Heart rate recovery after orthostatic challenge and cardiopulmonary exercise testing in older individuals: prospective multicentre observational cohort study.

Background: Impaired vagal function in older individuals, quantified by the 'gold standard' delayed heart rate recovery after maximal exercise (HRRexercise), is an independent predictor of cardiorespiratory capacity and mortality (particularly when HRR ≤12 beats min-1). Heart rate also often declines after orthostatic challenge (HRRorthostatic), but the mechanism remains unclear. We tested whether HRRorthostatic reflects similar vagal autonomic characteristics as HRRexercise. 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 (HRRorthostatic). HRRexercise 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 HRRorthostatic and peak VO2 compared between individuals with HRRexercise <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 (R2=0.81; P<0.0001). HRRorthostatic was unchanged in individuals with HRRexercise ≤12 beats min-1 (n=27), but was lower when HRRexercise >12 beats min-1 (n=60; mean difference: 3 beats min-1 [95% confidence interval 1-5 beats min-1]; P<0.0001). Slower HRRorthostatic was associated with lower peak VO2 (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.

Effect of transauricular nerve stimulation on perioperative pain: a single-blind, analyser-masked, randomised controlled trial.

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 ms2 [0.01-0.37 ms2]). 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.

Trans-auricular vagus nerve stimulation to reduce perioperative pain and morbidity: protocol for a single-blind analyser-masked randomised controlled trial.

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.

The potential for autonomic neuromodulation to reduce perioperative complications and pain: a systematic review and meta-analysis.

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; I2 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; I2=97%) and inflammation (n=6 studies; SMD=1.31 [0.45-2.18]; P=0.003; I2=91%), and improved cognition (n=11 studies; SMD=1.74 [0.96-2.52]; P<0.0001; I2=94%) and cardiovascular function (n=6 studies; SMD=3.28 [1.96-4.59]; P<0.00001; I2=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.

Neuromodulation of innate immunity by remote ischaemic conditioning in humans: Experimental cross-over study.

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 ß2-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 â€‹± â€‹19 years; 53% female) underwent ultrasound-guided injection of local anaesthetic within the brachial plexus before applying 3 â€‹× â€‹8 min cycles of brachial artery occlusion using a blood pressure cuff (RICblock). RIC was repeated 6 weeks later without brachial plexus block. Masked analysers quantified vagal activity (heart rate, heart rate variability (HRV)) before, and 10 â€‹min after, the last cycle of RIC. RR-interval increased after RIC (reduced heart rate) by 40 â€‹ms (95% confidence intervals (95%CI):13-66; n â€‹= â€‹17 subjects; P â€‹= â€‹0.003). RR-interval did not change after brachial plexus blockade (mean difference: 20 â€‹ms (95%CI:-11 to 50); P â€‹= â€‹0.19). The high-frequency component of HRV was reduced after RICblock, but remained unchanged after RIC (P â€‹< â€‹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 RICblock. 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.

Postoperative goal-directed therapy and development of acute kidney injury following major elective noncardiac surgery: post-hoc analysis of POM-O randomized controlled trial.

Background: The role of goal-directed therapy (GDT) in preventing creatinine rise following noncardiac surgery is unclear. We performed a post-hoc analysis of a randomized controlled trial to assess the relationship between postoperative optimization of oxygen delivery and development of acute kidney injury (AKI)/creatinine rise following noncardiac surgery. Methods: Patients were randomly assigned immediately postoperatively to receive either fluid and/or dobutamine therapy to maintain/restore their preoperative oxygen delivery, or protocolized standard care (oxygen delivery only recorded). Primary end point was serial changes in postoperative creatinine within 48 h postoperatively. Secondary outcomes were development of AKI (KDIGO criteria) and minimal creatinine rise (MCR; no decline from preoperative creatinine), related to all-cause morbidity and length of stay. Results: Postoperative reductions in serum creatinine were similar (P = 0.76) in patients randomized to GDT [10 µmol/L (95% confidence interval, CI: 17 to -1); n = 95] or protocolized care [8 µmol/L (95% CI: 17 to -6); n = 92]. Postoperative haemodynamic management was not associated with the development of MCR [78/187 (41.7%)] or AKI [13/187; (7.0%)]. Intraoperative requirement for norepinephrine was more likely in patients who developed postoperative rises in creatinine [relative risk (RR): 1.66 (95% CI: 1.04-2.67); P = 0.04], despite similar volumes of intraoperative fluid being administered. Persistently higher lactate during the intervention period was associated with AKI (mean difference: 1.15 mmol/L (95% CI: 0.48-1.81); P = 0.01]. Prolonged hospital stay was associated with AKI but not MCR [RR: 2.71 (95% CI: 1.51-4.87); P = 0.0008]. Conclusion: These data provide further insights into how perioperative haemodynamic alterations relate to postoperative increases in creatinine once systemic inflammation is established.

Cardiopulmonary Exercise Testing and Prognosis in Hypertrophic Cardiomyopathy.

BACKGROUND: Exercise testing is performed in patients with hypertrophic cardiomyopathy to evaluate blood pressure response, a risk factor for sudden cardiac death. The prognostic role of exercise gas exchange variables is unknown. METHODS AND RESULTS: Between 1998 and 2010, 1898 patients (age 47±15 years, range 16-86 years; 67% male) with hypertrophic cardiomyopathy underwent cardiopulmonary exercise testing. A total of 178 (9.4%) patients reached the primary end point of all-cause mortality or heart transplant (death/transplant) during a median follow-up of 5.6 years (interquartile range 2.6-8.9), giving an annual event rate of 1.6% per person year. Peak oxygen consumption (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.77-0.88, P<0.001), ventilatory efficiency (adjusted HR 1.10, 95% CI 1.00-1.22, P=0.049), and ventilatory anaerobic threshold (adjusted HR 0.82, 95% CI 0.70-0.96, P=0.016) were predictors of the primary outcome after correction for age, sex, left atrial size, nonsustained ventricular tachycardia, and ejection fraction. The overall adjusted death/transplant estimates for patients in the lowest quartile with peak oxygen consumption ≤15.3 mL/kg/min were 14% at 5 years and 31% at 10 years. Peak oxygen consumption (HR 0.81, 95% CI 0.77-0.86, P<0.01) and ventilation to carbon dioxide production (HR 1.10, 95% CI 1.08-1.13, P<0.001) were predictors of death because of heart failure or transplantation but not sudden cardiac death or implantable cardioverter defibrillator shocks. CONCLUSIONS: Cardiopulmonary exercise testing provides prognostic information in patients with hypertrophic cardiomyopathy. Submaximal exercise parameters, such as ventilatory efficiency and anaerobic threshold, measured alone or in combination with peak oxygen consumption, predict death from heart failure.

Non-inferiority of retrospective data collection for assessing perioperative morbidity.

Background. Postoperative morbidity has immediate and delayed consequences for surgical patients, including excess risk of premature death. Capturing these data objectively and routinely in large electronic databases using tools such as the Postoperative Morbidity Survey (POMS) would offer tremendous clinical and translational potential. However, POMS has thus far only utilised prospective data collection by research staff. We hypothesised that retrospective data collection from routinely collated hospital data from paper and electronic charts, medical and nursing notes was non-inferior to prospective data collection requiring research staff capturing POMS-defined morbidity in real-time. Methods. Morbidity was recorded by a trained investigator as defined by POMS prospectively on postoperative days 3 and 7. Separately, an independent investigator blinded to prospectively acquired data retrospectively assessed the same patients' morbidity as defined by POMS criteria, using medical charts, nursing summaries and electronic data. Equivalence was accepted when the confidence limits for both modes of data collection fell completely inside the equivalence bounds, with the maximum equivalence difference (i.e., the largest value of the difference in sensitivities deemed to reach a conclusion of equivalence) set a priori at 0.2. Differences for confidence limits between retrospective and prospective data collection were based on Nam's RMLE method. The relationship between morbidity on postoperative day 3 as recorded by each data collection method on time to become morbidity free and length of hospital stay was compared using the log-rank test. Results. POMS data from 85 patients undergoing elective or emergency surgery were analyzed. At postoperative day 3, POMS-defined morbidity was similar regardless of whether data were collected prospectively or retrospectively (95% CI [-0.13-0.013]; p < 0.001). Non-inferiority for sensitivity was observed for all other POMS domains and timepoints. Time to become morbidity free Kaplan-Meier plots were indistinguishable between POMS obtained prospectively or retrospectively (hazard ratio: 1.09 (95% CI [0.76-1.57]); p = 0.33, log rank test). Similarly, the mode of data collection did not alter the association between early postoperative morbidity on postoperative day 3 and delayed hospital discharge. Conclusions. Postoperative morbidity as defined by the Post Operative Morbidity Survey can be assessed retrospectively. These data may therefore be easily captured using electronic patient record systems, thereby expanding the potential for bioinformatics approaches to generate new clinical and translational insights into recovery from surgery.

Improving safety of sedation for transoesophageal echocardiography.

This project aimed to develop solutions for optimal, safe sedation, in transoesophageal echocardiagraphy (TOE). Prescription and dosage errors arise from physicians failing to approach experienced operators for assistance, and lack of familiarity with Trust TOE guidelines. We conducted a retrospective analysis of 319 patients who were referred for TOE over a nine-month period. Data was obtained from the hospital medical records and database. Midazolam doses exceeding Trust guidelines were being administered, posing unnecessary risks for under 18 and over 60 year-olds especially. This quality improvement project intervened by: 1. Adding a paediatric section with sedation dosage advice to Trust guidelines; 2. Increasing awareness of the need for lower sedation doses in over 60 year-olds, by updating the pre-procedure checklist with an age and maximum recommended midazolam dose section. These changes were accepted following presentation of the audit at the monthly Clinical Governance Meeting, and early indications reported increased confidence in midazolam dosing and awareness of the risks of not following the guidelines. Operator confidence in these changes requires re-audit, in order to confirm the findings, and continue improvement to the Trust TOE guidelines and patient safety.