Recurrent hypoxemia in children is associated with increased analgesic sensitivity to opiates.

BACKGROUND: Postsurgical administration of opiates in patients with obstructive sleep apnea (OSA) has recently been linked to an increased risk for respiratory complications. The authors have attributed this association to an effect of recurrent oxygen desaturation accompanying OSA on endogenous opioid mechanisms that, in turn, alter responsiveness to subsequent administration of exogenous opiates. In a retrospective study, the authors have shown that oxygen desaturation and young age in children with OSA are correlated with a reduced opiate requirement for postoperative analgesia. METHODS: The current study was designed to test that conclusion prospectively in 22 children with OSA scheduled to undergo adenotonsillectomy. The children were stratified to those having displayed < 85% or > or = 85% oxygen saturation nadir during sleep preoperatively. Using a blinded design, the children were given morphine postoperatively to achieve an identical behavioral pain score. RESULTS: As compared with children in the > or = 85% group, the < 85% oxygen saturation nadir group required one half the total analgesic morphine dose postoperatively, indicating heightened analgesic sensitivity to morphine after recurrent hypoxemia. CONCLUSIONS: Previous recurrent hypoxemia in OSA is associated with increased analgesic sensitivity to subsequent morphine administration. Therefore, opiate dosing in children with OSA must take into account a history of recurrent hypoxemia.

Recurrent hypoxia in rats during development increases subsequent respiratory sensitivity to fentanyl.

BACKGROUND: In children with a history of significant obstructive sleep apnea who undergo adenotonsillectomy, postsurgical administration of opiates has been alleged to be associated with an increased risk for respiratory complications, including respiratory depression. The authors hypothesize that this association is due to an effect of recurrent hypoxemia that accompanies more severe obstructive sleep apnea on altered responsiveness to subsequent exogenous opiates. METHODS: The current study was designed to test the effect of recurrent hypoxia in the developing rat on respiratory responses to subsequent administration of the mu-opioid agonist fentanyl. Rats were exposed to 12% oxygen balance nitrogen for 7 h daily for 17 days, from postnatal day 17 to 33, a period equivalent to human childhood. After 17 additional days in room air, rats were given a fentanyl dose and tested for their respiratory response to fentanyl using a whole body plethysmograph. Rats undergoing similar protocols without recurrent hypoxia served as controls. RESULTS: As compared with controls, rats preexposed to recurrent hypoxia displayed a more profound depression with fentanyl in minute ventilation, respiratory frequency, tidal volume, and tidal volume divided by inspiratory time that represents respiratory drive. These results indicated an increased respiratory sensitivity to fentanyl after recurrent hypoxia. CONCLUSIONS: Previous recurrent hypoxia increases respiratory sensitivity to subsequent opiate agonists. If these findings are applicable to humans, opiate dosing in children must be adjusted depending on history of recurrent hypoxemia to avoid respiratory depression.

Long-term recurrent hypoxia in developing rat attenuates respiratory responses to subsequent acute hypoxia.

Whereas definitive treatment of pediatric conditions associated with hypoxemia reverses many pathologic symptoms, some physiologic dysfunctions appear to persist. These abnormalities are attributed to long-lasting central effects of prior hypoxia. To investigate such effects in an animal model, male rats were exposed to FiO2 = 0.12 continuously for 7 h daily from postnatal day (p) 17 (representing early childhood) through p33 (representing adolescence), defined as recurrent hypoxia. Respiratory responses during and following 20 min FiO2 = 0.12 were measured on p35 and p47. To control for early weaning on p15 (normal weaning = p21), male rats were weaned on either p15 or p21, raised in normoxia, and also tested for respiratory responsiveness to acute hypoxia. To assess sex differences, female rats were assigned to similar groups and protocols. Minute ventilation, respiratory frequency, tidal volume, and respiratory drive were measured in unsedated animals using whole-body plethysmography. After recurrent hypoxia, male rats displayed an attenuation of ventilation, frequency, and drive during hypoxia, and of all functions after hypoxia on both p35 and p47. There were no differences between test days during hypoxia, and greater attenuation of tidal volume and respiratory drive on p47 during recovery from hypoxia. Respiratory responses displayed no effect of sex on p35, and occasional effects of early weaning on p35 and p47. Thus, recurrent hypoxia produces long-lasting attenuation in respiratory responsiveness to subsequent acute hypoxia. Such long-lasting attenuation, if present in humans, may diminish the protection of children with a history of recurrent hypoxemia against future hypoxic events.

Canadian Association of Neuroscience Review: Respiratory control and behavior in humans: lessons from imaging and experiments of nature.

The purpose of this review is to demonstrate that respiration is a complex behavior comprising both brainstem autonomic control and supramedullary influences, including volition. Whereas some fundamental mechanisms had to be established using animal models, this review focuses on clinical cases and physiological studies in humans to illustrate normal and abnormal respiratory behavior. To summarize, central respiratory drive is generated in the rostroventrolateral medulla, and transmitted to both the upper airway and to the main and accessory respiratory muscles. Afferent feedback is provided from lung and muscle mechnoreceptors, peripheral carotid and aortic chemoreceptors, and multiple central chemoreceptors. Supramedullary regions, including cortex and subcortex, modulate or initiate breathing with volition, emotion and at the onset of exercise. Autonomic breathing control can be perturbed by brainstem pathology including space occupying lesions, compression, congenital central hypoventilation syndrome and sudden infant death syndrome. Sleep-wake states are important in regulating breathing. Thus, respiratory control abnormalities are most often evident during sleep, or during transition from sleep to wakefulness. Previously undiagnosed structural brainstem pathology may be revealed by abnormal breathing during sleep. Ondine's curse and 'the locked-in syndrome' serve to distinguish brainstem from supramedullary regulatory mechanisms in humans: The former comprises loss of autonomic respiratory control and requires volitional breathing for survival, and the latter entails loss of corticospinal or corticobulbar tracts required for volitional breathing, but preserves autonomic respiratory control.

Ontogeny of respiratory sensitivity and tolerance to the mu-opioid agonist fentanyl in rat.

Whereas developmental changes in analgesic sensitivity and tolerance to the mu-opioid agonist fentanyl have been reported, knowledge of respiratory responses to that drug is lacking. Using 7- and 14-day-old (P7, P14) and adult conscious rats, we first established, using whole body plethysmography, the fentanyl dose that decreased minute ventilation by 50% (ED50) at each age. ED50 increased with postnatal age (40, 60 and 120 microg/kg sc, respectively), indicating a high sensitivity to fentanyl in the youngest rats that decreased with maturation. In separate rat groups of the 3 ages, we injected each ED50 dose, once a day, for several consecutive days, until tolerance was established. Tolerance was defined as a reduction in respiratory depression from 50% to 75% of baseline. All age groups reached tolerance in minute ventilation, respiratory frequency, tidal volume and instantaneous flow (equivalent to respiratory drive). The P14 rat pups attained tolerance more rapidly (at 2.6 days) than did either the younger (5.1 days) or the adult rats (4.4 days). These results indicate that respiratory sensitivity and tolerance to fentanyl in rat vary in a distinct manner during maturation.

Respiratory responses to intermittent hypoxia in unsedated piglets: relation to substance P binding in brainstem.

Respiratory responses to single intermittent hypoxia (5 min 21% O(2), 5 min 8% O(2) X6) in 5-6, 10-11, 21-22 and 26-27 day-old piglets, and to recurrent six daily intermittent hypoxia in 10-11 and 26-27 day-old piglets were assessed. Substance P binding in the piglets' brainstem immediately after the last hypoxic episode was measured. All piglets hyperventilated during hypoxia. Weight adjusted inspired ventilation, tidal volume and instantaneous flow decreased with age. The oldest piglets uniquely displayed attenuated ventilation and tidal volume during the sixth versus first hypoxic episode with single intermittent hypoxia, and reduced inspired ventilation and tidal volume during the first hypoxic episode on the sixth daily hypoxia compared to single hypoxia. By contrast, substance P binding was greatly reduced in the solitary, hypoglossal, paraambigual and lateral reticular brainstem nuclei of both younger and older piglets following either single or recurrent intermittent hypoxia. Thus, the reduction in membrane-bound neurokinin receptors by intermittent hypoxia, presumably consequent to endogenously released substance P, does not exclusively determine whether the ventilatory response to that hypoxia will be attenuated or not.

Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia.

BACKGROUND: Obstructive sleep apnea (OSA) in children is often associated with recurrent hypoxemia during sleep. In developing animals, central opioid neuropeptide content is high, and opioid receptors are up-regulated after recurrent hypoxia. The authors hypothesized that children with recurrent hypoxemia due to OSA might have altered central opioid functionality that could affect their responsiveness to opioid drugs. Using a retrospective database, we assessed the relation of age and preoperative oxygen saturation to the cumulative postoperative morphine dose administered for analgesia in children with OSA undergoing adenotonsillectomy. METHODS: Inclusion criteria were (1) adenotonsillectomy for OSA; (2) no concomitant pathology; (3) intraoperative administration of short-acting opioid drugs; (4) endotracheal extubation on awakening in the operating room; and (5) morphine as the parenteral, postoperative analgesic. RESULTS: Forty-six children (16 girls) fulfilled the inclusion criteria. Age and preoperative arterial oxygen saturation (SaO2) nadir, either individually (P = 0.023, P = 0.0003, respectively) or in combination (P = 0.00009), exhibited a significant correlation to the morphine dose required for analgesia. Four of these children, aged 26.5 +/- 13.2 months, with a preoperative SaO2 nadir of 70.3 +/- 12.9%, did not require any postoperative morphine for analgesia at all. CONCLUSIONS: The authors speculate that the reduced morphine requirement for analgesia in children displaying oxygen desaturation associated with severe OSA may be related to their young age and to an up-regulation of central opioid receptors consequent to recurrent hypoxemia. In evaluating OSA in children, preoperative determination of the SaO2 nadir is important for predicting the postoperative opioid dosage required for analgesia.

Neurokinin-1 versus mu-opioid receptor binding in rat nucleus tractus solitarius after single and recurrent intermittent hypoxia.

G protein-coupled excitatory neurokinin-1 and inhibitory mu-opioid receptors exist in respiratory brainstem with their peptides and influence breathing. To assess their putative role in respiratory responses to hypoxia, neurokinin-1, and mu-opioid receptor binding was determined in the respiratory nucleus tractus solitarius of the mature rat after single and recurrent intermittent hypoxia versus normoxia. Hypoxia comprised six 5-min bouts of 8% O(2)-92% N(2) interceded by 5-min bouts in 21% O(2)-79% N(2) (normoxia), either on 6 consecutive days (recurrent intermittent hypoxia) or on the 6th day only (single intermittent hypoxia). Controls comprised six daily sessions in normoxia. To examine the plasticity in receptor response, brains were collected 5min, 2h, or 24h after the last gaseous exposure. Sections from each brainstem underwent quantitative film autoradiography with iodinated substance P and DAMGO for neurokinin-1 and mu-opioid receptors, respectively. Neurokinin-1 receptor binding decreased 5min after single and recurrent hypoxia and 2h after recurrent hypoxia, whereas mu-opioid binding remained unchanged. The binding of both receptors increased 24h after recurrent intermittent hypoxia. Neurokinin versus mu-opioid binding differences immediately posthypoxia might affect physiological responses to episodic hypoxia.

Maturation of respiratory control in the behaving mammal.

Whereas in vitro techniques have contributed greatly to our understanding of detailed neuronal mechanisms of respiratory control, the integrated function of respiratory behavior requires studying conscious, unsedated subjects. Noninvasive approaches, meticulous chronic instrumentation for the recording of multiple respiratory indices, and correlations with brain studies performed after physiological manipulations in vivo can all be employed to get to some understanding of the maturation of respiratory control in the mammal. This article is a selective and critical overview of recent literature on methodologies that can be used in behaving subjects, the relationship of respiration to sleep-wake states, respiratory patterns during normoxia, and on respiratory responsiveness to hypercarbia and hypoxia, all emphasizing processes during development. It is hoped that this review will encourage new investigators interested in the regulation of breathing to resort to experimental approaches that will reveal the mysteries of respiratory behavior in the integrated organism.

Central neuropeptide systems and respiratory control during development.

The substance P/neurotachykinin-1 (NK-1) and the mu-opioid G protein-coupled receptor systems endow brainstem respiratory regions and display discrete developmental patterns. Hypoxia-induced neuropeptide release may increase receptor endocytosis, reducing receptor accessibility to ligands. We wondered whether the attenuated respiratory response to hypoxia of developing piglets after single (Respir. Physiol. 92 (1993a) 115) or repeated daily hypoxic exposure (J. Appl. Physiol. 83 (1997) 522) is influenced by differential endocytosis of NK-1 vs mu-opioid receptors. Whereas the long-term (24 h) response of both receptors to recurrent hypoxia in piglet brainstem is similar, i.e. upregulation, the short-term (5 min) response to single or recurrent hypoxia, albeit in rats, is different: radiolabelled NK-1 receptors are greatly reduced, suggesting enhanced endocytosis, but mu-opioid receptors remain unchanged, implying unaltered endocytosis. If confirmed in piglet brainstem, this difference would produce relatively more available mu-opioid receptors to opioid peptides in hypoxia that might contribute to the attenuated respiratory responses to single and repeated hypoxia during development.