Anesthesiology, September 2025 edition

Integrated human ICU observations and a longitudinal rat sepsis model showed that early HDL-C decline and reduced cardiomyocyte membrane cholesterol were associated with blunted dobutamine responsiveness. HDL or liposomal cholesterol infusion restored membrane cholesterol, adrenergic signaling, and inotropic responsiveness in the animal model, identifying a potentially reversible mechanism of catecholamine-refractory septic shock.

Impact: The study links a measurable lipid abnormality to impaired myocardial catecholamine responsiveness and demonstrates functional reversal with cholesterol replacement, creating a clear translational pathway toward biomarker-guided therapy.

Clinical Implications: HDL-C and related lipoprotein measurements may help phenotype catecholamine-refractory septic shock. Cholesterol repletion should be evaluated in carefully designed clinical trials before clinical adoption, with particular attention to safety, formulation, dosing, and thromboinflammatory effects.

Multi-omics and functional preclinical studies identified selective activation of RIPK1 in type II alveolar epithelial cells during sepsis. RIPK1 activated JAK1-STAT3 signaling and increased CXCL1, promoting neutrophil recruitment and lung injury. Genetic or pharmacologic RIPK1 inhibition reduced inflammation, preserved the epithelial barrier, and improved survival in septic mice.

Impact: The paper defines a cell-specific inflammatory amplifier with an experimentally validated druggable pathway and an in vivo survival signal, providing a strong foundation for translational development in sepsis-associated lung injury.

Clinical Implications: Selective RIPK1 inhibition merits further pharmacology, toxicology, and biomarker studies before early-phase human trials. CXCL1 and JAK1-STAT3 activity could potentially support response enrichment, although the current evidence remains preclinical.

A translational study combining a mouse model, single-cell brain transcriptomics, and human biomarker data found that impaired Apelin-APJ signaling contributed to muscle atrophy, neuroinflammation, and behavioral deficits resembling post-intensive care syndrome. Muscle-specific Apelin overexpression reduced systemic IL-6 and multisystem abnormalities, while ICU survivors with weakness had lower plasma Apelin and higher IL-6.

Impact: The paper identifies a biologically plausible and potentially modifiable pathway connecting muscle, immune, and neuroinflammatory processes, supported by cross-species evidence and human biomarker correlations.

Clinical Implications: Plasma Apelin and IL-6 may eventually support risk stratification and post-ICU surveillance, but their predictive performance requires validation in larger prospective cohorts. Apelin agonism or tissue-targeted modulation remains investigational and should not yet be used clinically.

This translational study combined epidemiologic data with first-in-human testing of a thoracic epidural electrical stimulation system designed for autonomic blood-pressure control after spinal cord injury. In 14 participants, targeted stimulation produced immediate pressor responses, reduced chronic hypotensive complications, decreased reliance on conservative therapies, and improved quality of life and activities of daily living.

Impact: The study provides early human evidence for a targeted implantable therapy addressing refractory autonomic hypotension, with immediate physiologic effects and patient-centered functional benefits.

Clinical Implications: Thoracic epidural stimulation may become an option for selected patients with refractory hypotension after spinal cord injury, but broader adoption requires larger controlled studies, device durability data, procedural training, and multidisciplinary rehabilitation pathways.

In a multicenter, double-blind randomized trial of 6,982 patients aged 65 years or older, BIS-guided anesthetic titration targeting 40-60 did not reduce one-year mortality or 30-day moderate-to-severe complications compared with routine management. Achieved BIS values were nearly identical between groups, indicating limited separation in hypnotic depth.

Impact: This large and rigorous trial directly addresses whether routine BIS-guided titration improves hard clinical outcomes in older noncardiac surgical patients, with immediate implications for monitoring policy and resource allocation.

Clinical Implications: Routine BIS use solely to reduce mortality or major complications is not supported by this trial. BIS may remain appropriate for selected situations such as high-risk total intravenous anesthesia, awareness-risk management, or when clinical assessment of hypnotic depth is unreliable.