Why do some patients stop breathing after taking narcotics? Ventilatory chemosensitivity as a predictor of opioid-induced respiratory depression

OPIOID-INDUCED RESPIRATORY depression (OIRD) is a serious public health and patient safety concern. In 2010, drug overdose was the leading cause of injury death in the United States (32), with 75% of these deaths involving opioid analgesics (2, 10). The problem is not limited to outpatients: severe respiratory depression and death occur even in hospitals using closedloop administration devices [patient controlled analgesia (PCA)] and continuous pulse oximetry (13, 18). This phenomenon has drawn the attention of the Joint Commission, which recently issued a Sentinel Alert (29). The incidence of postoperative OIRD is estimated to be 0.5–2% (4, 7, 31) but may be higher in certain patient populations and is almost certainly under recognized and under reported (6, 18, 27). There is clearly a need for greater understanding of risk factors for OIRD and development of monitoring techniques that can accurately and reliably detect respiratory depression. Prediction of patients at risk for OIRD is difficult and tends to be inaccurate. Some associations have been identified, including advanced age, American Society of Anesthesiologists (ASA) status 3, chronic opioid use, obesity, obstructive sleep apnea (OSA), chronic pulmonary disease, and coadministration of sedative drugs (3, 28, 30). However, although these factors are statistically associated with OIRD, they are often poorly predictive in individual patients. Moreover, OIRD occurs unpredictably in patients who are not considered “high risk. ” For example, in 102 consecutive opioid-related respiratory events at Duke Hospital, 50% occurred in patients younger than 60 years. There must therefore be additional potent factors that remain to be identified. An overlooked factor in the development of OIRD may be an individual’s baseline respiratory chemoreceptor responsiveness and the degree to which it is suppressed by opioids and possibly sleep. Opioid receptors are found throughout the respiratory control centers of the brain stem, carotid bodies, vagus nerve, and walls of the airways. Exogenous administration of opioids causes a dose-dependent decrease in sensitivity to hypoxia and hypercarbia via inhibition of central and peripheral chemoreceptor activity. Both hypoxia and hypercapnia induce hyperventilation, and formal techniques for the assessment of both effects [hypoxic ventilatory response (HVR) and hypercapnic ventilatory response (HCVR)] in humans were described over 50 years ago. Although HVR (dependent on peripheral chemoreceptors) is influenced by PCO2, and HCVR (dependent on both peripheral and central chemoreceptors) by PO2, a technique to measure both has been developed (5). It is widely known that in the normal population the HVR varies several fold (8, 19). The HCVR varies even more. In a series of 211 healthy volunteers aged 10–53 years in whom HCVR was published in the literature (20, 23, 26) or measured in Institutional Review Board-approved studies in our lab, there was an 80-fold difference between the lowest and the highest HCVR. HVR and HCVR have been shown to remain relatively constant between repeated measurements in a single day but demonstrate some between-day variability over a period of weeks or months (9, 25). HCVR has also been shown to decrease and increase in an individual as a function of aerobic training and deconditioning, respectively (14). Low HCVR can be increased with respiratory muscle training (16). Address for reprint requests and other correspondence: R. E. Moon, Box 3094, Duke Univ. Medical Center, Durham, NC 27710 (e-mail: richard.moon@duke.edu).