Citations

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

IMPORTANCE: Phenobarbital use in ICU alcohol withdrawal syndrome (AWS) may reflect severe or refractory withdrawal and treatment escalation, making multicenter data important to understand its use within ICU practice and its relationship with clinical outcomes. OBJECTIVES: To evaluate phenobarbital use in real-world ICU AWS as a marker of severe or refractory withdrawal and treatment escalation. We also examined its association with time-to-discharge and safety outcomes compared with nonphenobarbital regimens. DESIGN, SETTING, AND PARTICIPANTS: Multicenter retrospective cohort study using multiple imputation and propensity score matching. Adults with AWS, defined as Clinical Institute Withdrawal Assessment for Alcohol, revised (CIWA-Ar) score greater than or equal to 10, were included if they received a phenobarbital-based or nonphenobarbital-based regimen in ICUs across a large academic health system from June 30, 2017, to July 1, 2024. Postoperative ICU admissions were excluded. MAIN OUTCOMES AND MEASURES: Primary outcomes were time to ICU and hospital discharge alive from treatment initiation. Safety outcomes were hypotension, new intubation, and aspiration within 48 hours. RESULTS: Of 1216 patients, 345 (28.4%) received phenobarbital. Before matching, phenobarbital-treated patients had higher CIWA-Ar, Acute Physiology and Chronic Health Evaluation III, and pre-ICU benzodiazepine exposure, consistent with more severe or refractory withdrawal. In adjusted time-to-discharge models, phenobarbital use was not significantly associated with time to hospital discharge alive (discharge rate ratio [DRR], 0.91; 95% CI, 0.74–1.12; p = 0.370) or ICU discharge alive (DRR, 0.77; 95% CI, 0.59–1.01; p = 0.057). Hypotension and intubation were similar, and aspiration was less frequent with phenobarbital. CONCLUSIONS: In a contemporary ICU cohort, phenobarbital use reflected treatment escalation in patients with more severe or refractory AWS. After adjustment, time to ICU and hospital discharge alive did not differ significantly, hypotension and intubation were similar, and aspiration was less frequent with phenobarbital. Future studies should define optimal timing, dosing, and patient selection.

Introduction Sepsis is a global health priority with nearly 50 million cases annually. Cardiovascular dysfunction is common, frequently manifesting as hypotension that persists despite fluid resuscitation. Most affected patients require the use of intravenous (IV) vasoactive agents, typically necessitating intensive care unit (ICU)-level monitoring, invasive interventions and contributing substantially to healthcare costs. Midodrine, an oral alpha-1 agonist approved for orthostatic hypotension, has increasingly been used off-label as a vasopressor-sparing (reducing IV vasopressor use) strategy in sepsis, despite limited and inconsistent evidence. This pragmatic, randomised, open-label trial evaluates the efficacy and safety of midodrine in patients with sepsis-associated hypotension. We hypothesise that, compared with standard care, midodrine administration will reduce the duration of IV vasopressor use. Methods and analysis A total of 308 adult patients with sepsis-associated hypotension will be enrolled (154 per arm). The intervention group will, in addition to standard of care, receive enteral midodrine 10 mg three times daily. Outcomes will be ascertained pragmatically via electronic health record-based data retrieval and adjudicated by research coordinators blinded to treatment assignment. The primary outcome is time alive and off IV vasopressors in the first 28 days (in hours) after randomisation. Secondary outcomes include cumulative vasopressor exposure; use and duration of central venous access; cumulative fluid balance over the first 48 hours and up to 7 days of ICU stay; ICU and hospital length of stay; and ICU-, hospital-, and organ support-free days through day 28. Safety outcomes include adverse events potentially attributable to midodrine during hospitalisation including acute kidney injury. Primary analyses will follow an intention-to-treat framework, including all randomised participants according to their assigned treatment groups. Primary and secondary outcomes will be compared using a van Elteren test stratified by randomisation factors. A predefined secondary Bayesian analysis of the primary outcome will provide complementary estimates of treatment effect. Safety outcomes will be summarised descriptively without formal between-arm hypothesis testing. Ethics and dissemination The Mayo Clinic Institutional Review Board approved this protocol and required written informed consent from all participants (IRB# 24–0 00 121). Findings will be disseminated through peer-reviewed publications and international conference presentations. Trial registration number NCT06319248 .

IMPORTANCE: Patients admitted to the ICU often experience gastrointestinal complications. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have become increasingly prevalent in the treatment of type 2 diabetes mellitus and obesity, and there is evidence that their use may be associated with an increased risk of clinically significant gastrointestinal events. However, their impact on critically ill patients admitted to the medical ICU is unknown. OBJECTIVES: This study examined whether pre-ICU use of GLP-1RAs was associated with increased incidence of gastrointestinal complications and hospitalization outcomes. DESIGN, SETTING AND PARTICIPANTS: Multicenter, retrospective cohort study of critically ill patients admitted to academic and community hospitals of Mayo Clinic Health System from January 1, 2018, to December 31, 2023. Patients who were admitted to surgical ICUs and those who were exposed to GLP-1RA medications before but did not have an active prescription within 30 days of admission were excluded. Patients exposed to GLP-1RA were matched with those nonexposed in a 1:1 fashion based on demographic factors, factors affecting gastrointestinal motility, overall illness burden, and clinical acuity. MAIN OUTCOMES AND MEASURES: Outcomes of interest were the development of gastrointestinal dysfunction, ICU- and hospital-free days, and mortality. RESULTS: A total of 31,327 patients with diabetes or obesity were identified of whom these, 631 were exposed to GLP-1RA before admission. In the matched cohort of 1262 patients, baseline variables were evenly distributed between the two groups. There were no significant differences in the odds of developing nausea/vomiting, constipation, ileus, obstruction, impaction, or aspiration pneumonia between the GLP-1RA exposed and unexposed groups. Similarly, ICU and hospital mortality rates were comparable across the two groups. However, GLP-1RA exposed patients had significantly more hospital-free days compared with unexposed patients (estimate, 1.19; 95% CI, 0.38–2.0; p = 0.004). CONCLUSIONS AND RELEVANCE: GLP-1RA exposure was not associated with increased odds of clinically significant gastrointestinal complications in nonsurgical critically ill patients. Increased hospital-free days observed among GLP-1RA exposed patients requires further study.

Abstract Objective: Patients with Opioid Use Disorder (OUD) are prone to Multidrug-Resistant Organism (MDRO) colonization and infections, thus at risk for worse outcomes during critical illness. Understanding the prevalence and predictors of MDRO infections is essential to optimize interventions and treatments. Design: Retrospective cohort study. Methods: The study evaluated the prevalence of MDRO isolation among adults with OUD admitted to an intensive care unit (ICU) between January 1, 2018, and July 31, 2023. It included adults admitted to an ICU with bacterial infections and positive cultures obtained within 48 hours of admission. Demographics, clinical traits, and MDRO isolation rates were analyzed using descriptive statistics, univariate methods, and Least Absolute Shrinkage and Selection Operator (LASSO) regression. Results: MDRO isolation occurred in 178 of 790 patients (22.5%), with methicillin-resistant Staphylococcus aureus as the most frequently isolated organism. LASSO regression identified housing insecurity (OR: 1.79, 95% CI 1.09–2.93, P = .022), no receipt of medications for OUD treatment (OR: 1.56, 95% CI 1.06–2.29, P = .023), positive hepatitis C virus (HCV) status (OR: 2.19, 95% CI 1.19–4.03, P = .012), and intravenous antibiotic use in the prior 90 days (OR: 1.04 per 24 h, 95% CI 1.01–1.07, P = .007) as significant predictors of MDRO isolation. Conclusions: The study highlights a high prevalence of MDRO isolation in critically ill OUD patients admitted for infection-related issues with positive cultures obtained within 48 hours of admission, influenced by factors like housing insecurity, no receipt of medications for OUD treatment, HCV status, and prior antibiotic use.

Abstract Background The opioid crisis and the increasing prevalence of multi-drug resistant organism (MDRO) infections pose a threat to public health. Opioid Use Disorder (OUD) patient are prone to MDRO colonization and infections, thus potentially leading to adverse outcomes during periods of critical illness. Understanding the prevalence and predictors of MDRO infections within this vulnerable population is critical to improving patient outcomes by optimizing interventions and treatment plans. Methods We conducted a retrospective, multicenter, cohort study to evaluate the prevalence of MDRO isolation among adults with OUD admitted to an intensive care unit (ICU) with an infection across four Mayo Clinic regions. Patients were classified to the MDRO cohort if an MDRO was isolated from standard cultures or rapid diagnostic testing within 48 hours of admission. We utilized descriptive statistics, univariate and multivariate least absolute shrinkage and selection operator (LASSO) regression analysis including random effect to account for site variability, to analyze demographic data, clinical characteristics, and outcomes. Results 790 critically ill adult OUD patients with infection-related admission were included in the study cohort. The prevalence of MDRO isolation was 22.5% (n=178), with MRSA being the predominant isolated MDRO. In LASSO regression analyses, we identified homelessness (OR: 1.79, p = 0.022), no Medications for OUD (MOUD) treatment (OR: 1.56, p=0.023), and positive Hepatitis C Virus (HCV) status (OR: 2.19, p = 0.012) as significant predictors for isolation of an MDRO. Intravenous (IV) antibiotic use in the preceding 90 days was also positively associated (OR: 1.04 per 24 hours, p = 0.007), alongside mental health disorders (OR: 2.03, p < 0.001) and diabetes (OR: 1.54, p = 0.023). Conclusion The high prevalence of MDRO isolation in critically ill OUD patients with infection is associated with complex social and clinical factors. Disclosures All Authors: No reported disclosures

Abstract Rationale Propofol is one of the first-line sedative-hypnotic agents for critically ill adults requiring mechanical ventilation. Although propofol can elevate triglyceride levels, and the latter is a risk factor for pancreatitis, the association between propofol and acute pancreatitis is unclear. Objectives We sought to determine the clinical impact and potential associations between propofol infusion, hypertriglyceridemia, and acute pancreatitis. Methods This is an observational multicenter study of adults (⩾18 yr old) who were admitted to an intensive care unit, who required mechanical ventilation and received continuous propofol infusion for at least 24 hours. The primary outcomes were the frequency of hypertriglyceridemia (>400 mg/dl) and acute pancreatitis. Further analyses were done to determine the clinical impact of elevated triglyceride levels (i.e., sedation changes) and risk factors for pancreatitis development. Results Of 11,828 patients included, 33.2% (n = 3,922) had triglyceride levels measured, of whom 21.7% (n = 851) had hypertriglyceridemia at 4.5 days (SD = 6.8) after propofol initiation. Of those still requiring sedation, 70.4% (n = 576/818) received alternative sedatives after developing hypertriglyceridemia. Pancreatitis occurred in 1.2% of patients (n = 47/3,922) and was more frequent in those with hypertriglyceridemia (3.2%, 27/851; vs. 0.7%, 20/3,071; P < 0.001). After adjustment for potential confounding variables, each 100 mg/dl increase in triglyceride levels was associated with an 11% increase in risk of pancreatitis. Propofol dose was not associated with pancreatitis development. Conclusions Acute pancreatitis is uncommon in patients receiving propofol infusion, and it occurs over a wide range of triglyceride levels, indicating a multifactorial pathophysiology. Hypertriglyceridemia frequently prompts the use of alternative sedatives. Further study is needed to determine how to best monitor and treat hypertriglyceridemia in critically ill patients receiving propofol infusion.