Brain-based measures of nociception during general anesthesia with remifentanil: A randomized controlled trial

Abstract

Background: Catheter radiofrequency (RF) ablation for cardiac arrhythmias is a painful procedure. Prior work using functional near-infrared spectroscopy (fNIRS) in patients under general anesthesia has indicated that ablation results in activity in pain-related cortical regions, presumably due to inadequate blockade of afferent nociceptors originating within the cardiac system. Having an objective brain-based measure for nociception and analgesia may in the future allow for enhanced analgesic control during surgical procedures. Hence, the primary aim of this study is to demonstrate that the administration of remifentanil, an opioid widely used during surgery, can attenuate the fNIRS cortical responses to cardiac ablation.

Methods and findings: We investigated the effects of continuous remifentanil on cortical hemodynamics during cardiac ablation under anesthesia. In a randomized, double-blinded, placebo (PL)-controlled trial, we examined 32 pediatric patients (mean age of 15.8 years,16 females) undergoing catheter ablation for cardiac arrhythmias at the Cardiology Department of Boston Children's Hospital from October 2016 to March 2020; 9 received 0.9% NaCl, 12 received low-dose (LD) remifentanil (0.25 mcg/kg/min), and 11 received high-dose (HD) remifentanil (0.5 mcg/kg/min). The hemodynamic changes of primary somatosensory and prefrontal cortices were recorded during surgery using a continuous wave fNIRS system. The primary outcome measures were the changes in oxyhemoglobin concentration (NadirHbO, i.e., lowest oxyhemoglobin concentration and PeakHbO, i.e., peak change and area under the curve) of medial frontopolar cortex (mFPC), lateral prefrontal cortex (lPFC) and primary somatosensory cortex (S1) to ablation in PL versus remifentanil groups. Secondary measures included the fNIRS response to an auditory control condition. The data analysis was performed on an intention-to-treat (ITT) basis. Remifentanil group (dosage subgroups combined) was compared with PL, and a post hoc analysis was performed to identify dose effects. There were no adverse events. The groups were comparable in age, sex, and number of ablations. Results comparing remifentanil versus PL show that PL group exhibit greater NadirHbO in inferior mFPC (mean difference (MD) = 1.229, 95% confidence interval [CI] = 0.334, 2.124, p < 0.001) and superior mFPC (MD = 1.206, 95% CI = 0.303, 2.109, p = 0.001) and greater PeakHbO in inferior mFPC (MD = -1.138, 95% CI = -2.062, -0.214, p = 0.002) and superior mFPC (MD = -0.999, 95% CI = -1.961, -0.036, p = 0.008) in response to ablation. S1 activation from ablation was greatest in PL, then LD, and HD groups, but failed to reach significance, whereas lPFC activation to ablation was similar in all groups. Ablation versus auditory stimuli resulted in higher PeakHbO in inferior mFPC (MD = 0.053, 95% CI = 0.004, 0.101, p = 0.004) and superior mFPC (MD = 0.052, 95% CI = 0.013, 0.091, p < 0.001) and higher NadirHbO in posterior superior S1 (Pos. SS1; MD = -0.342, 95% CI = -0.680, -0.004, p = 0.007) during ablation of all patients. Remifentanil group had smaller NadirHbO in inferior mFPC (MD = 0.098, 95% CI = 0.009, 0.130, p = 0.003) and superior mFPC (MD = 0.096, 95% CI = 0.008, 0.116, p = 0.003) and smaller PeakHbO in superior mFPC (MD = -0.092, 95% CI = -0.680, -0.004, p = 0.007) during both the stimuli. Study limitations were small sample size, motion from surgery, indirect measure of nociception, and shallow penetration depth of fNIRS only allowing access to superficial cortical layers.

Conclusions: We observed cortical activity related to nociception during cardiac ablation under general anesthesia with remifentanil. It highlights the potential of fNIRS to provide an objective pain measure in unconscious patients, where cortical-based measures may be more accurate than current evaluation methods. Future research may expand on this application to produce a real-time indication of pain that will aid clinicians in providing immediate and adequate pain treatment.

Trial registration: ClinicalTrials.gov NCT02703090.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. CONSORT participant flow diagram.

CONSORT, Consolidated Standards of Reporting Trials.

Fig 2. fNIRS optode layout and study paradigm.

(A) Brain map of customized optode placement where red represent optical sources (sources A to I), blue represent long-separation detectors (detectors 1 to 12, placed 3 cm from the source), and yellow represent the short-separation detectors (0.8 cm from the source). A long-separation detector and source pair form a channel and are represented by the black lines connecting the sources (in red) and detectors (in blue). A short-separation detector (in yellow) and source (in red) pair are called the short-separation channel and measure the extracerebral hemodynamic changes. (B) Brain map of 24 channel locations (green, orange, and yellow) and the cortical ROI. (C) A resting state and an audio run, each lasting for 200 seconds, were collected before the induction of anesthesia. IV infusion of the test drug (either PL, LD remifentanil, or HD remifentanil) was started at the same time as intraoperative fNIRS data collection. The time, number, and duration of ablations varied between patients and was determined by the cardiologist. Time stamps of each ablation was noted in the fNIRS data. An audio run was collected at least once starting 45 minutes after the initiation of the infusion and fNIRS data collection. fNIRS, functional near-infrared spectroscopy; HD, high-dose; IV, intravenous; LD, low-dose; ROI, region of interest.

Fig 3. Group-averaged hemodynamic response to ablation in the 6 ROIs.

(A) Remifentanil (HD + LD = black) and PL (blue) groups. (B) Remifentanil subgroups (HD = black; LD = red) and PL (blue) group. The dotted black line indicates the start of ablation. The shaded region represents the standard error of mean. Ant. SS1, anterior superior somatosensory cortex; HD, high-dose; Inf. lPFC, inferior lateral prefrontal cortex; Inf. mFPC, inferior medial frontopolar cortex; LD, low-dose; PL, placebo; Pos. SS1, posterior superior somatosensory cortex; ROI, region of interest; Sup. lPFC, superior lateral prefrontal cortex; Sup. mPFC, superior medial frontopolar cortex.

Fig 4. Group-level hemodynamic measures of activation to ablation in PL and 2 subgroups of remifentanil.

(A) PeakHbO concentration. (B) Nadir of ΔHbO concentration. (C) AUC. The plot on the right describes the measures calculated from a standard hemodynamic response. ** indicates significant effects between PL and remifentanil using 2-sample t tests at FDR-corrected p < 0.05. The FDR-p threshold = 0.008. * indicates significant effects using 2-sample t tests at uncorrected p < 0.05. Error bars represent the standard error of mean. Ant. SS1, anterior superior somatosensory cortex; AUC, area under the ΔHbO curve; FDR, false discovery rate; Inf. lPFC, inferior lateral prefrontal cortex; Inf. mFPC, inferior medial frontopolar cortex; PeakHbO, Peak ΔHbO; PL, placebo; Pos. SS1, posterior superior somatosensory cortex; Sup. lPFC, superior lateral prefrontal cortex; Sup. mPFC, superior medial frontopolar cortex.

Fig 5. Sex-related effects in response to ablation in male versus female patients under general anesthesia.

(A) PeakHbO concentration. (B) Nadir of ΔHbO concentration. (C) AUC. * indicates significant effects between male and female patients using 2-sample t tests at uncorrected p < 0.05. Error bars represent the standard error of mean. Ant. SS1, anterior superior somatosensory cortex; AUC, area under the ΔHbO curve; Inf. lPFC, inferior lateral prefrontal cortex; Inf. mFPC, inferior medial frontopolar cortex; PeakHbO, Peak ΔHbO; Pos. SS1, posterior superior somatosensory cortex; Sup. lPFC, superior lateral prefrontal cortex; Sup. mPFC, superior medial frontopolar cortex.

Fig 6. Hemodynamic response to painful versus auditory stimuli under general anesthesia.

(A) Block-averaged hemodynamic response to pain/ablation (blue) and auditory (green) stimuli in the 2 groups for the 6 regions of the interest. Shaded areas represent the standard error of mean. (B) PeakHbO concentration when compared to baseline, following painful versus auditory stimuli in the 6 ROIs classified based on drug group. Mixed ANOVA revealed significant effects at FDR-corrected p < 0.05 (FDR-p threshold = 0.007). (C) Nadir of ΔHbO concentration following painful versus auditory stimuli in the 6 ROIs classified based on drug group. Mixed ANOVA revealed significant effects at FDR-corrected p < 0.05 (FDR-p threshold = 0.007). ptask indicates the p-value for mean effect of task (pain versus audio); pgroup indicates the p-value for mean effect of drug group (PL versus remifentanil); and pgroup × task indicates the p-value for interaction effect of task and drug group (Pain versus Audio in PL and remifentanil). ** indicates significant effects at FDR-corrected p < 0.05. Error bars indicate the standard error of mean. ANOVA, analysis of variance; Ant. SS1, anterior superior somatosensory cortex; FDR, false discovery rate; Inf. lPFC, inferior lateral prefrontal cortex; Inf. mFPC, inferior medial frontopolar cortex; PeakHbO, Peak ΔHbO; Pos. SS1, posterior superior somatosensory cortex; ROI, region of interest; Sup. lPFC, superior lateral prefrontal cortex; Sup. mPFC, superior medial frontopolar cortex.