Anesthesiology, Q2 2025 edition

This preclinical study identified SBI-810, a beta-arrestin-biased positive allosteric modulator of NTSR1, as an analgesic in postoperative, inflammatory, and neuropathic pain models. Its effects required NTSR1 and beta-arrestin-2 and involved suppression of NMDA/ERK signaling, reduced Nav1.7 surface expression, and decreased neuronal firing. Behavioral testing suggested less reward, constipation, and withdrawal liability than conventional opioids.

Impact: SBI-810 introduces a mechanistically distinct non-opioid analgesic strategy with activity across multiple pain phenotypes and a potentially improved behavioral safety profile.

Clinical Implications: The findings justify pharmacokinetic, pharmacodynamic, toxicology, and early-phase human studies, but they do not establish clinical efficacy or safety. If translated successfully, the approach could expand multimodal analgesia and reduce opioid exposure.

This randomized crossover study of 92 healthy adults used 7T fMRI and painful stimulation to compare commonly used sedatives. Propofol most strongly impaired next-day recollection and reduced hippocampal and amygdala encoding activity, dexmedetomidine relatively preserved memory, and fentanyl produced a distinct pattern of somatosensory and limbic activation.

Impact: The study supplied unusually high-resolution mechanistic evidence for matching sedative choice to desired amnesia, memory preservation, and analgesia.

Clinical Implications: Sedative selection may eventually be individualized according to the desired cognitive and analgesic profile, although translation to older, medically complex, or surgical populations remains uncertain.

Using TRAP2 labeling, electrophysiology, and chemogenetics in mice, this study identified a GABAergic central amygdala population activated by general anesthesia that increased nociceptive thresholds in normal and subacute nerve-injury states. Antinociception was weaker in chronic injury, which was associated with hyperexcitability of Fos-negative neurons and downregulation of KCC2.

Impact: The study linked anesthesia-induced analgesia to a defined amygdala circuit and provided a plausible mechanism for the loss of anesthetic antinociception during pain chronification.

Clinical Implications: The findings support future studies of KCC2-directed or circuit-informed strategies for persistent postsurgical pain, but the relevance of the mouse circuit to human perioperative pain remains to be established.

Using multimodal circuit-level approaches, this preclinical study showed that orexinergic inputs to the nucleus accumbens are activated during emergence from isoflurane anesthesia. Optogenetic or pharmacologic activation shortened emergence, reduced burst suppression, and restored nucleus accumbens–frontal cortex communication through OX1R signaling in D1 receptor-positive neurons.

Impact: The study defined a specific arousal circuit and receptor mechanism, creating a mechanistic framework for actively modulating emergence rather than merely waiting for anesthetic elimination.

Clinical Implications: Orexinergic or OX1R-directed agents may eventually be studied as emergence-modulating therapies, but cardiovascular, neurobehavioral, and emergence-agitation risks must be evaluated in humans.

In 136 patients with chronic kidney disease undergoing cardiac surgery with cardiopulmonary bypass, perioperative inhaled nitric oxide reduced 7-day acute kidney injury from 39.7% to 23.5%. The intervention also improved 6-month GFR without major signals for methemoglobinemia, nitrogen dioxide toxicity, bleeding, or transfusion.

Impact: The trial connected a biologically plausible perioperative intervention with both short-term renal protection and a longer-term functional outcome in a high-risk surgical population.

Clinical Implications: Inhaled nitric oxide may be considered for selected chronic kidney disease patients undergoing cardiopulmonary bypass where delivery and monitoring are available. Confirmatory multicenter studies should assess generalizability, cost, and patient-centered outcomes.

This translational study combined mechanistic, preclinical, and phase II clinical data on HIF1A stabilization during SARS-CoV-2-associated lung injury. In a multicenter randomized trial of 448 patients, vadadustat induced HIF target genes and produced a modest overall reduction in severe lung injury at day 14, with a stronger signal in patients requiring baseline FiO2 of at least 80%.

Impact: The study connected a molecular target with randomized human evidence and illustrated how biologically enriched subgroups may be identified for targeted treatment of hypoxic lung injury.

Clinical Implications: Vadadustat should not yet be used routinely for SARS-CoV-2-associated lung injury. The findings justify confirmatory trials enriched for patients with severe baseline hypoxemia and careful assessment of HIF-pathway safety.

This 11-center randomized noninferiority trial included 389 patients undergoing thoracoscopic anatomical lung resection. Single-shot intercostal nerve block was noninferior to thoracic epidural analgesia for pain over postoperative days 0 to 2, while reducing opioid use, improving recovery quality and mobilization, and shortening hospital stay. Continuous paravertebral block was inferior for pain despite opioid-sparing effects.

Impact: The trial provided multicenter evidence that a simpler and less invasive technique can replace thoracic epidural analgesia for many thoracoscopic lung surgery patients while improving recovery-related outcomes.

Clinical Implications: Single-shot intercostal nerve block should be considered within enhanced-recovery pathways for appropriate thoracoscopic lung surgery patients. Local anesthetic dosing, duration of analgesia, and patient selection remain important.

The TRANSFUSE model was developed and externally validated in 816,618 surgical cases using 24 preoperative variables. It achieved an AUC of 0.93 and a negative predictive value of 99.7%, outperforming an established clinical score and supporting targeted crossmatching and blood conservation.

Impact: Its scale, external validation, and direct connection to EHR workflow made it one of the quarter's strongest methodological contributions to perioperative resource stewardship.

Clinical Implications: Integration into preoperative systems could reduce unnecessary crossmatching and prioritize conservation strategies for high-risk patients, but prospective implementation, local recalibration, and safety monitoring are required.

In a single-center randomized trial of 122 patients with severe aortic stenosis undergoing TAVR, cipepofol produced a smaller mean arterial pressure deficit during the first 15 minutes after induction than propofol. Post-induction hypotension occurred less often and norepinephrine requirements were lower with cipepofol at comparable anesthetic depth.

Impact: The trial provided directly actionable randomized evidence for induction-agent selection in a population where hypotension can cause substantial myocardial and cerebral risk.

Clinical Implications: Cipepofol may be considered as an alternative to propofol for selected patients with severe aortic stenosis or undergoing TAVR, pending multicenter confirmation of clinical outcomes, cost, and generalizability.

In a single-center randomized trial of 136 frail elderly patients undergoing hip surgery, remimazolam-based total intravenous anesthesia reduced postoperative delirium from 17.6% to 4.4% compared with propofol. Remimazolam also reduced induction hypotension, vasopressor requirements, and EEG burst-suppression duration.

Impact: The trial identified anesthetic choice as a potentially modifiable determinant of delirium and linked a patient-centered outcome to hemodynamic and EEG mechanisms.

Clinical Implications: Remimazolam may be considered for selected frail older adults at high risk of delirium or induction hypotension. Broader multicenter replication, standardized delirium assessment, cost evaluation, and longer-term cognitive follow-up are needed.