Daily Anesthesiology Research Analysis

BACKGROUND: Orexin neuropeptides help regulate sleep/wake states, respiration, and pain. However, their potential role in regulating breathing, particularly in perioperative settings, is not well understood. TAK-925 (danavorexton), a novel orexin receptor 2-selective agonist, directly activates neurons associated with respiratory control in the brain and improves respiratory parameters in rodents undergoing fentanyl-induced sedation. This study assessed the safety and effect of danavorexton on ventilation in healthy men in an established remifentanil-induced respiratory depression model. METHODS: This single-center, double-blind, placebo-controlled, two-way crossover, phase 1 trial randomized (1:1) 13 healthy men to danavorexton (11 mg [low-dose], then 19 mg [high-dose]) or placebo, under remifentanil infusion, on two occasions separated by a 36-h or longer washout period. Remifentanil infusion was titrated under isohypercapnic conditions to achieve an approximately 30 to 40% decrease in minute ventilation (from approximately 20 to approximately 14 l/min) before danavorexton/placebo administration. Assessments included safety, ventilation measurements, sedation, and pain tolerance. RESULTS: A total of four (30.8%) danavorexton-treated participants and one (8.3%) placebo-treated participant experienced treatment-emergent adverse events (all mild in severity). Insomnia, lasting 1 day, occurred in one participant, and was considered related to danavorexton. Compared with placebo, low- and high-dose danavorexton significantly increased ventilation variables (observed mean [95% CI] change, sensitivity analysis model-based P values) including minute volume (8.2 [95% CI, 5.0 to 11.4] and 13.0 [95% CI, 9.4 to 16.5] l/min), tidal volume (312 [95% CI, 180 to 443] and 483 [95% CI, 309 to 657] ml), and respiratory rate (3.8 [95% CI, 1.9 to 5.7] and 5.2 [95% CI, 2.7 to 7.7] breaths/min; all P < 0.001). High-dose danavorexton significantly decreased sedation on a visual analog scale (-29.7 [95% CI, -54.1 to -5.3] mm; P < 0.001) and the Richmond Agitation Sedation Scale (0.4 [95% CI, 0.0 to 0.7]; P < 0.001) compared with placebo. Improvements in respiratory variables continued beyond completion of danavorexton infusion. No significant differences in pain tolerance were observed between danavorexton doses or between danavorexton and placebo (approximately 13% increase from baseline; low dose, P = 0.491; high dose, P = 0.140). CONCLUSIONS: Danavorexton has effects on respiration and wakefulness in an opioid-induced respiratory depression setting without reversing opioid analgesia.

BACKGROUND: Cardiogenic shock (CS) is a heterogeneous clinical syndrome, making it challenging to predict patient trajectory and response to treatment. This study aims to identify biological/molecular CS subphenotypes, evaluate their association with outcome, and explore their impact on heterogeneity of treatment effect (ShockCO-OP, NCT06376318). METHODS: We used unsupervised clustering to integrate plasma biomarker data from two prospective cohorts of CS patients: CardShock (N = 205 [2010-2012, NCT01374867]) and the French and European Outcome reGistry in Intensive Care Units (FROG-ICU) (N = 228 [2011-2013, NCT01367093]) to determine the optimal number of classes. Thereafter, a simplified classifier (Euclidean distances) was used to assign the identified CS subphenotypes in three completed randomized controlled trials (RCTs) (OptimaCC, N = 57 [2011-2016, NCT01367743]; DOREMI, N = 192 [2017-2020, NCT03207165]; and CULPRIT-SHOCK, N = 434 [2013-2017, NCT01927549]) and explore heterogeneity of treatment effect with respect to 28-day mortality (primary outcome). FINDINGS: Four biomarker-driven CS subphenotypes ('adaptive', 'non-inflammatory', 'cardiopathic', and 'inflammatory') were identified separately in the two cohorts. Patients in the inflammatory and cardiopathic subphenotypes had the highest 28-day mortality (p (log-rank test) = 0.0099 and 0.0055 in the CardShock and FROG-ICU cohorts, respectively). Subphenotype membership significantly improved risk stratification when added to traditional risk factors including the Society for Cardiovascular Angiography and Interventions (SCAI) shock stages (increase in Harrell's C-index by 4% ( INTERPRETATION: Subphenotypes with the highest concentration of biomarkers of endothelial dysfunction and inflammation (inflammatory) or myocardial injury/fibrosis (cardiopathic) were associated with mortality independently from the SCAI shock stages. FUNDING: Dr Sabri Soussi was awarded the Canadian Institutes of Health Research (CIHR) Doctoral Foreign Study Award (DFSA) and the Merit Awards Program (Department of Anesthesiology and Pain Medicine, University of Toronto, Canada) for the current study.

BACKGROUND: Effective pain recognition and treatment in perioperative environments reduce length of stay and decrease risk of delirium and chronic pain. The authors sought to develop and validate preliminary computer vision-based approaches for nociception detection in hospitalized patients. METHODS: This was a prospective observational cohort study using red-green-blue camera detection of perioperative patients. Adults (18 yr or older) admitted for surgical procedures to the San Francisco Veterans Affairs Medical Center (San Francisco, California) were included across two study phases: (1) the algorithm development phase and (2) the internal validation phase. Continuous recordings occurred perioperatively across any postoperative setting. The authors inputted facial images into convolutional neural networks using a pretrained backbone to classify (1) the Critical Care Pain Observation Tool (CPOT) and (2) the numeric rating scale. Outcomes were binary pain/no pain. We performed external validation for CPOT and numerical rating scale classification on data from the University of Northern British Columbia (Prince George, Canada)-McMaster University (Hamilton, Canada) and the Delaware Pain Database. Perturbation models were used for explainability. RESULTS: The study included 130 patients for development, 77 patients for the validation cohort, and 25 patients from University of Northern British Columbia-McMaster University and 229 patients from Delaware datasets for external validation. Model areas under the curve of the receiver operating characteristic for CPOT models were 0.71 (95% CI, 0.70 to 0.74) on the development cohort, 0.91 (95% CI, 0.90 to 0.92) on the San Francisco Veterans Affairs Medical Center validation cohort, 0.91 (95% CI, 0.89 to 0.93) on University of Northern British Columbia-McMaster University, and 0.80 (95% CI, 0.75 to 0.85) on Delaware. The numeric rating scale model had lower performance (area under the receiver operating characteristics curve, 0.58 [95% CI, 0.55 to 0.61]). Brier scores improved after calibration across multiple different techniques. Perturbation models for CPOT models revealed eyebrows, nose, lips, and forehead were most important for model prediction. CONCLUSIONS: Automated nociception detection using computer vision alone is feasible but requires additional testing and validation given the small datasets used. Future multicenter observational studies are required to better understand the potential for automated continuous assessments for nociception detection in hospitalized patients.