Dose‐dependent multiple physiologic effects of systemic fentanyl in awake adult goats

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It is well known that opioid analgesics induce life-threatening respiratory depression. A few studies have also documented additional deleterious effects of opioids on multiple physiologic functions. Moreover, there are reports of interindividual variation in susceptibility, magnitude, and duration of physiologic effects of opioids such as fentanyl. Here we tested the dose-dependent effects of intravenous injected fentanyl on physiologic functions in 7 awake, adult goats. Goats were instrumented for recording of multiple cardiorespiratory variables including respiratory pump and airway muscle activity. After a 30-minute control period, 0, 10, 20, or 50 µg/kg fentanyl was infused intravenously. We found that rapid IV infusion of fentanyl over 2 min caused a dose-dependent decrease in minute ventilation due to dramatic suppression of breathing frequency within 5 min after IV injection. These effects were coupled with dose-dependent increases in VT, which represents a more human like ventilatory response to opioids. The major suppression of ventilation occurred in 5 of the 7 goats, whereas in 2 of the goats IV fentanyl injections increased breathing frequency in a dose-dependent manner. This variation in ventilatory response to opioids agrees with findings that in a subset of humans, opioids have an excitatory effect on physiologic functions (Br. J. Anaesth 81, 1998). The suppression of ventilation seen in the majority of goats is transient, lasting for 3-10 minutes post-injection and is accompanied by an increased or normal VT up to 30-90 minutes. Over the initial 10 minutes after injection, there were obstructive and central apneas often exceeding one minute resulting in arterial hypoxemia (PaO2<50 mmHg) and hypercapnia (PaCO2>50mmHg). Heart rate was decreased for up to 15 minutes following 50µg/kg injection, whereas arterial blood pressure was increased for at least 90 minutes post-injection. Particularly over the initial minutes after 50µg/kg, fentanyl infusion decreased the duration but increased the intensity of diaphragm and intercostal muscle activity while increasing tonic activity of abdominal and airway muscles. Infusion of naloxone before or after infusion of fentanyl prevented or reversed the acute and delayed physiologic effects induced by fentanyl. Injection of Naloxone alone had no effect on physiological measures of goats. We conclude that goats have multiple dose- and individual-dependent physiologic responses to systemic infusion of fentanyl. Furthermore, our reversal data suggests the effects of fentanyl in goats are likely mediated by activation of µ-opioid receptors.