Daily Anesthesiology Research Analysis
Three impactful studies span mechanistic neuroscience, intraoperative sedative strategy, and sepsis coagulopathy. A mechanistic paper in Anesthesiology maps a sex-specific LC→DRN GABA circuit and α1-adrenergic signaling that accelerates emergence from isoflurane after acute stress. A randomized, double-blind trial shows remimazolam is non-inferior to dexmedetomidine for preventing postoperative delirium and emergence agitation in elderly thoracoscopic surgery with better hemodynamic stability, w
Summary
Three impactful studies span mechanistic neuroscience, intraoperative sedative strategy, and sepsis coagulopathy. A mechanistic paper in Anesthesiology maps a sex-specific LC→DRN GABA circuit and α1-adrenergic signaling that accelerates emergence from isoflurane after acute stress. A randomized, double-blind trial shows remimazolam is non-inferior to dexmedetomidine for preventing postoperative delirium and emergence agitation in elderly thoracoscopic surgery with better hemodynamic stability, while a JTH study identifies the Nur77–thrombomodulin axis as a therapeutic target for sepsis-induced coagulopathy via cytosporone B.
Research Themes
- Stress–anesthesia neurocircuitry and sex differences
- Perioperative delirium prevention and sedative selection in elderly
- Mechanistic targeting of sepsis-induced coagulopathy (Nur77–TM axis)
Selected Articles
1. Sex-specific Effects of Acute Stress on Emergence from Isoflurane Anesthesia via Brainstem Circuitry in Mice.
Acute restraint stress accelerated emergence from isoflurane anesthesia in male mice but not females. The effect required locus coeruleus norepinephrine projections to DRN GABA neurons and α1-adrenergic receptors in DRN; disrupting this circuit or receptor signaling abolished stress-induced changes in anesthetic efficacy.
Impact: This rigorously dissects a sex-specific brainstem circuit linking acute stress to anesthetic emergence, offering mechanistic insight into perioperative variability in anesthetic requirements.
Clinical Implications: Preoperative stress may lower volatile anesthetic requirements and hasten emergence in men; α1-adrenergic modulation or LC–DRN GABA circuit targeting could become strategies to personalize anesthetic dosing and emergence.
Key Findings
- Acute stress shortened emergence time from isoflurane in males (≈16 to 6.8 min; P<0.0001) but not females.
- LC norepinephrine neuron activation increased after stress; chemogenetic inhibition abolished the emergence-accelerating effect.
- LC→DRN GABA projection and α1-adrenergic receptors in DRN neurons were necessary; disrupting either eliminated stress-induced modulation.
Methodological Strengths
- Multimodal causal mapping (EEG, c-Fos, fiber photometry, opto/chemogenetics, pharmacology, shRNA).
- Sex-stratified analyses with clear effect sizes and replication across techniques.
Limitations
- Preclinical mouse model; translatability to human perioperative care remains to be established.
- Focused on isoflurane and acute restraint stress; mechanisms in females and with other anesthetics/stressors were not delineated.
Future Directions: Test pharmacologic α1-adrenergic modulation in human experimental paradigms; evaluate circuit biomarkers to guide anesthetic titration; explore mechanisms underlying female resilience.
BACKGROUND: Preoperative stress is a well documented phenomenon in surgical patients and leads to clinically significant variability in anesthetic requirements. This variability poses important challenges for safe anesthesia practice, as stress may alter the function of neural circuits targeted by general anesthetics. However, the specific mechanisms linking stress to changes in anesthetic efficacy remain unclear. This study aimed to investigate how acute stress affects the efficacy of isoflurane anesthesia and to uncover the associated neural circuitry and receptor mechanisms. METHODS: Using 30-min restraint stress in mice, this study assessed isoflurane anesthesia through both loss and recovery of righting reflex alongside electroencephalography spectral analysis. Circuit mechanisms were identified through immunofluorescence staining, fiber photometry, and viral-based optogenetics/chemogenetics. Pharmacologic and short hairpin RNA approaches were carried out to verify receptor involvement in stress-driven modulation of isoflurane anesthesia. RESULTS: Acute stress reduced isoflurane anesthesia depth and shortened emergence time in male mice (15.78 ± 3.17 vs. 6.84 ± 1.77 min; P < 0.0001), whereas these effects were absent in females. c-Fos immunofluorescence staining and fiber photometry revealed heightened activation of locus coeruleus norepinephrine (LC NE ) neurons during anesthesia after restraint stress in males. pharmacologic lesioning or chemogenetic inhibition of LC NE neurons abolished these stress-induced effects (EYFP + stress vs. hM4Di + stress: 7.76 ± 1.20 vs. 20.22 ± 5.93 min; P < 0.0001). Downstream tracing showed LC NE neurons projecting to γ-aminobutyric acid (GABA)-mediated neurons in the dorsal raphe nucleus (DRN). Optogenetic or chemogenetic inhibition of the LC NE → DRN GABA circuit, as well as pharmacologic or genetic disruption of α1-adrenergic receptors in DRN neurons, eliminated stress-induced modulation of anesthesia in males (scramble + stress vs. short hairpin RNA + stress: 8.06 ± 1.94 vs. 23.38 ± 4.61 min; P = 0.0002). CONCLUSIONS: This study identifies the LC NE → DRN GABA circuit and α1-adrenergic receptors in DRN GABA neurons as critical mediators in acute stress-induced emergence acceleration from isoflurane anesthesia in male mice.
2. Cytosporone B ameliorates hypercoagulability in sepsis by agonizing the Nur77-thrombomodulin pathway.
Using CLP sepsis models and endothelial-specific Nur77 knockout, the study shows that cytosporone B upregulates endothelial Nur77 to increase thrombomodulin and APC activation, restore fibrinolysis, and reduce complement activation, thereby correcting hypercoagulability. Endothelial Nur77 deletion abrogated these benefits, establishing pathway dependence.
Impact: Identifies a druggable endothelial transcriptional pathway (Nur77–TM) that mechanistically restores anticoagulant balance in sepsis, offering a promising target for SIC where effective therapies are scarce.
Clinical Implications: If translated, Nur77 agonism (e.g., cytosporone B) could complement current supportive care by restoring TM/APC and fibrinolytic balance in SIC. It suggests endothelial-targeted therapy to mitigate microthrombosis and organ injury in sepsis.
Key Findings
- Endothelial Nur77 is upregulated in sepsis; its conditional knockout worsened organ injury and early coagulopathy after CLP.
- Cytosporone B reduced procoagulant responses in HUVECs via the Nur77–thrombomodulin pathway and improved coagulation balance in vivo.
- Benefits included increased TM–APC activation, restoration of fibrinolysis, and inhibition of complement C3/C5 activation; effects required endothelial Nur77.
Methodological Strengths
- Use of CLP sepsis model with vascular endothelial-specific Nur77 knockout to establish causality.
- Integrated in vitro (HUVEC siRNA) and in vivo readouts (coagulation factors, APC, fibrinolysis, complement, histopathology).
Limitations
- Preclinical; dosing, safety, and translational efficacy of cytosporone B in humans are unknown.
- Timing of intervention relative to sepsis onset and interactions with standard anticoagulant/antiplatelet therapies require evaluation.
Future Directions: Conduct pharmacokinetics/toxicology and early-phase trials of Nur77 agonists; validate TM/APC and complement biomarkers in SIC patients; explore combinatorial strategies with supportive anticoagulation.
BACKGROUND: Sepsis-induced coagulopathy (SIC) is often a sign of high mortality and poor prognosis in patients with sepsis. Thrombomodulin (TM) plays an important anticoagulant role by activating protein (AP)C. OBJECTIVES: Our previous study has shown that the overexpression of Nur77 upregulates TM expression in human umbilical vein endothelial cells (HUVECs). This study aimed to investigate whether upregulation of Nur77 using cytosporone (Csn)-B could ameliorate SIC. METHODS: A mouse model of SIC was prepared by cecum ligation and puncture (CLP) operation. Five hours after CLP, coagulation-related indicators and histopathologic injury of the liver, lungs, and kidneys were investigated. The effect of Csn-B on the clotting time of HUVECs transfected with Nur77 or TM small-interfering RNA in response to tumor necrosis factor α stimulation was observed. The effects of Csn-B on survival, organ damage, microthrombosis, coagulation factors, TM activated protein C anticoagulant system, fibrinolytic system, and complement system were observed in vascular endothelial conditional knockout Nur77 mice after CLP. RESULTS: Sepsis-induced upregulation of Nur77 in vascular endothelial cells. Knockout of Nur77 in vascular endothelium exacerbated organ damage and early coagulation dysfunction in sepsis. Csn-B attenuated the procoagulant response of HUVEC to tumor necrosis factor α stimulation, which is dependent on the activation of Nur77-TM pathway. Furthermore, Csn-B relied on activation of vascular endothelial Nur77 to inhibit the increase of coagulation factors, enhance activation of TM activated protein C, restore fibrinolysis homeostasis, and inhibit C3 and C5 activation to ameliorate hypercoagulability in SIC. CONCLUSION: Csn-B improves early coagulopathy in sepsis by increasing endogenous TM through upregulating Nur77 in the vascular endothelium.
3. Comparison of Remimazolam and Dexmedetomidine on Postoperative Delirium and Emergence Agitation in Elderly Patients Undergoing Thoracoscopic Surgery: A Randomized, Double-Blind, Non-Inferiority Trial.
In 176 elderly VATS patients, remimazolam was non-inferior to dexmedetomidine for preventing postoperative delirium and emergence agitation over 5 days post-op. Remimazolam also improved hemodynamic stability and reduced intraoperative opioid and vasopressor requirements.
Impact: Provides randomized, double-blind evidence to guide sedative choice in elderly thoracoscopic surgery, balancing neurocognitive outcomes and hemodynamic safety.
Clinical Implications: Remimazolam is a viable alternative to dexmedetomidine to mitigate POD/EA in elderly VATS, with potential advantages in hemodynamic stability and reduced opioid/vasopressor use.
Key Findings
- Non-inferiority of remimazolam versus dexmedetomidine for POD and EA within 5 postoperative days.
- Remimazolam improved intraoperative hemodynamic stability and reduced opioid/vasopressor requirements.
- Patient-reported recovery (QoR-15) and sleep (AIS) were assessed alongside neurocognitive endpoints.
Methodological Strengths
- Randomized, double-blind, non-inferiority design with prespecified outcomes.
- Elderly surgical population with clinically relevant multi-domain endpoints (neurocognitive, hemodynamic, recovery).
Limitations
- Generalizability may be limited to VATS for lung cancer; multicenter validation is needed.
- Follow-up restricted to 5 days for POD/EA; longer-term cognitive outcomes were not evaluated.
Future Directions: Confirm findings in multicenter trials across surgical types; evaluate long-term cognitive outcomes and cost-effectiveness; define optimal dosing and TCI strategies.
BACKGROUND AND AIM: Postoperative delirium (POD) and emergence agitation (EA) are common complications in older patients undergoing video-assisted thoracoscopic surgery (VATS), significantly impacting recovery. This study was designed to examine whether remimazolam is noninferior to dexmedetomidine for preventing POD and EA in elderly patients following VATS. PATIENTS AND METHODS: A total of 176 elderly patients scheduled for VATS due to lung cancer were randomly assigned to receive either dexmedetomidine (Group D, n = 88) or remimazolam (Group R, n = 88). Group D received dexmedetomidine at 0.5 μg/kg/h starting 3 minutes before anesthesia induction until surgery completion. Group R received remimazolam at 0.5 mg/kg/h over the same period. The primary outcomes were the incidence of EA and POD within 5 days after surgery. Secondary outcomes included Quality of Recovery-15 (QoR-15) score, Athens Insomnia Scale (AIS), and numeric rating scale (NRS) for pain. Correlations among hypotension, EA, and POD were also analyzed. RESULTS: The incidence of POD and EA in Group R was non-inferior to that in Group D (non-inferiority CONCLUSION: Remimazolam was non-inferior to dexmedetomidine in preventing POD and EA in elderly patients undergoing VATS while providing improved hemodynamic stability and reducing the need for intraoperative opioids and vasopressors.