British Journal of Anaesthesia

BackgroundThere is disparity between the incidence of malignant hyperthermia (MH) reactions and the prevalence of variants in the RYR1 gene associated with susceptibility to MH (where susceptibility is determined by in vitro contracture tests). Our aims were to use clinical and genetic data from the UK to explain this disparity and to examine if these data are consistent with the clinical risk of MH being inherited as an autosomal dominant trait. MethodsClinical MH and genotyping data were extracted from the UK MH registry. The numbers of general anaesthetics delivered in the UK were estimated from national surveys and reports, with population data obtained from government statistics. The prevalence of RYR1 variants in the UK population was estimated using UK Biobank data. The incidence of MH reactions 1988-93 was used to estimate the prevalence of the clinical risk of MH in the UK. Bayesian modelling, calibrated against actual data, was used to evaluate the likely mode of inheritance of the clinical risk of MH and the relative risk of clinical MH associated with different RYR1 variants. ResultsThe probability of index cases developing MH with each general anaesthetic can be expressed as a constant hazard of 0.46 (95% CI 0.42 - 0.50, n=375). We used peak incidence data (1988-93) to estimate the prevalence of the risk of MH as 1 in 44,000 (95% credibility interval, 1 in 40,000 to 1 in 48,000). The incidence of MH has declined over the past 22 years but the rate of decline is inconsistent with autosomal dominant inheritance (P < 10-10). The risk of MH varied by up to 150-fold between carriers of 28 recurrent RYR1 variants. ConclusionThese findings support a threshold inheritance model for clinical MH and have implications for diagnostics, both genotyping and in vitro contracture test phenotyping.

BackgroundDelirium is a frequent complication in hospitalized older adults post-surgery associated with adverse outcomes. Although anaesthesia is traditionally linked to increased delirium risk, the causal relationship remains uncertain. MethodsWe conducted Mendelian randomization (MR) analyses using genome-wide association studies (GWAS) summary statistics to explore the causal effects of different anaesthesia types (general, regional, and local) on delirium risk. We employed the weighted median, MR-Egger, and MR-PRESSO methods for estimation and conducted sensitivity analyses to address pleiotropy and heterogeneity. ResultsGenetically determined anaesthesia types showed no significant causal effect on delirium risk. Sensitivity analyses confirmed the robustness of these findings, with no evidence of horizontal pleiotropy or significant heterogeneity. ConclusionsMendelian randomization provides strong evidence against a causal link between genetically determined anaesthesia and increased delirium risk.

Background One in four surgical patients carries a drug allergy label, of which an estimated 90% are incorrect. Avoidance of first-choice drug therapies may lead to worse postoperative outcomes. We sought to determine the nature and extent of any association between drug allergy labels and postoperative complications. Methods A multicentre observational study in 21 NHS hospitals. Eligible patients were 18 years or older, undergoing common surgical procedures: primary hip or knee replacement; internal fixation of closed long bone fracture; colorectal resection; trans-urethral resection of prostate or bladder tumour; caesarean section; hysterectomy. Exclusion criteria: use of antibiotics in the two weeks prior to surgery, previous participation in the study. Primary outcome was postoperative complications within 30 days following surgery, a composite outcome comprising: all postoperative infections, anastomotic leak, acute respiratory distress syndrome, myocardial infarction, postoperative bleed, pulmonary embolism, stroke, antimicrobial side effects, death. Results Among 13,646 patients, 3924 (29%) carried greater than or equal to1 drug allergy labels. Labelled patients were more likely to develop postoperative complications (989/3924 (25%) vs 1926/9722 (20%); OR 1.21 [1.10-1.34]; p<0.001). They were more likely to develop surgical site infections (337/3924 (9%) vs 760/9722 (8%); OR 1.19 [1.03 -1.38]; p<0.018), and any postoperative infection (750/3924 (19%) vs 1472/9722 (15%); OR 1.24 [1.11-1.38] p<0.001). Labelled patients experienced increased risk of allergic drug reactions (31/3924 (0.01%) vs 29/9722 (<0.01%); OR 3.00 [1.77-5.09]; p<0.001), but no increase in mortality. Conclusions Drug allergy labels are common, but often incorrect. Labelled patients experience worse postoperative outcomes, including infective and non-infective complications and increased risk of allergic drug reactions. Trial registration Registered with ISRCTN registry, ISRCTN15775657.

BackgroundThe Balanced trial was designed to answer the question of whether anaesthetic depth affects postoperative mortality when a vulnerable patient undergoes major surgery. Patients were recruited between 2012 and 2017 at 73 centres in seven countries. In the intention-to-treat analysis (n=6644), there was no significant difference in one year mortality between patients randomised to surgery under deep (target BIS 35) or light anaesthesia (target BIS 50). However the separation between randomised groups was only 8.4 BIS units and the trial was criticised for being underpowered. MethodsIn a secondary analysis of this trials data, we made alternative per-protocol estimates designed to improve the power of the trial. We added an additional covariate - each patients deviation from target BIS - to the original analysis, statistically recreating the desired separation of 15 BIS units between randomised groups. We used multiple imputation to recover missing BIS values. We also assessed whether a proportional hazards Cox model was appropriate for the analysis of one year mortality. ResultsOur alternative per-protocol estimates did not differ materially from the original per-protocol estimate. The gain in precision through using all intent-to-treat patients for our per-protocol estimates was offset by the additional variance introduced when modelling missing BIS values. When modelling missing BIS, we found regional differences: in China, the separation between randomised groups was far higher (13.6 BIS units) than in any other region. Estimates and plots assessing proportional hazards suggested increasing late mortality under deep anaesthesia, most notably in China. ConclusionOur hypothesis is that deep anaesthesia in the Balance trial led to higher postoperative delirium, which in turn led to an increase in late mortality. In future trials, patients should be followed for more than a year and cause of death recorded. Key pointsO_LIWe added an additional covariate - each patients deviation from their target BIS - to the original analyses of data from the Balanced trial, statistically recreating the desired separation of 15 BIS units between randomised groups. C_LIO_LIOur alternative per-protocol estimates for the effect of deep anaesthesia on one year mortality did not differ materially from the original per-protocol estimate. C_LIO_LIIn China, the separation between randomised groups was far higher (13.6 BIS units) than in any other region (at most 7.7 BIS units). C_LIO_LIEstimates and plots assessing proportional hazards suggested increasing late mortality under deep anaesthesia, most notably in China. C_LIO_LIOur hypothesis is that deep anaesthesia in the Balance trial led to higher postoperative delirium, which in turn led to an increase in late mortality. C_LI

Background: Perioperative observational studies are increasingly used to evaluate anesthesia practices that are difficult to test in randomized trials, but treatment selection is influenced by surgical procedure type. Scalable and robust methods are needed to adjust for procedure-level confounding across heterogeneous surgical cohorts. Methods: We developed and assessed the utility of a surgical-name embedding framework using free-text procedure names from 627,624 adult perioperative records. Procedure names were embedded using open-source sentence-embedding models, reduced with principal components analysis, and incorporated into entropy-balanced observational analyses. We compared unweighted, clinical covariate adjustment, and clinical covariate plus surgical-name embedding adjustment across three replications of recent perioperative randomized trials: GA-CARES for total intravenous versus volatile anesthesia on cancer mortality, PADDI for dexamethasone and surgical site infection, and GAP for perioperative gabapentin and postoperative length of stay. Results: In the GA-CARES replication, unweighted and clinical covariate adjustment suggested lower two-year mortality with total intravenous anesthesia, whereas adding surgical-name embeddings attenuated the estimate to a nonsignificant association consistent with the randomized trial (OR 0.84 [95% CI, 0.62-1.14]; p=0.274). In the PADDI replication, adding surgical-name adjustment reproduced the trial's overall non-harm finding for 30-day surgical site infection (OR 0.72 [95% CI 0.69-0.76], p<0.001) while preserving the expected protective association with postoperative nausea and/or vomiting. In the GAP replication, the full cohort was null across adjustment strategies, but surgical-name embeddings were required to recover trial-consistent null length-of-stay estimates across cardiac, thoracic, and abdominal subgroups. Department indicators and randomly generated covariates did not reproduce the effect of surgical-name embeddings, supporting the presence and importance of procedure-specific information. Conclusions: Free-text surgical-name embeddings provide a scalable method for representing surgical context in perioperative observational studies. Surgical-name adjustment improved concordance with randomized trial benchmarks while preserving expected treatment effects, supporting its use as an additional layer of confounding adjustment in large perioperative datasets.

Structured AbstractO_ST_ABSImportanceC_ST_ABSMany patients undergoing thoracotomy suffer from debilitating chronic post-thoracotomy pain (CPTP) lasting months or years postoperatively. The effectiveness of the commonly used two analgesic techniques, paravertebral blockade (PVB) and thoracic epidural blockade (TEB), on the incidence of CPTP is unknown. ObjectiveTo test the hypothesis that PVB reduces the incidence of CPTP compared with TEB. DesignPragmatic, open-label, allocation-concealed randomized controlled trial. Participants were recruited between January 8th, 2019 and September 29th, 2023. Setting15 UK thoracic centers. Participants770 eligible adult patients undergoing thoracotomy were randomly assigned (1:1) to TEB or PVB using a web-based randomization service. Intervention(s)Participants in the PVB group received three single-shot paravertebral injections of local anesthetic before knife-to-skin, followed by placement of a paravertebral catheter. Participants in the TEB group had a thoracic epidural catheter placed and loaded with local anaesthetic before knife-to-skin. Main Outcome(s) and Measure(s)The primary outcome was the incidence of CPTP at 6 months post-randomization, defined as a 100mm Visual Analogue Score (VAS) greater than or equal to 40mm (indicating moderate pain) when considering worst chest pain over the last week. Secondary outcomes included additional measures of chronic/acute pain, complications and quality of life. ResultsThe trial enrolled 770 patients (342 female patients (44.4%); mean (SD) age, 66.6 (11.0) years). After 33 post-randomisation exclusions of patients who did not proceed to thoracotomy, 737 were included in the modified intention-to-treat population (364 PVB, 373 TEB). At 6-months, 59 (22%) of 272 participants in the PVB group and 47 (16%) of 292 participants in the TEB group developed CPTP (adjusted risk ratio=1{middle dot}32 [95%CI 0{middle dot}93 to 1{middle dot}86]; adjusted risk difference=0{middle dot}05 [95%CI -0{middle dot}01 to 0{middle dot}11]; p=0{middle dot}12). During the acute phase, pain was greater on day 1 with PVB, but not different on days 2-3. Hypotension was less common in the PVB group; complications were similar otherwise. Conclusions and RelevancePVB did not reduce the incidence of CPTP at 6 months compared to TEB. TEB appeared to provide marginally better acute pain relief on postoperative day 1, but there was no difference thereafter. Postoperative complications were comparable between groups. The findings support the ongoing utility of both techniques. Trial RegistrationThis trial is registered with ClinicalTrials.gov, NCT03677856. Funding OrganisationNIHR HTA reference-16.111.111 Key PointsO_ST_ABSQuestionC_ST_ABSDoes paravertebral blockade (PVB) reduce the incidence of chronic post-thoracotomy pain (CPTP) compared to thoracic epidural blockade (TEB)? FindingsIn this open-label, allocation-concealed, multicenter randomised clinical trial that included 770 adults, paravertebral blockade did not significantly reduce the incidence of CPTP six months postoperatively compared to thoracic epidural blockade (22% with PVB vs 16% with TEB). MeaningIn adult patients undergoing thoracotomy, providing acute perioperative analgesia with PVB does not reduce the incidence of CPTP compared to TEB.

Background Observational studies have reported an association between inflammation and postoperative complications but it is unclear whether these associations are causal. It is also unknown whether postoperative outcomes share a causal architecture with chronic, all-cause disease. Methods We performed bi-directional two-sample Mendelian randomization to investigate potential causal effects of 19 genetically-proxied inflammatory markers on postoperative acute kidney injury, atrial fibrillation (AF), delirium, myocardial infarction, stroke and surgical site infection, and their all-cause equivalents. Genetic instruments for inflammatory markers were sourced from nine GWAS of up to 204,402 European participants with outcome data derived from UK Biobank. Results The primary postoperative analysis showed a protective effect of down-regulated IL-6 signalling on stroke risk (OR (95% CI) 0.27 (0.11--0.69), p=0.006). However, in the all-cause analysis a causal effect on stroke was not present (OR (95% CI) 1.14 (0.75--1.24), p=0.78), whilst a robust protective effect was seen for down-regulated IL-6 with AF across all three instruments studied (all p<0.009). In postoperative and all-cause analyses, genome-wide variants for CRP showed a protective effect on delirium that was not present in cis-restricted analyses. Conclusions We found evidence supporting a potential causal role for IL-6 signalling in perioperative stroke. However, the divergence in IL-6 effects between postoperative and all-cause outcomes suggests that the inflammatory architecture of acute postoperative complications may differ from chronic disease states. Furthermore, our findings suggest previously reported associations between CRP and delirium likely represent horizontal pleiotropy rather than direct causation. Future work should interrogate local tissue responses and the immediate perioperative period.

BackgroundIntraoperative opioid administration for cardiac surgery varies greatly, with most of this variability arising from anesthesiologist and institutional practices. Anesthesiologists administer intraoperative opioids via intermittent boluses and continuous infusions. Real-world data have shown infusion administration to be a strong determinant of high intraoperative opioid exposure, but whether bolus or infusion administration of sufentanil affects post-operative outcomes is unknown. MethodsWe conducted a prospective, randomized, single-blind controlled trial to compare the impact of intraoperative intermittent bolus administration versus continuous infusion of sufentanil on time to extubation in adult patients undergoing nonemergent cardiac surgery with cardiopulmonary bypass at a single tertiary referral university hospital in the United States. ResultsThe primary endpoint was the time from operating room departure to extubation in the intensive care unit. The study was terminated early for futility after an interim analysis of 50 subjects. The infusion group received statistically higher doses of intraoperative opioid. The per-protocol analysis found no statistical difference in time to extubation between the bolus group (median 2.9 hours) and infusion group (median 2.6 hours). Secondary outcomes, including post-operative pain scores, opioid consumption, ICU length of stay, and hospital stay, and adverse event rates were comparable between groups. ConclusionsIntraoperative administration of sufentanil via bolus or infusion results in similar time to extubation and recovery metrics. Since continuous infusions are a strong predictor of higher total intraoperative opioid doses, protocols emphasizing administration via intermittent boluses may reduce opioid exposure without compromising recovery. Key PointsO_ST_ABSQuestionC_ST_ABSDoes the method of intraoperative sufentanil administration, either by intermittent bolus or infusion, affect weaning from mechanical ventilation in the intensive care unit after cardiac surgery? FindingsThe method of sufentanil administration did not affect time to extubation after cardiac surgery, but the infusion group received significantly higher intraoperative opioid doses compared to the intermittent bolus group. MeaningIntermittent opioid bolus administration may reduce intraoperative opioid dosage without negatively impacting recovery after cardiac surgery.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic multisystem disease characterized by profound fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Its pathophysiology is incompletely understood and likely involves complex interactions between immune, autonomic, and metabolic dysregulation. Despite features with potential relevance for anesthesia and perioperative care, evidence to guide anesthetic management in individuals with ME/CFS remains limited. We therefore performed a retrospective matched-pair analysis to generate clinical data on perioperative responses and identify areas for future research. Methods: We conducted a retrospective matched-pair analysis at a single tertiary center. All patients with ME/CFS undergoing general anesthesia from 2015 to 2026 were identified using ICD-10 codes (G93.3 and U09.9) with additional manual verification and matched 1:1 to controls for comparison. Patients with confounding diagnoses or American Society of Anesthesiologists physical status above III were excluded. The analysis focused on intraoperative hemodynamic parameters, including baseline, post-induction, median, and lowest recorded systolic blood pressure and heart rate, as well as early postoperative outcomes in the post-anesthesia care unit (PACU), including maximum pain scores and requirement for rescue analgesia. Results: Out of 189 individuals identified through ICD-10 codes, 15 matched pairs were included after application of exclusion criteria. ME/CFS patients exhibited lower lowest recorded intraoperative systolic blood pressure (90 [82.5-95.0] mmHg in ME/CFS vs 100 [90.0-110.0] mmHg in controls, p = 0.044) as well as lower lowest heart rate (50 [40.0-57.5] bpm in ME/CFS vs 60 [50.0-65.0] bpm in controls, p = 0.012). Vasopressor use and fluid administration did not differ, and no episodes of severe hypotension or perioperative adverse events were observed. Postoperative pain was higher in ME/CFS, with higher maximum pain scores (NRS 5.0 [4.0-6.0] in ME/CFS vs 1.0 [0.0-4.0] in controls, p = 0.008) and more frequent opioid rescue analgesia (80% in ME/CFS vs 33% in controls, p = 0.039). Postoperative nausea or vomiting, oxygen supplementation, and PACU length of stay were similar between groups. Conclusions: General anesthesia appears hemodynamically well tolerated in individuals with ME/CFS. In contrast, postoperative pain burden is increased and may require tailored analgesic strategies. Post-exertional malaise, a key disease feature with potentially delayed onset and significant impact, was not captured in this study and remains an important target for future research. These hypothesis-generating findings highlight the need for prospective studies to optimize perioperative management and evaluate patient-relevant outcomes in ME/CFS.

BackgroundHypertension therapy in older adults is often suboptimal, in part due to inadequate suppression of the renin-angiotensin-aldosterone system (RAAS). We hypothesised that distinct endotypes of RAAS activation before noncardiac surgery are associated with increased risk of myocardial injury. MethodsThis was a pre-specified analysis of a multicentre randomised controlled trial (ISRCTN17251494) which randomised patients [&ge;]60 years undergoing elective non-cardiac surgery to either continue, or stop, RAAS inhibitors (determined by pharmacokinetic profiles). Unsupervised hierarchical cluster analysis identified distinct groups of patients with similar RAAS activation from samples obtained before induction of anesthesia, quantified by enzyme-linked immunoassays for plasma renin, aldosterone, angiotensin-converting enzyme 2 (ACE2) and dipeptidyl peptidase-3 (DPP3). The primary outcome, masked to investigators and participants, was myocardial injury (plasma high-sensitivity troponin-T). ResultsWe identified three clusters, with similar proportions of RAAS inhibitors randomised to stop/continue. Cluster 1 (n=52; mean age (SD), 75{+/-}8 years; 54% female) and cluster 3 (n=25; 75{+/-}6 years; 44% female) had higher rates of myocardial injury (23/52 (44%) and 13/25 (52%), respectively), compared with 51/164 (31.1%) in cluster 2 (n=153; 70{+/-}6 years; 46% female; odds ratio:1.95, 95% CI:1.12-3.39, p=0.018). Cluster 2 was characterized by lower NT-proBNP (mean difference, 698pg.ml-1, 95% CI, 576-820) and higher renin (mean difference:350pg.ml-1, 95% CI:123-577), compared with clusters 1 and 3 with the higher rate of myocardial injury. ConclusionEffective preoperative RAAS inhibition is associated with lower risk of myocardial injury before non-cardiac surgery, independent of stopping/continuing RAAS inhibitors before surgery.

BackgroundChronic postsurgical pain after caesarean delivery impairs postpartum recovery and maternal quality of life. Existing risk models focus on demographic or procedural factors, limiting opportunities for early intervention. This study developed and prospectively evaluated a biopsychosocial predictive model, SPACE-Postpartum (Sleep, Pain, Affect, Cognition, Energy), which assesses early postpartum symptoms across five domains. MethodsIn this prospective cohort study, adults undergoing caesarean delivery at a tertiary centre completed validated patient-reported outcome measures at baseline, 2 weeks, and 3 months postpartum. Chronic pain was defined as pain at any site persisting >3 months. A five-item model with one early postpartum indicator from each SPACE domain was derived using logistic regression with ridge regularisation, supported by latent class and causal mediation analyses. ResultsOf 143 participants, 100 (70%) completed 3-month follow-up; 40% reported chronic pain. The SPACE ridge model demonstrated good discrimination (AUC 0.76, 95% CI 0.67-0.85) with internal validation and acceptable calibration. Higher acute pain intensity, pain interference, and sleep disturbance, with a trend for reduced perceived control, predicted chronic pain. Latent class analysis identified an early high-burden SPACE profile (52%) associated with greater pain interference at 3 months. Mediation analysis indicated acute pain exerted a direct effect, while sleep disturbance acted as an independent prognostic marker. Exploratory sensitivity analyses suggested potential incremental value of quadratic models (AUC 0.83-0.87), although these risked overfitting in this small dataset. ConclusionsChronic pain after caesarean delivery is common and linked to potentially modifiable early symptoms, particularly sleep disturbance and pain-related interference. Across predictive, phenotypic, and causal analyses, pain and sleep symptoms consistently demonstrated prognostic value. This single-centre proof-of-concept study provides early internal validation of the SPACE-Postpartum model. Multicentre external validation is warranted to confirm generalisability and support development of symptom-informed decision tools.

BackgroundGastric cancer management remains fraught with high morbidity and mortality rates owing to surgical interventions. Postoperative complications and extended hospitalisation profoundly affect patient survival, with elderly and medically compromised patients facing greater risks. We hypothesised that regional anaesthesia may reduce the surgical stress response and thus mortality. Hence, this study was aimed at investigating whether adjunctive application of regional anaesthesia during gastric cancer surgery attenuates the stress response to surgery, thereby improving postoperative survival outcomes. MethodsIn this study, we critically examined the potential role of regional anaesthesia in modulating perioperative immune and inflammatory responses, which are vital for improving oncological outcomes. Previous studies using diverse methodologies have provided heterogeneous and inconclusive results regarding the effectiveness of regional anaesthesia in enhancing cancer-related survival. Our study addresses these inconsistencies using a robust research design that was focused on a well-defined patient cohort. ResultsPreliminary evidence suggests that regional anaesthesia can modulate immune responses. However, its clinical benefits in cancer recurrence and survival have not been consistently demonstrated. The extant literature reflects a gap between preclinical promise and clinical efficacy, with no substantial evidence supporting a reduction in cancer recurrence after gastroesophageal cancer surgery under regional anaesthesia. ConclusionThis study provides new insights into the role of regional anaesthesia in reducing the overall mortality in gastric cancer surgery. By employing stringent inclusion criteria and a well-defined patient cohort, this study aimed to provide clarity in a field marked by inconclusive evidence and guide future clinical practices and high-quality research initiatives.

Background: Postoperative delirium is a common syndrome of acute changes in attention, cognition, and consciousness that may result from inflammation and/or neuroinflammation, but few studies have distinguished the relationships of preoperative and 24-hour postoperative systemic inflammation (i.e. in blood) versus neuroinflammation (i.e. in cerebrospinal fluid, or CSF) in postoperative delirium. Methods: We measured CSF and plasma cytokine levels before and 24-hours after non-cardiac/non-neurologic surgery in 199 patients age [&ge;] 60 years who were enrolled in two prospective cohort studies. Delirium was assessed with the confusion assessment method (CAM), 3-minute diagnostic interview for CAM-defined delirium, or the CAM for the Intensive Care Unit (CAM-ICU) in patients who remained intubated postoperatively and validated chart review. Cytokines were measured with immunoassays for IL-6, IL-7, IL-8, IL-10, IL-16, TARC, MCP-1, and IP-10. Associations of CSF and plasma cytokine levels with postoperative delirium were assessed with univariable and multivariable logistic regression analyses with Holm correction for family-wise error. Results: Surgery was associated with significant changes in nearly all measured CSF and plasma cytokines (p < 0.05) except plasma IL-16 and MCP-1. In multivariable analyses adjusted for preoperative Mini-Mental Status Exam (MMSE) score and surgery duration, higher preoperative CSF IL-6 (OR 1.80, 95% CI 1.18-2.75, Holm p=0.049) and CSF IL-8 (OR 1.94, 95% CI 1.22-3.06, Holm p = 0.040) levels were independently associated with postoperative delirium. Higher 24-hour postoperative CSF IL-10 was nominally associated with delirium (OR 1.57, 95% CI 1.06-2.33, p = 0.026) in a multivariable regression controlling MMSE and surgery duration, but this association did not remain significant after multiple-comparison correction (Holm p = 0.21). No other preoperative or 24-hour postoperative CSF or plasma cytokine levels were associated with delirium (p > 0.05). Conclusions: Surgery elicited robust postoperative changes in CSF and plasma cytokines, but 24-hour postoperative cytokine elevations were not significantly associated with postoperative delirium after multiple-comparison correction. In contrast, elevated preoperative CSF IL-6 and IL-8 levels were associated with postoperative delirium independent of baseline cognitive status and surgery duration. Thus, our findings support an important role for preoperative neuroinflammation in postoperative delirium in older elective surgery patients.

BackgroundNeuromuscular blocking agents (NMBAs) are the leading cause of perioperative anaphylaxis (POA), most reactions being IgE mediated. Allergic sensitization induced by environmental exposure to other quaternary ammonium-containing compounds, such as pholcodine, has been suggested. The aim of this study was to assess the relationship between pholcodine exposure and NMBA-related POA. MethodsALPHO is a multicentre case-control study, comparing pholcodine exposure within a year before anaesthesia between patients with NMBA-related POA (cases) and control patients with uneventful anaesthesia. Each case was matched to two controls by age, sex, type of NMBA, geographic area, and season. Pholcodine exposure was assessed by a self-administered questionnaire and pharmaceutical history retrieved from pharmacy records. The diagnostic values of anti-pholcodine and anti-quaternary ammonium specific IgE (sIgE) were also evaluated. ResultsOverall, 167 cases were matched with 334 controls. NMBA-related POA was significantly associated with pholcodine consumption (OR =4.2; CI95% 2.3-7.0) and occupational exposure to quaternary ammoniums (OR = 6.1; CI95% 2.7-13.6). Anti-pholcodine and anti-quaternary ammonium sIgEs had a high negative predictive value (99.9%) but a very low positive predictive value (< 3%) for identifying NMBA-related POA. ConclusionPatients exposed to pholcodine 12 months prior to NMBA exposure have a significantly higher risk of a NMBA-related POA. The low positive predictive values of pholcodine and quaternary ammonium sIgEs precludes their use to identify a population with a high risk of NMBA-related POA. The strong association of NMBA-related POA with occupational exposure suggests that other environmental factors may also lead to sensitization to NMBAs.

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) and weak opioids such as tramadol are cornerstones of multimodal analgesia, particu-larly in settings with limited access to potent opioids. However, cross-class equianalgesic data comparing these agents remain scarce. This pilot ran-domised controlled trial aimed to explore the analgesic equivalence of ke-torolac, diclofenac, and tramadol administered as premedication in patients undergoing minimally invasive surgery. MethodsIn this double-blind, parallel-group pilot trial, 30 patients scheduled for elective minimally invasive surgery (28 laparoscopic cholecys-tectomies, 2 laparoscopic abdominal wall repairs) under balanced general anaesthesia were randomised to receive intravenous tramadol 150 mg, ke-torolac 60 mg, or diclofenac 150 mg 45 minutes before skin incision. The primary outcome was pain intensity measured using the Numerical Rating Scale (NRS, 0-10) at recovery room arrival (T0) and at 30 (T1), 60 (T2), and 90 (T3) minutes thereafter. Secondary outcomes included Verbal Rating Scale (VRS) scores, rescue morphine consumption, and safety. Between-group comparisons were performed using Kruskal-Wallis tests with Dunn post-hoc corrections; within-group trajectories were analysed using Fried-man tests. Effect sizes were estimated with epsilon-squared and Kendalls W. ResultsAll 30 patients completed the study. At T0 and T1, NRS scores were higher in the ketorolac group (median 1.5 and 3, respectively) compared with tramadol and diclofenac (both median 0 at T0; T1: tramadol 1, diclofenac 2; p < 0.05 for both). However, by T2 and T3, all three groups converged to a median NRS of 2 (p > 0.05 for between-group differences). Rescue analgesia requirements at T1 were 0/10 (tramadol), 3/10 (ketorolac), and 2/10 (diclofenac), with no statistically significant differences (p = 0.19). No hypersensitivity reactions occurred. Within-group analyses showed con-sistent pain trajectories, with Kendalls W ranging from 0.31 (ketorolac) to 0.64 (tramadol). ConclusionsIn this pilot study, equianalgesic doses of tramadol, ke-torolac, and diclofenac provided comparable postoperative pain control over 90 minutes following minimally invasive surgery. All agents were well toler-ated. These findings support the feasibility of a larger definitive trial and offer clinically useful guidance for analgesic selection in resource-limited settings. Trial registrationClinicalTrials.gov - NCT07500454 (retrospectively registered). HighlightsO_LIDouble-blind pilot RCT compared equianalgesic doses of tramadol, ke-torolac, and diclofenac. C_LIO_LIAll three groups converged to median NRS 2 by 60 minutes postoper-atively. C_LIO_LIEarly higher pain in the ketorolac group was partly attributed to age imbalance ({rho}=0.49, p=0.006). C_LIO_LINo hypersensitivity reactions occurred in any group. C_LIO_LIDefinitive trial requires 27 patients per group (90 total with 10% attri-tion). C_LI

BackgroundRegional anesthesia as a sole modality for total shoulder arthroplasty (TSA) remains rare in the U.S., typically <2% of cases. Benefits--reduced opioid use, shorter recovery, fewer airway/general anesthesia complications--are well-known, but real-world ambulatory data remain scarce. We aimed to evaluate efficacy and safety of interscalene block with sedation as the primary anesthesia modality in an outpatient TSA population. MethodsThis retrospective study reviewed 330 adult elective primary TSAs from January 2018 to December 2024 at a tertiary academic center. Interscalene block using 0.5% long acting local anesthetic with sedation was used in all. Primary outcomes included: ambulatory discharge success, conversion to general anesthesia. Secondary outcomes included: PACU duration, time from anesthesia start to ready, complications, 30-day readmission. Data were compared to national benchmarks. ResultsConversion to general anesthesia was required in 4 of 330 cases (1.2%). Ambulatory discharge success rate, was achieved in 95.9% of patients. Mean PACU stay was 57.4 {+/-} 14.8 minutes. Anesthesia start-to-ready time was 12.1 {+/-} 3.6 minutes. No major anesthesia-related complications occurred except for transient hemidiaphragmatic paresis seen in 1.2% of patients. Readmission rate was 2.7%, none anesthesia-related. ConclusionsRegional with sedation anesthesia for TSA demonstrated a high ambulatory discharge success rate with minimal complications. This model is feasible for high-throughput ambulatory centers.

BackgroundPropofol dosing guidelines recommend age-based reductions because hypnotic sensitivity increases in older adults. Most real-world evaluations of induction practice, however, have relied on total weight-normalized dose (mg/kg) rather than estimating cerebral exposure using pharmacokinetic models. Because age-related pharmacokinetic changes alter the relationship between administered dose and peak effect-site concentration (Ce,max), mg/kg surrogates may misrepresent true age-dependent exposure during induction. MethodsA retrospective reconstruction of 250,640 adult anesthetic inductions was performed using high-fidelity EHR medication timestamps. Propofol effect-site concentration trajectories were simulated at 1-second resolution using the Eleveld model. Ce,maxwas benchmarked against age-adjusted hypnotic requirements (Ce50) derived from the Eleveld model (standardized to a target Bispectral Index{approx} 47). Age-exposure relationships were estimated using covariate-adjusted natural cubic splines, controlling for BMI, sex, and ASA physical status. ResultsFrom young adulthood (18-24 years) to the oldest cohort (85-89 years), weight-normalized induction doses were reduced by 32% (3.16 to 2.16 mg/kg). However, modeled Ce,max declined by only 17% (3.70 to 3.06 {micro}g/mL), while the estimated physiological requirement declined by 34% (3.37 to 2.21 {micro}g/mL), creating a widening titration offset with age. At age 75, the adjusted probability of exceeding the individual hypnotic requirement was 89.6% (95% CI: 89.3-89.8%). Notably, 54.7% (95% CI: 54.2-55.2%) of 75-year-old patients achieved peak exposures exceeding the aver-age requirement of a healthy 20-year-old, indicating persistent anchoring of exposure to youthful levels. Findings were robust across model specifications and inclusion criteria. ConclusionsIn over a quarter-million inductions, real-world age-based dose re-ductions did not produce proportional reductions in peak propofol brain exposure. Achieved concentrations declined far more slowly than modeled geriatric sensitivity increases, consistent with systematic over-exposure in older adults. These findings suggest that weight-based dosing heuristics inadequately capture age-dependent exposure and support a transition toward exposure-informed and neurophysiologically guided induction titration in geriatric anesthesia.

BACKGROUNDConventional vital signs lack the specificity for intraoperative nociception. The Surgical Pleth Index (SPI), calculated from photoplethysmographic waveforms, provides a quantitative measure of nociceptive status ranging from 0 to 100. Elevated SPI values correspond to increased nociceptive intensity. While some evidence suggests that SPI may help predict pain, its accuracy in forecasting postoperative pain requires further validation. AIMThis study aimed to assess the capacity of the Surgical Pleth Index (SPI) to predict moderate to severe pain following surgery. METHODSWe conducted a systematic literature search across three databases to identify studies investigating SPIs predictive value for postoperative pain. A random-effects model was applied to pool summary estimates of sensitivity, specificity, and the area under the summary receiver operating characteristic curve (SROC-AUC). RESULTSAnalysis included ten studies encompassing 1,042 patients. Pooled sensitivity and specificity were 0.74 (95% CI: 0.67-0.80) and 0.65 (95% CI: 0.55-0.74), respectively. The SROC-AUC reached 0.76, suggesting a moderate level of predictive accuracy. Significant heterogeneity was observed and not explained by differences in SPI cutoff values. CONCLUSIONThe SPI demonstrates moderate accuracy in forecasting moderate-to-severe postoperative pain and may serve as a useful adjunct to conventional clinical assessment. What is known?The Surgical Pleth Index has been suggested as a reliable monitor for nociceptive states. What new information does this article contribute?The Surgical Pleth Index (SPI) demonstrated moderate accuracy in predicting moderate-to-severe postoperative pain. Current evidence supports its role as a validated supplementary instrument to guide analgesic administration during surgery. Core Tip:This meta-analysis confirms that the Surgical Pleth Index (SPI) provides moderate predictive accuracy for moderate-to-severe postoperative pain and, as such, has a complementary role in guiding intraoperative analgesia, provided its outputs are interpreted within the context of a comprehensive clinical assessment.

Background Informed consent depends on patients' understanding of anaesthesia risk, yet comprehension remains poor despite routine preoperative consultation. Conversational artificial intelligence (AI) could establish patient-reported understanding before clinician contact, but whether such systems can achieve patient-reported understanding comparable to clinician-delivered education remains unknown. Methods We conducted a randomised equivalence trial (n = 130) of PEAR (Preoperative Education of Anaesthesia Risks), a multilingual retrieval-augmented conversational AI grounded in institutional consent materials, versus standard preoperative consultation in adults undergoing elective surgery. Results A total of 130 adults (mean age 52.4 +/- 14.5 years) were enrolled. Post-consultation understanding scores in the PEAR group met the pre-specified equivalence criterion compared with standard consultation across all three primary measures. Patients who interacted with PEAR before clinician contact achieved understanding scores comparable to those receiving standard face-to-face consultation alone. PEAR reduced documentation and consultation time, corresponding to a projected annual net benefit of approximately SGD 0.99 million (USD 0.78 million) at a single tertiary centre. Conclusions A retrieval-augmented conversational AI achieved patient-reported understanding of anaesthesia risk equivalent to standard preoperative consultation while substantially improving workflow efficiency. These findings support supervised deployment of conversational AI within perioperative care pathways while preserving clinician oversight for verification and patient-specific decision-making.

IntroductionPostoperative complications after major surgery have substantial impacts on morbidity and resource utilisation. We investigated whether adding high-dimensional metabolomic and proteomic data to standard clinical variables would improve the prediction of a range of postoperative complications. MethodsWe analysed data from UK Biobank, a large prospective cohort study. Participants who underwent major surgery and had metabolomic and/or proteomic data were included. The primary outcomes were postoperative atrial fibrillation, acute kidney injury, acute myocardial infarction, delirium, stroke and surgical site infection. We trained machine learning models (elastic net penalised regression) with a range of feature sets to predict these outcomes. For outcomes where sample sizes were below recommended levels for predictive modelling, we employed transfer learning from the non-postoperative domain. We compared the predictive performance (AUROC, sensitivity, specificity) of models using only baseline clinical variables with those integrating single- and multiomic datasets. ResultsThe dataset included 158,156 individuals undergoing qualifying surgery. The numbers of cases with omic data varied across outcome phenotypes and feature sets: metabolomic: 144-1596, proteomic: 27-289 and multiomic: 15-219. Baseline clinical models achieved robust predictive performance (AUROC 0.72-0.88, sensitivity 0.71-0.80). The addition of metabolomic and/or proteomic features, using a variety of integration approaches, provided no clinically meaningful improvement in performance across any of the clinical phenotypes. Transfer learning from the non-postoperative domain improved model performance and stability but did not outperform baseline clinical models. ConclusionsThe addition of metabolomic and/or proteomic data from samples collected at a temporal distance from surgery does not improve pre-operative risk prediction compared to standard clinical variables. The lack of incremental predictive value likely reflects the extended gap between biobank sampling and the surgical event. The success of transfer learning from non-postoperative settings suggests shared biological risk between chronic and acute phenotypes.