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.

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.

BackgroundBalancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. Concern about inadequate analgesia after discharge contributes to excessive opioid prescribing, but the benefits of opioid prescription following discharge remains unclear. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures. MethodsThis international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain during the first week following discharge, and patient-reported satisfaction with pain relief 7 days following discharge. Secondary outcomes included patient-reported quality of life, representations to healthcare for inadequately treated pain, and representations for side effects of pain medication. Data were collected by in-hospital chart review and patient telephone interview one week after discharge. Mixed-effects multivariate models, adjusted for patient comorbidity, operative characteristics, postoperative factors, country, and centre, with and without propensity score matching, were used to analyse outcomes. FindingsThe study recruited 4,273 patients from 144 centres in 25 countries. Overall, 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10% (IQR 1 to 30%) of the first week after discharge and rated satisfaction with analgesia as 9/10 (IQR 8 to 10). On negative binomial regression, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio=1.52, 95% CI 1.31 to 1.76, p<0.001) but not with analgesia satisfaction (beta coefficient=0.92, 95% CI -1.52 to 3.36, p=0.468) when compared to opioid-free analgesia. Opioid analgesia on discharge was associated with an increased risk of representation to healthcare providers for medication side effects (OR 2.38 95%CI 1.36 to 4.17, p=0.004). While opioid prescribing varied dramatically between high income and low and middle income countries, patient reported outcomes did not. InterpretationOpioid analgesia prescription on discharge is not associated with decreased pain severity or satisfaction with analgesia after surgical discharge, but is associated with higher risk of representation for medication side effects. For many operations, opioid-free analgesia at surgical discharge should be routinely adopted without concern for uncontrolled pain or reduced patient satisfaction. What this study addsO_ST_ABSEvidence before this studyC_ST_ABSWe conducted a literature search between November 2019 and February 2021 for studies on the relationship between opioid prescription and patient reported satisfaction or pain after discharge from surgery. We searched MEDLINE, Google Scholar and ClinicalTrials.gov using the search terms "opioid", "surgery", "discharge" without any language restrictions. Several single centre and retrospective surgical series examined opioid prescription practices after surgery demonstrating overprescription. Global studies examining variations in opioid prescribing between countries are less common but demonstrate significant global variation in prescription practices. One recent systematic review and meta-analysis examined randomised controlled trials comparing opioid and opioid-free analgesia in the post-surgical-discharge, and showed no difference between the two groups, but was limited to elective minor and moderate surgical procedures. Added value of this studyThis large study provides patient-reported data on pain and patient satisfaction after discharge from surgery. This adds to the previous knowledge by including both minor and major operations in an acute and elective context, and multiple specialties. After adjustment, opioid analgesia on discharge was not associated with decreased time in severe pain or increased patient satisfaction, but was associated with an increased risk of re-presentation for medication side effects. We also demonstrate marked geographical variation in opioid prescribing practices with higher amounts prescribed in high income countries compared to low and middle income countries, without a similar variation in patient reported pain or satisfaction. Implications of all the available evidenceOpioids are often prescribed at the time of discharge from hospital following surgery, but the benefit of post-discharge opioids has been called into question. We found that that opioids do not reduce severity of pain during the first week after discharge and do not increase patient satisfaction. These data suggest that opioid-free analgesia at surgical discharge is feasible without the risk of increased pain or decreased satisfaction, and that opioids should be prescribed more selectively. Variation in opioid prescribing between countries is not associated with variations in pain or satisfaction, and suggests that a more uniform approach to analgesia prescribing is warranted.

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.

BackgroundAlthough transitional pain service (TPS) has been proposed to manage patients at risk for persistent postsurgical opioid use, no standard criteria exist to identify high-risk patients for TPS management. Specifically, the 2-3 months following surgery are critical for the transition from short-term to persistent opioid use, yet little is known about opioid refills during this period. MethodsThis retrospective cohort study included 11,087 adult patients, regardless of opioid-naive status, who underwent spine surgery at an academic medical center and were discharged between January 2017 and December 2023. Data were analyzed using multiple logistic and linear regressions and Fishers exact test. ResultsOf the patients, 25.4% and 14.8% received opioid refills at 31-60 and 61-90 days post-discharge, respectively. Among the independent risk factors, a refill at 31-60 days was the strongest predictor of a refill at 61-90 days (aOR 6.71, 95% CI 5.90-7.65), regardless of preoperative opioid use, cervical or lumbar procedures, or surgical service. Refill rates at 31-60 and 61-90 days were linearly correlated (p<0.0001, slope=0.73). A refill at 31-60 days predicted a refill at 61-90 days with a negative predictive value (NPV) of 94.3% and a positive predictive value of 41.5%, with consistently high NPVs across subgroups defined by preoperative opioid use, surgical procedure, or surgeon. A refill at 1-30 days; preoperative use of opioids, marijuana, and benzodiazepine; the first postoperative pain score recorded on hospital floor; and depression were all associated with increased odds of refills at both 31-60 and 61-90 days. In contrast, the total dose of discharge opioid prescriptions had minimal impact on refills. ConclusionA refill at 31-60 days after discharge may serve as a screening marker for identifying high-risk patients who could benefit from TPS management to mitigate further opioid use. Moreover, each refill prescription should be carefully managed to prevent subsequent refills.

BackgroundSocial Determinants of Health (SDoH) continue to drive persistent disparities in perioperative care. Our team has previously demonstrated racial and socioeconomic disparities in perioperative processes, notably in the administration of antiemetic prophylaxis, in several large perioperative registries. Given how neighborhoods are socially segregated in the US, we examined geospatial clustering of perioperative antiemetic disparities. MethodsWe conducted a retrospective cohort study of anesthetic records from the University of Utah Hospital with 19,477 patients meeting inclusion criteria. We geocoded patient home addresses and combined them with the Census Block Group(CBG) level neighborhood disadvantage (ND), a composite index of from the National Neighborhood Data Archive (NaNDA). We stratified our patients by antiemetic risk score and calculated the number of anti-emetic interventions. We utilized Poisson Spatial Scan Statistics, implemented in SaTScan, to detect geographic clusters of under-treatment. ResultsWe identified one significant cluster (p < .001) of undertreated perioperative antiemetic prophylaxis cases. The relative risk (RR) of the whole cluster is 1.44, implying that patients within the cluster are 1.44 times more likely to receive fewer antiemetics after controlling for antiemetic risk. Patients from more disadvantaged neighborhoods were more likely to receive below median antiemetic prophylaxis after controlling for risk. ConclusionsTo our knowledge, this is the first geospatial cluster analysis of perioperative process disparities; we leveraged innovative geostatistical methods and identified a spatially defined, geographic cluster of patients whose home address census-tract level neighborhood deprivation index predicted disparities in risk adjusted antiemetic prophylaxis.

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.

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.

ImportancePrehabilitation (prehab) programs are increasingly recognized for their potential to improve surgical outcomes. However, their efficacy remains debated, largely due to a lack of pathophysiologically-driven implementation and limited personalization. ObjectiveTo determine the impact of personalized versus standard prehab on preoperative physical, cognitive, and immune function and postoperative outcomes. Design, Setting, and ParticipantsIn this prospective, single-blinded, interventional trial conducted from October 2020 to April 2024 in a single academic medical center, 58 patients undergoing major elective surgery were randomized to standard (n=30) or personalized prehab (n=28) using block randomization. InterventionThe personalized group received weekly remote coaching tailored to individual progress in four domains (nutrition, physical activity, cognitive training, and mindfulness), while the standard group followed a paper-based program without individualized support. Main Outcomes and MeasuresPrimary clinical outcomes included cognitive assessments and physical performance measures, including the Wall Squat Test, Timed-up-and-go Test, 6-Minute Walk Test (6MWT). The primary immunological outcomes included major innate and adaptive immune cell frequencies and intracellular signaling responses measured using a 47-plex mass cytometry immunoassay. ResultsFifty-four of 58 patients completed the study (n=27 per group). The personalized group exhibited significant improvements in physical measures (e.g., 6MWT; p=0.03) and fewer severe postoperative complications (4 vs. 11 Clavien-Dindo grade >1; p=0.04). Multivariable modeling identified profound and cell-type specific immune alterations post-prehab compared to baseline (AUROC=0.88 [0.79, 0.97], p=2-06; leave-one-out cross-validation), including dampened pERK1/2 signaling in classical monocytes and myeloid-derived suppressor cells after interleukin (IL)-2,4,6 stimulation, and reduced pCREB signaling in Th1 cells. In contrast, the standard group showed only moderate clinical improvements and no immune changes (AUROC=0.63, p=0.11). Conclusions and RelevanceOur study demonstrates personalized prehab significantly altered the immunome before surgery, dampening inflammatory signaling responses previously implicated in the pathophysiology of key surgical outcomes, including surgical site infections and postoperative neurocognitive decline. These changes were accompanied by improved physical and cognitive function before surgery and decreased postoperative complications. Our findings support utilization of personalized prehab and provide an avenue for biologically-driven risk- stratification for patient selection, and individual tailoring of programs to optimize surgical readiness and recovery. Trial Registration: NCT04498208 KEY POINTS QuestionHow do personalized prehabilitation programs modulate the peripheral immune system in patients undergoing major elective surgery? FindingsIn a randomized trial, patients scheduled for major elective surgery received either personalized or standard prehabilitation. High-dimensional immune profiling with mass cytometry revealed profound and cell type-specific dampening of pro-inflammatory signaling responses in the personalized prehabilitation group (AUROC=0.88, n=27), but not in the standard group (AUROC=0.63, n=27). Patients in the personalized prehabilitation group also showed significant improvements in both physical and cognitive function, with significantly fewer severe postoperative complications (4 vs. 11). MeaningPersonalized prehabilitation dampens patients pre-operative inflammatory state and enhances recovery by improving physical and cognitive outcomes, suggesting tailored interventions may optimize surgical preparedness and reduce complications.

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.

PurposeWe investigated if the use of peripheral nerve blockade (PNB) was associated with a lower incidence of prescription opioid fill within 30 days post-surgery and persistent postoperative opioid use (PPOU) in patients undergoing foot and ankle surgery. MethodsWe identified adults who had undergone foot or ankle surgery between 2012 and 2018 and did or did not receive PNB in an Optums de-identified Integrated Claims-Clinical dataset (n=12,643). Pharmacy data was used to track opioid prescription fill date and supply. PPOU was defined as >90 days of continuous opioid use. Entropy balancing was used to control differences in the distribution of covariates. Log-binomial models in unweighted and weighted data estimated crude and adjusted relative risk (RR) with 95% confidence intervals (CI) for the outcomes. ResultsOne-third of the sample filled an opioid within 30 days of surgery, and among these patients, 57.3% continued use for > 90 days. Performance of PNB was associated with an increased risk for filling opioid prescriptions within 30 days post-surgery before (RR=1.40; 95%CI:1.32-1.49) and after (RR=1.31; 95%CI:1.22-1.41; p<0.0001) controlling for confounding. However, the group that received a PNB showed significantly lower risk of PPOU before (0.91; 95%CI:0.85-0.98; p=0.016) and after controlling for confounding (RR=0.92; 95%CI:0.85-0.99; p=0.029). ConclusionPerformance of PNB for patients undergoing foot and ankle surgery was associated with a 31% increased risk of any opioid prescription fill within 30 days after surgery. However, among the patients that initially filled their prescriptions, patients that received PNB had a significantly (8%) lower risk for PPOU.

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.

BackgroundA growing body of literature suggests that intraoperative opioid administration can lead to both increased post-operative pain and opioid requirements. However, there has been minimal data regarding the effects of the intraoperative administration of intermediate duration opioids such as hydromorphone on post-operative outcomes. Causal inference using observational studies is often hampered by unmeasured confounding, where classical adjustment techniques, such as multivariable regression, are insufficient. Instrumental variable analysis is able to generate unbiased causal effect estimates in the presence of unmeasured confounding, assuming a valid instrumental variable can be found. We previously demonstrated, using a natural experiment, how hydromorphone presentation dose, i.e. the unit dose provided to the clinician, affects intraoperative administration dose, with the switch from a 2-mg to a 1-mg vial associated with decreased administration. As the change in hydromorphone presentation dose was unrelated to any external factors, presentation dose could serve as an instrumental variable to estimate the effect of intraoperative hydromorphone administration dose on post-operative outcomes. MethodsIn this observational study with 6,751 patients, an instrumental variable analysis was employed to estimate the causal effect of an increased intraoperative administration dose of hydromorphone on post-operative pain and opioid administration. The study population included patients who received intraoperative hydromorphone as part of an anesthetic at the University of California, Los Angeles, from October 2016 to November 2018. Before July 2017, hydromorphone was available as a 2-mg unit dose. From July 1, 2017 to November 20, 2017, hydromorphone was only available in a 1-mg unit dose. A two-stage least squares regression analysis was performed to estimate the effect of intraoperative hydromorphone administration dose on post-operative pain scores and opioid administration. ResultsAn increase in hydromorphone administration caused a statistically significant decrease in Post-Anesthesia Care Unit pain scores as well as maximum and mean pain scores on post-operative days one and two, without a statistically significant effect on post-operative opioid administration. Various sensitivity analyses support the validity of the instrumental variable assumptions and suggest that the results are robust against violations of these assumptions. ConclusionsThe results of this study suggests that the intraoperative administration of intermediate duration opioids do not cause the same effects as short acting opioids with respect to post-operative pain. Instrumental variables, when identified, can be invaluable in estimating causal effects using observation data whereby unmeasured confounding is likely present.

BackgroundChronic postsurgical pain after caesarean delivery affects 10-20% of women at 3-6 months postpartum, yet its broader impact on recovery is underexplored. This study examined lived experiences of chronic postsurgical pain and identified key domains of impact. MethodsTwenty-four women with self-reported pain at 3-6 months after intrapartum or planned caesarean delivery were recruited from two prospective studies. Semi-structured interviews, conducted in English or Spanish via secure video call, were transcribed and analysed using inductive reflexive thematic analysis. ResultsParticipants described a multidimensional, interconnected symptom burden. Pain persisted or worsened unpredictably, interfering with mobility, infant care, and daily life. Poor sleep and fatigue compounded distress. Cognitive and affective disruptions, including anxiety and fear, were common. Many avoided strong analgesics due to concerns about alertness or breastfeeding. Participants sometimes reported feeling dismissed or unsupported by healthcare professionals. Ten themes were identified: pain and sensory disruption; functional limitations and fatigue; interference with infant care and identity; psychological distress and cognitive load; sleep disruption; control and coping; intimacy and embodied recovery; healthcare gaps; peer and online normalisation; and reflections on future health. ConclusionsChronic pain after caesarean rarely occurs in isolation. Inter-related symptoms across sleep, pain, affect, cognition, and energy domains contribute to the lived experience of chronic caesarean delivery pain. These findings align with the multidomain SPACE-Postpartum framework, and support its further evaluation as a model for understanding and predicting postpartum pain outcomes. HighlightsO_LIChronic postsurgical pain (CPSP) after caesarean delivery is a multidimensional burden beyond pain intensity. C_LIO_LITen CPSP themes spanned physical, emotional, social, and care impacts. C_LIO_LISymptoms reinforced each other, compounding recovery challenges. C_LIO_LINarratives align with the SPACE (Sleep, Pain, Affect, Cognition, Energy) - Postpartum framework of domains. C_LI

BackgroundNeuroinflammation is thought to contribute to postoperative central nervous system (CNS)-related complications, and the apolipoprotein E (APOE)-mimetic peptide CN-105 blocks neuroinflammation in animal models. Thus, here we examined postoperative cerebrospinal fluid (CSF) proteome changes and their modulation by CN-105. ObjectiveTo evaluate postoperative changes in the CSF proteome, and their modulation by the APOE mimetic peptide CN-105. MethodsWe performed mass spectrometry-based proteomics on preoperative and 24-hour postoperative CSF samples from 137 non-cardiac/non-neurologic surgery MARBLE trial patients (age>60; ct.gov identifier: NCT03802396), who were randomized to receive APOE mimetic peptide CN-105 (or placebo), and in an independent replication cohort. Linear regression evaluated postoperative changes in CSF protein and pathway scores (quantified by singe set gene set enrichment assay [ssGSEA] pathway scores), with false discovery rate (FDR)-based multiple comparison correction. Results24-hour postoperative changes were observed in 881 of 2,086 proteins (57 of which showed a log2 fold change >0.5 or <-0.5) and in 1001 of 1854 pathways (p-FDR<0.05). Similar magnitude temporal effects were seen in these proteins and pathways in a replication cohort. The most significantly upregulated CSF pathways involved smooth muscle cell migration/regulation or apoptotic signaling/regulation; the 5 most significantly downregulated CSF pathways included NF-{kappa}B signal transduction regulation, leukocyte apoptotic process, and sulfur and proteoglycan metabolic processes. There was no significant CN-105 effect on 24-hour postoperative changes in CSF protein levels or ssGSEA pathway scores (p-FDR>0.05 for all). ConclusionsSignificant postoperative changes occurred in over 40% of proteins and over 50% of pathways in the CSF, particularly in smooth muscle, endothelial, leukocyte, and apoptosis pathways.

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.

BackgroundSpinal anaesthesia is commonly used for many surgical procedures. One of its potential complications is arterial hypotension, which is nowadays prevented by an empirical fluid administration without any hemodynamic status assessment. However, this practice could increase the risk of volume overload in cardiovascular high-risk patients. Two non-invasive tests are performed to identify fluid-responsiveness: the Inferior Vena Cava Ultrasound (IVCUS) and the Passive Leg Raising Test (PLRT). Aim of this post-hoc analysis was to compare these two methods in spontaneous-breathing patients to assess fluid responsiveness before spinal anaesthesia. Primary outcome was to analyze the incidence of arterial hypotension after spinal anaesthesia in elective surgery patients. Secondary endpoints compared the total fluids amount, the vasoactive drugs administered and the time needed to accomplish the whole procedure in both groups. ResultsThe patients analyzed were 132 in the IVCUS group and 148 in the PLRT group; 39.6% of all patients developed arterial hypotension after spinal anaesthesia, 34.8% in the IVCUS group and 43.9% in the PLRT group (Chi-square 2.39, df = 1, p = 0.77). The mean total fluids amount was 794 {+/-} 592 ml; 925 {+/-} 631 ml for IVCUS group and 678 {+/-} 529 ml for PLRT group (p < 0.001). Patients needed vasoactive drugs to restore normal arterial pressure were 18.2% of total, 15% in the IVCUS group and 20% in the PLRT group (p = 0.136). The mean time required to complete the entire procedure was 52 {+/-} 18 min, 48 {+/-} 10 min in the IVCUS group and 56 {+/-} 13 min in the PLRT group (p < 0.001). Complications or out of protocol treatment were registered in 4.6% patients. ConclusionsFluid responsiveness assessment in spontaneous breathing patients before spinal anaesthesia could potentially prevent the risk of post-spinal hypotension. In elective surgery, IVCUS could be an accurate method to guide fluid administration in patients undergoing spinal anaesthesia, reducing the incidence of post-spinal hypotension when compared to PLRT.

BackgroundBuprenorphine use in the intensive care unit (ICU) remains not well studied despite growing perioperative guidance supporting its continuation and initiation for patients with opioid use disorder (OUD). Trauma ICU admissions represent a critical opportunity to address untreated OUD, as well as continuation of an already established treatment plan for OUD, yet barriers limit its adoption in this setting. MethodsThis single-center quality improvement study evaluated for inpatient buprenorphine prescribing patterns following provider education at a tertiary academic trauma center. Adult trauma ICU patients with OUD admitted between 2016-2024 were identified through the institutional trauma registry. Patients with pre-admission buprenorphine were excluded, yielding a cohort of 95 patients: 24 buprenorphine-exposed (initiated in the hospital) and 71 controls. Primary outcomes included pain scores and opioid requirements (morphine milligram equivalents, MME) during the first 48 hours. Secondary outcomes included hospital length of stay (LOS), discharge disposition, and 90-day readmission. ResultsBaseline characteristics were similar between groups. No statistically significant differences were observed in first recorded pain scores (median 8 vs. 10; p=0.35), mean 48-hour pain scores (7.40 vs. 7.76; p=0.44), or total opioid consumption (232 vs. 119 mg MME; p=0.45). Median hospital LOS (16 vs. 19 days; p=0.48) and 90-day readmission rates (42.3% vs. 33.3%; p=0.40) were also comparable. ConclusionInpatient buprenorphine initiation in trauma ICU patients with OUD was not associated with worse pain control, increased opioid requirements, or adverse clinical outcomes. These findings support the integration of buprenorphine into critical care pathways as a safe strategy to address OUD during hospitalization and improve long-term recovery continuity.

BackgroundIntraoperative hypertension (IOH) is a frequent anesthetic challenge linked to myocardial ischemia, arrhythmias, cerebrovascular events, and increased surgical bleeding. Despite its impact, structured evaluation of IOH management is inconsistent, especially in resource-limited hospitals. ObjectiveTo evaluate recognition, documentation, precipitating causes, and management of IOH at THQ Hospital Sadiq Abad, and to identify gaps relative to accepted standards. MethodsA retrospective audit of 75 adult patients (18-75 years) with documented IOH episodes from January to June 2025 was conducted. Data extracted from anesthesia records included demographics, ASA grade, type of surgery, anesthetic technique, recorded trigger(s), interventions, and immediate outcomes. Audit standards were adapted from the Association of Anaesthetists peri-operative hypertension guidance. Descriptive statistics were used to summarize findings and guide recommendations. ResultsIOH was documented in all 75 cases (100%). A precipitating cause was recorded in 52%. The most common first-line response was deepening anesthesia (42%), followed by opioid boluses (28%) and antihypertensives (16%). Targeted correction of reversible triggers (e.g., bladder decompression, ventilatory adjustment) was documented in 14%. No peri-operative mortality occurred; however, prolonged IOH (>15 minutes) was noted in a minority of cases. ConclusionWhile recognition of IOH was universal, documentation of triggers and targeted, protocolized management were suboptimal. Introducing a structured proforma, theatre-posted algorithms, and focused teaching--followed by re- audit in 6-12 months--may improve patient safety.

PurposeThere is mounting evidence supporting a role for intranasal (IN) ketamine for procedural sedation in children due to its less invasive delivery. Drug administration and monitoring is largely performed by nurses and clinical uptake requires understanding their perceptions. We explored nursing perspectives of IN ketamine for procedural sedation in children to understand facilitators and barriers and inform institutional guidelines. Design and MethodsFrom January to February, 2018, we conducted 2 focus groups with 8 registered nurses in a Canadian tertiary care paediatric ED. Following professional transcription, data were analyzed using an inductive qualitative approach. ResultsSeven of 8 participants had experience administering IN ketamine to children for procedural sedation. Nurses perceived that IN ketamine had the potential to reduce childrens distress and improve nursing resource use. Perceived barriers included: 1) uncertainty regarding sedation effectiveness and incorporation into institutional sedation protocols, 2) perceptions that IN ketamine produced a relatively lighter, slower-onset, and less titratable sedation, and 3) healthcare providers lack of familiarity with IN ketamine and reluctance to change their current approach to sedation. ConclusionsWe identified barriers to adoption of IN ketamine such as uncertainty regarding its pharmacodynamic properties, safety, and impact on workflow, along with facilitators such as fewer adverse events and nursing resources, and less procedural distress for children. Practice ImplicationsProvider education should focus on IN ketamines pharmacodynamic properties and development of institutional sedation guidelines that define indications for use, support engagement of child life specialists, and operationalize the type and duration of monitoring requirements. CLINICIANS CAPSULEO_ST_ABSWhat is known about the topic?C_ST_ABSO_LIIntranasal ketamine is an emerging agent for procedural sedation and analgesia in the emergency department due to ease of administration. C_LI What did this study ask?O_LIWhat are paediatric nurses perspectives on intranasal ketamine for procedural sedation among children in the emergency department? C_LI What did this study find?O_LINurses identified advantages to intranasal ketamine but expressed considerable uncertainty regarding its pharmacodynamic properties and its incorporation into clinical practice. C_LI Why does this study matter to clinicians?O_LIProvider education may overcome some uncertainty and should focus on intranasal ketamines pharmacodynamic properties and incorporation into institutional sedation protocols. C_LI MeetingsPediatric Academic Societies (Baltimore, Maryland, April 30, 2019); Canadian Association of Emergency Physicians (Halifax, Nova Scotia, May 29, 2019); Canadian Paediatric Society (Toronto, Ontario, June 7, 2019)