Daily Anesthesiology Research Analysis

Chronic primary pain conditions (CPPCs), such as fibromyalgia and vestibulodynia, affect over 100 million Americans, predominantly women, and pose a substantial healthcare challenge. CPPCs arise from genetic and environmental factors that enhance catecholamine tone, potentially through miRNA dysregulation following catecholamine activation of beta-adrenergic receptors. Here, we identified miR-133a-3p as a biomarker of CPPC status and investigated its functions using in vivo and in vitro approaches. Plasma levels of miR-133a-3p were consistently downregulated in humans with ≥1 CPPC and in rat and mouse models of primary pain. Our data suggest that miR-133a-3p is packaged in extracellular vesicles that are secreted by adipocytes and trafficked to the spinal cord. Activation of adrenergic receptors on white adipocytes resulted in downregulation of miR-133a-3p which negatively regulated pain-related genes in the spinal cord, such as MAP3K3, which is critical for sensory neuron activation. Adipose-specific overexpression of miR-133a-3p in a mouse model of primary pain reversed mechanical hypersensitivity in both sexes. These findings implicate miR-133a-3p dysregulation in primary pain across conditions and species and establish its role in multi-site mechanical hypersensitivity. Further, miR-133a-3p overexpression shows therapeutic potential for the millions of individuals with CPPCs.

BACKGROUND: Preoperative blood Tau phosphorylated at threonine 217 (Tau-PT217), a newly identified blood biomarker of Alzheimer's disease, is associated with postoperative delirium in patients. Anesthesia/surgery is also associated with postoperative increased blood Tau-PT217 amounts in patients. Moreover, in female aged mice, anesthesia/surgery increases Tau-PT217 in lungs, blood and brain tissues, leading to behavioral changes. However, whether these effects are sex-dependent remain largely undetermined. METHODS: Eighteen-month-old female and male mice (C57BL/6J) underwent abdominal surgery under general anesthesia (1.4% isoflurane and 40% oxygen). Levels of Tau-PT217, inflammatory markers, and GSK3β activity were measured in lungs, blood, and brain tissues of aged mice using nanoneedle technology, Western blot, immunohistochemistry, RT-PCR and others. Postoperative delirium-like behavior was assessed using a battery of behavioral tests (buried food, open filed and Y maze). To explore causality, we performed orchiectomy and administered androgen receptor antagonist enzalutamide in aged male mice. Finally, testosterone was delivered via inhalation to aged female mice. RESULTS: Anesthesia/surgery increased the amounts of Tau-PT217 in lungs (2.29±0.16 fold versus 1.15±0.71 fold, P<0.01), blood, and brain tissues of aged female, but not male, mice compared to control condition, leading to postoperative delirium-like behavior, as evidenced by increases in the composite Z score (3.74±1.46 versus 0.60±1.17, P<0.01), in the aged female, but not male, mice. Anesthesia/surgery elevated inflammatory markers and GSK3β activity in aged female mice, which exhibited lower baseline testosterone levels and androgen receptor expression in lungs compared to males. Both orchiectomy and enzalutamide treatment in male mice reduced testosterone levels and androgen receptor expression, leading to elevation of Tau-PT217 amounts and behavior changes following anesthesia/surgery. Conversely, testosterone inhalation in aged female mice mitigated the anesthesia/surgery-induced elevation of Tau-PT217 amounts and behavior changes. CONCLUSIONS: Testosterone and androgen receptor signaling may contribute to the sex-dependent differences in Tau phosphorylation and postoperative behavior changes in aged mice.

BACKGROUND: Ephedrine has been shown to improve cerebral microcirculation and perfusion compared with phenylephrine. However, prospective intraoperative data are lacking, and possible interactions with anesthetic choice remain untested. METHODS: Forty adults undergoing shoulder surgery in the beach chair position were recruited between Feb and November 2024 at St. Joseph's Hospital (London, Ontario, Canada). Patients were randomized in a 2×2 factorial design to anesthetic maintenance (propofol vs. sevoflurane) and vasopressor strategy (phenylephrine infusion vs. ephedrine boluses). Relative tissue oxygenation saturation (rStO2) and the relative cerebral metabolic rate of oxygen (rCMRO2), the co-primary outcomes, were monitored using an in-house hybrid optical system combining time-resolved near-infrared spectroscopy and diffuse correlation spectroscopy. Only data from the first 30 minutes after positioning were analyzed. Outcomes and interactions were assessed using linear mixed-effects models. RESULTS: Of the 40 patients, 39 were analyzed. Neither anesthetic nor vasopressor choice showed a significant main effect on average rStO2 or rCMRO2 over the 30 min period. However, analysis of temporal changes revealed rStO2 declined over time (β = -0.005 per minute, χ²(1) = 10.2, p = 0.001), while rCMRO₂ increased (β = 3.2 per minute, χ²(1) = 35.2, p < 0.001). There was a Time×Vasopressor interaction for rStO2 (β = -0.0014, χ²(1) = 8.4, p = 0.004), with phenylephrine producing a 9% greater decline over 30 minutes compared to ephedrine, while for relative rCMRO2 (β = 2.2, 95% CI 0.6 to 3.8, p = 0.007), phenylephrine produced a 70% increase over 30 minutes. DISCUSSIONS: This trial found no overall effect of anesthetic or vasopressor choice on rStO2 or rCMRO2 during the first 30 minutes of surgery, suggesting that initial cerebral physiological responses were comparable across treatment combinations. However, phenylephrine was associated with progressive cerebral desaturation and increasing metabolic demand over time.