Scientific Principles |
|Part B:||Intravenous Anesthetics|
|Chapter 10:||Intravenous Opioid Anesthetics|
Factors Affecting Opioid-Induced Respiratory Depression
Many factors can change both the magnitude and duration of respiratory depression after opioid administration (Table 10–10). Patients who are sleeping are usually more sensitive to the respiratory-depressant effects of opioids. 333, 334 Even small doses of opioids markedly potentiate the normal right shift of the PaCO2-alveolar ventilation curve that occurs during natural nonrapid eye movement sleep. 333, 334 For several days postoperatively, sleep is associated with hypoxemia. 335 The mechanisms and implications of postoperative sleep disturbances are complex and relate not only to respiratory problems, but also to cognitive and hemodynamic disturbances. 336 Both sleep and morphine relatively spare the diaphragmatic, but decrease the thoracic (ribcage), component of breathing. 337 Sleep also impairs tonic and phasic upper airway muscle activity that accompanies breathing. 338 This can be troublesome when patients have an opioid-based anesthetic and an operation that results in little or no postoperative pain. In such patients, apparently adequate breathing can become insufficient with the onset of sleep. In patients with conditions that impair abdominal breathing or airway function, such as patients with marked obesity or sleep apnea, an increased risk of adverse respiratory events is likely with the administration of opioid analgesia.
TABLE 10–10. Factors Increasing the Magnitude and/or Duration of Opioid-Induced Respiratory Depression
Older patients are more sensitive to the anesthetic 217 and respiratory-depressant effects of opioids. 1 Older patients experience higher plasma concentrations of opioids administered on a weight basis. 322 Although older patients tend to have a lower blood volume than younger patients, the precise reason for higher plasma concentrations after similar doses is unknown. Conflicting reports argue for or against differences in pharmacokinetics (decreased clearance, increased elimination half-life) and/or pharmacodynamics (increased brain sensitivity) as the basis for the presence or absence of agerelated increases in sensitivity to fentanyl. 136, 339 Older patients also have more frequent apnea, periodic breathing, and obstruction after morphine than young adults. 340
Morphine alone produces greater respiratory depression on a weight basis in neonates than adults. Its low lipid solubility normally limits blood-brain barrier penetration. In neonates and infants with incomplete blood-brain barriers, morphine easily penetrates the brain. Neonates are not unduly sensitive to the more lipid-soluble opioids (meperidine, fentanyl, and sufentanil) because penetration of these drugs into the brain is not affected by blood-brain barrier maturity. 341 Endogenous opioid activity may also be increased in the neonate and possibly contributes to the depressed ventilatory response to hypoxia observed in such young individuals. Support for this hypothesis comes from studies demonstrating that naloxone shortens the apneic phase and stimulates the response to hypoxia in newborns but not in older infants. 91
The respiratory-depressant effects of opioids are increased and/or prolonged when administered with other CNS depressants, including the potent inhaled anesthetics, 342 alcohol, 1 barbiturates, 1 benzodiazepines, 343 and most of the IV sedatives and hypnotics. Drug interactions and synergistic depression of the ventilatory response to hypercarbia and/or hypoxia can result in bradypnea or apnea. Exceptions are droperidol, scopolamine, and clonidine, which do not enhance the respiratory-depressant effects of fentanyl or other opioids. 324, 344, 345, 346, 347 Sedation and sleep may accompany a2 -adrenergic agonists and possibly may explain some of their reported mild respiratory-depressant actions. 348
Pain, particularly surgically induced pain, is thought to counteract the respiratory-depressant effects of opioids. However, the contrary has been suggested by some investigators. 301, 349 For example, certain postsurgical breathing patterns are not predominantly determined by the level or mode of pain relief. 350 Acute pain does not reverse the depression of the ventilatory response to hypoxemia that is produced by sedation with sevoflurane. 351 An investigation of the effect of experimental pain on ventilatory control suggests that pain causes a chemoreflex-independent increase in tonic ventilatory drive. 352
It is interesting to note that although some acute tolerance to opioid-induced respiratory depression can develop, 5 to 8 months of opioid exposure may be necessary for significant tolerance to the respiratory-depressant actions of opioids on hypoxic ventilatory responses to develop. 90 Cross-tolerance to the respiratory-depressant actions of different opioids also may be neither complete nor predictable. 91 Infants of mothers receiving methadone maintenance demonstrate impaired central chemosensitivity to CO2 . They may also be at higher than normal risk for sudden infant death syndrome.
Although opioid action is usually dissipated via redistribution and hepatic metabolism, rather than by urinary excretion (see the section on pharmacokinetics), adequacy of renal function may influence the duration of opioid activity. It was previously thought that in renal insufficiency, the more potent respiratory-depressant properties of the morphine metabolite morphine-6-glucuronide (M6G) would become evident as it accumulated. 353 However, one study indicates that M6G is a somewhat weaker respiratory depressant than morphine. 354 Nevertheless, morphine or meperidine and/or some of their metabolites can accumulate in patients with renal insufficiency and may result in greater respiratory depression (see later).
Hypocapnic hyperventilation has been shown to enhance and prolong postoperative respiratory depression after fentanyl (10 and 25 mgkg 1 ). 326 Intraoperative hypercarbia produces the opposite effects. 355 Possible explanations for these findings include increased brain opioid penetration (increased un-ionized fentanyl with hypocarbia) and removal (decreased CBF with hypocarbia). Decreased liver clearance related to decreased cardiac output and hepatic blood flow may also explain this phenomenon. In addition, intraoperative hyperventilation depletes CO2 stores and can result in a posthyperventilation hypoventilation syndrome. Following hyperventilation, CO2 stores are repleted. This process removes CO2 from the blood and lowers minute ventilatory requirements, resulting in hypoventilation. In this circumstance, a normal PaCO2 does not necessarily indicate normal or adequate minute ventilatory volumes. In patients who hyperventilate because of anxiety and/or pain, even small doses of IV opioids can result in transient apnea because of acute shifts in apneic thresholds.
Some authors suggest that the administration of opioids in anesthesia leads to increased respiratory problems. 356, 357 However, most of the studies performed to date have failed to isolate perioperative opioid administration as particularly associated with increased respiratory problems 358 Although Beard et al 356 found an increase in adverse respiratory events in the recovery room associated with the use of muscle relaxants and fentanyl, the frequency of a serious problem with fentanyl was rare (1/886 patients). In another study, patients receiving IV morphine for postoperative pain after general anesthesia experienced more respiratory side effects than those who received regional anesthesia. Interestingly, desaturations of significance were always associated with sleep and were related to obstruction, paradoxic breathing, or slow respiratory rates. 359 The analgesic dose of morphine used in the latter study was large (>12 mg70 kg 1 IM).
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