ENDOCRINOLOGIC EFFECTS OF OPIOIDS

The main components of the neuroendocrine stress response are the corticotropin-releasing hormone brain centers (e.g., paraventricular hypothalamic nucleus) and the locus caeruleus-norepinephrine secreting areas of the autonomic nervous system.^[217] Increased levels of stress hormones are considered undesirable because they promote hemodynamic instability and intraoperative and post-operative metabolic catabolism. In some circumstances, hormonal and metabolic responses to surgery are extreme and are thought to contribute to operative mortality.^[218]

Opioids are capable of reducing the stress response by modulating nociception at several different levels of the neuraxis, as well as by influencing centrally mediated neuroendocrine responses. Opioids are potent inhibitors of the pituitary-adrenal axis.^[219] Endogenous opioid peptides may serve as stress hormones themselves and not just as modulators of the secretion of other hormones. This activity is suggested by the finding that β-endorphin and adrenocorticotropic hormone (ACTH) are derived from the same precursor preproopiomelanocortin and are cosecreted during stress.

Morphine modifies hormonal responses to surgical trauma in a dose-related fashion. Morphine can prevent ACTH release, suppress surgically induced increases in plasma cortisol, and attenuate the pituitary-adrenal response to surgical stress. Morphine can increase some stress-responding hormones due to increases in plasma histamine release, adrenal medullary release mechanisms, and catecholamine release from sympathetic nerve endings.

Fentanyl and its congeners are more effective than morphine in modifying hormonal responses to surgery. The efficacy of fentanyl in controlling the hormonal manifestations of the stress response can be dose-dependent.^[220] Fentanyl, in doses of at least 50 µg/kg, prevents increases in blood glucose, plasma catecholamines, antidiuretic hormone (ADH), renin, aldosterone, cortisol, and growth hormone (GH) concentrations before, but not consistently during or after, cardiopulmonary bypass. Fentanyl doses greater than or equal to 50 µg/kg can help reduce the hyperglycemic response to cardiac surgery in pediatric patients to less than 200 mg/dL throughout operation.^[221]

Sufentanil may be superior to fentanyl in modifying the stress response.^[222] However, it has been demonstrated that neither fentanyl nor sufentanil alone can completely block sympathetic and hormonal stress responses and that perhaps no dose-response relationship exists for opioid-associated stress response control.^[59] The stress response to cardiopulmonary bypass is difficult to suppress with sufentanil, as with fentanyl.

Alfentanil can cause hormone-modifying effects similar to those of sufentanil. Alfentanil can suppress increases in plasma cortisol and catecholamines before but not during cardiopulmonary bypass and may prevent increases in ADH and GH throughout coronary artery bypass surgery. High-dose alfentanil-N₂ O anesthesia (150 µg/kg loading dose plus 3 µg/kg/min infusion) better suppresses intraoperative cortisol and glucose elevation than droperidol-fentanyl-N₂ O anesthesia in patients undergoing abdominal surgery.^[223]

Stress Reduction and Outcome

Some evidence suggests that anesthetic techniques or agents that minimize this stress response may reduce morbidity and mortality in a variety of circumstances.^[224] Sufentanil appears to be the most likely opioid to modify stress responses and outcomes successfully.^{[225] [226]} Other investigators suggest that neither the opioid administered nor the anesthetic technique has an impact on outcome.^{[207] [227]} Anand and colleagues^[225] evaluated the impact of sufentanil versus morphine-halothane anesthesia on hormonal and metabolic responses and morbidity and mortality in neonates undergoing cardiac surgery.

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Many different hormonal changes induced by surgery have been described. However, the concomitant neural, cellular, immune, and biochemical changes have been less well defined, and little is understood or proven with regard to how modifying hormonal responses alters outcome.^[228] Additional studies are necessary for complete elucidation of the relationship between control of surgery-induced hormonal responses and outcome.