IN this issue of Anesthesiology, two complementary and fascinating studies focus our attention on chronic intermittent nocturnal desaturation (CIND) in children with sleep-disordered breathing (SDB). In the first study, Moss et al.  1exposed developing rats to chronic intermittent hypoxia during their sleep cycle and found that they were more sensitive to the respiratory depressant effects of opioids than nonhypoxic rats. In the second, Brown et al.  2determined that children whose minimum nocturnal desaturation was less than 85% required one half the dose of opioids for similar pain scores after tonsillectomy and adenoidectomy (T&A) surgery compared with children whose minimum saturation was 85% or greater. These observations provide compelling evidence for the cautious and individualized dosing of opioids in children with SDB.

Sleep-disordered breathing is a continuum that ranges from normal breathing to obstructive sleep apnea (OSA).3–5SDB is caused by a narrowing of the upper airway, which in turn may be attributed to adenotonsillar hypertrophy, decreased neuromuscular tone, obesity, and/or craniofacial abnormalities. As the severity of the airway resistance increases, hypercapnia, hypoxia, and/or intermittent upper airway obstruction begins to develop. Polysomnography is the accepted standard for diagnosing SDB and its level of severity, although its use in children has been limited. For most children who present for T&A surgery, the diagnoses of OSA and other SDB patterns are largely based on clinical criteria and/or portable techniques (i.e. , nocturnal oximetry), although neither can reliably predict OSA.6,7 

With an increasing number of children with a diagnosis of OSA presenting for T&A surgery, understanding the nature of the 10-fold greater incidence of perioperative respiratory complications in those with OSA compared with those without has become paramount.8–10In a retrospective review, Wilson et al.  10noted that four factors increased the risk of perioperative respiratory complications after T&A surgery, including CIND. They noted that the incidence of respiratory complications was two and one half times more common in children whose minimum nocturnal saturation was less than 80% compared with those whose saturation was greater than 80%.10Their observations were consistent with a prospective study by Waters et al. ,11who reported that children with OSA undergoing T&A surgery demonstrated diminished minute ventilation during spontaneous ventilation with halothane but, more importantly, demonstrated a 10-fold greater incidence of apnea after fentanyl (0.5 μg/kg) compared with children without OSA. The attenuated ventilation during halothane is consistent with the flattened carbon dioxide response reported in children with OSA.12However, the greater incidence of apnea after fentanyl in children with OSA was surprising. Brown et al.  13subsequently confirmed these observations, noting that perioperative morphine requirements in children with OSA correlated with age and the severity of nocturnal desaturation.

Is CIND, in isolation, sufficient to alter opioid sensitivity? Moss et al.  1investigated the respiratory responses to opioids in developing rats that were rendered intermittently hypoxic during their diurnal sleep cycle. They found that hypoxic rats were more likely to develop apnea in response to fentanyl than normoxic rats.1In humans, however, CIND is unlikely to occur in isolation. Rather, it occurs in combination with a pathologic condition such as OSA. These data from rats suggest that CIND, not OSA, is the putative trigger for the increased opioid sensitivity observed.

Knowing that the respiratory and analgesic effects of opioids are tightly linked to μ-subreceptors, Brown et al.  2posited that children with CIND may require less opioid for posttonsillectomy analgesia than those without CIND. Not surprisingly, they found that children whose minimum saturation was less than 85% required one half the dose of opioids as those whose minimum saturation was 85% or greater for the same pain scores.2The theme echoed by all of these studies is that children with OSA/CIND are very sensitive to opioids.

The molecular basis for the CIND-induced increase in opioid sensitivity is incompletely understood. CIND preconditions the brain by both directly and indirectly activating intermediate early responsive genes such as c-FOS and c-Jun as well as several transcription factors, including activator protein 1 and hypoxia inducible factor 1 (HIF-1).14HIF-1, known as the “master regulator,” slowly modulates gene expression for oxygen homeostasis (including erythropoiesis and angiogenesis) during both continuous or intermittent and acute or chronic hypoxia.15This includes remodeling of the pulmonary vascular and carotid body activity during episodes of hypoxia.15Another mechanism is a fast response to hypoxia, which may be mediated through oxygen-sensing ion channels in specific cells.16For both of these responses, several intracellular signaling pathways (including the protein kinases) are involved and may in fact modulate both the fast and slow responses.14,16Unraveling the molecular basis for remodeling opioid receptors during CIND remains one of our major challenges.

Chronic intermittent hypoxia up-regulates opioid receptors by tipping the balance of excitatory neurokinin 1 and inhibitory μ receptors in favor of the latter. This occurs in part because of hypoxia-induced endocytosis of the neurokinin-1 receptors.17The activity of the μ-receptors is further augmented by a transient decrease in the neurokinin-1 receptor binding capacity that occurs after acute hypoxia.18The net effect is a predominance of μ receptors and an increased sensitivity to opioids.

That SDB occurs in children who are scheduled to undergo T&A surgery is widely appreciated, but that it can also occur in children who present for non-T&A surgery is not. Unexpected slow emergence, apnea, and/or respiratory events after extubation and in the postanesthesia care unit after non-T&A surgery may suggest an increased sensitivity to opioids, possibly resulting from OSA and CIND. To identify those at risk for OSA, a history of growth retardation, behavior disturbances, enuresis, and poor school performance, as well as snoring and nocturnal apnea, should be sought preoperatively.19,20As the relation between OSA/CIND and opioid sensitivity becomes firmly established, it is time to insist on more reliable and portable means of quickly and accurately diagnosing those who are and are not at risk for OSA/CIND.

How should anesthesiologists modify their practices in lieu of these findings? When a child presents for T&A surgery with a tentative diagnosis of OSA, it seems prudent to assume the child is at risk for CIND and more sensitive to opioids than usual. After induction of anesthesia, tracheal intubation, and the return of spontaneous ventilation, the carbon dioxide response to surgery and inhalational anesthesia should be carefully monitored. Small incremental doses of an opioid (10–20 μg/kg morphine or 0.2–0.5 μg/kg fentanyl) should be titrated intravenously while the capnogram is observed for apnea. If apnea occurs, either no additional doses or a very small dose of an opioid should be administered before extubation. If apnea does not occur, incremental doses of opioids may be given until a therapeutic response has been achieved. If ventilation is controlled during surgery, testing for an exaggerated response to opioids during surgery is precluded. In this case, a small dose of opioid may be administered during surgery and supplemental doses titrated postoperatively until the pain is controlled. Children with OSA and CIND or those identified as sensitive to opioids should be extubated awake. Postanesthesia care unit and ward staff should be apprised of the child’s sensitivity to opioids and cautioned regarding the dose and frequency of supplemental opioids. Finally, because children with OSA/CIND may obstruct their airways and desaturate on the first posttonsillectomy night, overnight monitoring should include pulse oximetry.21 

In this issue of the Journal, two studies provide compelling evidence for the judicious use of opioids in children with OSA/CIND as a means of providing adequate analgesia as well as attenuating perioperative respiratory events.1,2By recognizing that SDB and OSA/CIND may occur in children who are scheduled to undergo T&A as well as other types of surgery, and by adjusting opioid doses accordingly, perioperative respiratory events in these children may be obviated.

Women and Children’s Hospital of Buffalo and Strong Hospital, University of Rochester, Rochester, New York, and St. Christopher’s Hospital for Children, Philadelphia, Pennsylvania.

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