Newly Published
Perioperative Medicine  |   September 2018
Non–steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea
Author Notes
  • From the Department of Anesthesiology, Perioperative and Pain Medicine (A.G.D., S.L.S.), the Department of Psychiatry and Behavioral Sciences, and Stanford Center for Sleep Sciences and Medicine (C.A.K.); and the Department of Otolaryngology Head & Neck Surgery (R.C.), Stanford University School of Medicine, Stanford, California; the Outcomes Research Consortium, Cleveland, Ohio (A.G.D.); and the Department of Otorhinolaryngology, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Selangor, Malaysia (N.H.A.R.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Submitted for publication January 2, 2018. Accepted for publication August 8, 2018.
    Submitted for publication January 2, 2018. Accepted for publication August 8, 2018.×
  • Acknowledgments: The authors thank their colleagues from the Ear, Nose and Throat surgery anesthesia team at the Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, who have greatly facilitated this project by allowing us the extra time required for the experiment before anesthetic induction, and Ronald G. Pearl, M.D., Ph.D., Chair at the Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, for the useful discussions on parts of the methods.
    Acknowledgments: The authors thank their colleagues from the Ear, Nose and Throat surgery anesthesia team at the Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California, who have greatly facilitated this project by allowing us the extra time required for the experiment before anesthetic induction, and Ronald G. Pearl, M.D., Ph.D., Chair at the Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, for the useful discussions on parts of the methods.×
  • Research Support: Support was provided solely from departmental sources.
    Research Support: Support was provided solely from departmental sources.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Doufas: Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, California 94305. agdoufas@stanford.edu. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology / Respiratory System / Sleep Medicine / Opioid
Perioperative Medicine   |   September 2018
Non–steady State Modeling of the Ventilatory Depressant Effect of Remifentanil in Awake Patients Experiencing Moderate-to-severe Obstructive Sleep Apnea
Anesthesiology Newly Published on September 21, 2018. doi:10.1097/ALN.0000000000002430
Anesthesiology Newly Published on September 21, 2018. doi:10.1097/ALN.0000000000002430
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Patients with obstructive sleep apnea are often said to have increased sensitivity to opioid-induced ventilatory depression

What This Article Tells Us That Is New:

  • The hypothesis that patients with moderate-to-severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression was tested in 20 control patients with mild or no obstructive sleep apnea and 30 patients with moderate-to-severe obstructive sleep apnea, defined as an apnea/hypopnea index of 15 or more episodes per hour of sleep

  • The predicted remifentanil effect site concentration at which half-maximal depression of minute ventilation occurred in awake patients receiving a remifentanil infusion of 0.2 µg · kg −1 of ideal body weight per minute did not differ between control patients and patients with moderate-to-severe obstructive sleep apnea

  • This does not support the notion that adults with moderate-to-severe obstructive sleep apnea have increased sensitivity to opioid-induced ventilatory depression

Background: Evidence suggests that obstructive sleep apnea promotes postoperative pulmonary complications by enhancing vulnerability to opioid-induced ventilatory depression. We hypothesized that patients with moderate-to-severe obstructive sleep apnea are more sensitive to remifentanil-induced ventilatory depression than controls.

Methods: After institutional approval and written informed consent, patients received a brief remifentanil infusion during continuous monitoring of ventilation. We compared minute ventilation in 30 patients with moderate-to-severe obstructive sleep apnea diagnosed by polysomnography and 20 controls with no to mild obstructive sleep apnea per polysomnography. Effect site concentrations were estimated by a published pharmacologic model. We modeled minute ventilation as a function of effect site concentration and the estimated carbon dioxide. Obstructive sleep apnea status, body mass index, sex, age, use of continuous positive airway pressure, apnea/hypopnea events per hour of sleep, and minimum nocturnal oxygen saturation measured by pulse oximetry in polysomnography were tested as covariates for remifentanil effect site concentration at half-maximal depression of minute ventilation (Ce50) and included in the model if a threshold of 6.63 (P < 0.01) in the reduction of objective function was reached and improved model fit.

Results: Our model described the observed minute ventilation with reasonable accuracy (22% median absolute error). We estimated a remifentanil Ce50 of 2.20 ng · ml–1 (95% CI, 2.09 to 2.33). The estimated value for Ce50 was 2.1 ng · ml–1 (95% CI, 1.9 to 2.3) in patients without obstructive sleep apnea and 2.3 ng · ml–1 (95% CI, 2.2 to 2.5) in patients with obstructive sleep apnea, a statistically nonsignificant difference (P = 0.081). None of the tested covariates demonstrated a significant effect on Ce50. Likelihood profiling with the model including obstructive sleep apnea suggested that the effect of obstructive sleep apnea on remifentanil Ce50 was less than 5%.

Conclusions: Obstructive sleep apnea status, apnea/hypopnea events per hour of sleep, or minimum nocturnal oxygen saturation measured by pulse oximetry did not influence the sensitivity to remifentanil-induced ventilatory depression in awake patients receiving a remifentanil infusion of 0.2 μg · kg–1 of ideal body weight per minute.