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Stratifying preoperative risk and guiding perioperative therapy objectively has acquired critical importance, given robust data demonstrating that morbidity following non-cardiac surgery confers substantially increased risk of death, even beyond hospital discharge. The development of useful perioperative biomarkers depends fundamentally on both prospective morbidity data that enable the identification of higher risk patients as well as the translational understanding of pathophysiological mechanisms underlying postoperative organ dysfunction, the development of which may be specific to the perioperative environment. The emergence of cardiac insufficiency, rather than cardiac ischaemia, as the dominant factor associated with excess risk of prolonged postoperative morbidity has promoted the application of biomarkers used commonly in cardiovascular medicine. Several novel, organ specific biomarkers offer potential perioperative application. Nevertheless, common tests/biomarkers that are widely available do provide valuable, objective information that is perhaps under-utilised perioperatively. Despite significant challenges, perioperative medicine presents exciting-arguably unique-opportunities for novel biomarker development. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To explore the hypothesis that beta-1 adrenoreceptor blockade may be protective through the attenuation of sympathetic hyperactivity and catecholaminergic inflammatory effects on cardiac and hepatic function. DESIGN: Prospective, randomized, controlled study. SETTING: Animal laboratory in a university medical center. SUBJECTS: Male adult Wistar rats. INTERVENTIONS: Peripheral beta1-adrenoceptor blockade through daily intraperitoneal injection (metoprolol, 100 mg x kg(-1); atenolol, 6 mg x kg(-1)) or central nervous system beta1-adrenoceptor blockade (intracerebroventricular metoprolol, 25 microg) to achieve approximately 20% heart rate reduction in rats for 2 days before or after the induction of lethal endotoxemia, cecal ligation and puncture, or fecal peritonitis. MEASUREMENTS AND MAIN RESULTS: Peripheral beta1-adrenoceptor blockade established for 2 days before lethal endotoxemia markedly improved survival in both metoprolol-treated (n = 16; log rank test, p = .002) and atenolol-treated (n = 15; p = .03) rats. Overall mortality in cecal ligation and puncture was similar between metoprolol (40%; n = 10) and saline (50%; n = 10) pretreatment (p = .56), but the median time to death was increased by 33 hrs in metoprolol-treated rats (p = .03). Metoprolol pretreatment reduced hepatic expression of proinflammatory cytokines and lowered plasma interleukin-6 (both p < .05). Myocardial protein expression of interleukin-18 and monocyte chemoattractant protein-1, key mediators of cardiac dysfunction in sepsis, were also reduced (p < .05). Peripheral beta1-adrenoceptor blockade commenced 6 hrs after lethal endotoxemia or fecal peritonitis did not improve survival. However, arterial blood pressure was preserved and left ventricular contractility restored similar to that found in nonseptic controls. Central nervous system beta1-adrenoceptor blockade (metoprolol) did not reduce plasma cytokines or mortality, despite enhancing parasympathetic tone. CONCLUSIONS: Peripheral beta1-adrenoceptor blockade offers anti-inflammatory and cardioprotective effects, with mortality reduction if commenced before a septic insult. Its role in sepsis should be explored further. [ABSTRACT FROM AUTHOR]

Introduction: Battle's sign is a classical clinical sign that has long been held to be synonymous with fracture of the basal skull. As such the presence of Battle's sign is a strong indicator that a basal skull fracture could be present in the head injured patient, as exemplified by its inclusion as a major risk factor in scoring systems designed to assess the likelihood of basal skull fracture.Discussion: We present a case that describes the occurrence of this classic clinical sign in an unlikely setting and, for the first time since it was described more than 120 years ago, re-examine the pathologic basis for its appearance. [ABSTRACT FROM AUTHOR]

Background and Aims: Vagal parasympathetic dysfunction is strongly associated with impaired exercise tolerance, indicating that coordinated autonomic control is essential for optimizing exercise performance. This study tested the hypothesis that autonomic neuromodulation by non-invasive transcutaneous vagus nerve stimulation (tVNS) can improve exercise capacity in humans., Methods: This single-centre, randomized, double-blind, sham-controlled, crossover trial in 28 healthy volunteers evaluated the effect of bilateral transcutaneous stimulation of vagal auricular innervation, applied for 30 min daily for 7 days, on measures of cardiorespiratory fitness (peak oxygen consumption (VO2peak)) during progressive exercise to exhaustion. Secondary endpoints included peak work rate, cardiorespiratory measures, and the whole blood inflammatory response to lipopolysaccharide ex vivo., Results: tVNS applied for 30 min daily over 7 consecutive days increased VO2peak by 1.04 mL/kg/min (95% CI: .34-1.73; P = .005), compared with no change after sham stimulation (-0.54 mL/kg/min; 95% CI: -1.52 to .45). No carry-over effect was observed following the 2-week washout period. tVNS increased work rate (by 6 W; 95% CI: 2-10; P = .006), heart rate (by 4 bpm; 95% CI: 1-7; P = .011), and respiratory rate (by 4 breaths/min; 95% CI: 2-6; P < .001) at peak exercise. Analysis of the whole blood transcriptomic response to lipopolysaccharide in serial samples obtained from five participants showed that tVNS reduced the inflammatory response., Conclusions: Non-invasive vagal stimulation improves measures of cardiorespiratory fitness and attenuates inflammation, offering an inexpensive, safe, and scalable approach to improve exercise capacity., (© The Author(s) 2025. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Hypertension therapy in older adults is often suboptimal, in part because of 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., Methods: This was a prespecified exploratory analysis of a multicentre randomised controlled trial (ISRCTN17251494) which randomised patients ≥60 yr old undergoing elective noncardiac 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 anaesthesia, quantified by enzyme-linked immunoassays for plasma renin, aldosterone, angiotensin-converting enzyme 2, and dipeptidyl peptidase-3. The primary outcome, masked to investigators and participants, was myocardial injury (plasma high-sensitivity troponin-T)., Results: We identified three clusters, with similar proportions of RAAS inhibitors randomised to stop or continue. Cluster 1 (n=52; mean age [standard deviation], 75 yr [8 yr]; 54% female) and cluster 3 (n=25; 75 yr [6 yr]; 44% female) had higher rates of myocardial injury (23/52 [44%] and 13/25 [52%], respectively), compared with cluster 2 with 51/164 (31.1%; n=153; 70 yr [6] yr; 46% female; odds ratio: 1.95, 95% confidence interval (CI) 1.12-3.39, P=0.018). Cluster 2 was characterised by lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration (mean difference 698 pg ml -1 , 95% CI 576-820 pg ml -1 ) and higher renin concentration (mean difference 350 pg ml -1 , 95% CI 123-577 pg ml -1 ), compared with clusters 1 and 3 which had higher rates of myocardial injury., Conclusions: This mechanistic exploratory analysis suggests that effective preoperative RAAS inhibition is associated with lower risk of myocardial injury after noncardiac surgery, independent of stopping or continuing RAAS inhibitors before surgery., Clinical Trial Registration: ISRCTN17251494., Competing Interests: Declarations of interest GLA, RMP, DB, TEFA receive support from NIHR (National Institute for Health and Care Research). GLA and RMP are editors of the British Journal of Anaesthesia, and TEFA is the social media editor. The remaining authors have no disclosures to report., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Targeted beta-blockade after severe traumatic brain injury may reduce secondary brain injury by attenuating the sympathoadrenal response. The potential role and optimal dosage for esmolol, a selective, short-acting, titratable beta-1 beta-blocker, as a safe, putative early therapy after major traumatic brain injury has not been assessed., Methods: We conducted a single-center, open-label dose-finding study using an adaptive model-based design. Adults (18 years or older) with severe traumatic brain injury and intracranial pressure monitoring received esmolol within 24 h of injury to reduce their heart rate by 15% from baseline of the preceding 4 h while ensuring cerebral perfusion pressure was maintained above 60 mm Hg. In cohorts of three, the starting dosage and dosage increments were escalated according to a prespecified plan in the absence of dose-limiting toxicity. Dose-limiting toxicity was defined as failure to maintain cerebral perfusion pressure, triggering cessation of esmolol infusion. The primary outcome was the maximum tolerated dosage schedule of esmolol, defined as that associated with less than 10% probability of dose-limiting toxicity. Secondary outcomes include 6-month mortality and 6-month extended Glasgow Outcome Scale score., Results: Sixteen patients (6 [37.5%] female patients; mean age 36 years [standard deviation 13 years]) with a median Glasgow Coma Scale score of 6.5 (interquartile range 5-7) received esmolol. The optimal starting dosage of esmolol was 10 μg/kg/min, with increments every 30 min of 5 μg/kg/min, as it was the highest dosage with less than 10% estimated probability of dose-limiting toxicity (7%). All-cause mortality was 12.5% at 6 months (corresponding to a standardized mortality ratio of 0.63). One dose-limiting toxicity event and no serious adverse hemodynamic effects were seen., Conclusions: Esmolol administration, titrated to a heart rate reduction of 15%, is feasible within 24 h of severe traumatic brain injury. The probability of dose-limiting toxicity requiring withdrawal of esmolol when using the optimized schedule is low. Trial registrationI SRCTN, ISRCTN11038397, registered retrospectively January 7, 2021 ( https://www.isrctn.com/ISRCTN11038397 )., Competing Interests: Conflicts of interest: North Bristol NHS Trust (MT and KH); University of the West of England, Bristol (PW); Queen Mary University of London (GLA); and University of Bristol (LC and AEP) received funding from the National Institute for Health and Care Research for this study. AR, CB, and TB have no conflicts of interest to declare. Ethical Approval/Informed Consent: The study described in this article adheres to the ethical guidelines laid down in the Declaration of Helsinki (1964), has Health Research Authority approval, and seeks to obtain informed consent from all participants., (© 2024. The Author(s).)

Recent epidemiological studies suggest that chronic pain is a clinically under-recognised cause for cardiovascular morbidity and mortality. Up to 30% of patients undergoing surgery report chronic pain, but the impact of pre-existing pain on postoperative cardiovascular outcomes is not known. Chronic pain and cardiovascular dysfunction share fundamental pathological mechanisms. Chronic pain is a modifiable risk factor for perioperative cardiovascular morbidity., Competing Interests: Declaration of interest GLA is an editor of the British Journal of Anaesthesia. The authors declare no other conflicts., (Copyright © 2024 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply 1,2 . Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism 3,4 , but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood 5,6 . Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3',5'-monophosphate-protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory., (© 2024. The Author(s).)

Sepsis, the dysregulated host response to infection causing life-threatening organ dysfunction, is a global health challenge requiring better understanding of pathophysiology and new therapeutic approaches. Here, we applied high-throughput tandem mass spectrometry to delineate the plasma proteome for sepsis and comparator groups (noninfected critical illness, postoperative inflammation, and healthy volunteers) involving 2612 samples (from 1611 patients) and 4553 liquid chromatography-mass spectrometry analyses acquired through a single batch of continuous measurements, with a throughput of 100 samples per day. We show how this scale of data can delineate proteins, pathways, and coexpression modules in sepsis and be integrated with paired leukocyte transcriptomic data (837 samples from n = 649 patients). We mapped the plasma proteomic landscape of the host response in sepsis, including changes over time, and identified features relating to etiology, clinical phenotypes (including organ failures), and severity. This work reveals subphenotypes informative for sepsis response state, disease processes, and outcome; identifies potential biomarkers; and advances opportunities for a precision medicine approach to sepsis.

Background: Patients with elevated preoperative plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP >100 pg ml -1 ) experience more complications after noncardiac surgery. Individuals prescribed renin-angiotensin system (RAS) inhibitors for cardiometabolic disease are at particular risk of perioperative myocardial injury and complications. We hypothesised that stopping RAS inhibitors before surgery increases the risk of perioperative myocardial injury, depending on preoperative risk stratified by plasma NT-proBNP concentrations., Methods: In a preplanned analysis of a phase 2a trial in six UK centres, patients ≥60 yr old undergoing elective noncardiac surgery were randomly assigned either to stop or continue RAS inhibitors before surgery. The pharmacokinetic profile of individual RAS inhibitors determined for how long they were stopped before surgery. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury (plasma high-sensitivity troponin-T ≥15 ng L -1 or a ≥5 ng L -1 increase, when preoperative high-sensitivity troponin-T ≥15 ng L -1 ) within 48 h after surgery. The co-exposures of interest were preoperative plasma NT-proBNP (< or >100 pg ml -1 ) and stopping or continuing RAS inhibitors., Results: Of 241 participants, 101 (41.9%; mean age 71 [7] yr; 48% females) had preoperative NT-proBNP >100 pg ml -1 (median 339 [160-833] pg ml -1 ), of whom 9/101 (8.9%) had a formal diagnosis of cardiac failure. Myocardial injury occurred in 63/101 (62.4%) subjects with NT-proBNP >100 pg ml -1 , compared with 45/140 (32.1%) subjects with NT-proBNP <100 pg ml -1 {odds ratio (OR) 3.50 (95% confidence interval [CI] 2.05-5.99); P<0.0001}. For subjects with preoperative NT-proBNP <100 pg ml -1 , 30/75 (40%) who stopped RAS inhibitors had myocardial injury, compared with 15/65 (23.1%) who continued RAS inhibitors (OR for stopping 2.22 [95% CI 1.06-4.65]; P=0.03). For preoperative NT-proBNP >100 pg ml -1 , myocardial injury rates were similar regardless of stopping (62.2%) or continuing (62.5%) RAS inhibitors (OR for stopping 0.98 [95% CI 0.44-2.22])., Conclusions: Stopping renin-angiotensin system inhibitors in lower-risk patients (preoperative NT-proBNP <100 pg ml -1 ) increased the likelihood of myocardial injury before noncardiac surgery., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Assay-specific increases in circulating cardiac troponin are observed in 20-40% of patients after noncardiac surgery, depending on patient age, type of surgery, and comorbidities. Increased cardiac troponin is consistently associated with excess morbidity and mortality after noncardiac surgery. Despite these findings, the underlying mechanisms are unclear. The majority of interventional trials have been designed on the premise that ischaemic cardiac disease drives elevated perioperative cardiac troponin concentrations. We consider data showing that elevated circulating cardiac troponin after surgery could be a nonspecific marker of cardiomyocyte stress. Elevated concentrations of circulating cardiac troponin could reflect coordinated pathological processes underpinning organ injury that are not necessarily caused by ischaemia. Laboratory studies suggest that matching of coronary artery autoregulation and myocardial perfusion-contraction coupling limit the impact of systemic haemodynamic changes in the myocardium, and that type 2 ischaemia might not be the likeliest explanation for cardiac troponin elevation in noncardiac surgery. The perioperative period triggers multiple pathological mechanisms that might cause cardiac troponin to cross the sarcolemma. A two-hit model involving two or more triggers including systemic inflammation, haemodynamic strain, adrenergic stress, and autonomic dysfunction might exacerbate or initiate acute myocardial injury directly in the absence of cell death. Consideration of these diverse mechanisms is pivotal for the design and interpretation of interventional perioperative trials., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin-angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear., Methods: From 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin-angiotensin system inhibitors were withheld for different durations (2-3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy., Results: Two hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45-1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16-1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)]., Conclusions: Discontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Introduction: Patients undergoing vascular procedures are prone to developing postoperative complications affecting their short‑term mortality. Prospective reports describing the incidence of long‑term complications after vascular surgery are lacking., Objectives: We aimed to describe the incidence of complications 1 year after vascular surgery and to evaluate an association between myocardial injury after noncardiac surgery (MINS) and 1‑year mortality., Patients and Methods: This is a substudy of a large prospective cohort study Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION). Recruitment took place in 28 centers across 14 countries from August 2007 to November 2013. We enrolled patients aged 45 years or older undergoing vascular surgery, receiving general or regional anesthesia, and hospitalized for at least 1 night postoperatively. Plasma cardiac troponin T concentration was measured before the surgery and on the first, second, and third postoperative day. The patients or their relatives were contacted 1 year after the procedure to assess the incidence of major postoperative complications., Results: We enrolled 2641 patients who underwent vascular surgery, 2534 (95.9%) of whom completed 1‑year follow‑up. Their mean (SD) age was 68.2 (9.8) years, and the cohort was predominantly male (77.5%). The most frequent 1‑year complications were myocardial infarction (224/2534, 8.8%), amputation (187/2534, 7.4%), and congestive heart failure (67/2534, 2.6%). The 1‑year mortality rate was 8.8% (223/2534). MINS occurred in 633 patients (24%) and was associated with an increased 1‑year mortality (hazard ratio, 2.82; 95% CI, 2.14-3.72; P <0.001)., Conclusions: The incidence of major postoperative complications after vascular surgery is high. The occurrence of MINS is associated with a nearly 3‑fold increase in 1‑year mortality.

Heart failure is a major clinical problem, with treatments involving medication, devices, and emerging neuromodulation therapies such as vagus nerve stimulation (VNS). Considering the ongoing interest in using VNS to treat cardiovascular disease, it is important to understand the genetic and molecular changes developing in the heart in response to this form of autonomic neuromodulation. This experimental animal (rat) study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity using an optogenetic approach. Vagal preganglionic neurons in the dorsal motor nucleus of the vagus nerve were genetically targeted to express light-sensitive chimeric channelrhodopsin variant ChIEF and stimulated using light. RNA sequencing of the left ventricular myocardium identified 294 differentially expressed genes (false discovery rate < 0.05). Qiagen Ingenuity Pathway Analysis (IPA) highlighted 118 canonical pathways that were significantly modulated by vagal activity, of which 14 had a z score of ≥2/≤-2, including EIF-2, IL-2, integrin, and NFAT-regulated cardiac hypertrophy. IPA revealed the effect of efferent vagus stimulation on protein synthesis, autophagy, fibrosis, autonomic signaling, inflammation, and hypertrophy. IPA further predicted that the identified differentially expressed genes were the targets of 50 upstream regulators, including transcription factors (e.g., MYC and NRF1) and microRNAs (e.g., miR-335-3p and miR-338-3p). These data demonstrate that the vagus nerve has a major impact on the myocardial expression of genes involved in the regulation of key biological pathways. The transcriptional response of the ventricular myocardium induced by stimulation of vagal efferents is consistent with the beneficial effect of maintained/increased vagal activity on the heart. NEW & NOTEWORTHY This experimental animal study investigated the immediate transcriptional response of the ventricular myocardium to selective stimulation of vagal efferent activity. Vagal stimulation induced significant transcriptional changes in the heart involving the pathways controlling autonomic signaling, inflammation, fibrosis, and hypertrophy. This study provides the first direct evidence that myocardial gene expression is modulated by the activity of the autonomic nervous system.

Background: In previous analyses, myocardial injury after noncardiac surgery, major bleeding, and sepsis were independently associated with most deaths in the 30 days after noncardiac surgery, but most of these deaths occurred during the index hospitalization for surgery. The authors set out to describe outcomes after discharge from hospital up to 1 yr after inpatient noncardiac surgery and associations between predischarge complications and postdischarge death up to 1 yr after surgery., Methods: This study was an analysis of patients discharged after inpatient noncardiac surgery in a large international prospective cohort study across 28 centers from 2007 to 2013 of patients aged 45 yr or older followed to 1 yr after surgery. The study estimated (1) the cumulative postdischarge incidence of death and other outcomes up to a year after surgery and (2) the adjusted time-varying associations between postdischarge death and predischarge complications including myocardial injury after noncardiac surgery, major bleeding, sepsis, infection without sepsis, stroke, congestive heart failure, clinically important atrial fibrillation or flutter, amputation, venous thromboembolism, and acute kidney injury managed with dialysis., Results: Among 38,898 patients discharged after surgery, the cumulative 1-yr incidence was 5.8% (95% CI, 5.5 to 6.0%) for all-cause death and 24.7% (95% CI, 24.2 to 25.1%) for all-cause hospital readmission. Predischarge complications were associated with 33.7% (95% CI, 27.2 to 40.2%) of deaths up to 30 days after discharge and 15.0% (95% CI, 12.0 to 17.9%) up to 1 yr. Most of the association with death was due to myocardial injury after noncardiac surgery (15.6% [95% CI, 9.3 to 21.9%] of deaths within 30 days, 6.4% [95% CI, 4.1 to 8.7%] within 1 yr), major bleeding (15.0% [95% CI, 8.3 to 21.7%] within 30 days, 4.7% [95% CI, 2.2 to 7.2%] within 1 yr), and sepsis (5.4% [95% CI, 2.2 to 8.6%] within 30 days, 2.1% [95% CI, 1.0 to 3.1%] within 1 yr)., Conclusions: One in 18 patients 45 yr old or older discharged after inpatient noncardiac surgery died within 1 yr, and one quarter were readmitted to the hospital. The risk of death associated with predischarge perioperative complications persists for weeks to months after discharge., (Copyright © 2023 American Society of Anesthesiologists. All Rights Reserved.)

Background: Labile blood pressure after acute ischaemic stroke requiring mechanical thrombectomy is independently associated with poor patient outcomes., Objectives: This study protocol describes is designed to determine whether transauricular nerve stimulation, improves baroreflex sensitivity, reduces blood pressure variability in the first 24 hours after acute ischaemic stroke requiring mechanical thrombectomy., Design: Phase 2a, Proof-Of-Concept, Sham-Controlled Randomised Trial: Methods and Analysis: 36 individuals undergoing mechanical thrombectomy for acute ischaemic stroke with established hypertension aged >18 years will be randomly allocated to receive bilateral active or sham transauricular nerve stimulation for the duration of the mechanical thrombectomy procedure (AffeX-CT/001 investigational device). The intervention will be repeated for 1h the morning following the mechanical thrombectomy. Non-invasive blood pressure will be measured ≥2h for 24h after mechanical thrombectomy. Holter electrocardiographic monitoring will be recorded during transauricular nerve stimulation. Participants, clinicians and investigators will be masked to treatment allocations. The primary outcome will be the coefficient of variation of systolic blood pressure. Secondary outcomes include additional estimates of blood pressure variability and time/frequency-domain measures of autonomic cardiac modulation An adjusted sample size of 36 patients is required to have a 90% chance of detecting, as significant at the 5% level, a difference in the coefficient of variation in systolic blood pressure of 5±4mmHg between sham and active stimulation [assuming 5% non-compliance rate in each group]. Ethics: confirmed on 16 March 2023 by HRA and Health and Care Research Wales ethics committee (reference 23/WA/0013)., Discussion: This study will provide proof-of-concept data that examines whether non-invasive autonomic neuromodulation can be used to favourably modify blood pressure and autonomic control after acute ischaemic stroke requiring mechanical thrombectomy., Trial Registration: Trial registration number: NCT05417009., Competing Interests: INNOVATE-UK. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., (Copyright: © 2023 Ackland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Impaired vagal function in older individuals, quantified by the 'gold standard' delayed heart rate recovery after maximal exercise (HRR exercise ), is an independent predictor of cardiorespiratory capacity and mortality (particularly when HRR ≤12 beats min -1 ). Heart rate also often declines after orthostatic challenge (HRR orthostatic ), but the mechanism remains unclear. We tested whether HRR orthostatic reflects similar vagal autonomic characteristics as HRR exercise ., Methods: Prospective multicentre cohort study of subjects scheduled for cardiopulmonary exercise testing (CPET) as part of routine care. Before undergoing CPET, heart rate was measured with participants seated for 3 min, before standing for 3 min (HRR orthostatic ). HRR exercise 1 min after the end of CPET was recorded. The primary outcome was the correlation between mean heart rate change every 10 s for 1 min after peak heart rate was attained on standing and after exercise for each participant. Secondary outcomes were HRR orthostatic and peak VO 2 compared between individuals with HRR exercise <12 beats min -1 ., Results: A total of 87 participants (mean age: 64 yr [95%CI: 61-66]; 48 (55%) females) completed both tests. Mean heart rate change every 10 s for 1 min after peak heart rate after standing and exercise was significantly correlated ( R 2 =0.81; P <0.0001). HRR orthostatic was unchanged in individuals with HRR exercise ≤12 beats min -1 ( n =27), but was lower when HRR exercise >12 beats min -1 ( n =60; mean difference: 3 beats min -1 [95% confidence interval 1-5 beats min -1 ]; P <0.0001). Slower HRR orthostatic was associated with lower peak VO 2 (mean difference: 3.7 ml kg -1 min -1 [95% confidence interval 0.7-6.8 ml kg -1 min -1 ]; P =0.039)., Conclusion: Prognostically significant heart rate recovery after exhaustive exercise is characterised by quantitative differences in heart rate recovery after orthostatic challenge. These data suggest that orthostatic challenge is a valid, simple test indicating vagal impairment., Clinical Trial Registration: researchregistry6550., (© 2023 The Authors.)

Aims: The brain controls the heart by dynamic recruitment and withdrawal of cardiac parasympathetic (vagal) and sympathetic activity. Autonomic control is essential for the development of cardiovascular responses during exercise, however, the patterns of changes in the activity of the two autonomic limbs, and their functional interactions in orchestrating physiological responses during exercise, are not fully understood. The aim of this study was to characterize changes in vagal parasympathetic drive in response to exercise and exercise training by directly recording the electrical activity of vagal preganglionic neurons in experimental animals (rats)., Methods and Results: Single unit recordings were made using carbon-fibre microelectrodes from the populations of vagal preganglionic neurons of the nucleus ambiguus (NA) and the dorsal vagal motor nucleus of the brainstem. It was found that (i) vagal preganglionic neurons of the NA and the dorsal vagal motor nucleus are strongly activated during bouts of acute exercise, and (ii) exercise training markedly increases the resting activity of both populations of vagal preganglionic neurons and augments the excitatory responses of NA neurons during exercise., Conclusions: These data show that central vagal drive increases during exercise and provide the first direct neurophysiological evidence that exercise training increases vagal tone. The data argue against the notion of exercise-induced central vagal withdrawal during exercise. We propose that robust increases in the activity of vagal preganglionic neurons during bouts of exercise underlie activity-dependent plasticity, leading to higher resting vagal tone that confers multiple health benefits associated with regular exercise., Competing Interests: Conflict of interest: The authors declare no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Neutrophils are white blood cells that are critical to acute inflammatory and adaptive immune responses. Their swarming-pattern behavior is controlled by multiple cellular cascades involving calcium-dependent release of various signaling molecules. Previous studies have reported that neutrophils express glutamate receptors and can release glutamate but evidence of direct neutrophil-neutrophil communication has been elusive. Here, we hold semi-suspended cultured human neutrophils in patch-clamp whole-cell mode to find that calcium mobilization induced by stimulating one neutrophil can trigger an N-methyl-D-aspartate (NMDA) receptor-driven membrane current and calcium signal in neighboring neutrophils. We employ an enzymatic-based imaging assay to image, in real time, glutamate release from neutrophils induced by glutamate released from their neighbors. These observations provide direct evidence for a positive-feedback inter-neutrophil communication that could contribute to mechanisms regulating communal neutrophil behavior., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Background: Activation of central autonomic pathways, including those regulating the arterial baroreflex, might reduce acute pain. We tested the hypothesis that transcutaneous auricular nerve stimulation (TAN) reduces pain after orthopaedic trauma surgery through autonomic modulation., Methods: A total of 86 participants aged >18 yr were randomly assigned to 50 min of either sham or active bilateral TAN, undertaken before, and again 24 h after, surgery for orthopaedic trauma. The primary outcome was absolute change in pain 24 h postoperatively, comparing the 100 mm visual analogue scale (VAS) before and after TAN. Secondary outcomes included the minimal clinically important difference in pain (>10 mm increase or reduction in VAS) before/after surgery, using intention-to-treat analysis. Holter monitoring, the analysis of which was masked to allocation, quantified autonomic modulation of heart rate., Results: From June 22, 2021 to July 7, 2022, 79/86 participants (49 yr; 45% female) completed TAN before and after surgery. For the primary outcome, the mean reduction in VAS was 19 mm (95% confidence interval [CI]: 12-26) after active TAN (n=40), vs 10 mm (95% CI: 3-17) after sham TAN (n=39; P=0.023). A minimally clinically important reduction in postoperative pain occurred in 31/40 (78%) participants after active TAN, compared with 15/39 (38%) allocated to sham TAN (odds ratio 5.51 [95% CI: 2.06-14.73]; P=0.001). Only active TAN increased heart rate variability (log low-frequency power increased by 0.19 ms 2 [0.01-0.37 ms 2 ]). Prespecified adverse events (auricular skin irritation) occurred in six participants receiving active TAN, compared with two receiving sham TAN., Conclusion: Bilateral TAN reduces perioperative pain through autonomic modulation. These proof-of-concept data support a non-pharmacological, generalisable approach to improve perioperative analgesia., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Early intraoperative hypotension is associated with acute kidney and myocardial injury in patients undergoing noncardiac surgery. Precise arterial blood pressure measurement before and during the induction of general anaesthesia may avert early intraoperative hypotension. However, rapid arterial cannulation in anxious, conscious patients can be challenging. We describe the protocol for a randomised controlled trial designed to test the hypothesis that readily available, handheld ultrasound-guided arterial cannulation is the optimal method in conscious patients undergoing noncardiac surgery., Methods: Participants >45 yr undergoing noncardiac surgery expected to last >120 min and requiring an overnight hospital stay will be eligible. We will randomly allocate participants to undergo cannulation of the radial artery in the non-dominant arm before the induction of general or regional anaesthesia using either handheld ultrasound-guided dynamic needle position technique or palpation. The primary outcome is first-pass successful arterial cannulation, analysed by intention-to-treat. Secondary outcomes include adequacy/characteristics of the arterial waveform and complications within 24 h of cannulation. We will require 118 patients to demonstrate a doubling of successful first-pass arterial cannulation, from ∼30% using the palpation approach (α=0.05; 1-β=0.1)., Results: This study has been approved by the NHS Health Research Authority and Health Care Research Wales (21/WA/0403) and commenced recruitment in May 2022., Conclusions: This study will establish whether handheld ultrasound-guided arterial cannulation before the induction of anaesthesia should be the standard of care in patients at risk of developing perioperative organ injury after noncardiac surgery., Clinical Trial Registration: NCT05249036., (© 2022 The Author(s).)

Background: Sex differences in sepsis are underexplored and incompletely understood. Cardiac function in early sepsis is pivotal in determining survival; hyperdynamic left ventricular ejection fraction is associated with higher mortality. Female sex may be cardioprotective, but variable experimental findings have not controlled for hypovolaemia. Sex-specific local cardiac versus peripheral inflammation in causing cardiovascular dysfunction also remain unclear. We therefore examined whether there are sex-specific differences in cardiac function in early sepsis, controlling for volaemic status and sex-specific differences in the peripheral inflammatory response initiated by tumour necrosis factor (TNFα)., Methods: We used an experimental polymicrobial sepsis (faecal slurry) model titrated to minimise hypovolaemia as a confounding factor. We quantified cardiac function (transthoracic cardiac echocardiography) 1 week before, and 18 h after, sepsis. Cardiac injury (troponin I), inflammation and immune cell infiltration (flow cytometry) were quantified in naïve and septic female and male mice 18 h after sepsis. To evaluate the sex-specific influence of TNFα derived from peripheral leukocytes, we repeated the experiments in iRHOM2 -/- mice that are unable to shed TNFα exclusively from circulating leucocytes., Results: Serum troponin I increased to 1.39 ± 0.38 ng mL -1 (from undetectable levels in controls) 18 h after onset of normovolaemic sepsis to a similar extent in both sexes. Stroke volume in male mice increased by 8 µL [(3-13); p = 0.004], compared to individualised pre-sepsis values. By contrast, stroke volume remained at baseline levels in females [mean difference: 4 µL (- 1 to 9)]. Messenger RNA levels of markers for cardiac injury/inflammation after sepsis (real-time polymerase-chain reaction) were elevated in male wild-type mice compared to female wild types (n = 10/sex), with higher cardiac mRNA levels of atrial natriuretic peptide, inflammation (TNFα) and oxidative stress (superoxide dismutase-1), although serum troponin I values were similarly elevated. Flow cytometry analysis of cardiac tissue showed doubling of CD4 + leukocyte infiltration in male mice. Sex-specific cardiac physiologic differences were similar in iRHOM2 -/- mice that are unable to shed TNFα exclusively from leucocytes., Conclusions: In early normovolaemic polymicrobial sepsis, a relative hyperdynamic response develops in male mice. Myocardial stress/injury after early sepsis is limited in females, with less cardiac infiltration of CD4 + leukocytes but independent of shedding of TNFα from peripheral circulating leukocytes., (© 2022. The Author(s).)

Perioperative hypotension has been repeatedly associated with organ injury and worse outcome, yet many interventions to reduce morbidity by attempting to avoid or reverse hypotension have floundered. In part, this reflects uncertainty as to what threshold of hypotension is relevant in the perioperative setting. Shifting population-based definitions for hypertension, plus uncertainty regarding individualised norms before surgery, both present major challenges in constructing useful clinical guidelines that may help improve clinical outcomes. Aside from these major pragmatic challenges, a wealth of biological mechanisms that underpin the development of higher blood pressure, particularly with increasing age, suggest that hypotension (however defined) or lower blood pressure per se does not account solely for developing organ injury after major surgery. The mosaic theory of hypertension, first proposed more than 60 yr ago, incorporates multiple, complementary mechanistic pathways through which clinical (macrovascular) attempts to minimise perioperative organ injury may unintentionally subvert protective or adaptive pathways that are fundamental in shaping the integrative host response to injury and inflammation. Consideration of the mosaic framework is critical for a more complete understanding of the perioperative response to acute sterile and infectious inflammation. The largely arbitrary treatment of perioperative blood pressure remains rudimentary in the context of multiple complex adaptive hypertensive endotypes, defined by distinct functional or pathobiological mechanisms, including the regulation of reactive oxygen species, autonomic dysfunction, and inflammation. Developing coherent strategies for the management of perioperative hypotension requires smarter, mechanistically solid interventions delivered by RCTs where observer bias is minimised., (Copyright © 2022 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Established or acquired loss of parasympathetic vagal tone is associated with complications, including pain, after noncardiac surgery. We describe a study protocol designed to test the hypothesis that transcutaneous auricular nerve stimulation may preserve efferent parasympathetic activity to reduce pain and morbidity after noncardiac surgery., Methods: Participants aged >18 yr scheduled for urgent/elective orthopaedic surgery ( n =86) will be randomly allocated to bilateral transcutaneous auricular nerve stimulation or sham protocol for 50 min at the same time of day, before and 24 h after surgery. Holter monitoring, the analysis of which is masked to allocation, will quantify autonomic modulation of HR. The primary outcome will be pain, quantified by absolute changes in VAS 24 h after surgery following sham or stimulation. Secondary outcomes include presence or absence of >10 mm change in the 100 mm VAS (which defines a minimum clinically important change) and postoperative morbidity (Postoperative Morbidity Survey) before and 24 h after surgery. The relationship between the explanatory variable (HR variability), VAS, and morbidity will be examined using a multilevel (mixed-error component) regression model. Safety and complications of the intervention will also be recorded. The study was approved by the NHS Research Ethics Committee (21/LO/0272). As of 25 December 2021, 34/86 participants (mean [standard deviation] age: 48 [19] yr; 14 females [41.2%]) have been recruited, with complete collection of Holter data., Conclusions: This phase 2b study will explore whether noninvasive autonomic neuromodulation may reduce pain or morbidity using trans-auricular vagus nerve stimulation, providing proof-of-concept data for a non-pharmacological, generalisable approach to improve perioperative outcomes., Clinical Trial Registration: Researchregistry7566., (© 2022 The Author(s).)

Background: Laboratory data suggest that insufficient circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural-related maternal fever, both of which increase the rate of obstetric interventions and antibiotic use during labour. Genetic polymorphisms strongly influence IL-1ra levels in the general population. We aim to examine the association between IL-1ra polymorphisms and epidural-related maternal fever using Mendelian randomization analysis., Methods: EPIFEVER-2 is a multicentre UK trial enrolling 637 women receiving epidural analgesia for labour. Blood samples obtained no later than four hours after epidural insertion will provide deoxyribonucleic acid for Taqman single-nucleotide polymorphism genotyping for presence/absence of rs6743376, rs1542176 alleles for IL-1ra, to establish the genetic score. The absence of both alleles is associated with the lowest IL-1ra levels. The primary outcome is pyrexia (>38°C) or intrapartum antibiotic administration. Secondary outcomes include mode of delivery, maternal and neonatal healthcare interventions., Results: The EPIFEVER-2 study was prospectively registered (ISRCTN99641204) following ethical approval. Participant recruitment began in May 2021, with 221 women recruited across three centres as of November 21, 2021., Conclusions: EPIFEVER-2 will generate the largest prospective dataset detailing the incidence and consequences of epidural-related maternal fever. Using Mendelian randomisation analysis, a causative role for lower IL1-ra levels in determining the risk of epidural-related maternal fever and/or antibiotic administration before delivery will be examined., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Lower circulating levels of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1ra) are associated with intrapartum inflammation and epidural analgesia-related maternal fever, both of which increase the rate of obstetric interventions. We hypothesised that genetic variants determining IL-1ra levels would be associated with Caesarean delivery rates after the onset of labour., Methods: We performed Mendelian randomisation analyses in parous women ≥16 yr old who received either non-neuraxial or neuraxial analgesia for their first two labours (UK Biobank). We used an established genetic score (calculated as 0-4, determined by the presence/absence of rs6743376 and rs1542176 alleles), in which the complete absence of both alleles causes the lowest IL-1ra levels. The primary outcome was Caesarean delivery after the onset of labour (odds ratio [OR]: 95% confidence intervals)., Results: There were 7731 women (mean [standard deviation] age at first birth: 25 [5] yr) who had complete genetic scores and delivery data. For women who received non-neuraxial analgesia, Caesarean delivery rates were different across allele scores (χ 2 =12.4; P=0.015): 104/596 (17.4%) women with zero allele score underwent Caesarean delivery, compared with 654/5015 (13.0%) with allele score ≥1 (OR 1.41; 1.12-1.77). For women who had neuraxial analgesia, Caesarean delivery was not different across allele scores, ranging from 18.1% to 20.8% (χ 2 =0.29; P=0.99). Caesarean delivery was independent of type of analgesia for 818/7731 (10.6%) women with zero allele scores (OR 0.93; 0.63-1.39), but was higher in women receiving neuraxial analgesia with allele scores ≥1 (OR 1.55; 1.35-1.79; P<0.001)., Conclusions: Mendelian randomisation analysis suggests that higher IL-1ra levels are associated with reduced Caesarean delivery rate. Neuraxial analgesia appears to disrupt this link., Clinical Trial Registration: UK Biobank study 62745., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Autonomic dysfunction promotes organ injury after major surgery through numerous pathological mechanisms. Vagal withdrawal is a key feature of autonomic dysfunction, and it may increase the severity of pain. We systematically evaluated studies that examined whether vagal neuromodulation can reduce perioperative complications and pain., Methods: Two independent reviewers searched PubMed, EMBASE, and the Cochrane Register of Controlled Clinical Trials for studies of vagal neuromodulation in humans. Risk of bias was assessed; I 2 index quantified heterogeneity. Primary outcomes were organ dysfunction (assessed by measures of cognition, cardiovascular function, and inflammation) and pain. Secondary outcomes were autonomic measures. Standardised mean difference (SMD) using the inverse variance random-effects model with 95% confidence interval (CI) summarised effect sizes for continuous outcomes., Results: From 1258 records, 166 full-text articles were retrieved, of which 31 studies involving patients (n=721) or volunteers (n=679) met the inclusion criteria. Six studies involved interventional cardiology or surgical patients. Indirect stimulation modalities (auricular [n=23] or cervical transcutaneous [n=5]) were most common. Vagal neuromodulation reduced pain (n=10 studies; SMD=2.29 [95% CI, 1.08-3.50]; P=0.0002; I 2 =97%) and inflammation (n=6 studies; SMD=1.31 [0.45-2.18]; P=0.003; I 2 =91%), and improved cognition (n=11 studies; SMD=1.74 [0.96-2.52]; P<0.0001; I 2 =94%) and cardiovascular function (n=6 studies; SMD=3.28 [1.96-4.59]; P<0.00001; I 2 =96%). Five of six studies demonstrated autonomic changes after vagal neuromodulation by measuring heart rate variability, muscle sympathetic nerve activity, or both., Conclusions: Indirect vagal neuromodulation improves physiological measures associated with limiting organ dysfunction, although studies are of low quality, are susceptible to bias and lack specific focus on perioperative patients., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Maintaining adequate oxygen delivery (DO 2 ) after major surgery is associated with minimising organ dysfunction. Skin is particularly vulnerable to reduced DO 2 . We tested the hypothesis that reduced perioperative DO 2 fuels inflammation in metabolically compromised skin after major surgery., Methods: Participants undergoing elective oesophagectomy were randomised immediately after surgery to standard of care or haemodynamic therapy to achieve their individualised preoperative DO 2 . Abdominal punch skin biopsies were snap-frozen before and 48 h after surgery. On-line two-dimensional liquid chromatography and ultra-high-definition label-free mass spectrometry was used to characterise the skin proteome. The primary outcome was proteomic changes compared between normal (≥preoperative value before induction of anaesthesia) and low DO 2 (2 after oesophagectomy. Failure to maintain preoperative DO 2 was associated with upregulation of proteins counteracting oxidative stress. Normal DO 2 after surgery was associated with pathways involving leucocyte recruitment and upregulation of an antimicrobial peptidoglycan recognition protein. Immunohistochemistry (n=6 patients) and immunoblots after liver resection (n=12 patients) supported the proteomic findings., Conclusions: Proteomic profiles in serial skin biopsies identified organ-protective mechanisms associated with normal DO 2 after major surgery., Clinical Trial Registration: ISRCTN76894700., Competing Interests: Declarations of interest GLA is an Editor of British Journal of Anaesthesia; and declares consultancy work for GlaxoSmithKline, unrelated to this work., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Experimental animal studies on the mechanisms of remote ischaemic conditioning (RIC)-induced cardioprotection against ischaemia/reperfusion injury demonstrate involvement of both neuronal and humoral pathways. Autonomic parasympathetic (vagal) pathways confer organ protection through both direct innervation and/or immunomodulation, but evidence in humans is lacking. During acute inflammation, vagal release of acetylcholine suppresses CD11b expression, a critical β2-integrin regulating neutrophil adhesion to the endothelium and transmigration to sites of injury. Here, we tested the hypothesis that RIC recruits vagal activity in humans and has an anti-inflammatory effect by reducing neutrophil CD11b expression. Participants (age:50 ​± ​19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 3 ​× ​8 min cycles of brachial artery occlusion using a blood pressure cuff (RIC block ). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate, heart rate variability (HRV)) before, and 10 ​min after, the last cycle of RIC. RR-interval increased after RIC (reduced heart rate) by 40 ​ms (95% confidence intervals (95%CI):13-66; n ​= ​17 subjects; P  ​= ​0.003). RR-interval did not change after brachial plexus blockade (mean difference: 20 ​ms (95%CI:-11 to 50); P  ​= ​0.19). The high-frequency component of HRV was reduced after RIC block , but remained unchanged after RIC ( P  ​< ​0.001), indicating that RIC preserved vagal activity. LPS-induced CD16 + CD11b + expression in whole blood (measured by flow cytometry) was reduced by RIC (3615 median fluorescence units (95%CI:475-6754); P = 0.026), compared with 2331 units (95%CI:-3921 to 8582); P = 0.726) after RIC block . These data suggest that in humans RIC recruits vagal cardiac and anti-inflammatory mechanisms via ischaemia/reperfusion-induced activation of sensory nerve fibres that innervate the organ undergoing RIC., (© 2021 The Author(s).)

Background: In the general adult population, lymphopaenia is associated with an increased risk for hospitalisation with infection and infection-related death. The quality of evidence and strength of association between perioperative lymphopaenia across different surgical procedures and mortality/morbidity has not been examined by systematic review or meta-analysis., Methods: We searched MEDLINE, Embase, Web of Science, Google Scholar, and Cochrane databases from their inception to June 29, 2020 for observational studies reporting lymphocyte count and in-hospital mortality rate in adults. We defined preoperative lymphopaenia as a lymphocyte count 1.0-1.5×10 9 L -1 . Meta-analysis was performed using either fixed or random effects models. Quality was assessed using the Newcastle-Ottawa Scale. The I 2 index was used to quantify heterogeneity. The primary outcome was in-hospital mortality rate and mortality rate at 30 days., Results: Eight studies met the inclusion criteria for meta-analysis, comprising 4811 patients (age range, 46-91 yr; female, 20-79%). These studies examined preoperative lymphocyte count exclusively. Studies were of moderate to high quality overall, ranking >7 using the Newcastle-Ottawa Scale. Preoperative lymphopaenia was associated with a threefold increase in mortality rate (risk ratio [RR]=3.22; 95% confidence interval [CI], 2.19-4.72; P<0.01, I 2 =0%) and more frequent major postoperative complications (RR=1.33; 95% CI, 1.21-1.45; P<0.01, I 2 =6%), including cardiovascular morbidity (RR=1.77; 95% CI, 1.45-2.15; P<0.01, I 2 =0%), infections (RR=1.45; 95% CI, 1.19-1.76; P<0.01, I 2 =0%), and acute renal dysfunction (RR=2.66; 95% CI, 1.49-4.77; P<0.01, I 2 =1%)., Conclusion: Preoperative lymphopaenia is associated with death and complications more frequently, independent of the type of surgery., Prospero Registry Number: CRD42020190702., (Copyright © 2021 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)

Background: Control of blood pressure remains a key goal of peri-operative care, because hypotension is associated with adverse outcomes after surgery., Objectives: We explored whether increased vigilance afforded by intra-arterial blood pressure monitoring may be associated with less morbidity after surgery., Design: A prospective observational cohort study., Setting: Four UK secondary care hospitals., Patients: A total of 4342 patients ≥45 years who underwent noncardiac surgery., Methods: We compared outcome of patients who received peri-operative intra-arterial blood pressure monitoring with those whose blood pressure was measured noninvasively., Outcomes: The primary outcome was peri-operative myocardial injury (high-sensitivity troponin-T ≥ 15 ng l-1 within 72 h after surgery), compared between patients who received intra-arterial versus noninvasive blood pressure monitoring. Secondary outcomes were morbidity within 72 h of surgery (postoperative morbidity survey), and vasopressor and fluid therapy. Multivariable logistic regression analysis explored associations between morbidity and age, sex, location of postoperative care, mode of blood pressure/haemodynamic monitoring and Revised Cardiac Risk Index., Results: Intra-arterial monitoring was used in 1137/4342 (26.2%) patients. Myocardial injury occurred in 440/1137 (38.7%) patients with intra-arterial monitoring compared with 824/3205 (25.7%) with noninvasive monitoring [OR 1.82 (95% CI 1.58 to 2.11), P < 0.001]. Intra-arterial monitoring remained associated with myocardial injury when adjusted for potentially confounding variables [adjusted OR 1.56 (1.29 to 1.89), P < 0.001). The results were similar for planned ICU versus ward postoperative care., Conclusions: Intra-arterial monitoring is associated with greater risk of morbidity after noncardiac surgery, after controlling for surgical and patient factors. These data provide useful insights into the design of a definitive monitoring trial., (Copyright © 2021 European Society of Anaesthesiology and Intensive Care. Unauthorized reproduction of this article is prohibited.)

Given its non-invasive nature, there is increasing interest in the use of transcutaneous vagus nerve stimulation (tVNS) across basic, translational and clinical research. Contemporaneously, tVNS can be achieved by stimulating either the auricular branch or the cervical bundle of the vagus nerve, referred to as transcutaneous auricular vagus nerve stimulation(VNS) and transcutaneous cervical VNS, respectively. In order to advance the field in a systematic manner, studies using these technologies need to adequately report sufficient methodological detail to enable comparison of results between studies, replication of studies, as well as enhancing study participant safety. We systematically reviewed the existing tVNS literature to evaluate current reporting practices. Based on this review, and consensus among participating authors, we propose a set of minimal reporting items to guide future tVNS studies. The suggested items address specific technical aspects of the device and stimulation parameters. We also cover general recommendations including inclusion and exclusion criteria for participants, outcome parameters and the detailed reporting of side effects. Furthermore, we review strategies used to identify the optimal stimulation parameters for a given research setting and summarize ongoing developments in animal research with potential implications for the application of tVNS in humans. Finally, we discuss the potential of tVNS in future research as well as the associated challenges across several disciplines in research and clinical practice., Competing Interests: EK and SK are employed by company SzeleSTIM GmbH. JS received honoraria from SzeleSTIM GmbH and owns patents in the field of the auricular vagus nerve stimulation. EK, SK, and JS are shareholders of SzeleSTIM GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer TS declared a shared affiliation, with no collaboration, with one of the authors HJ, to the handling editor at the time of review., (Copyright © 2021 Farmer, Strzelczyk, Finisguerra, Gourine, Gharabaghi, Hasan, Burger, Jaramillo, Mertens, Majid, Verkuil, Badran, Ventura-Bort, Gaul, Beste, Warren, Quintana, Hämmerer, Freri, Frangos, Tobaldini, Kaniusas, Rosenow, Capone, Panetsos, Ackland, Kaithwas, O'Leary, Genheimer, Jacobs, Van Diest, Schoenen, Redgrave, Fang, Deuchars, Széles, Thayer, More, Vonck, Steenbergen, Vianna, McTeague, Ludwig, Veldhuizen, De Couck, Casazza, Keute, Bikson, Andreatta, D'Agostini, Weymar, Betts, Prigge, Kaess, Roden, Thai, Schuster, Montano, Hansen, Kroemer, Rong, Fischer, Howland, Sclocco, Sellaro, Garcia, Bauer, Gancheva, Stavrakis, Kampusch, Deuchars, Wehner, Laborde, Usichenko, Polak, Zaehle, Borges, Teckentrup, Jandackova, Napadow and Koenig.)

Background: Acute global shortages of neuromuscular blocking agents (NMBA) threaten to impact adversely on perioperative and critical care. The use of pharmacological adjuncts may reduce NMBA dose. However, the magnitude of any putative effects remains unclear., Methods: We conducted a systematic review and meta-analysis of RCTs. We searched Medline, Embase, Web of Science, and Cochrane Database (1970-2020) for RCTs comparing use of pharmacological adjuncts for NMBAs. We excluded RCTs not reporting perioperative NMBA dose. The primary outcome was total NMBA dose used to achieve a clinically acceptable depth of neuromuscular block. We assessed the quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) criteria. Data are presented as the standardised mean difference (SMD); I 2 indicates percentage of variance attributable to heterogeneity., Results: From 3082 records, the full texts of 159 trials were retrieved. Thirty-one perioperative RCTs met the inclusion criteria for meta-analysis (n=1962). No studies were conducted in critically ill patients. Reduction in NMBA dose was associated with use of magnesium (SMD: -1.10 [-1.44 to -0.76], P<0.001; I 2 =85%; GRADE=moderate), dexmedetomidine (SMD: -0.89 [-1.55 to -0.22]; P=0.009; I 2 =87%; GRADE=low), and clonidine (SMD: -0.67 [-1.13 to -0.22]; P=0.004; I 2 =0%; GRADE=low) but not lidocaine (SMD: -0.46 [-1.01 to -0.09]; P=0.10; I 2 =68%; GRADE=moderate). Meta-analyses for nicardipine, diltiazem, and dexamethasone were not possible owing to the low numbers of studies. We estimated that 30-50 mg kg -1 magnesium preoperatively (8-15 mg kg h -1 intraoperatively) reduces rocuronium dose by 25.5% (inter-quartile range, 14.7-31)., Conclusions: Magnesium, dexmedetomidine, and clonidine may confer a clinically relevant sparing effect on the required dose of neuromuscular block ing drugs in the perioperative setting., Systematic Review Registration: PROSPERO: CRD42020183969., (Copyright © 2020 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved.)