Weekly Anesthesiology Research Analysis
This week produced several high-impact findings across translational and clinical anesthesiology. A multinational randomized trial (BigpAK-2, Lancet) showed that urinary biomarker–enriched selection plus a KDIGO-aligned prevention bundle significantly reduced moderate-to-severe postoperative AKI. Structural biology (Nature Communications) resolved Ryanodine Receptor domain interactions with dantrolene/azumolene, enabling structure-guided inhibitor discovery for malignant hyperthermia. Mechanisti
Summary
This week produced several high-impact findings across translational and clinical anesthesiology. A multinational randomized trial (BigpAK-2, Lancet) showed that urinary biomarker–enriched selection plus a KDIGO-aligned prevention bundle significantly reduced moderate-to-severe postoperative AKI. Structural biology (Nature Communications) resolved Ryanodine Receptor domain interactions with dantrolene/azumolene, enabling structure-guided inhibitor discovery for malignant hyperthermia. Mechanistic work (British Journal of Anaesthesia) revealed a peripheral c‑Jun–Mrgprd–DS‑lncRNA–Ehmt2/G9a–Oprm1 axis controlling morphine tolerance, opening peripheral targets to mitigate opioid tolerance.
Selected Articles
1. A preventive care strategy to reduce moderate or severe acute kidney injury after major surgery (BigpAK-2); a multinational, randomised clinical trial.
BigpAK-2 randomized high‑risk major surgery patients (biomarker-enriched) to a KDIGO-aligned prevention bundle versus usual care and found a reduction in moderate-to-severe AKI within 72 hours (14.4% vs 22.3%; OR 0.57; NNT ≈12) without increased adverse events.
Impact: A large, multinational RCT that demonstrates a pragmatic, biomarker-directed strategy can prevent clinically meaningful AKI after major surgery — high immediate impact for perioperative practice and policy.
Clinical Implications: Implement urinary tubular stress biomarker screening for high-risk patients and deploy KDIGO-aligned bundles (advanced hemodynamic monitoring, volume/pressure optimization, nephrotoxin/contrast avoidance, glycemic control) to reduce moderate-to-severe AKI.
Key Findings
- Moderate/severe AKI within 72 hours: 14.4% (intervention) vs 22.3% (control); OR 0.57; NNT ≈12.
- No increase in adverse events (atrial fibrillation, bleeding, reoperation) with the bundle.
- Biomarker-enriched selection combined with KDIGO-based supportive measures produced clinically meaningful benefit.
2. Crystal structures of Ryanodine Receptor reveal dantrolene and azumolene interactions guiding inhibitor development.
High-resolution R12-domain crystal structures show cooperative binding of dantrolene/azumolene and nucleotides, identify key Trp contacts and clamshell closure, quantify nucleotide-enhanced affinity (ITC), and support structure-based screening that yielded new binders — directly enabling next-generation RyR inhibitor discovery.
Impact: Provides the structural basis for rational RyR inhibitor design — a transformative advance for developing safer, more effective alternatives to dantrolene for malignant hyperthermia and other RyR-mediated crises.
Clinical Implications: Enables medicinal chemistry programs to pursue structure-guided RyR inhibitors with improved safety/pharmacokinetics; long-term, this could change management options for malignant hyperthermia and perioperative RyR crises.
Key Findings
- Resolved R12-domain structures with dantrolene/azumolene and nucleotides showing cooperative binding in a pseudosymmetric cleft.
- Key interacting residues (Trp880, Trp994) and clamshell-like domain closure upon ligand binding.
- ITC demonstrated nucleotide-enhanced affinity; structure-based screening found new potent binder at the same pocket.
3. Modulation of morphine tolerance by Mas-related G protein-coupled receptor D signalling in the mouse dorsal root ganglion.
Time-course DRG transcriptomics and in vivo gain/loss experiments identified a peripheral c‑Jun–Mrgprd–DS‑lncRNA–Ehmt2/G9a–Oprm1 pathway where Mrgprd suppression delays morphine tolerance via DS‑lncRNA and Ehmt2/G9a modulation; targeting this peripheral axis modified MOR expression and tolerance dynamics in mice.
Impact: Shifts conceptual focus from central-only mechanisms of opioid tolerance to a druggable peripheral pathway, providing new targets to sustain opioid analgesia and reduce dose escalation.
Clinical Implications: Although preclinical, this identifies peripheral molecular nodes (Mrgprd, DS‑lncRNA, Ehmt2/G9a) for development of therapies to mitigate opioid tolerance, with potential to improve perioperative and chronic pain management pending translational work.
Key Findings
- Acute morphine reduced DRG Mrgprd expression ~70% at 6–24 h; Mrgprd knockdown delayed tolerance while overexpression accelerated it.
- c‑Jun binds Mrgprd promoter; Mrgprd suppression increased Oprm1/MOR via DS‑lncRNA upregulation and Ehmt2/G9a downregulation.
- DS‑lncRNA knockdown restored Ehmt2 and reinstated tolerance, demonstrating pathway causality.