Pharmacology 101: Naloxone-Associated Pulmonary Edema

In a previous Pharmacology 101 article, I wrote about naloxone, with a portion of the article discussing potential side effects. A couple of sentences briefly mentioned the potential for pulmonary edema, almost as if in passing. However, with the very recent publication of a case series by Kummer et al on naloxone-associated pulmonary edema in the American Journal of Emergency Medicine,¹ I thought it would be a good idea to unpack this specific side effect and devote more time to exploring a topic that has been gaining more attention in recent years.

Hitherto, naloxone has been often described as being relatively harmless with few native side effects (aside from the potential of precipitating an opioid withdrawal syndrome). However, acute pulmonary edema has been described with increasing frequency in the medical literature in recent years.

Let’s take a look at the case series. Dr. Kummer was the chief resident in internal medicine at Hennepin Healthcare from July 2021–June 2022, and is now a physician fellow in pulmonary and critical care medicine at the University of Minnesota. When asked how she became interested in this topic, she stated that her research mentor, Dr. Matthew Prekker, had encountered several suspected cases of naloxone-associated pulmonary edema. After encountering a case during her time as a resident, they worked with their team to put together a case series. “Our objective was to describe our clinical experience caring for these patients to better help prehospital and emergency providers with expectant management,” she said. “While severe acute pulmonary edema has been described following naloxone administration in the postoperative setting there is a paucity of literature describing pulmonary edema following naloxone reversal of recreational opioid overdose.”

The case series at hand was published recently and was a single-center retrospective review of patients with a presumptive diagnosis of naloxone-associated pulmonary edema, defined by an acute onset of respiratory distress, hypoxemia, and radiographic pulmonary edema after naloxone administration in patients with opioid intoxication, with rapid improvement in gas exchange and radiographic abnormalities. They excluded cases in which aspiration of gastric contents was suspected. The cases occurred in the emergency department at Hennepin County Medical Center between January 1, 2017 and September 30, 2019.

Their inclusion criteria were the following:

• Age ≥ 18 years
• Presumed opioid overdose with subsequent naloxone administration
• Attended by emergency medical services (EMS) with survival to hospital admission
• Acute development of hypoxemic respiratory failure with radiographic pulmonary edema that rapidly improved over 24–48 hours.

The authors reported a final tally of 10 cases (of which nine were male) with a median age of 23 years. A majority (n=9) had a history of opioid use disorder and six had positive urine tests for other intoxicating agents. Heroin, oxycodone, and methadone were reported to be the offending agents. Nine of the patients received naloxone from prehospital caregivers, and after receiving the reversal agent were able to reach the hospital without the need for intubation. However, after receiving naloxone, the patients then went into acute respiratory failure and chest X-rays were consistent with pulmonary edema, and seven patients subsequently required intubation.

Fortunately, the authors note that the edema saw quick resolution and respiratory status improved within 48 hours. The median cumulative dose was 4.3 mg. Dr. Kummer commented on the quick resolution, stating “While these patients tend to become critically ill and require intensive care for a time, our experience is that they also recover quickly from a respiratory standpoint. They are usually able to come off the ventilator in one or two days but are often hospitalized for longer due to complications of their critical illness.”

When asked about her reaction to the results of their study, Dr. Kummer said, “The thing that stands out most from our case series is how critically ill these patients became over a very short time following naloxone administration. Most required intubation and mechanical ventilation prior to or shortly after arrival to the emergency department. One patient in our 10-patient case series required veno-venous extracorporeal membrane oxygenation (VV-ECMO) for management of refractory hypoxemia.”

A smaller case series published in 2021 described two patients with a history of heroin abuse who developed acute pulmonary edema following naloxone administration, one of whom required subsequent intubation after a cumulative dose of 8 mg.² The article is titled Naloxone-Induced Acute Pulmonary Edema is Dose-Dependent: A Case Series, though this title seems to be based on very limited data.

Severity and Mechanism

The astute reader may wonder, Does the risk of pulmonary edema increase with the dose of naloxone? This question was asked by Farkas et al. as they conducted a retrospective study using a dataset based on 1831 patients treated with naloxone by the City of Pittsburgh Bureau of Emergency Medical Services.

Published in the Annals of Emergency Medicine in January 2020,³ they found that a total dose of naloxone exceeding 4.4 mg increased the risk for pulmonary complications (a composite of pulmonary edema, aspiration pneumonia, and aspiration pneumonitis) by 62%, but were unable to demonstrate a statistically significant effect of the dose on pulmonary edema when evaluated in isolation. Dr. Kummer and colleagues commented in their case series, “Patients who received the largest total doses of naloxone did not necessarily have the most profound hypoxemia, suggesting there may be other important risk factors for pulmonary edema severity.”¹ Naloxone-associated pulmonary edema has been described in perioperative settings with doses as low as 0.08 mg and 0.2 mg.^4,5 At this point in time, there does not seem to be conclusive evidence that the risk of pulmonary edema is dose-dependent.

The mechanism of naloxone-associated pulmonary edema is still being elucidated. Leading theories include a pulmonary vasoconstriction and hypertension due to sympathetic catecholamine surge following opioid reversal with increased capillary permeability, and the negative pressure caused by forced inspiration against a closed glottis.^1,3,6,7

Take-home Points

While the precise mechanisms, risk factors, and doses that lead to naloxone-associated pulmonary edema are still being explored, there is emerging evidence that demonstrates a sufficient risk that prehospital and emergency department caregivers should be aware of its existence. Clear communication of prehospital naloxone administration is important between EMS and receiving emergency department teams when patients are brought to the hospital.

Dr. Kummer’s take-home message for prehospital and emergency caregivers is this: “Naloxone is a lifesaving medication and should be used liberally where there is a possibility of opioid overdose, especially in the prehospital setting. There are infrequent, but possibly increasing, cases of profound pulmonary edema after opioid overdose and Naloxone administration. It is important for prehospital and emergency providers to be aware of this complication and be prepared to manage the patient appropriately.”

The views and opinions expressed in this article are those of the author and do not necessarily reflect those of people, institutions, or organizations they have been, currently are, or will be affiliated with.

References

1. Kummer RL, Kempainen RR, Olives TD, Leatherman JW, Prekker ME. Naloxone-associated pulmonary edema following recreational opioid overdose: A case series. Am J Emerg Med. 2022;53:41-43. doi:10.1016/j.ajem.2021.12.030

2. Al-Azzawi M, Alshami A, Douedi S, Al-Taei M, Alsaoudi G, Costanzo E. Naloxone-induced acute pulmonary edema is dose-dependent: A case series. Am J Case Rep. 2021;22(1):1-3. doi:10.12659/AJCR.929412

3. Farkas A, Lynch MJ, Westover R, et al. Pulmonary Complications of Opioid Overdose Treated With Naloxone. Ann Emerg Med. 2020;75(1):39-48. doi:10.1016/j.annemergmed.2019.04.006

4. Horng HC, Ho MT, Huang CH, Yeh CC, Cherng CH. Negative pressure pulmonary edema following naloxone administration in a patient with fentanyl-induced respiratory depression. Acta Anaesthesiol Taiwanica. 2010;48(3):155-157. doi:10.1016/S1875-4597(10)60050-1

5. Jiwa N, Sheth H, Silverman R. Naloxone-Induced Non-Cardiogenic Pulmonary Edema: A Case Report. Drug Saf—Case Reports. 2018;5(1). doi:10.1007/s40800-018-0088-x

6. Elkattawy S, Alyacoub R, Ejikeme C, Noori MAM, Remolina C. Naloxone induced pulmonary edema. J Community Hosp Intern Med Perspect. 2021;11(1):139-142. doi:10.1080/20009666.2020.1854417

7. Patti R, Ponnusamy V, Somal N, et al. Naloxone-Induced Noncardiogenic Pulmonary Edema. Am J Ther. 2020;27(6):e672-e673. doi:10.1097/MJT.0000000000001037

Daniel Hu, PharmD, BCCCP, has a doctor of pharmacy degree and is a medical science liaison with a background in critical care and emergency medicine pharmacy.