Author: Anthony G. Doufas, M.D., Ph.D.
ASA Monitor 07 2017, Vol.81, 24-26.
Anthony G. Doufas, M.D., Ph.D., is Professor, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California.
Large, retrospective clinical cohorts suggest that preoperative diagnosis of obstructive sleep apnea (OSA) is associated with more than a two-fold increase in the risk for respiratory complications in the immediate postoperative period (i.e., the first 12 hours after surgery).1 –6 The contribution of OSA to the causal nature of these complications remains unclear; however, an increased vulnerability of OSA patients to anesthesia- and opioid-induced ventilatory compromise has been proposed as a likely mechanism.7,8
This hypothesis is supported by experimental and clinical evidence suggesting that chronic intermittent hypoxia, a hallmark phenotype of OSA, may enhance the sensitivity to the analgesic and respiratory-depressant effects of opioids.9 –15 Furthermore, retrospective analyses of life-threatening opioid-related respiratory events in the context of postoperative analgesia have shown that obesity, somnolence and OSA diagnosis were common among afflicted patients.6,7,16,17 Although hypoxemia due to opioid use in the immediate and short-term postoperative period is common and persistent,18 –20 the incidence of life-threatening opioid-induced respiratory depression (OIRD) is very low,21 suggesting that if OSA, a common and highly heterogeneous condition,22 –24 is a risk factor for OIRD, then certain OSA patients might be at relatively greater risk than others for this potentially lethal complication.
Sleep State-dependent Central Control of Ventilation
Three main types of brainstem respiratory neurons cooperate in fulfilling the breathing act25,26 : a) those with an inherent ability to generate respiratory rhythm, i.e., the endogenously active neuronal oscillators of the pre-Bötzinger Complex (preBötC; inspiratory drive) and the conditionally active oscillators at the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG; active expiration); b) the respiratory pre-motor neurons that control the spatiotemporal distribution of respiratory drive signal to different outputs27 ; and c) the cranial (i.e., hypoglossal and trigeminal motor nuclei) and spinal (i.e., phrenic nerve nuclei) motor neurons, which transfer the signal from respiratory pre-motor neurons to respiratory muscles, the final actuators of breathing.
“Seemingly diverse, these actions of opioids cannot be easily separated clinically, thus emphasizing the tight anatomical and functional association between arousal-control mechanisms and breathing, where both decreased wakefulness and depression of central respiratory drive impair pharyngeal muscles potentially through a common potassium channel (G-protein-gated inwardly rectifying potassium, or GIRK)-related pathway.”
Various types of cortical and autonomic (chemosensory, airway and lung stretch receptors) inputs shape the final breathing output25 by exerting their influences on the central respiratory circuits, while, according to the concept of dual respiratory drive,28 –31 respiratory muscles that are involved in non-respiratory-related functions, such as postural support (intercostal muscles) or upper-airway patency (pharyngeal dilators) during breathing present a different activation profile, with more tonic drive and less (or none) respiratory-related rhythmic drive than the main respiratory pump muscle of the diaphragm. This constant tonic respiratory drive on upper-airway muscles, being the result of the stimulation of respiratory pre-motor and motor neurons by reticular formation and chemoreceptor signals, is uniquely associated with the wakefulness stimulus on breathing and makes this group of muscles especially vulnerable at sleep onset, when their activity is suddenly diminished.31
This type of functional organization of respiratory control has a special relevance to OSA, where subjects with anatomical or functional impediments of their airway, requiring increased upper-muscle activation to secure adequate inspiratory airflow, might be at increased risk for airway obstruction and hypopnea when asleep or under sedatives.30 Indeed, clinical studies have shown that a large fraction of non-OSA patients can present with moderate to severe sleep-disordered breathing in the immediate postoperative period,32 presumably reflecting the potentiation of the airway-depressing effect of endogenous sleep-generating pathways as well as the suppression of arousal stimulatory effects by GABAergic anesthetics and opioids.30,31,33,34
Opioid Effects and Apnea Mechanisms in OSA
Opioids interfere with the chemical, behavioral and motor control of respiration.35,36 When administered at standard analgesic doses, opioids: a) suppress ventilatory responses to hypercapnia and hypoxia by acting on the central and peripheral chemoreceptors,37,38 b) decrease wakefulness stimulus for breathing through their action on various arousal-promoting pathways,36,39 –42 including cortical, subcortical and brainstem centers, and c) impair the performance and coordination of respiratory muscles (diaphragm, intercostal and upper-airway muscles) by acting on the brainstem pre-motor and cranial (e.g., hypoglossal) motorneurons.43 –46 Seemingly diverse, these actions of opioids cannot be easily separated clinically, thus emphasizing the tight anatomical and functional association between arousal-control mechanisms and breathing, where both decreased wakefulness and depression of central respiratory drive impair pharyngeal muscles potentially through a common potassium channel (G-protein-gated inwardly rectifying potassium, or GIRK)-related pathway.31,34,47,48 Recent human evidence shows that the degree of respiratory rate decrease after morphine analgesia was significantly related to the opioid-induced sedative effect, as this was indicated by a reduction in the β power of encephalogram.42 Furthermore, the µ-opioid-receptor-expressing neurons in the rhythm-generating preBötC, an important target for the respiratory depressant effects of opioids,45,48 have been recently found to participate in arousal promoting activities (i.e., breathing promotes arousal) via a distinct noradrenergic pathway.49
Functional competence of pharyngeal dilators and arousal threshold (i.e., the level of respiratory effort during airway obstruction that is associated with arousal and termination of hypopnea) are two important non-anatomical determinants of the clinical expression of OSA.50 Although the effects of opioids on respiratory function in patients with OSA remain poorly investigated, a theoretical insight would suggest that OSA phenotypes characterized by functional incompetence of pharyngeal muscles and a high arousal threshold would be at higher risk for severe OIRD than those with a low arousal threshold and airway dilators that are sufficiently responsive to chemical (hypercapnic and/or hypoxic) stimuli. In the former case, arousal and adequate restoration of airway patency may not occur before severe hypercapnia and/or hypoxia ensues, whereas in the latter, opioids, as is the case with other sedatives,51,52 might confer the benefit of more stable (arousal-free) sleep by allowing mild hypercapnia, due to carbon dioxide retention, to activate genioglossus muscle activity and decrease apneas.53
These are only two from the possible scenarios of how the phenotypic variability encountered in the OSA condition50,54 –56 might influence the riskfor OIRD in the postoperative patient. The respiratory outcomes in OSA patients under opioids, as well as their predisposition to OIRD, may depend on the quality of interaction between opioid pharmacology and the individual OSA phenotypes.57,58 In support of this hypothesis is the substantial variability in the observed respiratory effects of opioids in patients with OSA,59 –61 where both harmful62 and beneficial61 effects on apnea severity during sleep have been demonstrated, while the administration of a short-acting opioid in OSA subjects during polysomnography resulted in a bimodal effect on apnea pattern with 40 percent of subjects shifting from obstructive to central events.63 Although differences in the study design might have been responsible for the variable findings, the hidden phenotypic variability of OSA condition can also be a possible explanation.64 On the other hand, other important factors that play a role in the very dynamic physiological environment of short-term recovery after surgery – including the residual effect of anesthetics, sleep deprivation, opioid dose in the context of pain, and/or co-administration of other sedatives – should not be dismissed as potential confounders or modifiers of OSA-related physiologies.16,20,32,65 –69 In the epidemiology of opioid-related respiratory catastrophes, excessive somnolence is a recurrent finding as a precursor state of life-threatening OIRD.6,16,17 Clinicians should thus exercise extra caution when encountering excessively somnolent patients, patients with obesity hypoventilation syndrome,70,71 and/or those with high arousal thresholds and large arterial desaturations during polysomnography, as opioid administration in these patients may lead to severe airway compromise and asphyxia.
Mitigating Opioid-induced Respiratory Depression
At present, since we lack specific OSA-related risk phenotypes for OIRD,57 our strategies to prevent or mitigate opioid-related life-threatening respiratory toxicity should generally follow standard practices to lessen the use of opioids and/or hasten recovery without compromising analgesia or other patient-related outcomes. For example, the use of short-acting anesthetic agents to reduce somnolence in the immediate postoperative period and, when feasible, adoption of non-opioid-based analgesia, including the use of non-steroidal anti-inflammatory agents and/or regional anesthesia, are among general action plans to reduce opioid dose requirement postoperatively.
Drugs or adjuncts that could counteract or reduce the risk for OIRD without interfering with the analgesic effect of opioids72 include: a) ampakines, to stimulate respiratory rhythmogenesis via promoting glutamatergic transmission in the preBötC73 ; b) GAL-021, to stimulate ventilation by inhibiting potassium channels in the carotid body chemo-receptor74 ; and c) TRV130, a novel G-protein-biasedligand, which, via differential activation of µ-opioid receptors, can provide analgesia without the concomitant respiratory-related adverse effects of opioids.75 Furthermore, agents that could decrease sedation76,77 in the postoperative period or provide analgesia without suppressing the function of airway dilator muscles78 may also be useful adjuncts toward eliminating potentially severe OIRD or airway compromise.
Although the application of continuous positive airway pressure (CPAP), an airway stabilizing treatment, has been shown to reduce apnea severity79 and mitigate the impairing effects of opioids on ventilation80 in postoperative patients with OSA, the use of CPAP requires more intense investigation as a measure against OIRD, especially when considering issues such as opioid-induced central apnea or the development of complex (central) apnea in CPAP-naïve patients.81
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