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 (n¼721) or volunteers (n¼679) met the inclusion criteria. Six studies involved interventional cardiology or surgical patients. Indirect stimulation modalities (auricular [n¼23] or cervical transcutaneous [n¼5]) were most common. Vagal neuromodulation reduced pain (n¼10 studies; SMD¼2.29 [95% CI, 1.08e3.50]; P¼0.0002; I 2 ¼97%) and inflammation (n¼6 studies; SMD¼1.31 [0.45e2.18]; P¼0.003; I 2 ¼91%), and improved cognition (n¼11 studies; SMD¼1.74 [0.96e2.52]; P<0.0001; I 2 ¼94%) and cardiovascular function (n¼6 studies; SMD¼3.28 [1.96e4.59]; P<0.00001; I 2 ¼96%). 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.

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 1.0e1.5Â10 9 L À1 . Meta-analysis was performed using either fixed or random effects models. Quality was assessed using the NewcastleeOttawa 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, 46e91 yr; female, 20e79%). These studies examined preoperative lymphocyte count exclusively. Studies were of moderate to high quality overall, ranking >7 using the NewcastleeOttawa Scale. Preoperative lymphopaenia was associated with a threefold increase in mortality rate (risk ratio [RR]¼3.22; 95% confidence interval [CI], 2.19e4.72; P<0.01, I 2 ¼0%) and more frequent major postoperative complications (RR¼1.33; 95% CI, 1.21e1.45; P<0.01, I 2 ¼6%), including cardiovascular morbidity (RR¼1.77; 95% CI, 1.45e2.15; P<0.01, I 2 ¼0%), infections (RR¼1.45; 95% CI, 1.19e1.76; P<0.01, I 2 ¼0%), and acute renal dysfunction (RR¼2.66; 95% CI, 1.49e4.77; P<0.01, I 2 ¼1%). Conclusion: Preoperative lymphopaenia is associated with death and complications more frequently, independent of the type of surgery. Prospero registry number: CRD42020190702.

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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 (1970e2020) 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 (n¼1962). No studies were conducted in critically ill patients. Reduction in NMBA dose was associated with use of magnesium (SMD: e1.10 [e1.44 to e0.76], P<0.001; I 2 ¼85%; GRADE¼moderate), dexmedetomidine (SMD: e0.89 [e1.55 to e0.22]; P¼0.009; I 2 ¼87%; GRADE¼low), and clonidine (SMD: e0.67 [e1.13 to e0.22]; P¼0.004; I 2 ¼0%; GRADE¼low) but not lidocaine (SMD: e0.46 [e1.01 to e0.09]; P¼0.10; I 2 ¼68%; GRADE¼moderate). Meta-analyses for nicardipine, diltiazem, and dexamethasone were not possible owing to the low numbers of studies. We estimated that 30e50 mg kg À1 magnesium preoperatively (8e15 mg kg h À1 intraoperatively) reduces rocuronium dose by 25.5% (interquartile range, 14.7e31). 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.