Gajic, Ognjen

ABSTRACT Objective To compare outcomes of phenobarbital‐based versus benzodiazepine‐based pathways for alcohol withdrawal syndrome (AWS) in critically ill adults and evaluate whether pathway design and timing of phenobarbital use affect treatment outcomes. Data Sources A librarian‐led search of MEDLINE, Embase, Cochrane Central, CINAHL, Web of Science, Scopus, ClinicalTrials.gov , and the World Health Organization International Clinical Trials Registry Platform was conducted through July 2024, with updates in December 2024, August 2025, and December 2025. Search concepts included phenobarbital, benzodiazepines, and alcohol withdrawal. Study Selection and Data Extraction Comparative studies of adults admitted or transferred to an intensive care unit (ICU) with AWS and treated with phenobarbital‐based versus benzodiazepine‐based pathways were included. Sixteen nonrandomized studies were included in the qualitative synthesis, and 12 treatment‐oriented studies were included in the primary meta‐analysis. Multiple reviewers independently screened studies, extracted data, and assessed risk of bias using Risk Of Bias In Non‐randomized Studies—of Interventions (ROBINS‐I). Data Synthesis Phenobarbital‐based pathways were not associated with significantly different intubation (11 studies; odds ratio (OR), 0.62; 95% confidence interval (CI), 0.20–1.87; I 2 = 73%) or hospital length of stay (five studies; mean differences [MD], −1.75 days; 95% CI, −5.07 to 1.56; I 2 = 63%) compared with benzodiazepine‐based pathways. ICU length of stay was shorter with phenobarbital‐based pathways (eight studies; MD, −0.60 days; 95% CI, −0.79 to −0.41; I 2 = 0%). In exploratory subgroup analyses, front‐loaded, protocolized phenobarbital‐first pathways were associated with lower intubation and shorter hospital length of stay, but certainty of evidence was very low. Relevance to Patient Care and Clinical Practice This review distinguishes phenobarbital‐first, protocolized ICU pathways from adjunctive or mixed phenobarbital strategies, suggesting that implementation design may influence outcomes. Conclusions Although evidence remains very low certainty, these findings suggest that phenobarbital's role in ICU AWS may be pathway dependent. Front‐loaded, protocolized phenobarbital‐first pathways may be associated with favorable outcomes in exploratory analyses, but these findings should be considered hypothesis‐generating and require confirmation in prospective randomized trials. Trial Registration: CRD42024595819

Abstract Rationale Mechanically ventilated intensive care unit patients receive sedatives based on clinician observations of arousal and motor activity with potential for negative consequences and poor mitigation of symptoms. Objectives To test the preliminary efficacy of patient self-managed sedative therapy compared to usual care of nurse-administered sedation on self-reported anxiety, duration of mechanical ventilation, and delirium incidence (CAM-ICU). Methods A two-group, open-label, randomized, multicenter clinical trial in 5 Midwestern hospitals enrolled 161 patients receiving invasive mechanical ventilation who were willing and able to use a push-button device to self-administer sedation for up to 7 days. Patients were randomized 1:1 using center-stratified blocks to usual care (n = 81) or intervention (n = 80) with self-administered dexmedetomidine. Intervention patients were allowed 3 self-administered dexmedetomidine boluses per hour (0.25 mcg/kg) with 20-minute lock-outs. The initial basal infusion (0.2 mcg/kg/hr) was adjusted by nurses between 0.1-0.7 mcg/kg/hr based on patient-delivered boluses in the prior 2 hours. Analysis consisted of linear mixed-effects model for comparisons of anxiety ratings over time and duration of mechanical ventilation. Incidence of delirium was analyzed using generalized estimating equations. Measurement and Main Results Sample characteristics had a female (54.7%) and Caucasian preponderance (92.5%) with a median age of 62 years on protocol for a median of 88 hours. Nine intervention patients were extubated prior to protocol initiation. Patient self-reported three times daily anxiety ratings with a visual analog scale (VAS) ranged from 0-100 over time but were not significantly different between groups in either an intention-to-treat (ITT) or per protocol (PP) analysis (p = 0.94, p = 0.30 respectively). While intervention patients had shorter duration of MV [(mean 50.8(52.8) vs. usual care 68.7(58.2) hours), p = 0.02 ITT], PP analysis resulted in no difference between groups (mean 56.4 (53.0) vs. 68.7(58.2), p = 0.23). 10.2% of intervention patients developed new incidence of delirium vs. 8.5% of usual care which was not significantly different between groups by either ITT (p = 0.65) or PP analyses (p = 0.58). Conclusions Intervention patients had similar outcomes compared to usual care patients. Self-administration of sedative therapy is a safe, novel patient-centered intervention warranting further rigorous investigation for anxiety self-management.

Objectives There is substantial practice variation in the management strategies for atrial fibrillation (AF) with rapid ventricular rate (RVR) and hemodynamic instability in critically ill patients. This study aimed to evaluate the use and effectiveness of direct current cardioversion (DCCV) for unstable AF RVR in the intensive care unit (ICU). Design Multicenter retrospective cohort study. Setting Non-cardiac/cardiovascular surgery ICUs of the Mayo Clinic Hospitals in Minnesota, Wisconsin, Florida, and Arizona. Patients Adult patients who developed paroxysmal AF RVR with hemodynamic instability (heart rate ≥ 130 beats per minute and a documented SBP ≤ 90 mmHg or the need for vasopressors) during ICU stay. Interventions Emergency DCCV. Measurements and Main Results Primary outcomes were in-hospital mortality, hospital-, ICU-, and organ support-free days. Secondary outcomes were return to sinus rhythm rate before and after discharge. Among 691 patients eligible for inclusion, 47 (6.8%) received emergent DCCV in the ICU. The frequency of DCCV was higher for patients located in surgical ICUs (14.5% vs 6.1%, P = .04). Patients were 1:2 propensity-score matched. The comparative analyses were conducted on 141 patients. Those who underwent DCCV were more likely to restore sinus rhythm (odds ratio [95% confidence interval], 5.2 [1.30 20.8]). However, DCCV was not associated with increased odds of having sinus rhythm at discharge, lower mortality, or higher number of ICU-, or hospital-free days. The number of organ support-free days was significantly lower in the DCCV group (estimate ± standard error, −5.0 ± 2.0, P = .012). Conclusions Emergency DCCV is rarely used to treat unstable AF in non-cardiac ICUs. Despite increased likelihood of immediate sinus rhythm restoration, DCCV was not associated with improvement in patient-centered outcomes. Prospective studies are warranted to evaluate harms and benefits of DCCV in non-cardiac critically ill patients with unstable AF where the driver of hemodynamic instability is often an underlying condition rather than arrhythmia per se.

Background: The Sepsis-3 guidelines have incorporated serum lactate levels of >2 mmol/L in septic shock definition to account for higher observed mortality. Further evidence is needed to support this threshold in cirrhosis, as well as target mean arterial pressure (MAP) during resuscitation. Methods: This observational cohort study investigated the association between initial serum lactate and resuscitation MAP levels on in-hospital mortality in patients with and without cirrhosis. Patients admitted to the intensive care unit for the treatment of septic shock between 2006 and 2021 in a quaternary academic center were included. Patients with cirrhosis documented on imaging and International Classification of Disease codes (n=595) were compared to patients without cirrhosis (n=575). The association of intensive care unit admission lactate levels and median 2-hour MAP with in-hospital mortality and the need for continuous renal replacement therapy was assessed. The association between median 24-hour MAP and in-hospital mortality was analyzed post hoc. Results: Within the cirrhosis group, admission lactate levels of 2–4 and >4 mmol/L were associated with increased in-hospital mortality compared to lactate <2 mmol/L [adjusted odds ratio (aOR): 1.69, CI: 1.03–2.81, aOR: 4.02, CI: 2.53–6.52]. Median 24-hour MAP 60–65 and <60 mm Hg were also associated with increased in-hospital mortality compared with MAP >65 mm Hg (aOR: 2.84, CI: 1.64–4.92 and aOR: 7.34, CI: 3.17–18.76). In the noncirrhosis group, associations with in-hospital mortality were weaker for lactate 2–4 and >4 mmol/L (aOR: 1.32, CI: 0.77–2.27 and aOR: 2.25, CI: 1.40–3.67) and median 24-hour MAP 60–65 and <60 mm Hg (aOR: 1.70, CI: 0.65–4.14 and aOR: 4.41, CI: 0.79–29.38). Conclusions: These findings support utilizing lactate >2 mmol/L in the definition of septic shock, as well as a target MAP of >65 mm Hg during resuscitation in patients with cirrhosis.

Critically ill patients presenting with acute on chronic liver failure (ACLF) represent a particularly vulnerable population due to various considerations surrounding the syndrome definition, lack of robust prospective evaluation of outcomes, and allocation of resources such as organs for transplantation. Ninety-day mortality related to ACLF is high and patients who do leave the hospital are frequently readmitted. Artificial intelligence (AI), which encompasses various classical and modern machine learning techniques, natural language processing, and other methods of predictive, prognostic, probabilistic, and simulation modeling, has emerged as an effective tool in various areas of healthcare. These methods are now being leveraged to potentially minimize physician and provider cognitive load and impact both short-term and long-term patient outcomes. However, the enthusiasm is tempered by ethical considerations and a current lack of proven benefits. In addition to prognostic applications, AI models can likely help improve the understanding of various mechanisms of morbidity and mortality in ACLF. Their overall impact on patient-centered outcomes and countless other aspects of patient care remains unclear. In this review, we discuss various AI approaches being utilized in healthcare and discuss the recent and expected future impact of AI on patients with ACLF through prognostic modeling and AI-based approaches.

Abstract Background CERTAIN (Checklist for Early Recognition and Treatment of Acute Illness and iNjury) education program was developed to accelerate the global dissemination of a standardized, systemic, structured approach to critical care delivery. The coronavirus disease (COVID-19) pandemic prompted the evolution of this program from a live in-person course to a blended synchronous and asynchronous learning experience, including virtual simulation. Objectives We describe our experience and insights gained through this digital program transformation and highlight areas in need of further research to advance the delivery of high-quality online education offerings to global interprofessional audiences. Methods The CERTAIN education program was delivered to a broad international audience first in person (2016–2019) and then virtually during the COVID-19 global pandemic (2020–present). During this transition, we adopted a flipped classroom model to deliver the core content asynchronously using an online learning management system, supplemented by a novel synchronous online experience to provide learners with the opportunity to apply these concepts using a series of simulated clinical cases. Results A total of 400 participants attended 11 CERTAIN courses. We transitioned our 10-hour live course to a 3-hour virtual workshop. The duration of simulation activities (admission, rounding, and shared decision-making) remained constant. Didactic lectures were eliminated from the synchronous online course and presented as recorded videos in precourse materials. We collected 306 postcourse surveys (response rate, 76.5%). The majority of the overall course ratings were excellent (147 [49.5%]) and very good (97 [32.7%]), and learner responses were similar to live and online courses. Simulation activities were consistently the most popular elements of our program. Access to digital learning platforms and language barriers during simulation activities proved to be the greatest challenges during our transition. Delivering mobile-friendly online content and close coordination between dedicated bilingual faculty and local champions helped overcome these challenges. Conclusion Critical care education and case-based simulation workshops can be delivered to international interprofessional audiences with similar, high degrees of learner satisfaction to in-person offerings.

AbstractIntroductionCoronavirus disease 2019 (COVID‐19) is associated with high rates of morbidity and mortality. Primary hypothyroidism is a common comorbid condition, but little is known about its association with COVID‐19 severity and outcomes. This study aims to identify the frequency of hypothyroidism in hospitalized patients with COVID‐19 as well as describe the differences in outcomes between patients with and without pre‐existing hypothyroidism using an observational, multinational registry.MethodsIn an observational cohort study we enrolled patients 18 years or older, with laboratory‐confirmed severe acute respiratory syndrome coronavirus‐2 infection between March 2020 and February 2021. The primary outcomes were (1) the disease severity defined as per the World Health Organization Scale for Clinical Improvement, which is an ordinal outcome corresponding with the highest severity level recorded during a patient's index COVID‐19 hospitalization, (2) in‐hospital mortality and (3) hospital‐free days. Secondary outcomes were the rate of intensive care unit (ICU) admission and ICU mortality.ResultsAmong the 20,366 adult patients included in the study, pre‐existing hypothyroidism was identified in 1616 (7.9%). The median age for the Hypothyroidism group was 70 (interquartile range: 59–80) years, and 65% were female and 67% were White. The most common comorbidities were hypertension (68%), diabetes (42%), dyslipidemia (37%) and obesity (28%). After adjusting for age, body mass index, sex, admission date in the quarter year since March 2020, race, smoking history and other comorbid conditions (coronary artery disease, hypertension, diabetes and dyslipidemia), pre‐existing hypothyroidism was not associated with higher odds of severe disease using the World Health Organization disease severity index (odds ratio [OR]: 1.02; 95% confidence interval [CI]: 0.92, 1.13; p = .69), in‐hospital mortality (OR: 1.03; 95% CI: 0.92, 1.15; p = .58) or differences in hospital‐free days (estimated difference 0.01 days; 95% CI: −0.45, 0.47; p = .97). Pre‐existing hypothyroidism was not associated with ICU admission or ICU mortality in unadjusted as well as in adjusted analysis.ConclusionsIn an international registry, hypothyroidism was identified in around 1 of every 12 adult hospitalized patients with COVID‐19. Pre‐existing hypothyroidism in hospitalized patients with COVID‐19 was not associated with higher disease severity or increased risk of mortality or ICU admissions. However, more research on the possible effects of COVID‐19 on the thyroid gland and its function is needed in the future.