Department of Anesthesiology, Wilford Hall Medical Center, Lackland Air Force Base, Texas.
Accepted for publication September 17, 1996.
Address correspondence and reprint requests to Charles A. Henderson, MD, Department of Anesthesiology, Wilford Hall Medical Center/PSSA, 2200 Bergquist Dr., Suite 1, Lackland AFB, TX 78236-5300.
The acute onset of pulmonary edema after the administration of various doses of naloxone has been described [1-5]. Nalmefene is a newly available opioid antagonist whose principle advantage lies in its longer duration of action. We present a case in which the administration of nalmefene to a patient was associated with the acute onset of pulmonary edema.
A 21-yr-old, 80 -kg male with no significant past medical history presented for exploratory laparotomy for presumed appendicitis. He was premedicated with 2 mg of intravenous (IV) midazolam and 100 micro g of IV fentanyl. After a modified rapid sequence induction with thiopental and succinylcholine, the trachea was easily intubated with cricoid pressure. An additional 150 micro g of IV fentanyl was then administered. A bite block was inserted and remained for the duration of the procedure. Anesthesia was maintained with 0.6 minimum alveolar anesthetic concentration desflurane, 0.5 minimum alveolar anesthetic concentration nitrous oxide in oxygen, and a total of 7.5 mg of IV vecuronium. Forty minutes into the 80-min surgery, 2 mg of IV morphine was administered. The patient remained normothermic and hemodynamically stable with pulse oximeter readings of 100% throughout the procedure. He received a total of 1600 mL of lactated Ringer's solution and was breathing spontaneously at the conclusion of surgery. Neuromuscular blockade was reversed with 4 mg of IV neostigmine and 0.8 mg of IV glycopyrrolate. After maintaining a 5-s head lift, the patient was suctioned orally, tracheally extubated, and transported to the postanesthesia care unit while receiving oxygen by mask.
Upon arrival in the postanesthesia care unit, the patient was very somnolent with poor respiratory effort and a respiratory rate less than 10 breaths/min. Oxygen saturation by pulse oximeter fell to 90%. When stimulated, the patient had good ventilatory volumes with no sign of airway obstruction. Breath sounds were clear to auscultation. Respirations were supported with 100% oxygen by mask and chin lift for 20 min. Intravenous nalmefene, 75 micro g, was titrated in 25-micro g increments over 10 min. The patient became more alert, improved his respiratory effort, and no longer needed assistance to maintain his oxygen saturation.
Fifteen minutes later, the patient became dyspneic, began coughing, and expectorated more than 100 mL of frothy sputum. Oxygen saturation remained 98%-100%. Auscultation was significant for both inspiratory and expiratory crackles. A chest roentgenogram demonstrated patchy infiltrates throughout both lung fields and a heart size within normal limits. The presumptive diagnosis of noncardiogenic pulmonary edema was made. The patient was transferred to the intensive care unit for overnight observation receiving supplemental oxygen and was treated with furosemide. Clinical resolution of symptoms was prompt, but the chest roentgenogram did not improve for 36 h. The remainder of his postoperative course was unremarkable, and he left the hospital on the fourth postoperative day.
Nalmefene, recently approved by the Food and Drug Administration, joins naloxone as the only opioid antagonists available for parenteral use in the United States. These drugs are equipotent on a milligram per milligram basis . The primary advantage of nalmefene over naloxone is its longer duration of action. This prolonged antagonist effect provides a greater degree of protection from delayed respiratory depression as the antagonist is cleared. Compared with the one- to two-hour half-life of naloxone, the half-life of nalmefene is between 1.8  and 8.6 hours . Gal and DiFazio  reported that nalmefene produced significant opioid antagonism that was nearly four times the duration of equipotent doses of naloxone. This is thought to be secondary to the slower clearance of nalmefene (0.019 L/min) versus naloxone (0.049 L/min) . Nalmefene is metabolized by hepatic conjugation with less than 5% excreted unchanged in the urine [7,9].
The reported dose of nalmefene is 0.25 micro g/kg administered every two to five minutes until the desired effect is achieved with the total dose not exceeding 1 micro g/kg . The patient in this case received a total of 75 micro g of nalmefene over 10 minutes. Dixon et al.  reported only minor adverse drug effects in patients who received up to 24 mg (24,000 micro g) of nalmefene. These adverse effects included light-headedness, drowsiness, dizziness, and mental fatigue. Kaplan and Marx  administered up to 10 mg (10,000 micro g) of nalmefene to narcotized emergency room patients and reported satisfactory narcotic reversal without adverse drug effects. There is no previous report of acute pulmonary edema associated with nalmefene administration.
The rare occurrence of pulmonary edema has been reported multiple times in association with naloxone administration [1-5] and with the agonist-antagonist buprenorphine [11,12]. Earlier reports using larger doses of antagonist were noted for their evidence of increased sympathetic tone. This included hypertension and tachycardia preceding cerebral aneurysm rupture , cardiac arrest , dysrhythmias , and pulmonary edema [2,16]. Several studies have noted naloxone's pressor effects on the peripheral circulation [16-18]. Hence, many thought that pulmonary edema ensued from a catecholamine surge that caused increased ventricular workload and eventual failure . From the initial reports came recommendations for smaller dosing [14,20] and prudence when contemplating opioid antagonism in patients with compromised cardiac function. Reports of pulmonary edema secondary to naloxone persisted, with cases presenting in healthy patients after conservative doses [1,4]. These cases were not associated with obvious increases in sympathetic tone. Prough et al.  hypothesized that the noncardiac pulmonary edema seen in these healthy patients may be neurogenic in origin, with secondary central nervous system stimulation leading to pulmonary venoconstriction and pulmonary hypertension.
More likely causes of pulmonary edema should always be ruled out before a narcotic antagonist is considered the etiology. The patient in this case was a young, healthy individual with no history of cardiopulmonary disease. He received 1600 mL of crystalloid IV for an 80-minute procedure. There was no known period of airway obstruction; therefore, a diagnosis of negative pressure pulmonary edema would have been unlikely. Due to the temporal relationship between the administration of nalmefene and acute development of symptoms, we believe the pulmonary edema observed in our patient was related to the nalmefene.
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