To the Editor:
We read with interest the article by Montana et al.1 “Opioid Sensitivity in Children with and without Obstructive Sleep Apnea.” The authors are to be commended on their measurement of in vivo remifentanil concentrations—which interestingly were higher and more variable in their patient group with presumed obstructive sleep apnea—instead of pharmacologic extrapolation. This article provides evidence that serum remifentanil concentrations may not be constant independent of age or weight.
However, from the points of view of a pediatric anesthesiologist and a sleep apnea researcher, we have concerns regarding the presentation of the study findings. The study, while adding to our fund of knowledge regarding opioid effect on the pupillary sphincter in awake patients, was unable to draw any conclusions regarding the two groups’ sensitivity to opioid-induced respiratory depression. Although addressed in the discussion, this fact is not exactly highlighted in the abstract or in the Editor’s Perspective and is open to unintentional misinterpretation. We fear it may provide a false sense of security to those administering or prescribing opioids to children with obstructive sleep apnea and/or obesity.
The authors hypothesize that children with sleep apnea have an increased sensitivity to the miotic and respiratory depressant effects of remifentanil, and the study did not support this conclusion. It is not clear whether the method used to test the hypothesis, pupillary constriction, is appropriately sensitive to the clinical opioid effect we all seek to best understand, respiratory depression. The terms opioid sensitivity and opioid effect are used interchangeably and do not necessarily imply a linkage from pupil size to respiratory vulnerability. Thus, the summative statement, “this study questions the notion that all children with a clinical diagnosis of sleep apnea are more sensitive to opioids” is particularly concerning to us when the test itself lacked specificity for the clinically concerning effect in question. The actual conclusion is that the relationship between opioid effect and pupillary miosis as it relates to respiratory depression or analgesia remains unaddressed.
The second concern we have regarding the conclusion relates to the translation of opioid effects while awake to effects in the sleeping state. The authors distinctly note that although the aim was to achieve sleeping levels of sedation, this did not occur. Current evidence does not support the assumption that sensitivity to opioids while awake translates to risk of respiratory depression when asleep. Because most, if not all, pediatric posttonsillectomy deaths have been associated with opioids and sleep,2 we hope that readers of this study would not erroneously feel secure in translating findings in awake pediatric patients to their own practices in the postoperative setting.
Finally, we are not reassured that the obstructive sleep apnea group was functionally dissimilar to the control group, especially in light of the fact that only 9 of 15 study patients had overnight polysomnography and were not stratified according to Apnea–Hypopnea Index severity. In contrast, the adults in the similar study group of Doufas et al.3 all had polysomnography and were stratified according to severity. In fact, in the Doufas study, those with mild sleep apnea were sorted to the control/“no obstructive sleep apnea” group, and only the moderate or severe Apnea–Hypopnea Index diagnoses were considered the “obstructive sleep apnea” group. We wondered whether all nine of Montana’s study patients had mild apnea or whether the other six had obstructive sleep apnea at all. There is also no robust evidence that 14 of 15 children in the control group did not have obstructive sleep apnea. Why should a study on pediatric patients be held to different standards, especially with such a small sample size? We appreciate that recruitment of pediatric patients for research is difficult. However, this tempers our confidence in translating the results.
There is still much to be discovered regarding opioid sensitivity in children with sleep apnea, as the article by Montana et al. demonstrates. The relationship of pupillary miosis to analgesia, respiration, or even sleep-associated miotic changes in children with and without sleep apnea are all exciting areas for further research—and this study can help to inform them.
The authors declare no competing interests.