CASE REPORT edema, pulmonary, naloxone-induced; naloxone, complications, pulmonary Naloxone-lnduced Pulmonary Edema Jeffrey A Schwartz, MD Max D Koenigsberg, MD Chicago, Illinois From the Department of Emergency Medicine, The University of Illinois, Ghicago. Received for publication November 2t, 1986. Revision received April 27, 1987. Accepted for publication June 16, 1987. Address for reprints: Max D Koenigsberg, MD, Department of Emergency Medibine, Illinois Masonic Medical Center, 836 West Wellington Avenue, Chicago, Illinois 60657. We present the case of a 68-year-old woman with acute pulmonary edema secondary to the administration of naloxone to reverse an inadvertent nar- cotic overdose. The patient presented following a 12-hour history of in- creasingly bizarre behavior and confusion. A total IV close of 1.6 mg nalox- one was administered in an attempt to reverse the suspected overconsump- tion of a codeine-containing cough suppressant. She immediately became agitated, tachycardic, and diaphoretic; a clinical diagnosis of acute pulmo- nary edema was made. Following treatment with furosemide, nitroglycerin, and morphine sulfate, the patient recovered completely without further inci- dent. Although naloxone is thought to be a safe drug with few complica- tions, it should not be used indiscriminantly, and the smallest doses neces- sary to elicit the desired response should be used./Schwartz JA, Koemgsberg MD: Naloxone-induced pulmonary edema. Ann Emerg Med November 1987;16:1294-I296.] INTRODUCTION Naloxone is an opiate antagonist without intrinsic agonist activity used for the reversal of narcotic-induced respiratory depression and in the diag- nosis of suspected acute opiate overdosage. While being structurally similar to oxymorphine, it is essentially a pure narcotic antagonist that counteracts the effects of narcotics, including respiratory depression, coma, analgesia, pupillary constriction, seizures, and cardiovascular and gastrointestinal ef- fects. Naloxone may precipitate withdrawal symptoms in individuals with physical narcotic dependency. In general, naloxone is widely accepted to be a benign drug With few adverse side effects or contraindications. We present a case of acute pulmonary edema after naloxone administra- tion, an unusual adverse reaction previously unreported in the emergency medicine literature. CASE REPORT A 68-year-old woman was brought to the emergency department because of increasing confusion and hemoptysis. Her daughter stated that the patient had been coughing up small amounts of bright red blood-tinged sputum for two days. In addition, the patient's behavior had become increasingly bizarre, with increased confusion during the past 12 hours. Her medical history in- cluded tuberculosis treated with a right partial pneumonectomy 20 years earlier, hypertension, and multiple prior episodes of hemoptysis that were associated with numerous previous hospitalizations. Current medications in- cluded furosemide, a potassium supplement, and a codeine-containing cough syrup for a chronic cough. The patient's daughter also expressed some con- cern that her mother might be addicted to the codeine-containing cough syrup because she had been seen using it frequently. Physical examination revealed an elderly woman in no acute distress sit- ting in an upright position. Blood pressure was 112/64 mm Hg; pulse, 96; respirations, 20; and temperature, 36.9 C orally. Pupils were pinpoint, equal, and reactive bilaterally. Peripheral cyanosis was noted in a bluish discolora- tion of the patient's lips and nail beds. Breath sounds revealed scattered ex- piratory rhonchi with few inspiratory dry rhonchi at the left lung base. Car- diac examination revealed a regular rate and rhythm with normal heart sounds and no evidence of murmur, gallop, jugular venous distension, or 142/1294 Annals of Emergency Medicine 16:11 November 1987
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`peripheral edema. Although the patient was awake and alert, she was unable to answer questions appropriately and appeared confused when questioned. Additional testing involving the cranial nerves; sensory, motor, and cerebellar sys- tems; and deep-tendon reflexes were all grossly intact without focal neu- r01ogic deficits. Following the establishment of a pe- ripheral IV line of D5/.45 normal saline at 40 mL/hr, arterial blood gases were obtained on room air, and the pa- tient subsequently was begun on sup- plemental oxygen at 2 L/rain through a nasal cannula. In an attempt to re- verse the suspected narcotic over- dosage from an inadvertent over-con- sumption of codeine contained in the self-administered cough suppressant, naloxone was administered in total dose of 1.6 mg (four 0.4-mg preload ampules) IV over three minutes. Following completion of naloxone administration, the patient immedi- ately and dramatically became agi- tated, was tachycardic with a pulse of 124, and diaphoretic, and complained of severe dyspnea. Auscultation re- vealed inspiratory and expiratory wet rales throughout all lung fields. The clinical diagnosis of acute pulmonary edema was made. Within ten minutes following the administration of furo- semide 40 mg IV, nitroglycerin 0.04 mg sublingually, and morphine sulfate 2 mg IV, resolution of all subjective and objective signs of acute pulmo- nary edema occurred. Repeat physical examination at this time revealed a tremulous, slightly anxious patient with blood pressure of 140/50 mm Hg, pulse of 100, and respirations of 24. The patient's pupils were dilated bilat- erally. The skin and mucosal mem- branes were now pink, and the dia- phoresis had resolved. Cardiopulmo- nary examination revealed scattered wheezes in the upper lung fields and dry rhonchi at the bases bilaterally. The remainder of the physical exam- ination remained unchanged with the exception of a pulse of 112. Following resolution of the patient's condition, the initial ABG obtained on room air became available. The initial blood gas revealed pH, 7.33; pCO2, 72.4 mm Hg; PO2, 50.6 mm Hg; and HCO3, 37.1 m/EqL. Supplemental oxygen therapy was changed to 24% venti-mask at this time. Chest radio- graph revealed an old right upper pneumonectomy with a possible superimposed active infiltrate; no signs of acute pulmonary edema or congestive heart failure were noted. Additional laboratory tests, including CBC, PT, PTT, electrolytes, BUN, creatinine, and glucose, were normal. Following the patient's admission to the hospital, a codeine level of 1,188 mg/mL was found. While no addi- tional episodes of pulmonary edema were noted during hospitalization, • further evidence of acute narcotic withdrawal, including yawning, lacri- mation, piloerection, tremors, and in- somnia were seen. The patient was discharged from the hospital two days later, with no complications. DISCUSSION In recent years reports have ap- peared linking naloxone administra- tion to adverse cardiovascular effects in patients. Tanaka 1 first reported a case of severe hypertension and atrial tachycardia following administration of 0.4 mg naloxone to antagonize the respiratory depressant effects of mor- phine-nitrous oxide anesthesia in a 51- year-old man with a history of hyper- tension, hyperlipidemia, and diabetes mellitus. Michaelis et a12 observed ventricular fibrillation and tachycardia in two patients undergoing open heart surgery following 0.1 to 0.4 mg nalox- one administered to reverse morphine anesthesia. Flacke et a13 were the first to report the sudden onset of acute pulmonary edema in a patient under- going coronary bypass surgery follow- ing "high-dose" (0.4 mg) naloxone ad- ministration. While these adverse effects were noted in patients with pre-existing cardiac disease, recently reported cases include young, previously healthy individuals. In 1980, Andree 4 reported the death of two healthy women following narcotic reversal with naloxone leading to cardiac ar- rest. TaffS and Prough et a16 reported acute pulmonary edema following low-dose (0.04 to 0.10 rag) naloxone administration used to reverse anes- thesia in previously healthy young adults without underlying cardiovas- cular disease who were undergoing elective surgery. Most authors attribute the adverse cardiovascular effects of naloxone to the reversal of narcotic analgesia and the subsequent central release of en- dogenous catecholamines leading to a massive sympathetic response. 1,3,5-7 Others have suggested the precipita- tion of noncardiogenic pulmonary edema as similar to neurogenic pul- monary edema, a type of adult respira- tory distress syndrome that may occur in the absence of underlying cardiac pulmonary disease. 6 In addition, a possible unknown effect of naloxone on peripheral opioid receptors outside the central nervous system or drug- drug interactions of an unknown vari- ety have been conjectured. 7 The reac- tion does not appear to be allergic in nature, as the usual signs and symp- toms of an anaphylactic reaction were not present in any of the reports. The sudden and unexpected presen- tation of acute pulmonary edema im- mediately following the administra- tion of IV naloxone in our patient reiterates the findings previously lira- 16:11 November 1987 Annals of Emergency Medicine 1295/143
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`PULMONARY EDEMA Schwartz & Koenigsberg ited to the post-surgical and anesthe- sia literature. Our patient's confusion, lethargy, pupillary constriction, and cyanosis were thought to be secondary to inadvertent over-administration of a codeine- and alcohol-based elixir used as an antitussive. Naloxone was used to reverse the acute mental ob- tundation present. The acute pulmo- nary edema that developed immedi- ately following naloxone administra- tion was reversed quickly and never recurred during the patient's remain- ing hospitalization. Because vital signs were obtained neither immediately following nalox- one administration nor during the precipitious occurrence of acute pul- monary edema, we are unable to spec- ulate whether the cause of the pulmo- nary edema was due to a direct effect of the naloxone or to an indirect effect secondary to an outpouring of endo- genous catecholamines, yielding a massive sympathetic response leading to an acute hypertensive episode as the precipitating factor. SUMMARY Due to the immediate temporal re- lationship between the precipitous de- velopment of acute pulmonary edema and the administration of naloxone, we believe that the observed events in this patient were related to naloxone administration. This concept is sup- ported by the previously reported sim- ilar occurrences of precipitation of acute pulmonary edema following naloxone administration. 3-7 It is plau- sible that had we begun with 0.4 to 0.8 mg naloxone over five minutes rather than 1.6 mg over ~hree minutes, our patient might have experienced a controlled, partial reversal of the men- tal obtundation associated with co- deine intoxication without experienc- ing the observed morbidity and possible mortality of pulmonary edema. The authors express special appreciation to Rose Sturghill-Bradford for her as- sistance in the preparation of this man- uscript. REFERENCES i. Tanaka GY: Hypertensive reaction to nal- oxone. JAMA 1974;228:25-26. 2. Michaelis LL, Hickey PR, Clark TA, et al: Ventricular irritability associated with the use of naloxone hydrochloride. Ann Thorac Sdrg I984;18:608-614. 3. Flacke JW, Flacke WE, Williams GD: Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. ANEST 1977;47:376-378. 4. Andree RA: Sudden death following nalox- one administration. Anesth Analg 1980;59: 782-784. 5. Taft RH: Pulmonary edema following nalox- one administration in a patient without heart disease. ANEST 1983;59:576-577. 6. Prough D8, Roy R, Bumgarner J: Acute pul- monary edema in healthy teenagers following conservative doses of intravenous naloxone. ANES 1984;60:485-486. 7. Pallasch TJ, Gill CJ: Naloxone-associated morbidity and mortality. Oral Surg I981;52: 602-603. 144/1296 Annals of Emergency Medicine 16:11 November 1987
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