Reversal Agents : Naloxone, Flumazenil, and Sugammadex

Case Synopsis

An otherwise healthy 65-year-old, 80-kg man is given 2 mg of fentanyl intravenously (IV) during a 3-hour coronary artery bypass grafting procedure. Postoperatively, the patient remains intubated and mechanically ventilated and is transferred to the intensive care unit (ICU) in stable condition. The surgeons opt for early extubation of the patient, but he remains deeply sedated, does not respond to painful stimuli, and is not overbreathing the ventilator. He is given a total of 2 mg of naloxone IV, and over a 5-minute period becomes acutely hypoxemic, with increasing rales and frothy pulmonary secretions. A chest x-ray shows acute pulmonary edema. An electrocardiogram shows ventricular ectopy.

Definition

Naloxone (Narcan) is a nonselective, high-affinity opioid antagonist that is indicated primarily for use with (1) opioid-induced respiratory depression (i.e., in the postoperative period or in neonates secondary to maternal administration), (2) acute opioid overdose, and (3) opioid-induced pruritus (off-label indication). It is structurally related to morphine and oxymorphone, and competitively inhibits the effects of opioid agonists at all opioid receptors (mu > kappa = delta), though its primary clinical use focuses on reversal of sedation and respiratory depression (mu antagonism). Thus it must be titrated carefully ( Table 97.1 ), as the analgesia effects of opioids can also be reversed, inducing severe pain and/or acute opioid withdrawal–like symptoms. Significant cardiopulmonary instability (i.e., hypertension, cardiac arrhythmias, pulmonary edema, and cardiac arrest), agitation, and seizures have been described with various doses of naloxone, though these side effects are rare and are more likely to occur at higher doses.

Intravenous injection is the most common form of naloxone administration, though endotracheal, subcutaneous, and intramuscular delivery is also effective. Low bioavailability secondary to a high (95%) hepatic first-pass effect renders oral intake of naloxone ineffective. It is fast acting (<2 minutes) and has a dose-dependent duration of effect (30 to 240 minutes; Table 97.2 ), with primary hepatic metabolism with renal excretion of inactive metabolites. Most opioid agonists have a longer half-life than naloxone, so repeated doses must be delivered to prevent renarcotization.

Recognition

Cardiovascular complications can occur rapidly (i.e., within minutes) after naloxone administration, especially when large doses (i.e., 0.4 to 2 mg IV) are given. This is thought to be secondary to neurogenic cardiovascular excitation with significant catecholamine release resulting in hypertension, arrhythmias, pulmonary and systemic vasoconstriction, pulmonary edema, and seizures. Furthermore, sedation and respiratory depression may reappear if naloxone is eliminated faster than the residual opiates (renarcotization), so cardiovascular monitoring should always be established and naloxone redosed as necessary.

Risk Assessment

Although the exact incidence of complications after naloxone is not known, postoperative events are exceedingly rare, especially when low doses are judiciously titrated. Events are more likely in patients with a history of chronic opioid use/abuse or seizures and when other symptoms of withdrawal are present (e.g., nausea, vomiting, diaphoresis, agitation). Adverse events are also more common in ICU patients, likely because of higher opioid doses administered in this patient population (e.g., significant cardiac or noncardiac surgeries, opiate overdose admissions). Finally, physiologic stress may play a role in naloxone toxicity, as all case reports of naloxone toxicity occurred in patients who were experiencing severe pain and stress at the time of the event.

The incidence of opioid-related deaths has skyrocketed over the past decade with an estimated 69,000 attributable deaths worldwide, resulting in the World Health Organization calling for broad community access to naloxone. Prior prospective studies have demonstrated that the emergent use of naloxone for opiate overdose treatment resulted in a 1.3% complication rate (median dose 0.2 mg IV), though causality cannot be guaranteed. Animal studies show that avoidance of significant hypercapnea (mask ventilation) before administration of naloxone may mitigate cardiopulmonary side effects.

Implications

Although initial recommendations for naloxone use were to rapidly administer large bolus doses IV, it is now recommended to judiciously administer low doses intermittently (see Table 97.1 ) to decrease the possibility of cardiovascular and neurologic complications. Cardiovascular monitoring should be continued after it is administrated for several hours to monitor for renarcotization.