Nates, Joseph L.

Abstract Introduction Sedation is routinely administered to facilitate comfort and tolerance of life support for critically ill adults dependent on invasive mechanical ventilation. Isoflurane, a widely used anesthetic during surgery, has properties that may also benefit ICU patients requiring continuous sedation. However, efficacy as a sedative and safety in this population is not well established. Methods We conducted two identically designed multicenter randomized trials, INSPIRE ICU1 and INSPIRE ICU2, at hospitals across the US. Ventilator-dependent adults were randomly assigned in a 1.5:1 ratio to receive either inhaled isoflurane or intravenous propofol as the first-line sedative for up to 48 ± 6 hours, targeting a sedation depth between Richmond agitation-sedation scale (RASS) -1 (drowsy) to -4 (responsive only to physical stimuli). Isoflurane was administered via an anesthetic conserving device (Sedaconda ACD-S). In both arms, opioids were permitted at the lowest dose required to achieve freedom from pain. The primary outcome was the percentage of time at target sedation level, assessed as a noninferiority outcome with pre-specified margin of 15%. Secondary outcomes included opioid exposure, wake-up time after end of treatment, time to extubation, and proportion of time with spontaneous breathing effort. Results A total of 470 combined participants were included in the two trials. In each trial, 142 patients were randomly assigned to isoflurane and 93 to propofol. In INSPIRE ICU1, percentage of time within target sedation depth was 77.1 [53.2, 89.9] % with isoflurane and 80.9 [58.2, 96.4] % with propofol (difference -1.5 [-8.9, >99] %; p < 0.01 for noninferiority). In INSPIRE ICU2, percentage of time within target sedation depth was 72.6 [66.4, 78.9] % with isoflurane and 74.5 [67.5, 81.5] % with propofol (difference -1.9 [-9.4, >99] %; p < 0.01 for noninferiority). In both trials, patients assigned to isoflurane received significantly less opioid, measured as fentanyl equivalents, during the treatment period. In INSPIRE ICU2, participants receiving isoflurane were significantly likelier to exhibit spontaneous breathing efforts, but this finding was not replicated in INSPIRE ICU1. There were no significant differences in time to wake-up or time to extubation between groups in either trial. No episodes of malignant hyperthermia or propofol infusion syndrome were reported. Adverse events were comparable in type and frequency between groups. Conclusions In two US multicenter trials, isoflurane was noninferior to propofol for maintaining target sedation depth in adults undergoing invasive ventilation, and was associated with significantly lower opioid exposure. (NCT05327296, NCT05312385) This abstract is funded by: Sedana Medical

Abstract Rationale: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. They are also associated with life-threatening immune-related adverse events (irAEs), including the rare, poorly understood, and potentially fatal triad of myasthenia gravis, myocarditis, and myositis(triple M syndrome). We aimed to describe the management, intensive care unit (ICU)utilization, and outcomes of patients with irAEs with a specific focus on triple M syndrome. Methods: We conducted a retrospective chart review of patients with irAEs admitted to three quaternary care hospitals between December 2018 and 2023. We aimed to collect data on demographics, cancer type, treatment, ICU resource utilization, and outcomes including mortality. Results: Over this 5-year period, 140 patients were admitted for irAEs. Forty-nine percent were male, median age was 73 (IQR 64-80) years, 7% were of African American or Asian descent, and 32%required ICU admission. Median ICU and hospital length of stay (LOS) were 1.5 (IQR 0.7-2.9)and 7.2 (IQR 4.1-13.4) days, respectively. Among ICU patients, 14/140 (10%) had myositis,22/140 (16%) myocarditis, and 9/140 (6.4%) myasthenia gravis. Triple-M syndrome was diagnosed in 7/140 (5%) patients, including 3 with metastatic melanoma, 2 with genitourinary malignancies, 1 with metastatic lung and 1 with colon cancer. Four had received pembrolizumab and 3 nivolumab. Median ICU and hospital LOS were 3 (IQR 1-6) and 10 (IQR 8-21) days in this group. Three patients required mechanical ventilation, one required tracheostomy, and one required vasopressor support. Triple-M management included corticosteroids, IVIG, pyridostigmine, mycophenolate mofetil, and rituximab. Patients with triple-M syndrome were significantly older than other patients with ICI toxicity (P <0.009) and had higher mortality (57%vs 25%, p = 0.07). Patients discharged from the ICU had a median survival of 67 (IQR 26-201)days. Conclusions: Patients with irAEs frequently require ICU level of support with significant morbidity and mortality, especially with triple M syndrome. Clinicians should always consider the possibility of triple-M syndrome in patients with multiple irAEs as symptoms can be subtle and easily overlooked. Corticosteroids remain the primary treatment of irAEs and can be combined with other immunosuppressive agents such as infliximab, anti-thymocyte globulin, or pyridostigmine. Unfortunately, mortality due to triple-M syndrome remains high underscoring the importance of early recognition and prompt multidisciplinary management of these toxicities.