The Precision Resuscitation With Crystalloids in Sepsis (PRECISE) Trial: A Trial Protocol.

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.

Association between multiple intubation attempts and complications during emergency department airway management: A national emergency airway registry study.

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.

Design considerations for Factorial Adaptive Multi-Arm Multi-Stage (FAST) clinical trials.

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.

Toward Precision in Critical Care Research: Methods for Observational and Interventional Studies.

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.

Noninvasive Ventilation for Preoxygenation during Emergency Intubation.

BACKGROUND: Among critically ill adults undergoing tracheal intubation, hypoxemia increases the risk of cardiac arrest and death. The effect of preoxygenation with noninvasive ventilation, as compared with preoxygenation with an oxygen mask, on the incidence of hypoxemia during tracheal intubation is uncertain. METHODS: In a multicenter, randomized trial conducted at 24 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults (age, ≥18 years) undergoing tracheal intubation to receive preoxygenation with either noninvasive ventilation or an oxygen mask. The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation. RESULTS: Among the 1301 patients enrolled, hypoxemia occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (difference, -9.4 percentage points; 95% confidence interval [CI], -13.2 to -5.6; P<0.001). Cardiac arrest occurred in 1 patient (0.2%) in the noninvasive-ventilation group and in 7 patients (1.1%) in the oxygen-mask group (difference, -0.9 percentage points; 95% CI, -1.8 to -0.1). Aspiration occurred in 6 patients (0.9%) in the noninvasive-ventilation group and in 9 patients (1.4%) in the oxygen-mask group (difference, -0.4 percentage points; 95% CI, -1.6 to 0.7). CONCLUSIONS: Among critically ill adults undergoing tracheal intubation, preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask. (Funded by the U.S. Department of Defense; PREOXI ClinicalTrials.gov number, NCT05267652.).

Protocol and Statistical Analysis Plan for the Mode of Ventilation During Critical Illness (MODE) Trial.

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).

Machine Learning-Driven Analysis of Individualized Treatment Effects Comparing Buprenorphine and Naltrexone in Opioid Use Disorder Relapse Prevention.

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.

When to intubate in acute hypoxaemic respiratory failure? Options and opportunities for evidence-informed decision making in the intensive care unit.

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.

Determinants and Practice Variability of Oxygen Administration during Surgery in the United States: A Retrospective Cohort Study.

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.

Individualized Treatment Effects of Oxygen Targets in Mechanically Ventilated Critically Ill Adults.

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.

Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: NHLBI Workshop Report.

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.

Impact of fludrocortisone on the outcomes of subarachnoid hemorrhage patients: A retrospective analysis.

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.

Oxygen-Saturation Targets and Cognitive and Functional Outcomes in Mechanically Ventilated Adults.

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.

Balanced crystalloids versus saline for critically ill patients (BEST-Living): a systematic review and individual patient data meta-analysis.

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).