE trial compares the use of volume control, pressure control, and adaptive pressure control. The study ICU is assigned to a single-ventilator mode (volume control vs pressure control vs adaptive pressure control) for continuous mandatory ventilation during each 1-month study block. The assigned mode switches every month in a randomly generated sequence. The primary outcome is ventilator-free days to study day 28, defined as the number of days alive and free of invasive mechanical ventilation from the final receipt of mechanical ventilation to 28 days after enrollment. Enrollment began November 1, 2022, and will end on July 31, 2023., Results: This manuscript describes the protocol and statistical analysis plan for the MODE trial of ventilator modes comparing volume control, pressure control, and adaptive pressure control., Interpretation: Prespecifying the full statistical analysis plan prior to completion of enrollment increases rigor, reproducibility, and transparency of the trial results., Clinical Trial Registration: The trial was registered with clinicaltrials.gov on October 3, 2022, before initiation of patient enrollment on November 1, 2022 (ClinicalTrials.gov identifier: NCT05563779).

Background: The effect of balanced crystalloids compared with that of saline in critically ill patients overall and in specific subgroups is unclear. We aimed to assess whether use of balanced solutions, compared with 0·9% sodium chloride (saline), decreased in-hospital mortality in adult patients in intensive care units (ICUs)., Methods: For this systematic review and individual patient data meta-analysis, we searched PubMed, Embase, and CENTRAL databases from inception until March 1, 2022 (updated Sept 1, 2023) for individually randomised and cluster-randomised trials comparing balanced solutions with saline for adult patients in the ICU. Eligible trials were those that allocated patients to receive balanced solutions or saline for fluid resuscitation and maintenance fluids, or for maintenance fluids only; and administered the allocated fluid throughout ICU admission or, for trials using landmark mortality as their primary outcome, until the timepoint at which mortality was assessed (if ≥28 days). Authors of eligible trials were contacted to request individual patient data. Data obtained from eligible trials were merged, checked for accuracy, and centrally analysed by use of Bayesian regression models. The primary outcome was in-hospital mortality. Prespecified subgroups included patients with traumatic brain injury. This study was registered with PROSPERO (CRD42022299282)., Findings: Our search identified 5219 records, yielding six eligible randomised controlled trials. Data obtained for 34 685 participants from the six trials, 17 407 assigned to receive balanced crystalloids and 17 278 to receive saline, were included in the analysis. The mean age of participants was 58·8 years (SD 17·5). Of 34 653 participants with available data, 14 579 (42·1%) were female and 20 074 (57·9%) were male. Among patients who provided consent to report in-hospital mortality, 2907 (16·8%) of 17 313 assigned balanced solutions and 2975 (17·3%) of 17 166 assigned saline died in hospital (odds ratio [OR] 0·962 [95% CrI 0·909 to 1·019], absolute difference -0·4 percentage points [-1·5 to 0·2]). The posterior probability that balanced solutions reduced mortality was 0·895. In patients with traumatic brain injury, 191 (19·1%) of 999 assigned balanced and 141 (14·7%) of 962 assigned saline died (OR 1·424 [1·100 to 1·818], absolute difference 3·2 percentage points [0·7 to 8·7]). The probability that balanced solutions increased mortality in patients with traumatic brain injury was 0·975. In an independent risk of bias assessment, two trials were deemed to be at low risk of bias and four at high risk of bias., Interpretation: The probability that using balanced solutions in the ICU reduces in-hospital mortality is high, although the certainty of the evidence was moderate and the absolute risk reduction was small. In patients with traumatic brain injury, using balanced solutions was associated with increased in-hospital mortality., Funding: HCor (Brazil) and The George Institute for Global Health (Australia)., Competing Interests: Declaration of interests FGZ reports receiving consulting fees from Baxter (USA) and Bactiguard (Sweden), and grants, paid to his institution from Ionis Pharmaceuticals (USA), and receiving logistical support and donation of study materials from Baxter Hospitalar for the BaSICS trial. ABC reports receiving logistical support and donation of study materials from Baxter Hospitalar for the BaSICS trial. GLDT reports receiving consulting fees from Gilead paid to his then employer (The George Institute for Global Health) for work outside the scope of this paper. LPD reports receiving fees for statistical analysis from Nestlé and Endpoint Health, all unrelated to the scope of this study. NEH reports research funding and donation of study materials from Baxter Healthcare related to intravenous fluid therapy, research funding from Endpoint Health, and consulting fees from RevImmune unrelated to fluid therapy, all paid to her employer; and competitive research grants from the Australian National Health and Medical Research Council and Medical Research Future Fund. FRM reports receiving consulting fees from Baxter and receiving logistical support and donation of study materials from Baxter Hospitalar for the BaSICS trial. SM declares no competing interests. JM reports research funding and donation of study materials from Baxter Healthcare related to intravenous fluid therapy, paid to his employer; research funding from Endpoint Health unrelated to fluid therapy; and competitive research grants from the Australian National Health and Medical Research Council and Medical Research Future Fund. MR reports donation of study materials from Baxter Healthcare related to intravenous fluid therapy and competitive research grants from the Australian Medical Research Future Fund. BV reports donation of study materials from Baxter Healthcare related to intravenous fluid therapy, research funding from Endpoint Health unrelated to fluid therapy, and consulting fees from RevImmune unrelated to fluid therapy, all paid to his institution; and competitive research grants from the Australian National Health and Medical Research Council. TWR reports receiving consulting fees received from Cumberland Pharmaceuticals and Cytovale and fees for serving as a data safety and monitoring board member from Sanofi, all unrelated to the scope of this paper; and grants from the US National Institutes for Health, Centers for Disease Control, and Department of Defence, all paid to his institution. MWS reports receiving grants from the US National Institutes for Health and Department of Defence unrelated to the current work; and consulting fees and honoraria from Baxter Healthcare related to intravenous fluid therapy. PJY reports receiving competitive grants from the Health Research Council of New Zealand unrelated to this work; consulting fees from AM Pharma unrelated to this work; and consulting fees from Baxter Healthcare related to intravenous fluid therapy. SF reports competitive research grants from the Australian National Health and Medical Research Council, research funding and consulting fees from Baxter Healthcare related to intravenous fluid therapy, research funding and consulting fees from RevImmune unrelated to fluid therapy, and research funding from Endpoint Health unrelated to fluid therapy, all paid to his institution; and owning stock options in Sepsis Scout, unrelated to fluid therapy., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: Refractory hypoxemia can occur in patients with acute respiratory distress syndrome from COVID-19 despite support with venovenous (VV) extracorporeal membrane oxygenation (ECMO). Parallel ECMO circuits can be used to increase physiologic support. We report our clinical experience using ECMO circuits in parallel for select patients with persistent severe hypoxemia despite the use of a single ECMO circuit., Methods: We performed a retrospective cohort study of all patients with COVID-19-related acute respiratory distress syndrome who received VV-ECMO with an additional circuit in parallel at Vanderbilt University Medical Center between March 1, 2020, and March 1, 2022. We report demographic characteristics and clinical characteristics including ECMO settings, mechanical ventilator settings, use of adjunctive therapies, and arterial blood gas results after initial cannulation, before and after receipt of a second ECMO circuit in parallel, and before removal of the circuit in parallel, and outcomes., Results: Of 84 patients with COVID-19 who received VV-ECMO during the study period, 22 patients (26.2%) received a circuit in parallel. The median duration of ECMO was 40.0 days (interquartile range, 31.6-53.1 days), of which 19.0 days (interquartile range, 13.0-33.0 days) were spent with a circuit in parallel. Of the 22 patients who received a circuit in parallel, 16 (72.7%) survived to hospital discharge and 6 (27.3%) died before discharge., Conclusions: In select patients, the additional use of an ECMO circuit in parallel can increase ECMO blood flow and improve oxygenation while allowing for lung-protective mechanical ventilation and excellent outcomes., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Prior studies suggest associations between receipt of piperacillin-tazobactam and development of acute kidney injury and receipt of anti-pseudomonal cephalosporins and neurotoxicity. We compared clinically-relevant renal and neurologic outcomes in critically ill patients who received piperacillin-tazobactam versus anti-pseudomonal cephalosporins. Methods: We conducted a secondary analysis of data from the Isotonic Solutions and Major Adverse Renal Events Trial examining patients who received piperacillin-tazobactam or an anti-pseudomonal cephalosporin within 24 h of intensive care unit admission. We performed multivariable analysis using a proportional odds model to examine the association between the first antibiotic received and the outcomes of Major Adverse Kidney Events within 30 days (MAKE30) and days alive and free of delirium and coma to day 28. Results: 3199 were included in the study; 2375 (74%) receiving piperacillin-tazobactam and 824 (26%) receiving anti-pseudomonal cephalosporin. After adjustment for prespecified confounders, initial receipt of piperacillin-tazobactam, compared to anti-pseudomonal cephalosporins, was not associated with higher incidence of MAKE30 (adjusted odds ratio, 1.03; 95% CI, 0.83-1.27; P  = .80) but was associated with a greater number of days alive and free of delirium and coma (adjusted odds ratio, 1.18; 95% CI, 1.00-1.38; P  = .04). In a sensitivity analysis adjusting for baseline receipt of medications which may impact neuro function, this finding was not significant. Conclusion: Among critically ill adults, receipt of piperacillin-tazobactam was not associated with an increased incidence of death, renal replacement therapy, or persistent renal dysfunction or a greater number of days alive and free of delirium and coma. Randomized trials are needed to inform the choice of antibiotics for empiric treatment infection in critically ill adults., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Implementation of the "B" element-both spontaneous awakening trials (SATs) and spontaneous breathing trials (SBTs)-of the ABCDEF bundle improves the outcomes for mechanically ventilated patients. In 2021, the Pragmatic Investigation of optimal Oxygen Targets (PILOT) trial investigating optimal oxygenation targets in patients on mechanical ventilation was completed., Objectives: To compare SAT and SBT conduct between a randomized controlled trial and current clinical care., Methods: The 2008 Awakening and Breathing Controlled (ABC) Trial (2003-2006) randomized mechanically ventilated patients to paired SATs and SBTs versus sedation per usual care plus SBTs. The PILOT trial (2018-2021) enrolled patients years later where SAT + SBT conduct was observed. We compared SAT and SBT conduct in ABC's interventional group (SAT + SBT; n = 167, 1140 patient days) to that in PILOT (n = 2083, 8355 patient days)., Results: Spontaneous awakening trial safety screens were done in all 1140 ABC patient-days on sedation and/or analgesia and in 3889 of 4228 (92%) in PILOT. Spontaneous awakening trial safety screens were passed in 939 of 1140 (82%) instances in ABC versus only 1897 of 3889 (49%) in PILOT. Interestingly, SAT was performed in ≥95% of passed SAT safety screens in both trials and was passed in 837 of 895 (94%) in ABC versus 1145 of 1867 (61%) in PILOT. SBT safety screens were performed in all 983 ABC instances and 8031 of 8370 (96%) in PILOT. SBT safety screens were passed in 647 of 983 (66%) in ABC versus 4475 of 8031 (56%) in PILOT. Spontaneous breathing trial was performed in ≥93% of passed SBT safety screens in both trials and was passed in 319 of 603 (53%) in ABC versus 3337 of 4454 (75%) in PILOT., Conclusion: This study compared SAT/SBT conduction in an ideal setting to real-world practice, 13 years later. Performance of SAT/SBT safety screens, SATs, and SBTs between a definitive clinical trial (ABC) as compared to current clinical care (PILOT) remained high., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Importance: Cefepime and piperacillin-tazobactam are commonly administered to hospitalized adults for empirical treatment of infection. Although piperacillin-tazobactam has been hypothesized to cause acute kidney injury and cefepime has been hypothesized to cause neurological dysfunction, their comparative safety has not been evaluated in a randomized clinical trial., Objective: To determine whether the choice between cefepime and piperacillin-tazobactam affects the risks of acute kidney injury or neurological dysfunction., Design, Setting, and Participants: The Antibiotic Choice on Renal Outcomes (ACORN) randomized clinical trial compared cefepime vs piperacillin-tazobactam in adults for whom a clinician initiated an order for antipseudomonal antibiotics within 12 hours of presentation to the hospital in the emergency department or medical intensive care unit at an academic medical center in the US between November 10, 2021, and October 7, 2022. The final date of follow-up was November 4, 2022., Interventions: Patients were randomized in a 1:1 ratio to cefepime or piperacillin-tazobactam., Main Outcomes and Measures: The primary outcome was the highest stage of acute kidney injury or death by day 14, measured on a 5-level ordinal scale ranging from no acute kidney injury to death. The 2 secondary outcomes were the incidence of major adverse kidney events at day 14 and the number of days alive and free of delirium and coma within 14 days., Results: There were 2511 patients included in the primary analysis (median age, 58 years [IQR, 43-69 years]; 42.7% were female; 16.3% were Non-Hispanic Black; 5.4% were Hispanic; 94.7% were enrolled in the emergency department; and 77.2% were receiving vancomycin at enrollment). The highest stage of acute kidney injury or death was not significantly different between the cefepime group and the piperacillin-tazobactam group; there were 85 patients (n = 1214; 7.0%) in the cefepime group with stage 3 acute kidney injury and 92 (7.6%) who died vs 97 patients (n = 1297; 7.5%) in the piperacillin-tazobactam group with stage 3 acute kidney injury and 78 (6.0%) who died (odds ratio, 0.95 [95% CI, 0.80 to 1.13], P = .56). The incidence of major adverse kidney events at day 14 did not differ between groups (124 patients [10.2%] in the cefepime group vs 114 patients [8.8%] in the piperacillin-tazobactam group; absolute difference, 1.4% [95% CI, -1.0% to 3.8%]). Patients in the cefepime group experienced fewer days alive and free of delirium and coma within 14 days (mean [SD], 11.9 [4.6] days vs 12.2 [4.3] days in the piperacillin-tazobactam group; odds ratio, 0.79 [95% CI, 0.65 to 0.95])., Conclusions and Relevance: Among hospitalized adults in this randomized clinical trial, treatment with piperacillin-tazobactam did not increase the incidence of acute kidney injury or death. Treatment with cefepime resulted in more neurological dysfunction., Trial Registration: ClinicalTrials.gov Identifier: NCT05094154.

Objective: It remains unclear whether balanced solutions improve patient-centred outcomes in critically ill patients overall and whether the treatment effect is heterogeneous, with evidence that some populations of patients may be helped and others harmed. To provide the most up-to-date and comprehensive assessment of the totality of the evidence, we will perform an ongoing living systematic review with aggregated and individual patient data meta-analysis (IPDMA) comparing the use of balanced solutions with saline in critically ill adults. Design: Living systematic review using aggregated and individual patient data from randomised controlled trials. Data sources: We will conduct annual searches of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials. gov, the Australian New Zealand Clinical Trials Registry (ANZCTR), Japan's University Hospital Medical Information Network (UMIN) Center, and the Brazilian Registry of Clinical Trials (ReBEC). The first search was completed on 1 March 2022 and will be repeated annually. Authors of eligible trials will be invited to provide individual data for the IPDMA. The initial analysis will use all data received up to 30 June 2022. Review methods: We will include randomised controlled trials in adults treated in an intensive care unit that allocated individuals or clusters of patients to a balanced crystalloid solution or 0.9% saline for intravenous fluid therapy. Studies that used colloids as part of the intervention or that recruited only elective surgical patients will be excluded. The primary endpoint will be in-hospital mortality. The key secondary endpoint will be survival at longest follow-up for each trial. Data will be synthesised using both a random effect Bayesian meta-analysis and using hierarchical Bayesian models for individual patient data. Discussion: The use of balanced crystalloid solutions may reduce mortality and improve other outcomes in some critically ill patients. We will assess the totality of current and future evidence by performing an ongoing living systematic review with aggregated data and IPDMA. Protocol registration: CRD42022299282., Competing Interests: FGZ reports receiving grants for investigator-initiated trial from Ionis Pharmaceuticals (USA) and logistics support from Baxter Hospitalar (Brazil) for the BaSICS trial. SF / JM / NH / SM received unrestricted grants from Baxter and CSL (Paid to their institution)., (© 2022 College of Intensive Care Medicine of Australia and New Zealand.)

Study Objective: To compare the effect of the use of a video laryngoscope versus a direct laryngoscope on each step of emergency intubation: laryngoscopy (step 1) and intubation of the trachea (step 2)., Methods: In a secondary observational analysis of data from 2 multicenter, randomized trials that enrolled critically ill adults undergoing tracheal intubation but did not control for laryngoscope type (video laryngoscope vs direct laryngoscope), we fit mixed-effects logistic regression models examining the 1) the association between laryngoscope type (video laryngoscope vs direct laryngoscope) and the Cormack-Lehane grade of view and 2) the interaction between grade of view, laryngoscope type (video laryngoscope vs direct laryngoscope), and the incidence of successful intubation on the first attempt., Results: We analyzed 1,786 patients: 467 (26.2%) in the direct laryngoscope group and 1,319 (73.9%) in the video laryngoscope group. The use of a video laryngoscope was associated with an improved grade of view as compared with a direct laryngoscope (adjusted odds ratio for increasingly favorable grade of view 3.14, 95% confidence interval [CI] 2.47 to 3.99). Successful intubation on the first attempt occurred in 83.2% of patients in the video laryngoscope group and 72.2% of patients in the direct laryngoscope group (absolute difference 11.1%, 95% CI 6.5% to 15.6%). Video laryngoscope use modified the association between grade of view and successful intubation on the first attempt such that intubation on the first attempt was similar between video laryngoscope and direct laryngoscope at a grade 1 view and higher for video laryngoscope than direct laryngoscope at grade 2 to 4 views (P<.001 for interaction term)., Conclusions: Among critically ill adults undergoing tracheal intubation, the use of a video laryngoscope was associated both with a better view of the vocal cords and with a higher probability of successfully intubating the trachea when the view of the vocal cords was incomplete in this observational analysis. However, a multicenter, randomized trial directly comparing the effect of a video laryngoscope with a direct laryngoscope on the grade of view, success, and complications is needed., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Successful intubation on the first attempt has historically been defined as successful placement of an endotracheal tube (ETT) using a single laryngoscope insertion. More recent studies have defined successful placement of an ETT using a single laryngoscope insertion followed by a single ETT insertion. We sought to estimate the prevalence of first-attempt success using these 2 definitions and estimate their associations with the duration of intubation and serious complications., Methods: We performed a secondary analysis of data from 2 multicenter randomized trials of critically ill adults being intubated in the emergency department or ICU. We calculated the percent difference in successful intubations on the first attempt, median difference in the duration of intubation, and percent difference in the development of serious complications by definition., Results: The study population included 1,863 patients. Successful intubation on the first attempt decreased by 4.9% (95% confidence interval 2.5% to 7.3%) when defined as 1 laryngoscope insertion followed by 1 ETT insertion (81.2%) compared with when defined as only 1 laryngoscope insertion (86.0%). When successful intubation with 1 laryngoscope and 1 ETT insertion was compared with 1 laryngoscope and multiple ETT insertions, the median duration of intubation decreased by 35.0 seconds (95% confidence interval 8.9 to 61.1 seconds)., Conclusion: Defining successful intubation on the first attempt as placement of an ETT in the trachea using 1 laryngoscope and 1 ETT insertion identifies attempts with the shortest apneic time., (Copyright © 2023 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Background: We sought to identify potentially modifiable in-hospital factors associated with global cognition, post-traumatic stress disorder (PTSD) symptoms, and depression symptoms at 12 months., Methods: This was a multi-center prospective cohort study in adult hospitalized patients with acute COVID-19. The following in-hospital factors were assessed: delirium; frequency of in-person and virtual visits by friends and family; and hydroxychloroquine, corticosteroid, and remdesivir administration. Twelve-month global cognition was characterized by the MOCA-Blind. Twelve-month PTSD and depression were characterized using the PTSD Checklist for the DSM-V and Hospital Anxiety Depression Scale, respectively., Findings: Two hundred three patients completed the 12-month follow-up assessments. Remdesivir use was associated with significantly higher cognition at 12 months based on the MOCA-Blind (adjusted odds ratio [aOR] = 1.98, 95% CI: 1.06, 3.70). Delirium was associated with worsening 12-month PTSD (aOR = 3.44, 95% CI: 1.89, 6.28) and depression (aOR = 2.18, 95% CI: 1.23, 3.84) symptoms. Multiple virtual visits per day during hospitalization was associated with lower 12-month depression symptoms compared to those with less than daily virtual visits (aOR = 0.40, 95% CI: 0.19, 0.85)., Conclusion: Potentially modifiable factors associated with better long-term outcomes included remdesivir use (associated with better cognitive function), avoidance of delirium (associated with less PTSD and depression symptoms), and increased virtual interactions with friends and family (associated with less depression symptoms)., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Background: Whether video laryngoscopy as compared with direct laryngoscopy increases the likelihood of successful tracheal intubation on the first attempt among critically ill adults is uncertain., Methods: In a multicenter, randomized trial conducted at 17 emergency departments and intensive care units (ICUs), we randomly assigned critically ill adults undergoing tracheal intubation to the video-laryngoscope group or the direct-laryngoscope group. The primary outcome was successful intubation on the first attempt. The secondary outcome was the occurrence of severe complications during intubation; severe complications were defined as severe hypoxemia, severe hypotension, new or increased vasopressor use, cardiac arrest, or death., Results: The trial was stopped for efficacy at the time of the single preplanned interim analysis. Among 1417 patients who were included in the final analysis (91.5% of whom underwent intubation that was performed by an emergency medicine resident or a critical care fellow), successful intubation on the first attempt occurred in 600 of the 705 patients (85.1%) in the video-laryngoscope group and in 504 of the 712 patients (70.8%) in the direct-laryngoscope group (absolute risk difference, 14.3 percentage points; 95% confidence interval [CI], 9.9 to 18.7; P<0.001). A total of 151 patients (21.4%) in the video-laryngoscope group and 149 patients (20.9%) in the direct-laryngoscope group had a severe complication during intubation (absolute risk difference, 0.5 percentage points; 95% CI, -3.9 to 4.9). Safety outcomes, including esophageal intubation, injury to the teeth, and aspiration, were similar in the two groups., Conclusions: Among critically ill adults undergoing tracheal intubation in an emergency department or ICU, the use of a video laryngoscope resulted in a higher incidence of successful intubation on the first attempt than the use of a direct laryngoscope. (Funded by the U.S. Department of Defense; DEVICE ClinicalTrials.gov number, NCT05239195.)., (Copyright © 2023 Massachusetts Medical Society.)

Hypotension affects approximately 40% of critically ill patients undergoing emergency intubation and is associated with an increased risk of death. The objective of this study was to examine the association between prophylactic vasopressor administration and the incidence of peri-intubation hypotension and other clinical outcomes., Design: A secondary analysis of two multicenter randomized clinical trials. The clinical effect of prophylactic vasopressor administration was estimated using a one-to-one propensity-matched cohort of patients with and without prophylactic vasopressors., Setting: Seven emergency departments and 17 ICUs across the United States., Patients: One thousand seven hundred ninety-eight critically ill patients who underwent emergency intubation at the study sites between February 1, 2019, and May 24, 2021., Interventions: None., Measurements and Main Results: The primary outcome was peri-intubation hypotension defined as a systolic blood pressure less than 90 mm Hg occurring between induction and 2 minutes after tracheal intubation. A total of 187 patients (10%) received prophylactic vasopressors prior to intubation. Compared with patients who did not receive prophylactic vasopressors, those who did were older, had higher Acute Physiology and Chronic Health Evaluation II scores, were more likely to have a diagnosis of sepsis, had lower pre-induction systolic blood pressures, and were more likely to be on continuous vasopressor infusions prior to intubation. In our propensity-matched cohort, prophylactic vasopressor administration was not associated with reduced risk of peri-intubation hypotension (41% vs 32%; p = 0.08) or change in systolic blood pressure from baseline (-12 vs -11 mm Hg; p = 0.66)., Conclusions: The administration of prophylactic vasopressors was not associated with a lower incidence of peri-intubation hypotension in our propensity-matched analysis. To address potential residual confounding, randomized clinical trials should examine the effect of prophylactic vasopressor administration on peri-intubation outcomes., Competing Interests: Dr. Fuchita received a departmental seed grant from the University of Colorado, Department of Anesthesiology, for biostatistical support. Dr. Casey was supported in part by the National Institutes of Health (NIH) (K23HL153584). Dr. Semler was supported in part by the NIH (K23HL143053). The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Purpose/Background: Pharmacists have been shown to play an important role in the medication management of critically ill patients. Pharmacist interventions in the care of critically ill patients with coronavirus disease 2019 (COVID-19) have not been quantitatively described. Methodology: A single center, retrospective, observational study was conducted at Vanderbilt University Medical Center in Nashville, Tennessee. All adult patients admitted to the COVID-19 intensive care unit (ICU) or Medical ICU with a COVID-19 diagnosis between March 1, 2020, and June 30, 2021, were included. All interventions made by pharmacists were documented electronically, collected, categorized, and analyzed. The primary outcome of this study was the median number of interventions by pharmacists per patient. The secondary outcome was the number of different types of interventions performed. Results: A total of 768 patients were included in the analysis. The median age was 63 years old; 63% of patients were male and 71% were Caucasian. Median hospital length of stay (LOS) was 12 days (interquartile range (IQR) 7-21) and ICU LOS was 5 days (IQR 1-11). The median Sequential Organ Failure Assessment score was 4 (IQR 2-7) and Charlson Comorbidity Index was 3 (IQR 2-5). Mortality at 60 days occurred in 352 patients (46%). Pharmacists performed a total of 7027 interventions for 655 patients with a median number of pharmacist interventions per patient of 6 (IQR 3-14). The most common pharmacist interventions were medication discontinuation (24%), completion of components of the ICU liberation bundle (19%), medication dose adjustment (18%), therapeutic drug monitoring (15%), and medication initiation (10%). Conclusions: Pharmacists made multiple interventions related to medication use and management in critically ill patients with COVID-19. This study adds important information of the evolving role clinical pharmacists play in the care of critical illness, specifically during the COVID-19 pandemic.

Rationale: A recent randomized trial found that using a bougie did not increase the incidence of successful intubation on first attempt in critically ill adults. The average effect of treatment in a trial population, however, may differ from effects for individuals. Objective: We hypothesized that application of a machine learning model to data from a clinical trial could estimate the effect of treatment (bougie vs. stylet) for individual patients based on their baseline characteristics ("individualized treatment effects"). Methods: This was a secondary analysis of the BOUGIE (Bougie or Stylet in Patients Undergoing Intubation Emergently) trial. A causal forest algorithm was used to model differences in outcome probabilities by randomized group assignment (bougie vs. stylet) for each patient in the first half of the trial (training cohort). This model was used to predict individualized treatment effects for each patient in the second half (validation cohort). Measurements and Main Results: Of 1,102 patients in the BOUGIE trial, 558 (50.6%) were the training cohort, and 544 (49.4%) were the validation cohort. In the validation cohort, individualized treatment effects predicted by the model significantly modified the effect of trial group assignment on the primary outcome ( P value for interaction = 0.02; adjusted qini coefficient, 2.46). The most important model variables were difficult airway characteristics, body mass index, and Acute Physiology and Chronic Health Evaluation II score. Conclusions: In this hypothesis-generating secondary analysis of a randomized trial with no average treatment effect and no treatment effect in any prespecified subgroups, a causal forest machine learning algorithm identified patients who appeared to benefit from the use of a bougie over a stylet and from the use of a stylet over a bougie using complex interactions between baseline patient and operator characteristics.

Importance: Approximately 20% to 30% of patients admitted to an intensive care unit have sepsis. While fluid therapy typically begins in the emergency department, intravenous fluids in the intensive care unit are an essential component of therapy for sepsis., Observations: For patients with sepsis, intravenous fluid can increase cardiac output and blood pressure, maintain or increase intravascular fluid volume, and deliver medications. Fluid therapy can be conceptualized as 4 overlapping phases from early illness through resolution of sepsis: resuscitation (rapid fluid administered to restore perfusion); optimization (the risks and benefits of additional fluids to treat shock and ensure organ perfusion are evaluated); stabilization (fluid therapy is used only when there is a signal of fluid responsiveness); and evacuation (excess fluid accumulated during treatment of critical illness is eliminated). Among 3723 patients with sepsis who received 1 to 2 L of fluid, 3 randomized clinical trials (RCTs) reported that goal-directed therapy administering fluid boluses to attain a central venous pressure of 8 to 12 mm Hg, vasopressors to attain a mean arterial blood pressure of 65 to 90 mm Hg, and red blood cell transfusions or inotropes to attain a central venous oxygen saturation of at least 70% did not decrease mortality compared with unstructured clinical care (24.9% vs 25.4%; P = .68). Among 1563 patients with sepsis and hypotension who received 1 L of fluid, an RCT reported that favoring vasopressor treatment did not improve mortality compared with further fluid administration (14.0% vs 14.9%; P = .61). Another RCT reported that among 1554 patients in the intensive care unit with septic shock treated with at least 1 L of fluid compared with more liberal fluid administration, restricting fluid administration in the absence of severe hypoperfusion did not reduce mortality (42.3% vs 42.1%; P = .96). An RCT of 1000 patients with acute respiratory distress during the evacuation phase reported that limiting fluid administration and administering diuretics improved the number of days alive without mechanical ventilation compared with fluid treatment to attain higher intracardiac pressure (14.6 vs 12.1 days; P < .001), and it reported that hydroxyethyl starch significantly increased the incidence of kidney replacement therapy compared with saline (7.0% vs 5.8%; P = .04), Ringer lactate, or Ringer acetate., Conclusions and Relevance: Fluids are an important component of treating patients who are critically ill with sepsis. Although optimal fluid management in patients with sepsis remains uncertain, clinicians should consider the risks and benefits of fluid administration in each phase of critical illness, avoid use of hydroxyethyl starch, and facilitate fluid removal for patients recovering from acute respiratory distress syndrome.

Rationale: Optimal infusion rate for fluid challenges in critically ill patients is unknown. A large clinical trial comparing two different infusion rates yielded neutral results. Conditional average treatment effect (CATE) assessment may aid in tailoring therapy. Objectives: To estimate CATE in patients enrolled in the BaSICS trial and to assess the effects of receiving CATE model-recommended treatment in terms of hospital mortality. Methods: Post hoc analysis of the BaSICS trial assessing the effect of two infusion rates for the fluid challenge (fast, 999 ml/h, control group; vs. slow, 333 ml/h, intervention group) on hospital mortality. CATE was estimated as the difference in outcome for treatment arms in counterfactuals obtained from a Bayesian model trained in the first half of the trial adjusted for predictors hypothesized to interact with the intervention. The model recommended slow or fast infusion or made no recommendation in the second half. A threshold greater than 0.90 probability of benefit was considered. Results: A total of 10,465 patients were analyzed. The model was trained in 5,230 patients and tested in 5,235 patients. A recommendation could be made in the test set in 19% of patients (14% were recommended the control group and 5% the treatment group); for 81% of patients, no recommendation could be made. Slow infusion was more frequently recommended in cases of planned admissions in younger patients; fast infusion was recommended for older patients with sepsis. Slow infusion rate in the subgroup of patients in the test set in which slow infusion was recommended by the model was associated with an odds ratio of 0.58 (95% credible interval of 0.32-0.90; 0.99 posterior probability of benefit) for hospital mortality. Fast infusion in the subgroup in which the model recommended fast infusion was associated with an odds ratio of 0.72 (credible intervals from 0.54 to 0.91; probability of benefit >0.99). Conclusions: Estimation of CATEs from counterfactual probabilities in data from BaSICS provided additional information on trial data. Agreement between treatment recommendation and actual treatment was associated with lower hospital mortality. Clinical trial registered with clinicaltrials.gov (NCT02875873).

Introduction: Many patients who pass a spontaneous awakening trial (SAT) and spontaneous breathing trial (SBT) do not undergo extubation that day. We aimed to identify predictors of extubation on the day of passing an SBT and to develop prediction models for extubation among mechanically ventilated patients., Methods: In a cohort of mechanically ventilated patients who had passed an SBT in a single, academic medical intensive care unit (ICU) from 2018 to 2019, we developed a logistic regression model for identifying predictors of extubation., Results: Of 745 patients in our study, 77% were extubated the day they passed a SBT. Independent predictors of extubation included higher Richmond Agitation Sedation Scale (RASS) (-2 compared to -4: odds ratio (OR) 1.83, 95% confidence interval (CI) 1.56 to 2.14), receipt of sedation on the day prior (OR 2.12, 95% CI 1.63 to 2.74), absence of diagnosis of sepsis or septic shock (OR 0.77, 95% CI 0.59 to 1), absence of neurological illness (OR 0.59, 95% CI 0.37 to 0.96), indication for intubation of altered mental status, seizure, or agitation (OR 1.67, 95% CI 1.05 to 2.65), and absence of hemodynamic instability or cardiac arrest (OR 0.67, 95% CI 0.47 to 0.95)., Conclusion and Relevance: Patients on mechanical ventilation were more likely to be extubated on the day they passed an SBT if they had higher RASS scores, received sedation the day prior, or did not have diagnosis of sepsis, neurological illness, or hemodynamic instability. Future research should attempt to identify and address modifiable risk factors for failure to extubate after passing an SBT.

Purpose: The under-representation of Black people within critical care research limits the generalizability of randomized controlled trials (RCTs). This meta-epidemiologic study investigated the proportionate representation of Black people enrolled at USA and Canadian study sites from high impact critical care RCTs., Source: We searched for critical care RCTs published in general medicine and intensive care unit (ICU) journals between 1 January 2016 and 31 December 2020. We included RCTs that enrolled critically ill adults at USA or Canadian sites and provided race-based demographic data by study site. We compared study-based racial demographics with site-level city-based demographics and pooled representation of Black people across studies, cities, and centres using a random effects model. We used meta-regression to explore the impact of the following variables on Black representation in critical care RCTs: country, drug intervention, consent model, number of centres, funding, study site city, and year of publication., Principal Findings: We included 21 eligible RCTs. Of these, 17 enrolled at only USA sites, two at only Canadian sites, and two at both USA and Canadian sites. Black people were under-represented in critical care RCTs by 6% compared with population-based city demographics (95% confidence interval, 1 to 11). Using meta-regression, after controlling for pertinent variables, the country of the study site was the only significant source of heterogeneity (P = 0.02)., Conclusion: Black people are under-represented in critical care RCTs compared with site-level city-based demographics. Interventions are required to ensure adequate Black representation in critical care RCTs at both USA and Canadian study sites. Further research is needed to investigate the factors contributing to Black under-representation in critical care RCTs., (© 2023. Canadian Anesthesiologists' Society.)

Sepsis causes significant morbidity and mortality worldwide. Resuscitation is a cornerstone of management. This review covers five areas of evolving practice in the management of early sepsis-induced hypoperfusion: fluid resuscitation volume, timing of vasopressor initiation, resuscitation targets, route of vasopressor administration, and use of invasive blood pressure monitoring. For each topic, we review the seminal evidence, discuss the evolution of practice over time, and highlight questions for additional research. Intravenous fluids are a core component of early sepsis resuscitation. However, with growing concerns about the harms of fluid, practice is evolving toward smaller-volume resuscitation, which is often paired with earlier vasopressor initiation. Large trials of fluid-restrictive, vasopressor-early strategies are providing more information about the safety and potential benefit of these approaches. Lowering blood pressure targets is a means to prevent fluid overload and reduce exposure to vasopressors; mean arterial pressure targets of 60-65 mm Hg appear to be safe, at least in older patients. With the trend toward earlier vasopressor initiation, the need for central administration of vasopressors has been questioned, and peripheral vasopressor use is increasing, although it is not universally accepted. Similarly, although guidelines suggest the use of invasive blood pressure monitoring with arterial catheters in patients receiving vasopressors, blood pressure cuffs are less invasive and often sufficient. Overall, the management of early sepsis-induced hypoperfusion is evolving toward fluid-sparing and less-invasive strategies. However, many questions remain, and additional data are needed to further optimize our approach to resuscitation.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology., Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II., Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022., Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo., Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension., Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo., Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19., Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Introduction: Antibiotics are time-critical in the management of sepsis. When infectious organisms are unknown, patients are treated with empiric antibiotics to include coverage for gram-negative organisms, such as antipseudomonal cephalosporins and penicillins. However, in observational studies, some antipseudomonal cephalosporins (eg, cefepime) are associated with neurologic dysfunction while the most common antipseudomonal penicillin (piperacillin-tazobactam) is associated with acute kidney injury (AKI). No randomised control trials have compared these regimens. This manuscript describes the protocol and analysis plan for a trial designed to compare the effects of antipseudomonal cephalosporins and antipseudomonal penicillins among acutely ill patients receiving empiric antibiotics., Methods and Analysis: The Antibiotic Choice On ReNal outcomes trial is a prospective, single-centre, non-blinded randomised trial being conducted at Vanderbilt University Medical Center. The trial will enrol 2500 acutely ill adults receiving gram-negative coverage for treatment of infection. Eligible patients are randomised 1:1 to receive cefepime or piperacillin-tazobactam on first order entry of a broad-spectrum antibiotic covering gram-negative organisms. The primary outcome is the highest stage of AKI and death occurring between enrolment and 14 days after enrolment. This will be compared between patients randomised to cefepime and randomised to piperacillin-tazobactam using an unadjusted proportional odds regression model. The secondary outcomes are major adverse kidney events through day 14 and number of days alive and free of delirium and coma in 14 days after enrolment. Enrolment began on 10 November 2021 and is expected to be completed in December 2022., Ethics and Dissemination: The trial was approved by the Vanderbilt University Medical Center institutional review board (IRB#210591) with a waiver of informed consent. Results will be submitted to a peer-reviewed journal and presented at scientific conferences., Trial Registration Number: NCT05094154., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Tracheal intubation (TI) is a common procedure in critical care, often performed with a Macintosh curved blade used for direct laryngoscopy (DL). Minimal evidence informs the choice between Macintosh blade sizes during TI. We hypothesized that Macintosh 4 blade would have higher first-attempt success than Macintosh 3 blade during DL., Design: Retrospective analysis using a propensity score and inverse probability weighting of data from six prior multicenter randomized trials., Setting and Participants: Adult patients who underwent nonelective TI at participating emergency departments and ICUs. We compared the first-pass success of TI with DL in subjects intubated with a size 4 Macintosh blade on the first TI attempt to subjects with a size 3 Macintosh blade on the first TI attempt., Main Results: Among 979 subjects, 592 (60.5%) had TI using DL with a Macintosh blade, of whom 362 (37%) were intubated with a size 4 blade and 222 (22.7%) with a size 3 blade. We used inverse probability weighting with a propensity score for analyzing data. We found that patients intubated with a size 4 blade had a worse (higher) Cormack-Lehane grade of glottic view than patients intubated with a size 3 blade (adjusted odds ratio [aOR], 1.458; 95% CI, 1.064-2.003; p = 0.02). Patients intubated with a size 4 blade had a lower first pass success than those with a size 3 blade (71.1% vs 81.2%; aOR, 0.566; 95% CI, 0.372-0.850; p = 0.01)., Conclusions and Relevance: In critically ill adults undergoing TI using DL with a Macintosh blade, patients intubated using a size 4 blade on first attempt had a worse glottic view and a lower first pass success than patients intubated with a size 3 Macintosh blade. Further prospective studies are needed to examine the optimal approach to selecting laryngoscope blade size during TI of critically ill adults., Competing Interests: Dr. Khan has received research funding from Eli Lilly, AstraZeneca, Regeneron pharmaceuticals, United Therapeutics, Johnson & Johnson, Dompe Pharmaceuticals, and 4D Medical, as site Principal Investigator for research enrollment, and consulting fees from Dompe Pharmaceuticals for clinical trial design. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)