Daily Anesthesiology Research Analysis

IMPORTANCE: Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain. OBJECTIVE: To investigate whether precision immunotherapy guided by the presence of macrophage activation-like syndrome or sepsis-induced immunoparalysis improves organ dysfunction by day 9. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted in 6 countries. Patients with sepsis, defined by Sepsis-3, were included if they had community-acquired or hospital-acquired pneumonia or ventilator-associated pneumonia or bacteremia and sepsis and had displayed either macrophage activation-like syndrome (blood ferritin >4420 ng/mL) or sepsis-induced immunoparalysis (blood ferritin ≤4420 ng/mL and <5000 human leukocyte antigen DR receptors on CD45/CD14 monocytes). The first patient was enrolled August 5, 2021, and the last follow-up, April 29, 2024. INTERVENTIONS: Eligible patients were randomized to receive standard care and precision immunotherapy or standard care and placebo. Those in the precision immunotherapy group with macrophage activation-like syndrome received anakinra intravenously (IV) and placebo subcutaneously, and those with sepsis-induced immunoparalysis received subcutaneous recombinant human interferon gamma and IV placebo. Those in the placebo group received both IV and subcutaneous placebo. Treatment was administered for up to 15 days. MAIN OUTCOMES AND MEASURES: The primary end point was a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9. The SOFA score evaluates 6 organ systems, ranging from 0, no dysfunction, to 4, failure, and the total score ranges from 0, normal, to 24, most severe form of multiorgan failure. Key secondary outcomes included 28-day mortality. RESULTS: Of 672 patients assessed for eligibility, 281 were randomized and 276 were included in the primary analysis population (mean [SD] age, 70 [13] years; 93 females [33.7%]; median baseline SOFA score, 9 [IQR, 7-11]). The SOFA decrease end point was attained by 46 of 131 patients (35.1%) in the precision immunotherapy group and by 26 of 145 patients (17.9%) in the placebo group (difference, 17.2% [95% CI, 6.8% to 27.2%]; P = .002). Mortality at 28 days was not statistically significantly different between groups. A total of 1069 serious treatment-emergent adverse events (88.8%) were reported; increased incidence of anemia was noted in the anakinra group; and hemorrhage in the recombinant human interferon gamma group. CONCLUSIONS AND RELEVANCE: Among patients with sepsis, precision immunotherapy targeting macrophage activation-like syndrome and sepsis-induced immunoparalysis improved organ dysfunction by day 9 compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04990232.

BACKGROUND: Opium consumption was classified as "carcinogenic to humans" by the International Agency for Research on Cancer (IARC). We investigated whether use of pharmaceutical opioids, derived from or synthesized to mimic opium, is associated with cancer risk using separate observational and genetic analyses. METHODS: Observational analysis included 472,955 participants in the UK Biobank prospective cohort (2006-2022). Genetic analysis included 2-sample Mendelian Randomization (MR) analyses using data from 14 independent genome-wide-association-studies (N = 9931-357,292). Adjusted hazard ratios (a-HR) or odds ratios (ORs) associated with regular opioid use were assessed for six established opium-related cancers (lung, pancreatic, bladder, esophageal, oropharyngeal, and laryngeal) and seven non-opium-related cancers (prostate, breast, colon, endometrial, kidney, ovarian, and brain). FINDINGS: In UK Biobank, regular opioid use was associated with increased risk of opium-related cancers among ever-smoking [a-HR = 1.33 (95% CI = 1.22-1.43)] and never-smoking participants [a-HR = 1.32 (1.10-1.59)], but not non-opium-related cancers [a-HR = 0.96 (0.91-1.02)]. Risk increased with opioid strength [a-HR = 1.30 (1.20-1.40) for weak opioids; a-HR = 1.86 (1.43-2.40) for strong opioids, p-trend < 0.0001] and duration of action [a-HR = 1.32 (1.22-1.42) for short-acting; a-HR = 1.65 (1.24-2.18) for long-acting opioids, p-trend < 0.0001]. Both observational and genetic analyses showed increased risks for most opium-related cancers, including lung [a-HR = 1.39 (1.27-1.53); MR-Odds Ratio (OR) = 1.17 (1.07-1.29)], pancreas [a-HR = 1.24 (1.01-1.52); MR-OR = 1.34 (1.11-1.62)], bladder [a-HR = 1.26 (1.02-1.56); MR-OR = 1.15 (1.03-1.29)], esophagus [a-HR = 1.18 (0.94-1.49); MR-OR = 1.24 (1.01-1.52)], and larynx [a-HR = 1.37 (0.85-2.20); MR-OR = 1.29 (1.04-1.61)]. Except for an inverse association with prostate cancer [a-HR = 0.83 (0.76-0.91); MR-OR = 0.99 (0.92-1.05)], associations were null for non-opium-related cancers. INTERPRETATION: Regular use of pharmaceutical opioids was associated with elevated risk for cancers caused by opium, but not other cancers. FUNDING: US National Institutes of Health, French National Cancer Institute.

BACKGROUND: Postoperative delirium (POD) is a common complication following surgery, associated with extended hospital stays, cognitive decline, and increased mortality, yet effective pharmacological prevention remains elusive. Processed electroencephalography (p-EEG) guided general anesthesia is designed to reduce excessive neural suppression linked to POD development. However, conflicting evidence exists due to variations in devices and regional practices. METHODS: We systematically searched Medline, Embase, and the Cochrane Central Register of Controlled Trials from database inception to January 2025, randomized controlled trial (RCT) comparing p-EEG guided general anesthesia with standard care in adult surgical patients. Statistical analysis employed random-effects models calculated risk ratios (RR) and mean differences (MD) with 95% confidence intervals (CIs). The primary outcome was POD incidence. RESULTS: Twelve RCTs involving 4523 surgical patients were included. p-EEG guided general anesthesia reduced the incidence of POD compared with control group (RR 0.81, 95% CI 0.69-0.95, I2 = 46%), with pronounced benefits in elderly patients (≥60 years, RR 0.83, 95% CI 0.69-0.99) and non-cardiac surgeries (RR 0.78, 95% CI 0.64-0.95). Regional heterogeneity was significant: European and East Asian/Australasian trials demonstrated efficacy, whereas North American studies showed no benefit. In addition, p-EEG guided general anesthesia reduced postoperative cognitive dysfunction (RR 0.66, 95% CI 0.49-0.89), shortened hospital stays (MD -0.90 days, 95% CI -1.60 to -0.20), and lowered vasopressor requirements (RR 0.73, 95% CI 0.64-0.83). Mortality did not differ between groups. CONCLUSION: p-EEG guided general anesthesia demonstrates reduces POD incidence and associated complications, especially in elderly patients and non-cardiac surgeries. However, the effectiveness may vary due to differences in practice, anesthetic protocols, and cultural factors. Our findings support the implementation of tailored neuromonitoring in high-risk populations.