Immanuela R. Moss

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

BackgroundObstructive 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. MethodsInclusion 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. ResultsForty-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. ConclusionsThe 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.

Ontogeny of sleep/wake and cardiorespiratory behavior in unanesthetized piglets

Young and older piglets (2-15, 25-35 days old) underwent chronic recording of electrocorticogram, vertical and horizontal electrooculograms, electromyograms of submental muscles, diaphragm (EMGdi) and posterior cricoarytenoid (EMGpca), and heart rate, arterial pressure, pH and gas tensions. With age, (1) the distribution of percent time spent in various sleep-wake states differed; (2) heart rate decreased in all S/W, arterial pressure increased in wakefulness (W), transitional sleep (TS) and quiet sleep (QS); (3) respiratory frequency decreased, EMGdi and EMGpca duration and EMGpca amplitude increased in all S/W, EMGdi amplitude decreased in TS and QS and rate of rise of EMGdi and EMGpca decreased in W, TS and QS. Active sleep was characterized by smaller normalized EMGpca amplitudes in the young, short EMGpca to EMGdi intervals in both ages and predominance of prolonged diminished muscle activity (DMA) of either muscle. Discoordination between EMGpca and EMGdi activation and the occurrence of DMA were influenced by youth and male gender. These results provide insight into subtle expressions of gender and sleep influences on developmental respiratory control.

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 μ-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.

Hypoxia, sleep and respiration in relation to opioids in developing swine.

To test the role of mu and delta opioid systems in neonates during hypoxia, a total of sixteen, 4-11 (n = 7) and 26-33-day-old piglets (n = 9) were instrumented aseptically for assessment of sleep/wake states (S/W), electromyographic activities of the diaphragm and posterior cricoarytenoid muscles (EMGdi, EMG-pca, respectively), heart rate, and arterial pressures, pH and gas tensions. During daily sessions for 5 consecutive days, the piglets inhaled 10% O2/90% N2 for 10 min twice per session, first before any drug, then after either naltrexone (2 mg.kg-1 i.v.), a predominantly mu opioid antagonist, or naltrindole (4 mg.kg-1 i.v.), a specific delta opioid antagonist. During hypoxia, young, in contrast to older piglets, spent more time asleep, and increased sleep during the second half of the hypoxic exposure before, but not after each antagonist. They also exhibited, overall, higher breathing frequency, and lower slope, amplitude, area and initial area of EMGdi and EMGpca activity than older piglets. Naltrindole stimulated EMGpca activity in both age groups, and naltrexone increased the breathing frequency and slope of EMGdi in the older group. We conclude that hypoxia enhances the activation of central mu and delta opioid systems which influence S/W and respiration.

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.

Prenatal cocaine alters normoxic sleep-wake and diaphragmatic EMG patterns in piglets.

This study assessed in piglets the effects of prenatal cocaine administration on sleep‐wake states (SWS) and respiratory parameters, utilizing diaphragmatic electromyogram (EMGdi) recordings during normoxia before and after hypoxia (0.10 F  I,O 2 , 10 min). We asked whether the respiratory effects were linked to a specific SWS, and whether there was a difference in respiratory measures between the two normoxic conditions. Unsedated, chronically instrumented 3–9‐ or 21–31‐day‐old piglets, representing distinct stages in developmental respiratory control, were used.

Modulation by mu opioid antagonism of sleep and respiration in neonatal swine

Young (3-13 days) and older (26-34 days) piglets were instrumented aseptically for chronic recording of sleep/wake states (biparietal electrocorticogram, horizontal and vertical electrooculogram, submental muscle electromyogram (EMG)), heart rate, arterial pressure, pH and gas tensions, posterior cricoarytenoid and diaphragmatic EMG (EMGpca, EMGdi). After recovery from surgery, piglets underwent 1 h daily recordings for 5 consecutive days. Experimental sessions comprised control periods followed by study periods with CTOP (10-40 micrograms/kg i.v.), a somatostatin analogue with mu opioid antagonistic activity. In the young group, CTOP decreased percent time spent in active sleep (AS), increased heart rate during wakefulness, increased breathing frequency during transitional and quiet sleep (TS, QS) and decreased the duration of EMGdi activity during TS, QS and AS. In the older group, CTOP decreased the duration of EMGdi activity during QS. Changes in cardiorespiratory functions with age simulated those reported previously (Scott et al. (1990) Respir. Physiol. 80: 83-102). We conclude that, in early neonatal life, the mu opioid system influences both sleep pattern and respiratory timing, and that this influence diminishes with postnatal age.

Respiratory electromyographic estimates of ventilatory functions in piglets

The best electromyographic (EMG) predictors of respiratory drive (P100), tidal volume (VT) and ventilation (VE) were determined from diaphragmatic (DI) and posterior cricoarytenoid (PCA) EMG measures in 8-48-day-old, anesthetized piglets. Progressive hypercapnia was employed to obtain a wide range of muscle activity. A custom-designed, microcomputer-based system was employed to measure the duration, peak amplitude, rate of rise (initial slope) as well as the summed total and initial (first 100 ms) EMG activity from the DI and the PCA. For each respiratory function, the following combinations of EMG measures were identified as significant predictors using regression analyses: (1) for P100, DI amplitude, PCA initial area and PCA rate of rise; (2) for VT, DI amplitude, PCA duration and DI duration; (3) for VE, DI amplitude, DI initial area, PCA initial area, PCA rate of rise, PCA duration, DI area and DI rate of rise. Thus, whereas the traditionally employed measure of DI amplitude is an important correlate of P100, VT or VE, a complete estimate of these respiratory functions requires the inclusion of initial EMG measures and duration.

Effects of Pentobarbital on Proopiomelanocortin Opioid Products of Neonatal Piglets During Normoxia and Hypoxia

Endogenous opioids have been shown to suppress physiological functions in the neonate. It has been suggested that anesthesia with barbiturates might enhance this suppression by influencing opioid systems directly. To explore this possibility, naive piglets, 2.2±0.8 (x̄±SD) days old, underwent one of five protocols: 1) normoxia (control); 2) 10% 02/90% N2 (hypoxia); 3) saline injection ip during normoxia (sham anesthesia); 4) pentobarbital sodium, 25 mg/kg ip, during normoxia (barbiturate anesthesia); and 5) pentobarbital sodium, 25 mg/kg ip, during hypoxia (combined hypoxia and barbiturate anesthesia). Following the inhalation of either gas mixture for at least 30 min, and precisely 30 min after an injection, blood, cerebrospinal fluid and a dorsal medullary slice containing the nucleus tractus solitarii were collected and processed for measurement by radioimmunoassay of opioid proopiomelanocortin products. These comprised β‐lipotropin (the precursor), β‐endorphin‐like immunoreactivity (containing the active peptide β‐endorphin) and N‐acetyl β‐endorphin (a deactivated peptide).