Gajic, Ognjen

This systematic review examined multicenter randomized controlled trials (RCTs) conducted during the Sepsis-3 era that evaluated pharmaceutical and mechanistic interventions in adult patients with sepsis or septic shock, with a focus on identifying interventions that demonstrated mortality benefit. A comprehensive search was performed across Ovid MEDLINE, Embase, Cochrane Central, ClinicalTrials.gov, WHO ICTRP, and Web of Science for trials published since 2016. Studies were included if they enrolled adult patients with sepsis or septic shock using Sepsis-3 criteria and reported mortality as either a primary or secondary outcome. Data were extracted by two independent reviewers and included trial design characteristics, funding source, randomization methods, and reported outcomes. Among the 31 eligible multicenter RCTs enrolling over 7,000 patients across 550 centers, only four trials showed a mortality benefit. These included three studies from China—two evaluating herbal anti-inflammatory compounds and one evaluating aminophylline—and one European study assessing corticosteroid therapy in vasopressor-dependent septic shock. The remaining 27 trials reported no mortality benefit, and substantial heterogeneity was observed in patient populations, sepsis definitions, and outcome reporting. Median mortality in control arms was 31.6% (IQR 24.1–45.5), and 35.4% (IQR 25.7–49.6) in intervention arms. These findings suggest that despite extensive efforts, most interventions have not reduced mortality in multicenter sepsis trials. Future research should focus on optimizing trial design, refining patient selection, and incorporating patient-centered outcomes beyond mortality.

OBJECTIVE: To identify distinct phenotypes of acute respiratory distress syndrome (ARDS) developing after hematopoietic cell transplantation (HCT), using routinely available clinical data at ICU admission. DESIGN: Multicenter retrospective cohort study using latent class analysis. SETTING: ICUs across three Mayo Clinic campuses (Minnesota, Florida, and Arizona). PATIENTS: A total of 166 adult patients who developed ARDS within 120 days following HCT (96 allogeneic, 70 autologous). INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Model selection was based on multiple metrics including Bayesian information criteria, entropy, and Vuong-Lo-Mendell-Rubin Likelihood Ratio testing. A two-class model optimally described the cohort. Class 1 (n = 81) was characterized by worse hypoxemia (P/F ratio 157 vs. 210, p = 0.002), higher Pco 2 (41 vs. 36 mm Hg, p < 0.001), and higher bilirubin (1.4 vs. 0.9 mg/dL, p < 0.001) compared with class 2 (n = 85). Both classes included a mix of transplant types, transcending a simple autologous/allogeneic dichotomy, although class 1 had more allogeneic recipients (70.4% vs. 45.9%, p = 0.001). Although time-from-transplant was not a class-defining variable, class 1 occurred later after transplant (30.0 vs. 11.9 d, p < 0.001) with higher frequency of idiopathic pneumonia syndrome (14.8% vs. 2.4%, p = 0.004). Class 2 had more frequent neutropenia (leukocytes 0.4 vs. 5.9 × 109, p < 0.001) and higher frequency of peri-engraftment respiratory distress syndrome (29.4% vs. 9.9%, p = 0.005). Outcomes were significantly worse for class 1 (90-d mortality: 72.8% vs. 48.2%, p = 0.001). An exploratory parsimonious model had good classification accuracy (0.90) using just six variables: leukocyte count, platelet count, bilirubin, Pco 2, body mass index, and temperature. CONCLUSIONS: ARDS after HCT comprises two distinct phenotypes with distinct clinical characteristics and outcomes. These phenotypes align with recognized post-HCT lung injury syndromes and may reflect different underlying biological processes. This framework provides a foundation for investigating targeted therapeutic approaches.

IMPORTANCE: Propofol is a first-line sedative for adults receiving invasive mechanical ventilation (IMV). However, it can contribute to hemodynamic instability, especially during intubation. The magnitude, timing, risk factors, and variability of sedation-associated mean arterial pressure (MAP) changes remain poorly characterized in ICU settings. OBJECTIVES: To quantify MAP changes following propofol sedation, identify risk factors for hemodynamic instability, and characterize associated interventions. DESIGN: Retrospective cohort study. The primary outcome was MAP change within 2 hours following sedation. Secondary outcomes included vasopressor use and hypotension (MAP ≤ 60 mm Hg). Mixed-effects modeling was used to account for individual patient differences. SETTING AND PARTICIPANTS: Adults (≥ 18 yrs old) who required IMV and received greater than or equal to 6 consecutive hours of propofol infusion, between May 5th, 2018, and July 31st, 2024, in 11 ICUs across the Mayo Clinic, spanning 5 hospitals in 4 states. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in MAP within 2 hours following the initiation of propofol-based sedation. RESULTS: Across 16,418 patients, 25.2% were on vasopressors before sedation initiation. Among the remaining 12,281 patients, 40.3% required vasopressors and 7.7% experienced hypotension within 2 hours of sedation. Propofol-based sedation was associated with a MAP reduction within the first 30 minutes (–6.58 mm Hg; 95% CI, –6.85 to –6.32; p < 0.001). There was substantial interpatient variability in both baseline MAP, and MAP decline after sedation (9.5 and 40.9% between-patient differences, respectively). Higher Sequential Organ Failure Assessment (SOFA) scores (–0.31 mm Hg/point), older age (–0.04 mm Hg/yr), and male sex (–0.47 mm Hg) were associated with lower MAP. Patients with higher illness severity experienced progressively greater MAP decline over time (–0.20 mm Hg/hr/SOFA point; p < 0.001). CONCLUSIONS AND RELEVANCE: Propofol-based sedation was associated with clinically significant hemodynamic effects requiring intervention in the early post-intubation period. The marked interpatient variability in hemodynamic responses highlights the importance of personalized management approaches, including risk stratification based on age, sex, and illness severity.

Acute respiratory distress syndrome (ARDS) is a common and highly heterogeneous condition in the critically ill. The association between hyper- and hypo-inflammatory subphenotypes and clinical outcomes has generated significant interest in precise ARDS management. The value of identifying biomarkers to guide treatment and enrollment in future ARDS trials is undisputable. We describe multiple factors complicating the search for subphenotypes and their treatable traits. The observed heterogeneity seen in the clinical course of ARDS is dynamic and influenced by factors beyond lung pathophysiology, including variations in the delivery of best critical care practices, patient comorbidities, and functional status, and patient or family preferences. Current subphenotype definitions lack strong biological plausibility and without clear evidence of benefit from targeted treatments, their use in clinical practice is currently unwarranted.

Abstract Background Doxycycline is a frequently used alternative treatment for community-acquired pneumonia (CAP) in hospitalized patients; however, the evidence base is limited. We aimed to compare outcomes in CAP patients treated with doxycycline or azithromycin in combination with beta-lactams. Methods We evaluated patients with CAP admitted to Mayo Clinic hospitals from May 2018 to September 2022 and treated with either azithromycin or doxycycline in combination with a beta-lactam. Patients who received both antibiotics or were on either antibiotic as chronic therapy prior to admission were excluded. The primary outcome was mortality. Patients were 1-to-1 matched according to the presence of congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, human immunodeficiency virus infection, recent immunosuppressant use, and pneumonia severity index class. Results Among 8492 patients (5810 for azithromycin, 2682 for doxycycline), 2671 doxycycline-treated patients were matched with azithromycin-treated patients. In-hospital mortality was significantly lower in the azithromycin group than in the doxycycline group (odds ratio, 0.71; 95% confidence interval [CI], .56–.9), as was 90-day mortality (hazard ratio, 0.83; 95% CI, .73–.95). Patients on azithromycin also had significantly more hospital-free days (HFDs) than those on doxycycline (estimate, 1.37; 95% CI, .99–1.74). Conclusions Among hospitalized patients with CAP, azithromycin was associated with lower mortality and more HFDs compared with doxycycline in combination with beta-lactams. Randomized, controlled trials are needed to assess the effectiveness of each regimen and to compare their potential side effects.

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 Rationale: Propofol can increase the risk of hypertriglyceridemia and subsequent pancreatitis in critically ill patients. It is unclear whether modifying or continuing sedation regimens in patients experiencing hypertriglyceridemia while on propofol infusion influences the development of adverse events such as acute pancreatitis. This study compared the clinical outcomes of patients receiving invasive mechanical ventilation (IMV) who had their propofol regimen modified versus continued following the detection of hypertriglyceridemia. Methods: A targeted trial emulation was conducted using retrospective data from 5 Mayo Clinic hospitals between 05/05/2018 and 06/30/2023. Inclusion criteria included: 1) receiving IMV and continuous propofol infusion for &gt;24 hours, 2) experiencing triglyceride level &gt;400 mg/dL while on propofol, and 3) still requiring IMV at 24-hours after hypertriglyceridemia onset. Patients were then categorized based on whether they had their propofol regimen modified (i.e., dose reduction by ≥50% or any reduction with alternative sedatives started) versus continued (no reduction or &lt;50% reduction without alternative sedative initiation). Outcomes included 30-day ventilator-free days, successful extubation, acute pancreatitis (determined by chart review, in-duplicate), ICU and hospital length of stay, 30- and 90-days alive and at home, as well as all-cause mortality. Analyses were conducted using stabilized inverse probability of treatment weights with adjustments for covariates selected a priori. Sensitivity analyses, where only benzodiazepines or benzodiazepines and ketamine were considered to be eligible alternative sedatives, were done. Results: During the study period, 728 patients were included, of whom 422 had their propofol regimen modified (Image). The two groups had similar demographics, comorbidities, and illness severity. We identified 14 cases of acute pancreatitis possibly attributable to propofol, with 9 cases in the modified and 5 cases in the continued regimen group (2.1% versus 1.6%; P=0.63). Following adjustment for covariates, there were no significant differences in any outcomes of interest. After censoring for mortality, there was no significant difference in the 30-day cumulative incidence of successful extubation when comparing those with their regimen modified versus continued (Hazard ratio [HR] 0.95; 95% confidence intervals [CI] 0.77 to 1.18; P=0.70). There was also no significant difference in the 90-day survival rate between the two groups (HR 0.89; 95% CI 0.71 to 1.11; P=0.34). These findings remained consistent upon sensitivity analyses. Conclusion: There were no differences in outcomes among patients who had their propofol regimens modified versus continued following the detection of hypertriglyceridemia. Further prospective investigations are needed to identify the optimal strategy for managing sedative regimens in this patient population.

Abstract RATIONALE: Critical illness has been shown to disrupt gastrointestinal function, and patients admitted to the intensive care unit (ICU) often experience constipation, aspiration, ileus, and small bowel obstruction. Glucagon-like peptide 1 receptor agonists (GLP-1RA) have become increasingly prevalent in the treatment of type 2 diabetes mellitus and obesity. Pharmacovigilance studies suggest that use of GLP-1RAs may be associated with increased risk of clinically significant gastrointestinal effects. In this study, we assessed whether pre-ICU use of GLP-1RA for either diabetes or obesity was associated with adverse gastrointestinal outcomes. METHODS: This was a retrospective matched cohort study of patients with underlying obesity or diabetes admitted to a Mayo Clinic Medical ICU from 9/1/2018-12/31/2023. Patients who started GLP-1RA within &lt;30 days or stopped them &gt;30 days before admission were excluded. Out of 33,104 eligible patients, we identified 1,549 GLP-1RA exposed patients and matched these to three controls each based on age (±10), sex, body mass index (±5), presence of obesity, diabetes and complications, comorbidities associated with decreased motility, smoking status, alcoholism, abdominal surgeries, Apache score (±20), and Charlson comorbidity index (CCI). Development of gastrointestinal dysfunction (determined by ICD codes) and hospital- and ICU- free days were the outcomes. Conditional logistic regression and mixed linear models were used for the analyses. RESULTS: The final, matched cohort included 6,196 patients. Most patients were male (56.3%), the median age was 66 years (IQR 58-74), 69.9% had a diagnosis of obesity, and 97.5% had a diagnosis of diabetes. Of the patients, 22.9% had a history of abdominal surgery during their lifetime and 30% had surgery within 30 days of admission. When comparing GLP-1RA exposed and non-exposed patients, significant differences were noted in use of motility altering medications (p=0.001, OR 6.75, CI 2.11-21.56), BMI (p&lt;0.001, estimate=0.6, CI 0.47-0.72), and APACHE score (p&lt;0.001, estimate=14.75, CI14.45 – 15.06). Univariable analysis showed that rates of constipation, impaction, and nausea/vomiting were significantly higher among GLP-1RA exposed patients admitted to the ICU, while rates of obstruction were significantly lower (Table 1). After adjusting for APACHE score, only nausea/vomiting remained statistically significant. After controlling for APACHE, GLP-1RA use was associated with an increased number of hospital free days (Table 1). CONCLUSIONS: Our research suggests that in the medical ICU population, GLP-1RA use is unlikely to be associated with adverse GI outcomes. Furthermore, GLP-1RA may be associated with overall hospital length of stay but not ICU length of stay.

Abstract RATIONALE: Clinical practice guidelines recommend that mechanically ventilated patients (MVPs) receiving sedative therapy achieve a target goal of ‘awake and calm’ when medically possible. However, ICU sedation practices rely on clinicians’ administration of medications based on observations of patients’ arousal/motor activity that are not consistently based on symptom assessments nor consider patients’ preferences. We hypothesized that MVPs would safely self-manage sedative therapy (SMST) base on individual needs and perceived anxiety while experiencing less sedative exposure and delirium. METHODS: A two-group randomized clinical trial conducted in two Midwestern academic medical centers enrolled 161 MVPs willing and able to depress a medication delivery push-button device who remained on protocol for 7 days or until extubated, withdrew or died. Control group (CG) patients (n=81) received sedative medications administered by ICU nurses per unit protocols. Experimental SMST group patients (n=80) received a basal infusion of dexmedetomidine (0.2 mcg/kg/hr titrated per algorithm) + self-administered bolus doses (0.25 mcg/kg up to 3/hour). Primary outcomes were anxiety ratings using a 100-mm visual analog scale (VAS-A), sedation intensity score (aggregate summary of 9 intravenous sedative/opioid medications received range 0-36), and incidence of delirium using the CAM-ICU. Analyses were descriptive and parametric statistics and Generalized Estimating Equations. RESULTS: Patients were predominantly White (93%) females (55%), mean age 58.9+15.1 years receiving mechanical ventilation for respiratory failure (60%) with mean APACHE III of 84.5 + 32.5. Anxiety was highly variable over time wherein patients in both groups endorsed the full range from 0-100. VAS-A over time between groups was -0.06 (p=0.98) indicating that anxiety was 0.06 units lower for SMST patients versus CG. Median sedation intensity in SMST group 11.8 + 9.6, compared to CG 12.7 + 9.6 (p = 0.55) over 7 days. 10.2% of SMST patients had one or more incident delirium events compared to 8.5% of CG (p =.97). Hypotension was experienced equally between groups: 22 in SMST, 23 in CG (p = 1.0) as were device disruptions: 2 in SMST versus 3 in CG (p = 1.0). 82% of SMST were satisfied/very satisfied with ability to self-administer dexmedetomidine; 70% were satisfied/very satisfied with ability to control anxiety; 68% were satisfied/very satisfied with the level of relaxation experienced. CONCLUSIONS: Although there were no significant differences between groups on the primary outcomes, the experimental SMST intervention was safe with high patient-reported satisfaction. SMST may be a viable new paradigm for sedative therapy administration among select ICU patients.