Anesthesiology - Papers

Using the MIA model and human samples, the authors show that B cell–derived IgM autoantibodies drive nociceptive sensitization in osteoarthritic joints, with complement C5a upregulation. Passive transfer of IgM from MIA mice or OA patients induced sensitization, and intra-articular C5aR blockade reduced it.

In a double-blind crossover phase 1 study in 13 healthy men under remifentanil-induced respiratory depression, danavorexton (orexin-2 agonist) significantly increased minute ventilation, tidal volume, and respiratory rate, and reduced sedation without altering pain tolerance. Effects persisted beyond infusion with only mild adverse events (one transient insomnia).

In a double-blind randomized trial of 38 older adults undergoing joint replacement, perioperative infusions of a young donor plasma protein fraction significantly modulated proteomic and single-cell immune signaling responses to surgical trauma. Key inflammatory pathways (JAK-STAT, NF-κB, MAPK) were attenuated with corresponding cellular signaling changes, providing first-in-human proof of anti-inflammatory immunomodulation by young plasma components.

Using rocuronium-conjugates and single-cell antibody sequencing, the authors identified oligoclonal, high-affinity anti-rocuronium antibodies that, when expressed as human IgE, activated human mast cells/basophils and caused severe anaphylaxis in FcεRI-humanized mice. Cocrystal structures mapped distinct epitopes involving the ammonium group, establishing mechanistic foundations and the first murine model of NMBA anaphylaxis.

This cryo-EM study resolves THIK1 in a closed state, identifies a central pore gate formed by TM4 tyrosines, and maps a volatile anesthetic binding site required for inhibition. Multimodal validation links structural gating to anesthetic action on microglial K2P channels.

In mouse models of neuropathic pain, dynamic microvascular movements within injured dorsal root ganglia trigger episodic spontaneous pain via Piezo2 mechanotransduction in sensory neurons. Angiogenesis amplifies this phenomenon, and anti-VEGF therapy or targeting Piezo2 suppresses spontaneous pain and clustered neuronal firing.

Using clinical data and mechanistic mouse experiments, the authors show that bortezomib-associated neuropathic pain manifests earlier in females via ICAM-1–driven perivascular monocyte/macrophage accumulation in the spinal cord and CCL1-mediated neuronal activation. This sex-specific pathway provides actionable targets for prevention or early intervention in female patients.

Using EEG and micro-endoscopic calcium imaging in mice, the authors show that isoflurane-induced burst suppression is dominated by synchronized cortical pyramidal neuron activity. Chemogenetic manipulation of parvalbumin interneurons bidirectionally modulated this synchrony, whereas SST/Vip interneurons and subcortical structures showed minimal correlation.

Using photoaffinity labeling, mass spectrometry, and molecular dynamics, the authors identify a resting-state binding pocket for propofol in the HCN1 voltage sensor (S3–S4). Mutagenesis within this pocket abrogates propofol’s voltage-dependent inhibition, revealing a conformation-specific site that explains HCN modulation and guides design of selective HCN modulators.

Unsupervised clustering of plasma biomarkers in two prospective cohorts identified four reproducible cardiogenic shock subphenotypes with distinct biology and mortality risk. Applying a simplified classifier to three completed RCTs improved risk discrimination beyond SCAI staging and suggested heterogeneity of treatment effect.

In a 92-participant single-blind randomized crossover study with 7T fMRI and concurrent painful stimulation, propofol significantly impaired next-day recollection (reduced d') and decreased hippocampus/amygdala activation for memory encoding while attenuating pain-related activation in insula and anterior cingulate. Dexmedetomidine preserved recollection and pain ratings, with limited hippocampal effects. Fentanyl altered memory and pain network activity in a distinct pattern.

In mice, dorsal striatal D1 receptor neurons decreased activity before sevoflurane-induced LOC and recovered after emergence. Optogenetic activation triggered recovery of consciousness and cortical activation during steady sevoflurane anesthesia, while chemogenetic inhibition accelerated induction and delayed emergence; these manipulations had no effect under propofol. Findings indicate anesthetic-specific modulation of arousal circuitry.

In 528 randomized patients analyzed (primary analysis n=420), PCC achieved higher hemostatic effectiveness than frozen plasma (77.9% vs 60.4%; difference 17.6%; 95% CI 8.7%-26.4%; P<.001 for noninferiority and superiority), reduced allogeneic transfusion requirements, and lowered serious adverse events and AKI through day 30.

In neonatal mice, repeated sevoflurane exposure impaired fine motor and cognitive functions and disrupted myelination in hippocampus and corpus callosum via microglial activation and lipid droplet accumulation. Conditioned media from sevoflurane-treated microglia suppressed OPC proliferation/differentiation, while minocycline or CSF1R inhibitor PLX5622 mitigated neuroinflammation and hypomyelination.

At clinically relevant doses, sevoflurane—but not propofol—increased endothelial permeability in vitro and pulmonary vascular leakage in mice. Mechanistically, sevoflurane activated HIF-1α, upregulated VEGF, and HIF-1α knockdown abolished permeability changes, identifying a drug-specific HIF-1α/VEGF pathway.

Using an unsupervised autoencoder plus Gaussian mixture model, the authors identified four reproducible hypotension endotypes (vasodilation, hypovolaemia, myocardial depression, bradycardia) across surgical and ICU populations. The model outputs endotype probabilities at each hypotensive timepoint, enabling causal, physiology-directed therapy rather than treating blood pressure alone.

INCEPT is a pragmatic, Bayesian adaptive platform RCT infrastructure for ICU patients, organized into domains that evaluate commonly used but uncertain interventions. It defines core outcomes, uses response-adaptive randomization and pre-specified stopping rules, and aims to deliver faster, high-certainty evidence across multiple questions within one platform.

This NIH HEAL-backed tool standardizes MME calculations using evidence-based conversion factors for 29 opioids, reproduces most CDC ratios, and extends coverage to additional opioids and formulations. It implements four standardized time-window methods and GRADE-rated evidence, enabling harmonized opioid dose mapping across research networks.

This focused update synthesizes new evidence since 2016 and suggests using CCUS to guide management in septic shock, acute dyspnea/respiratory failure, and cardiogenic shock. Importantly, CCUS-guided targeted volume management is associated with improved mortality compared with usual care; evidence remains insufficient for cardiac arrest management.

Using LC/MS, the authors showed that intravenous oxytocin follows a robust two-compartment model, whereas intranasal oxytocin has very low bioavailability (~0.7%) and high intersubject variability. LC/MS concentrations exceeded ELISA, and a public simulator was released to inform dosing in future studies.

In a randomized, double-blind, partial-crossover study in healthy volunteers, cebranopadol produced potent analgesia with significantly less respiratory depression than oxycodone. Population PK/PD modeling showed markedly different respiratory C50 and greater analgesic potency for cebranopadol.

In a multicenter RCT of 2365 critically ill adults, ketamine did not reduce 28-day in-hospital mortality compared to etomidate for rapid sequence induction. Cardiovascular collapse during intubation was more frequent with ketamine, while other safety outcomes were similar.

In a dual-center, double-blind pilot RCT (n=132 randomized; 123 analyzed), a perioperative anti-inflammatory bundle (dexmedetomidine, glucocorticoid, ulinastatin, NSAIDs) reduced postoperative delirium from 44% to 15% (RR 0.33; P=0.001) without major adverse events. Lower postoperative CRP partially mediated the effect, supporting inflammation as a causal pathway.

In a multinational double-blind RCT of 276 patients, biomarker-guided immunotherapy (anakinra for macrophage activation-like syndrome or interferon-γ for sepsis-induced immunoparalysis) increased the proportion achieving a ≥1.4-point SOFA decrease by day 9 versus placebo. No significant difference in 28-day mortality was observed; adverse events included more anemia with anakinra and hemorrhage with interferon-γ.