Daily Anesthesiology Research Analysis
Three impactful anesthesia-related studies stood out today: a multicenter phase II RCT with mechanistic validation identifies HIF1A stabilization (vadadustat) as a promising strategy for SARS-CoV-2 lung injury; a nationwide Japanese cohort links postoperative temperature to mortality with a U-shaped relationship; and a two-center randomized trial shows sub-anesthetic esketamine reduces early postoperative sleep disturbance and pain after spine surgery.
Summary
Three impactful anesthesia-related studies stood out today: a multicenter phase II RCT with mechanistic validation identifies HIF1A stabilization (vadadustat) as a promising strategy for SARS-CoV-2 lung injury; a nationwide Japanese cohort links postoperative temperature to mortality with a U-shaped relationship; and a two-center randomized trial shows sub-anesthetic esketamine reduces early postoperative sleep disturbance and pain after spine surgery.
Research Themes
- Perioperative physiology and outcomes
- Novel therapeutics and repurposing in critical care
- Perioperative analgesia and sleep health
Selected Articles
1. Identification of HIF1A as a therapeutic target during SARS-CoV-2-associated lung injury.
In murine SARS-CoV-2 models and genetic studies, alveolar Hif1a mediated protection and vadadustat improved outcomes. In a multicenter, double-blind phase II RCT (n=448), vadadustat reduced the estimated probability of severe lung injury at day 14 vs placebo, with a striking benefit among patients with baseline FiO2 ≥80%. Safety was similar, and HIF target gene induction confirmed on-target effects.
Impact: This trial links mechanistic HIF1A biology to a randomized clinical signal, highlighting a repurposable, oral therapy for hypoxic viral lung injury with a potentially large effect in profound hypoxia.
Clinical Implications: HIF stabilizers like vadadustat may be considered for evaluation in severe hypoxic pneumonia; current data justify larger confirmatory trials and suggest stratifying by baseline hypoxemia severity.
Key Findings
- Vadadustat improved outcomes in murine SARS-CoV-2 lung injury models and induced HIF target genes in patients.
- In the phase II RCT (n=448), the estimated probability of severe lung injury at day 14 was 13.3% with vadadustat vs 16.9% with placebo.
- Marked benefit in patients with baseline FiO2 ≥80% (12.1% vadadustat vs 79.1% placebo).
- Safety profiles were similar between groups under blinded monitoring.
Methodological Strengths
- Randomized, double-blind, multicenter phase II design with mechanistic preclinical support
- Predefined clinical endpoint and on-target pharmacodynamic readouts (HIF gene induction)
Limitations
- Overall treatment effect on the primary endpoint was modest; subgroup findings may be underpowered and hypothesis-generating
- Phase II study not powered for mortality or long-term outcomes; external validation needed
Future Directions: Conduct adequately powered phase III trials in pathogen-associated lung injury with stratification by baseline hypoxemia; explore optimal dosing window and potential synergy with standard-of-care anti-inflammatory or antiviral therapies.
Hypoxia-inducible factors (HIFs) promote lung protection and pathogen eradication during acute lung injury. We, therefore, tested the theory that pharmacologic stabilization of HIFs dampens lung injury during SARS-CoV-2 pneumonia. Initial studies in murine SARS-CoV-2 models showed improved outcomes after treatment with the FDA-approved HIF stabilizer vadadustat. Subsequent studies in genetic models implicated alveolus-expressed Hif1a in mediating lung protection. Therefore, we performed a randomized, double-blinded, multicenter phase II trial in patients admitted for SARS-CoV-2 infection and concomitant hypoxia (SpO2 ≤ 94%). Patients (n = 448) were randomized to oral vadadustat (900 mg/day) or placebo for up to 14 days. Safety events were similar between the 2 groups. Vadadustat treatment induced surrogate HIF target genes. The primary outcome of severe lung injury requiring high oxygen support on day 14 occurred in 43 patients in the vadadustat group and 53 patients in the placebo group (estimated probability, 13.3% vs. 16.9%). Among patients with baseline fraction of inspired oxygen of 80% or higher (n = 106), the estimated probability of the primary outcome was 12.1% (vadadustat) versus 79.1% (placebo), indicating an even greater benefit in patients with more severe baseline hypoxia. HIF1A is a likely therapeutic target during SARS-CoV-2-associated lung injury. Robust clinical trials of HIF stabilizers during pathogen-associated lung injury are warranted.
2. Effects of sub-anesthetic doses of esketamine on postoperative sleep disturbance and pain in patients undergoing lumbar interbody fusion-A randomized, double-blind, placebo-controlled, two-center trial.
In a two-center, double-blind RCT (n=80), sub-anesthetic esketamine significantly reduced postoperative sleep disturbance on POD1 (33% vs 67%), lowered early postoperative pain at rest and with movement, and improved QoR-15 scores on POD1 and POD3.
Impact: Demonstrates a practical, scalable adjunct that improves early sleep and analgesia—two key determinants of recovery—using a randomized, blinded design.
Clinical Implications: Sub-anesthetic esketamine may be considered as an adjunct for lumbar fusion to reduce early postoperative sleep disturbance and pain and to enhance recovery quality, with attention to patient selection and monitoring.
Key Findings
- POD1 postoperative sleep disturbance: 33% with esketamine vs 67% with placebo (P=0.003).
- Lower VAS pain scores at rest at 1, 3, and 6 hours post-op with esketamine (all P<0.05).
- Lower VAS pain with movement at 1, 3, 6, and 24 hours post-op (all P<0.05).
- Improved QoR-15 on POD1 (median 107 vs 99) and POD3 (130 vs 124).
Methodological Strengths
- Randomized, double-blind, placebo-controlled design across two centers
- Use of validated outcomes (PSD incidence, VAS pain, QoR-15) with prespecified time points
Limitations
- Modest sample size and limited to lumbar interbody fusion; short follow-up window
- Dose and infusion details truncated in abstract; adverse event profile not fully detailed
Future Directions: Larger multicenter trials across diverse surgeries to validate efficacy and delineate optimal dosing, safety, and patient phenotypes most likely to benefit.
BACKGROUND: Postoperative sleep disturbance (PSD) is a common postoperative complication that significantly impacts patients' recovery, particularly after lumbar surgery. METHODS: This two-center, double-blind, placebo-controlled randomized trial was conducted between June 6, 2024, and November 26, 2024, in two hospitals in China. A total of 80 patients participated in this study and were randomly assigned to the esketamine group (n = 40) or the placebo group (n = 40). Patients in the esketamine group received 0.2 mg kg RESULTS: The incidence of PSD on POD 1 was significantly lower in the esketamine group compared to the placebo group (33% vs. 67%; P = 0.003). The Visual Analog Scale (VAS)-pain score at rest was lower in the esketamine group compared to the placebo group at 1, 3, and 6 h after surgery (P < 0.05). The VAS-pain score with movement was also lower in the esketamine group than the placebo group at 1, 3, 6, and 24 h after surgery (P < 0.05). Furthermore, the Quality of Recovery-15 (QoR-15) scores were significantly higher in the esketamine group than in the placebo group on POD 1 (107 [103-117] vs. 99 [96-108]; P = 0.005) and POD 3 (130 [122-136] vs. 124 [117-127]; P = 0.003). CONCLUSION: Sub-anesthetic doses of esketamine can reduce the incidence of PSD on POD 1, reduce postoperative pain, and improve QoR. CLINICAL TRIAL REGISTRATION: Chinese Clinical Trial Registry https://www.chictr.org.cn, ChiCTR2400083156.
3. Association between postoperative body temperature and in-hospital mortality: a nationwide cohort study of 157,028 critically ill patients in Japan.
In 157,028 critically ill surgical patients, postoperative temperature showed a U-shaped association with in-hospital mortality, with increased risk <36.0°C and >40.0°C and a nadir at 37.5–37.9°C. Low temperatures were harmful regardless of infection control surgery, whereas high temperatures were not associated with higher mortality after source-control operations.
Impact: Defines temperature–mortality relationships at national scale with actionable implications for perioperative thermal management and context-dependent fever response.
Clinical Implications: Avoid postoperative hypothermia aggressively; consider nuanced fever management—fever after source-control surgery may be less harmful than in non-infectious indications.
Key Findings
- U-shaped association between postoperative temperature and mortality with nadir at 37.5–37.9°C (adjusted OR 0.62).
- Increased mortality at temperatures <36.0°C (OR 2.15) and >40.0°C (OR 1.41).
- Low temperatures were harmful regardless of infection; high temperatures were not associated with higher mortality after source-control surgery.
Methodological Strengths
- Very large nationwide cohort with multivariable modeling and cubic spline analysis
- Clinically relevant subgrouping by surgical indication (source control vs others)
Limitations
- Observational design precludes causal inference; residual confounding likely
- Temperature measurement harmonization and perioperative confounders (e.g., active warming) may vary
Future Directions: Prospective interventional studies to test temperature targets by surgical context; explore mechanisms linking hypothermia and adverse outcomes.
PURPOSE: The association between postoperative body temperature and in-hospital mortality remains unclear. We sought to evaluate this association across all surgical patients and assessed whether it is affected by the indication for surgery (i.e., surgical source control of infection vs other indications). METHODS: In a nationwide cohort study, we included critically ill adult patients registered in the Japanese Intensive Care Patient Database who underwent surgery between 2015 and 2021. We evaluated whether the body temperature was associated with in-hospital mortality, and if a differential effect was observed in patients who underwent surgery for source control of infection vs other indications (control group). We categorized the highest body temperatures recorded in the 24 hr after admission following surgery in 0.5-°C intervals and evaluated them using multivariable regression. We conducted a subgroup analysis of patients who underwent surgery for infection control vs other indications. We report the summary estimates using adjusted odds ratios (ORs) and 95% confidence intervals (CIs). We examined the association between body temperature category and in-hospital mortality using cubic spline models to assess nonlinear associations. RESULTS: Among 157,028 patients, the overall in-hospital mortality was 2.9%. We observed a U-shaped association of temperature and mortality, with increased mortality at body temperatures < 36.0 °C (OR, 2.15; 95% CI, 1.62 to 2.86) and > 40.0 °C (OR, 1.41; 95% CI, 1.02 to 1.96). We observed the lowest mortality at 37.5-37.9 °C (OR, 0.62; 95% CI, 0.55 to 0.70). Low body temperatures were associated with increased mortality regardless of the presence or absence of infection, while high body temperatures were not associated with increased mortality in patients undergoing surgery for source control of infection. CONCLUSIONS: In this large nationwide cohort of critically ill surgical patients in Japan, we observed that low and high postoperative body temperatures were associated with increased in-hospital mortality. Nevertheless, we did not observe the association with high body temperature and increased mortality in the subgroup of patients having undergone surgery for infection control. RéSUMé: OBJECTIF: L’association entre la température corporelle postopératoire et la mortalité hospitalière demeure incertaine. Nous avons cherché à évaluer cette association chez toute la patientèle chirurgicale et à déterminer si elle est affectée par l’indication de la chirurgie (c’est-à-dire le contrôle chirurgical à la source de l’infection vs d’autres indications). MéTHODE: Dans une étude de cohorte à l’échelle nationale, nous avons inclus des adultes gravement malades enregistrés dans la base de données japonaise des personnes hospitalisées aux soins intensifs qui ont bénéficié d’une intervention chirurgicale entre 2015 et 2021. Nous avons évalué si la température corporelle était associée à la mortalité hospitalière et si un effet différentiel avait été observé chez les personnes ayant bénéficié d’une intervention chirurgicale pour contrôle à la source de l’infection vs d’autres indications (groupe témoin). Nous avons classé les températures corporelles les plus élevées enregistrées dans les 24 heures suivant l’admission après l’intervention chirurgicale à des intervalles de 0,5 °C et les avons évaluées à l’aide d’une régression multivariée. Nous avons réalisé une analyse de sous-groupe de personnes ayant bénéficié d’une intervention chirurgicale pour contrôler les infections vs pour d’autres indications. Nous rapportons les estimations sommaires à l’aide de rapports de cotes (RC) ajustés et d’intervalles de confiance (IC) à 95 %. Nous avons examiné l’association entre la catégorie de température corporelle et la mortalité à l’hôpital à l’aide de modèles de splines cubiques pour évaluer les associations non linéaires. RéSULTATS: Parmi 157 028 patients et patientes, la mortalité hospitalière globale était de 2,9 %. Nous avons observé une association en forme de U entre la température et la mortalité, avec une mortalité accrue à une température corporelle < 36,0 °C (RC, 2,15; IC 95 %, 1,62 à 2,86) et > 40,0 °C (RC, 1,41; IC 95 %, 1,02 à 1,96). Nous avons observé la mortalité la plus faible à une température située entre 37,5 et 37,9 °C (RC, 0,62; IC 95 %, 0,55 à 0,70). Une température corporelle basse était associée à une mortalité accrue indépendamment de la présence ou non d’infection, tandis qu’une température corporelle élevée n’était pas associée à une mortalité accrue chez les personnes bénéficant d’une intervention chirurgicale pour le contrôle à la source de l’infection. CONCLUSION: Dans cette vaste cohorte nationale de patientes et patients chirurgicaux gravement malades au Japon, nous avons observé que des températures corporelles postopératoires basses et élevées étaient associées à une augmentation de la mortalité hospitalière. Néanmoins, nous n’avons pas observé d’association avec une température corporelle élevée et une mortalité accrue dans le sous-groupe de personnes ayant bénéficié d’une intervention chirurgicale pour contrôler les infections.