[ Next ] [ Prev ] [ Abs ] [ Chi ] [ TOC ] [ Home ]
Chin Med J (Taipei) 1997;60:219-23.
Division of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei; and National Yang-Ming University School of Medicine, Taipei, Taiwan, R.O.C.
A 39-year-old man was diagnosed as having acute myeloid leukemia and received 6 courses of chemotherapy. The bone marrow revealed complete remission. He had no prior history of cardiac or pulmonary disease. HLA-matched unrelated bone marrow transplantation (BMT) was performed in September 1995. Pre-transplant studies including chest X-ray, electrocardiogram and pulmonary function test were normal. The procedure of BMT was smooth and serial bone marrow examination showed successful engraftment. Serial chest X-rays done every week after BMT were normal. There were no evidence of fluid overload but severe mucositis was noted. On the 38th day after BMT, intravenous injection of 10mg morphine was prescribed to relief severe oral pain. Respiratory depression developed right after, and naloxone 0.4mg was given by an intravenous route. One hour later, severe shortness of breath was noted and the emergent chest X-ray revealed acute pulmonary edema. He became unconscious 2 hours later and expired 24 hours after naloxone injection in spite of intensive medical treatment.
Naloxone-induced acute pulmonary edema is an extremely rare but lethal complication. Only a few cases have been reported in English literature. We report a case of acute myeloid leukemia receiving unrelated BMT to develop acute pulmonary edema rapidly after intravenous injection of naloxone. The clinical features and pathogenesis are discussed.
[Chin Med J (Taipei) 1997;60:219-23.]
Keywords: acute pulmonary edema, naloxone
Received: January 17, 1997.
Accepted: July 14, 1997.
Address reprint requests to: Wei-Shu Wang, M.D., Division of Medical Oncology, Department of Medicine, Veterans General Hospital-Taipei, 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan, R.O.C.
Naloxone is an opiate antagonist with little or no intrinsic agonist activity. It is often used to reverse the adverse effects of narcotics, especially opioid-induced ventilatory depression. Acute pulmonary edema following naloxone injection is extremely rare. Only a few cases have been reported in English literature in patients with congestive heart failure, during cardiopulmonary resuscitation, and in patients without heart disease [1-3]. Generally, the dose employed intravenously varied from 0.1 to 0.4 mg [4]. The majority of these patients survived after intravenous diuretics, oxygen supplement and ventilatory support. We present a case of acute myeloid leukemia without prior history of cardiac or pulmonary disease, who received unrelated bone marrow transplantation (BMT) to develop lethal acute pulmonary edema following intravenous injection of 0.4 mg naloxone.
A 39-year-old male patient had a one-year history of acute myeloid leukemia. Six courses of chemotherapy, including two courses of high-dose cytarabine plus mitoxantrone, was administered to achieve complete remission. The patient had no previous history of cardiac or pulmonary disease. No food or drug allergy history was identified. HLA-matched unrelated BMT was performed in September 1995. Pre-transplant studies including chest X-ray, electrocardiogram (EKG) and pulmonary function test were normal. Pre-transplant ejection fraction of the left and right ventricles was 54% and 43%, respectively. The procedure of BMT was smooth and serial bone marrow examination revealed successful engraftment. Patient's post-transplant condition was stable. Total daily intravenous fluid was 2000 ml with a balanced intake and output. Neither body weight gain nor hepatic veno-occlusive disease was found. There was no evidence of graft-versus-host disease (GVHD). The breathing sound showed not unusual. Serial chest X-rays examined every week after BMT were normal (Figure 1). Serial serum metabolites analysis including liver function test and renal function test were within normal limit. The major drug administered after BMT was immunosuppressive agent cyclosporin-A, given orally to prevent GVHD and graft rejection.
Severe oral mucositis developed during and after BMT, and oral analgesics were prescribed. On the 38th day after BMT, morphine 10 mg was given intravenously for 5 minutes for relief of severe oral pain. Unfortunately, respiratory depression was noted right after with manifestation of slow and shallow respiration. The consciousness of the patient was clear but both of his pupils showed extremely miotic. The breathing sound was clear. Under the impression of morphine-induced respiratory suppression, naloxone 0.4 mg was given by an intravenous route for 5 minutes. The symptoms and signs of respiratory suppression relieved immediately and the patient felt well without episode of chest tightness or arrhythmic sensation. One hour later, severe shortness of breath developed and the patient began to expectorate copious amount of pink frothy sputum. Oxygen 6 L/min was given immediately and the arterial blood gas analysis revealed PaO2 56 mmHg, PaCO2 54 mmHg, pH 7.24. The heart rate was 118 bpm, and the blood pressure was 156/88 mmHg. A portable supine chest X-ray was performed and severe bilateral pulmonary edema was demonstrated (Figure 2). Twelve-lead EKG was performed immediately and the EKG revealed no evidence of abnormal ST-T waves changes or Q-waves except for sinus tachycardia. Serum cardiac enzymes including creatinine kinase (CK) and its myocardial isozyme (CK-MB) were within normal limit.
The patient was intubated immediately and supported by mechanical ventilation. Unfortunately, copious amount of pink frothy sputum throughout the endotracheal tube was still noted and the arterial blood gas showed no improvement. He became unconscious 2 hours later and expired 24 hours after naloxone in spite of intensive cardiopulmonary resuscitation. Naloxone-induced pulmonary edema was highly suspected. Since there was no pre-existing lower respiratory tract infection or sepsis, no evidence of fluid overload, no prior history of cardiac or pulmonary disease and the serial chest X-rays and physical examination was not unusual.
Agonist-antagonist opioids generally produce respiratory depression, presumably mediated by u receptors [5]. The k receptors do not appear to mediate respiratory depression because highly selective k agonists have not been reported to cause respiratory depression in animals [6]. Naloxone is a pure antagonist of all three types of opioid receptors, especially u receptors. It has a terminal half-life of about 1 to 1.5 hours [7], and has a relatively short duration of action compared with many of the opioid agonists. It has also been given by intravenous infusion in attempts to antagonize opioid side effects such as ventilatory depression and pruritus while preserving analgesia [7].
The use of naloxone to antagonize opioid agonist overdosage has been reported to associate with serious cardiovascular problems including severe hypertension, cardiac arrhythmia and sudden death [2,8]. Acute life-threatening pulmonary edema secondary to naloxone administration has also been mentioned in English literature. Johnson et al. [1] firstly reported a 70-year-old man with congestive heart failure who received open-heart surgery to develop acute pulmonary edema following intravenous injection of 0.4 mg naloxone. Taff [3] has reported a 26-year-old young man without heart disease to develop acute pulmonary edema after intravenous naloxone, too. No well-defined adverse effects were associated with the dose and adverse effects of naloxone. Although some reports of severe complications following naloxone administration have emphasized the risk of naloxone given intravenously in 0.4 mg doses [1,2,8], Prough et al. [4] reported two healthy teenagers who received a smaller dose of 0.1 mg of naloxone and still developed acute pulmonary edema.
The mechanism of adverse effects of naloxone is still unknown, but there is evidence for the involvement of the sympathetic nervous system. Flacke et al. [9] reported that naloxone dramatically increases circulating catecholamine levels in unconscious, unstimulated dogs anesthesized by fentanyl, nitrous oxide, and enflurane. Certain parallels may exist between naloxone-induced pulmonary edema and neurogenic pulmonary edema, a type of adult respiratory distress syndrome (ARDS) that may occur in the absence of underlying cardiac or pulmonary disease [4]. Neurogenic pulmonary edema may develop quickly after profound stimulation of the central nervous system [10]. The toxicity of naloxone seems to result from an outpouring of adrenal catecholamines that may lead to an increase in pulmonary vascular permeability and pulmonary edema [11].
In this case we should remember that beside naloxone, morphine itself could lead to acute pulmonary edema. In a study conducted by Grellner et al. [12], histopathological changes of the lung were evaluated in 90 patients with clinically suspected morphine-associated deaths. Twelve of them revealed a picture of slight to moderate alveolar edema. In our patient, the time interval between morphine and naloxone administration was so close that it is difficult for us to differentiate the possibility of morphine- from naloxone-induced pulmonary edema. However, to the best of our knowledge, no morphine-induced pulmonary edema could go so fulminant and lethal clinical course in English literature. Furthermore, in our experiences of morphine administration for cancer patients, no morphine-induced pulmonary edema has been found. So, in this case, the diagnosis of naloxone- rather than morphine-induced lethal, acute pulmonary edema was considered.
In summary, we present a case without prior history of heart or pulmonary disease to develop acute, lethal pulmonary edema rapidly after naloxone injection for reversing opioid-induced ventilatory depression. This case emphasized the need for cautious use of naloxone and for careful observation of patients who receive naloxone to reverse narcotic side effects, even if they have no history of heart disease.
Copyright: 1997, Chinese Medical Association (Taipei)