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Once Diagnosed Only in Heroin Users, NCPE Makes a Comeback, a Result of Opioids

Roberts, James R. MD

doi: 10.1097/01.EEM.0000511945.58521.a5

Dr. Robertsis a professor of emergency medicine and toxicology at the Drexel University College of Medicine in Philadelphia. Read the Procedural Pause, a blog by Dr. Roberts and his daughter, Martha Roberts, ACNP, CEN, at, and read his past columns at





The opioid epidemic in this country has emergency clinicians treating some rather rare conditions that were previously only associated with heroin use. Most individuals overdosing on opioids die of respiratory arrest, followed by cardiac arrest, but some survive with a condition known as noncardiogenic pulmonary edema (NCPE). Opioid-induced pulmonary edema was first described in the early 1970s when heroin was the main culprit. It was also occasionally seen with methadone, but not generally associated with other opioids such as oxycodone, hydrocodone, or fentanyl.

The actual cause was never elucidated, and the condition waned and is still quite unusual today. Some young physicians have never seen it. The heroin of the 1970s was markedly different from the heroin of today, and NCPE may have been related to the way heroin was produced or to some unknown additive or contaminant. This condition appeared to correlate with outbreaks of heroin use in certain areas.

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A Clinical Study of an Epidemic of Heroin Intoxication and Heroin-Induced Pulmonary Edema

Duberstein JL, Kaufman DM

Am J Med


Heroin-induced pulmonary edema was one of the most frequent, dreaded, and dramatic complications of heroin use when this article was written. Apparently, an increase in heroin use in the 1970s in New York City spawned this report of 149 cases of heroin overdose that included 71 patients with pulmonary edema. The average age of those 71 patients with NCPE was 22, all young men except for three women. The vast majority of patients used the drug intravenously. About 10 percent of patients also used a sedative, most commonly glutethimide (Doriden), a drug no longer abused. The condition was associated with long-time and short-term use of heroin.

All patients presented with respiratory depression or apnea. The pulmonary examination showed clear lungs (56%), wheezes (18%), rhonchi and rales (13%), and pink froth emerging from the nose or mouth (10%). The finding of clear lung auscultation is quite puzzling. Most patients had obvious needle tracks from drug use and demonstrated cyanosis, and all were obtunded. A common method of attempted field resuscitation included ice to the testicles or pouring milk into the pharynx, street methods employed by fellow addicts in an attempt to revive affected individuals.

A peripheral white cell count demonstrated a wide range, from 3200 to 37,500 cell/mm3, with about 60 percent demonstrating a leukocytosis. The electrocardiogram and blood chemistries were variable and nonspecific, but six patients had atrial fibrillation. Arterial blood gas analysis generally demonstrated hypoxemia and respiratory acidosis. Most patients were given an opioid antagonist, nalorphine, by EMS with expected improvement in respiratory rate and mental status.

Thirteen of the 149 patients died with pulmonary edema. The majority of patients in this study came from economically depressed areas with predominantly black and Puerto Rican residents. Heroin use today has attracted individuals of all races, locations, and economic status.

Overall, almost 50 percent of 149 patients with heroin overdose demonstrated some degree of pulmonary edema. The mortality rate was eight percent. The vast majority had pulmonary edema upon presentation; a few developed it after reversal with nalorphine or within a few hours of admission. All of those who died demonstrated marked pulmonary congestion and edema at autopsy. The etiology of the pulmonary edema among these patients was never proven, but the authors suggested it may include a number of causes, such as hypersensitivity, adulterant toxicity, anoxia, aspiration, or prolonged hypoxia and acidosis.



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Heroin Related Noncardiogenic Pulmonary Edema: A Case Series

Sporer KA, Dorn E



The 27 patients in this retrospective review who presented with noncardiogenic pulmonary edema related to heroin use were all from the San Francisco area during a dramatic increase in heroin use in the late 1990s. Twenty-seven of 1278 heroin users in this series presented with NCPE. All patients received naloxone prior to hospitalization. The majority of patients were hypoxic on presentation, but a few patients developed worsening symptoms within four hours of admission. The hypoxic syndrome in the majority of patients, however, resolved spontaneously within eight to 24 hours.

Chest x-ray demonstrated bilateral pulmonary edema in most, but curiously four patients had unilateral findings. About a third of the patients required mechanical ventilation. The rest required only supplemental oxygen. The few patients who were studied further had normal or increased cardiac output, normal pulmonary capillary pressure, and only moderately elevated pulmonary artery pressure. The pulmonary fluid had a high protein content consistent with pulmonary capillary leaks, not pump failure.

Comment: Heroin-related noncardiogenic pulmonary edema was occasionally seen in the ED 20 to 30 years ago. It seemed to occur sporadically. One could not count on just the physical examination to clinch this diagnosis. The majority of patients were hypoxic and tachypneic upon arrival. Most responded to supplemental oxygen, but a few required mechanical ventilation. Pulmonary edema and congestion is the omnipresent hallmark of opioid toxicity on autopsy, but the incidence of clinically apparent heroin-related NCPE has markedly decreased. This is rather unusual because the purity of heroin is much higher now than it was in the past, so something other than simple heroin toxicity is to blame. Nonetheless, the emergency clinician must be aware of this entity and consider it in all opioid overdoses.

The illegal production of heroin has been elevated to a fine art, and many of the former non-opioid adulterants are no longer present. Heroin use is on the rise throughout the country, but NCPE has not made a ripple in the modern medical literature. Almost all heroin these days is cut with fentanyl or fentanyl derivatives, potent substances that cause rapid respiratory arrest. It has been suggested that the use of naloxone could somehow precipitate pulmonary edema, but this is unproven. The current trend of using smaller doses of naloxone to reverse opioid toxicity yet decrease severe withdrawal may have some beneficial effect on NCPE.



Individuals using opioids don't come to the ED with a minor overdose; they are usually unconscious or revived in the field with the increasing availability of naloxone to patients, family, and law enforcement. Those who have been fully revived are generally eager to leave the ED. Some of them are in withdrawal; others simply want to bolt because they were brought there against their will.

NCPE can be dramatic and is generally an initial finding in heroin overdose. Sometimes it occurs within seconds of injection, even with the needle still in the arm. It can also occur secondary to snorting heroin. It's interesting that the pulmonary findings are varied and may be subtle, and do not necessarily point to the diagnosis of pulmonary edema. All patients with this entity will, however, be hypoxic, and many will have an abnormal chest x-ray. All opioid overdoses should be monitored with pulse oximetry with the anticipation that late pulmonary edema could occur.

The previous tactic of pouring milk down the throat of patients with heroin overdose, which has largely been abandoned, could result in aspiration. Ice to the testicles can induce hypothermia. These patients are also subject to bacterial pneumonia, but true cardiogenic pulmonary edema would be rare because most of them are young and healthy.

Naloxone wears off in about 90 to 120 minutes, with longer duration of action with a higher dose, and all patients revived from opioid overdose should be observed for three to four hours in the ED. This is easier said than done. The temptation to leave is strong in individuals who have been put into withdrawal. Administering benzodiazepines and clonidine (0.2 to 0.3 mg every two to three hours) will ameliorate withdrawal in the vast majority. It's probably not difficult to convince a patient with hypoxia to stay in the ED, and NCPE rarely develops more than a few hours after overdose.

It would not be prudent to allow a recently revived opiate overdose patient to leave the ED soon after arrival and while the naloxone in their systems is still effective. Negotiating a longer stay is a time-consuming fine art that is not always successful, and restraining or otherwise sedating these individuals is likely the best tactic even though it's a royal pain for everybody. Some patients simply leave without telling anyone, a poor choice for sure. The ED is, unfortunately, still legally responsible for those who leave unnoticed.

Frank pulmonary edema usually occurs nearly immediately following heroin injection but can be delayed, rarely, for a few hours. All patients should be monitored with pulse oximetry in the ED. The vast majority will improve within 12 to 24 hours with simple oxygen administration, but those who continue to be hypoxic or whose condition worsens may require mechanical ventilation.

Diuretics, nitroglycerin, ACE inhibitors, and other medications used to treat cardiogenic pulmonary edema have no role here. A chest x-ray will usually be diagnostic, but mild cases will have few physical findings and often a normal chest x-ray. It would appear most reasonable to observe all patients with hypoxia that continues after naloxone reversal for 12 to 24 hours. An awake, alert, and otherwise asymptomatic recently resuscitated opioid overdose patient has a right to sign out of the hospital. Emergency physicians should write an extensive AMA note for those who leave early, describing delayed pulmonary edema and the return of toxicity once naloxone has worn off. And it's best if it is signed by the patient. One could argue that someone with an opioid on board cannot be expected to completely understand his poor decision to leave prematurely. Admission or prolonged observation for all patients with heroin overdose who have been resuscitated has the potential to fill up your ED or observation unit very quickly with today's epidemic.

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Characteristics of Heroin-Induced Noncardiogenic Pulmonary Edema

  • An unusual but potentially fatal consequence of heroin use
  • Rarely seen with today's heroin or other opioids
  • Most commonly seen in young males with IV heroin use
  • Can occur rapidly, often within minutes of heroin injection
  • Rarely can be delayed for a few hours
  • Physical findings and chest x-ray findings can be subtle, but hypoxemia is universal.
  • Most cases can be treated with supplemental oxygen only; mechanical ventilation is required occasionally.
  • Spontaneously resolves in 12-24 hours
  • Should be differentiated from aspiration and pneumonia
  • Medications used for cardiogenic pulmonary edema are not indicated.
  • Physiology is an accumulation of protein-rich fluid in the alveoli with decreased diffusing capacity, hypoxemia, and tachypnea.
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