The Case Files

Naloxone is given routinely in the hospital and prehospital setting without much concern for significant morbidity. Many providers are unaware of its potential complications, including pulmonary edema, and may be caught off guard when respiratory distress occurs in an awake patient who was previously rescued with naloxone. The use of naloxone is now common in anesthesiology and emergency medicine for patients with concern for opiate toxicity. Its use, however, is not without occasional morbidity, particularly cardiopulmonary complications including pulmonary edema. (J Toxicol Clin Toxicol 1996;34[4]:409; Expert Opin Drug Saf 2007;6[2]:125; Oral Surg Oral Med Oral Pathol 1981;52[6]:602; Anesthesiology 1977;47[4]:376.) Among reported cases, these episodes have occurred more frequently after postoperative opiate intoxications, though non-postoperative cases have also been described. (Anaesthesist 2012;61[2]:129.) The pathogenesis of naloxone-associated pulmonary edema remains controversial, and the emergency medicine literature on this phenomenon, including its potential emergence in the pre-hospital setting, is limited. Our patient was a 37-year-old previously healthy male inmate. He was “roughhousing” when he struck his head and went to sleep. Sometime later, the patient was witnessed sliding out of bed, unresponsive. Bystanders reported that the patient had taken heroin prior to the episode, and the facility's nursing staff reported small pupils on exam. EMS arrived and performed chest compressions for an unknown period of time. No epinephrine was given. EMS then gave two doses of naloxone 1mg IM with resulting arousal. An ECG showed normal sinus rhythm. The patient was taken to the ED of an outside hospital. He was hypoxic en route, with an oxygen saturation in the high 80s despite oxygen. Initial assessment revealed no abnormal neurological or cardiopulmonary findings. Shortly after arrival, he received another dose of naloxone, this time 1 mg IV, as well as 1 L of normal saline. Initial vital signs in the ED were normal with blood pressure of 115/76 mm Hg, heart rate of 86/min, and respiratory rate of 15/min. Initial SaO2, however, was 76% on nasal cannula at 6 L/min. He was switched to a 100% nonrebreather mask with improvement of SaO2 to the mid-90s. The patient then developed a cough with pink sputum, so a chest x-ray was ordered showing severe bilateral pulmonary edema.FigureThe patient was then given a 40 mg IV dose of furosemide and 3 mL nebulized ipratropium/albuterol. A head CT was unremarkable. A drug screen was negative, so the patient was given a diagnosis of “nontoxic overdose,” and transferred to our tertiary care center. On our initial examination, the patient had rales bilaterally in all lung fields. Repeat chest x-ray (Figure 1) showed a hazy right mid-lung opacity, which was read as asymmetric pulmonary edema versus pneumonia, without evidence of rib fractures or pneumothorax. He was then given another 40 mg IV dose of furosemide. A bedside transthoracic echocardiogram demonstrated no wall motion or valvular abnormalities and a grossly normal ejection fraction, which was later confirmed by a comprehensive echocardiogram. The patient's SaO2 stayed in the low-to-mid-90s on nasal cannula at 6 L/min. Other laboratory findings including troponin, BNP, and chemistries were unremarkable. A second drug urine screen collected nine hours after the initial incident was negative. The patient later admitted to taking some form of narcotics earlier in the day, however. He was admitted to an inpatient medicine service. After a one-day stay without complications, his oxygen was weaned and he was discharged in stable condition on room air. Naloxone has been used for treatment of opiate overdose since the 1960s. (Anaesthesist 2012;61[2]:129.) The first known case of pulmonary edema after its administration was published by JW Flacke et al. in 1977. (Anesthesiology 1977;47[4]:376.) Other cardiopulmonary complications associated with the drug, including various arrhythmias and hypertensive crisis, have also been described. (J Toxicol Clin Toxicol 1996;34[4]:409; Ann Thorac Surg 1974;18[6]:608; JAMA 1974;228[1]:25; Anesth Analg 1979;58[6]:524; Am J Med Sci 1985;290[2]:70.) A review by Lassen et al. in 2012 found 24 published cases of naloxone-associated pulmonary edema. Nineteen occurred in postoperative patients, while five occurred in non-postoperative patients. Three cases resulted in fatality. (Zhonghua Yi Xue Za Zhi 1997;60[4]:219; Anesth Analg 1980;59[10]:782; Anaesth Intensive Care 1989;17[3]:374.) Cases have occurred with as little as 80 μg of IV naloxone, and onset of symptoms after administration has ranged from 1 to 60 minutes. (Anaesthesist 2012;61[2]:129; J Clin Anesth 1995;7[4]:356; Anesthesiology 1986;65[6]:709.) The majority have occurred in previously healthy men below age 50. (Anaesthesist 2012;61[2]:129.) In three postoperative cases, opiates were not used prior to naloxone. (Minerva Anestesiol 1982;48[1-2]:43; Lakartidningen 1995;92[42]:3919.) Our patient initially denied but later admitted to opiate use, despite having an undetectable level on the urine screen. It is probable that it was opiate intoxication that caused the unresponsive episode necessitating chest compressions and naloxone administration by EMS. Based on the time course, imaging, and unremarkable echocardiogram, it is likely that our patient is another case of naloxone-associated pulmonary edema in the prehospital setting. Many past case reports have attempted to explain the pathophysiology of non-cardiogenic pulmonary edema after naloxone. After the earliest cases, it was proposed that the pathophysiology is a catecholamine surge induced by abrupt awakening and return of painful stimuli, causing increased pulmonary blood pressure and capillary permeability. (Anesthesiology 1977;47[4]:376; Minerva Anestesiol 1982;48[1-2]:43.) Later it was proposed that the catecholamine surge was neurally mediated, with naloxone antagonizing endogenous opioid receptors in the central nervous system leading to catecholamine release from the brainstem and adrenal medulla. (Anesthesiology 1984;60[5]:485.) The general principles of this mechanism were agreed upon by authors of several other case reports of naloxone-associated pulmonary edema in the 1990s and 2000s. (Chest 2007;132[4_MeetingAbstracts]:692; Anaesth intensive Care 1991;19[4]:578; Anesth Analg 1997;84[1]:218.) The 2012 review by Lassen et al. debated this mechanism. It stated that the evidence for a catecholamine surge after naloxone is controversial, with some animal studies showing increased catecholamine production, but one showing a decrease. (Anesthesiology 1998;88[5]:1154; Br J Anaesth 1977;49[6]:525; Anesth Analg 1988;67[8]:730; Acta Anaesthesiol Scand 2006;50[10]:1271.) They pointed out that in the only basic science study relating pulmonary capillary permeability to naloxone, the drug did not increase capillary blood flow or pressure. (Prog Clin Biol Res 1990;328:389.) The authors also mentioned that no experimental studies have been done where naloxone alone was able to induce pulmonary edema. (Anaesthesist 2012;61[2]:129.) They stated that hypoxia, which is not caused by naloxone, is a common precipitant for other types of non-cardiogenic pulmonary edema including that induced by opiates. They argue that hypoxia from opiates themselves may be the driving pathophysiology for pulmonary edema and not naloxone in many of the cases described. They are not the first to make this argument; similar points were made in a 1989 letter to the editor in Annals of Emergency Medicine and as a review of naloxone complications in the same journal in 2005. (18:116; 22[9]:612.) It is probable that a catecholamine surge has a pathophysiologic role in the development of naloxone-associated pulmonary edema. The only experimental study on the relationship between naloxone and pulmonary capillary permeability showed no link between the two, but catecholamine surge leading to pulmonary edema has been established in experimental studies on neurogenic pulmonary edema. (Lancet 1975;2[7938]:749.) Also, in several of the cases described, including ours, patients develop signs compatible with a catecholamine surge including tachycardia, elevated blood pressure, and diaphoresis. (Anesthesiology 1977;47[4]:376; Anesthesiology 1984;60[5]:485; Chest 2007;132:692; Ann Emerg Med 1987;16[11]:1294.) Cases of arrhythmias and hypertensive emergency associated with naloxone not resulting in pulmonary edema have also been reported. (Ann Thorac Surg 1974;18[6]:608; JAMA 1974;228[1]:25; Anesth Analg 1979;58[6]:524; Am J Med Sci 1985;290[2]:70.) It is possible, however, that opiate-induced hypoxia is also a component in naloxone-associated pulmonary edema. Our patient was likely hypoxic after being unresponsive prior to naloxone administration. He was also known to be hypoxic en route to the ED, prior to symptoms of pulmonary edema. Catecholamines and hypoxia play roles in vasoconstricting the pulmonary vasculature, so it is possible that these factors may contribute or be additive to inducing pulmonary edema in patients who receive naloxone after opiate intoxication. The full cause may not be elucidated until more basic science experiments are conducted in this area. The majority of case reports of naloxone-associated pulmonary edema have occurred in the postoperative period, but five non-postoperative cases have been reported. (Anaesthesist 2012;61[2]:129.) Four of those occurred in the emergency department. (J Toxicol Clin Toxicol 1996;34[4]:409; Chest 2007;132(4_Meeting Abstracts]:692; Med Clin (Barc) 1990;94[16]:637; J Opioid Manag 2013;9[5]:369.) Only one previously published case was the result of naloxone administration by EMS in the field, similar to our case. (Chest 2007;132:692.) The patients were quickly brought to EDs before the onset of symptoms and received treatment and supportive care in a controlled environment in these cases. Field administration presents a new set of difficulties in diagnosing and treating a patient with complications from naloxone. Pulmonary edema or other cardiopulmonary complications could occur after naloxone in patients who are not in a position to receive emergent medical care shortly thereafter. Legislation in various parts of the United States has now made naloxone available with civil and criminal protection from liability to bystanders or first responders such as police officers and EMS personnel, with the goal of bringing faster treatment to potentially lethal opiate intoxications. (J Opioid Manag 2013;9[5]:369.) It is well established in emergency medicine that recreational overdose on opiates is often deadly, usually before prehospital care is initiated. Severe cardiopulmonary complications from naloxone are rare, but fear of complications should never preclude the use of naloxone in suspected overdose, even in the prehospital setting by bystanders and first responders. It would be meaningful for first responder personnel to be aware of the potential complications of naloxone, and to have a plan to activate the proper emergency services in the event of an arrest or severe dyspnea. This could further limit the morbidity and mortality from recreational opiate intoxication. Our patient is another case of pulmonary edema associated with naloxone administration in the ED. It was previously thought that a catecholamine surge is the cause of the complication, but the mechanism remains controversial. Hypoxia from the opiates themselves has also been proposed to be the driving pathophysiology. This is the second-known case of pulmonary edema after administration of naloxone in the field. As naloxone use becomes more common among bystanders and first responder personnel, it is important to stress the need for emergent medical care should cardiopulmonary complications arise.