Pupillary unrest, opioid intensity, and the impact of environmental stimulation on respiratory depression

Abstract

Opioid-induced respiratory depression (OIRD) confers significant morbidity, but its onset can be challenging to recognize. Pain or stimulation effects of conversation may mask or attenuate common clinical manifestations of OIRD. We asked whether pupillary unrest could provide an objective signal of opioid exposure, and whether this signal would be independent from the confounding influence of extrinsic stimulation. We conducted a cross-over trial of healthy volunteers using identical remifentanil infusions separated by a washout period; in both, pupillary unrest in ambient light (PUAL) was measured at 2.5-min intervals. During one infusion, investigators continuously engaged the subject in conversation, while in the other, a quiet environment was maintained; measures of respiratory depression were compared under each condition. We tested PUAL's relationship to estimated opioid concentration under quiet conditions, measured PUAL's discrimination of lower versus higher opioid exposure using receiver operating characteristic (ROC) analysis, and assessed the effect of stimulation on PUAL versus opioid using mixed effects regression. Respiratory depression occurred more frequently under quiet conditions (p < 0.0001). Under both conditions, PUAL declined significantly over the course of the remifentanil infusion and rose during recovery (p < 0.0001). PUAL showed excellent discrimination in distinguishing higher versus absent-moderate opioid exposure (AUROC = 0.957 [0.929 to 0.985]), but was unaffected by interactive versus quiet conditions (mean difference, interactive - quiet = - 0.007, 95% CI - 0.016 to 0.002). PUAL is a consistent indicator of opioid effect, and distinguishes higher opioid concentrations independently of the stimulating effects of conversational interaction. Under equivalent opioid exposure, conversational interaction delayed the onset and minimized the severity of OIRD.Clinical trial registration: NCT04301895.

Keywords: Infrared pupillometry; Monitoring drug effects; Opioid induced respiratory depression; Opioid intoxication; Opioid medication; Opioid related patient safety; pupillary responses.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

Mean transcutaneous CO2 measurements during the 10-min remifentanil infusion and 25-min recovery period. Respiratory depression was more pronounced during the quiet versus interactive conditions, with CO2 increasing 37% versus 21% above baseline values respectively (p = 0.0002)

Fig. 2

a Oxyhemoglobin desaturation occurred more frequently (in 19/20 in versus 10/20 subjects) and earlier (median onset 6.2 versus 9.6 min) under quiet compared to interactive conditions (HR 0.135, p < 0.001, conditional Cox regression). In contrast to respiratory outcomes, PUAL decline did not differ under quiet versus interactive conditions. b Paired data shows onset of oxyhemoglobin desaturation in subjects under quiet and interactive conditions

Fig. 3

PUAL declined progressively as opioid concentration increased during the 10-min remifentanil infusion, from an average of 0.264 at baseline to 0.022 by 10 min under quiet conditions, and recovered as the infusion was discontinued (p 

Fig. 4

In 20 subjects under quiet conditions, PUAL showed excellent discrimination between high versus absent-moderate opioid effect: AUROC = 0.9459 (0.8957—0.9961) under quiet conditions and 0.9671 (0.9384–0.9958) under interactive conditions (p = 0.3588 for difference in ROC area under the two conditions). Compared to PUAL, CO2 showed weaker discrimination between high versus absent-moderate opioid effect: AUROC = 0.8079 (0.7284–0.8874) under quiet conditions and 0.6501 (0.5480–0.7521) under interactive conditions (p = 0.0202 for difference in CO2 ROC area under the two contrasting conditions, p = 0.0034 for difference between CO2 versus PUAL ROC area under quiet conditions, and p < 0.0001 for difference between CO2 versus PUAL ROC area under interactive conditions)

Fig. 5

Overall, ≥ 90% PUAL suppression occurred in 19/20 of subjects during quiet conditions versus 18/20 subjects during interactive conditions. The proportion of subjects reaching ≥ 90% PUAL suppression under each condition did not differ significantly, HR 1.193 (95% CI 0.624–2.278), p = 0.593