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

Abstract

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.

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

“… 2 Autonomic dysregulation is a pivotal feature of acute pain, impacting on a wide range of interconnected neurohormonal and immune pathways that limit organ injury and resolve inflammation and promote organ repair. 16 Our phase 2b study aims to provide data to demonstrate the feasibility and efficacy of the taVNS in reducing pain by boosting autonomic function and potentially accelerating functional rehabilitation ( Fig 2 ).…”

“…Studies of indirect vagal neuromodulation have usually been conducted in healthy volunteers and are susceptible to bias. 16 Our study addresses the lack of specific focus on perioperative patients, for whom multiple morbidities after surgery may benefit from autonomic neuromodulation. The use of sham stimulation is critical, as meta-regression analyses indicate that physical placebo interventions and patient-reported outcomes in pain are more likely to reveal significant placebo effects.…”

“…Provided that we can confirm in the acute care setting that autonomic changes after vagal neuromodulation occur by measuring HR variability, the low-cost, noninvasive device we are using suggests a very low potential risk-to-benefit ratio. Our systematic review identified the taVNS stimulation parameters that alter HR variability, 16 although we cannot be certain that there may be minimum thresholds for the duration or intensity required to be clinically effective in the surgical population. The emphasis in this study on acute effects does not rule out any putative benefit of a longer course of treatment after surgery.…”

“… 15 Our systematic review of the proof-of-concept literature has identified specific parameter ranges that appear to be effective in restoring efferent vagal activity. 16 Although the transcutaneous auricular vagus nerve approach is readily accessible, 15 studies in noncardiac surgery are lacking.…”

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

“…Notably, there is a paucity of interventional studies that specifically investigate the correlation between acute pain and autonomic measures. 17,18 Transcutaneous auricular neuromodulation may exert analgesic effects through numerous mechanisms, including reducing inflammation, subcortical modulation of locus coeruleusenoradrenergic signalling, and activation of serotonergic and endorphinergic analgesic pathways. 19 Proof-of-concept studies in human volunteers using noninvasive electrical stimulation of the (putative) auricular branch of the vagus nerve offer a feasible, accessible approach 17 to restoredor minimisedperioperative autonomic dysregulation and hence potentially impact on acute pain.…”