If a Little is Good, More Must be Better…Right?

If you are practicing medicine in any capacity, you have undoubtedly heard about Narcan campaigns aimed at saving lives compromised by narcotic overdoses. These campaigns have placed Narcan kits into the hands of police officers, EMS personnel, prison workers, and even the average citizen. We’ve heard the praises of Narcan, but are there any potential complications to the medication that we should know about? Consider the following patient scenarios.

The First Case

A 27-year-old incarcerated male with a history of substance abuse and depression who presented to the hospital by ambulance (EMS) after being found unresponsive in his jail cell and laying in large amounts of emesis. This patient had undergone a tooth extraction earlier in the day with no reports of complications. Per the Department of Corrections (DOC) officer, it is unclear whether the patient illegally obtained narcotics during the procedure, was passed narcotics by a visitor, or saved up his prescribed Zyprexa® medications and took multiple doses this day.

EMS administered a total of 10 mg of Narcan and continued with BVM respirations en route to the hospital. Upon arrival, the patient was hypoxic (SpO₂ 60-70%) and agitated. He was intubated using Etomidate and Rocuronium, and placed on the ventilator. A significant amount of pink frothy pulmonary edema was noted at the time of intubation. The hypoxia continued despite multiple ventilator manipulations. Blood gas (ABG) results revealed a pH of 7.11, PaCO₂ of 94.2 mmHg, PaO2 of 44.5 mmHg, Bicarbonate (HCO₃^–) of 29.5 mmol/L and an SaO₂ of 65.3% (7.11/94.2/44.5/29.5/65.3).

The critical care transport team arrived and promptly sedated and paralyzed the patient in an effort to decrease oxygen demand. He was given two push doses of epinephrine (10 – 20 mcg of a 1:100,000 solution) to support his blood pressure while a norepinephrine infusion was being prepared and given a 1-liter bolus of crystalloid. He was placed on Pressure-Controlled Mechanical Ventilation and 20 ppm of inhaled nitric oxide (iNO) with a repeat ABG of: 7.099/81.3/48/25.2/66%. Another attempt at ventilator manipulations included recruitment maneuvers, inverse I: E ratio ventilation, and increased in ventilating pressures. These maneuvers were unsuccessful and the patient was subsequently deemed “not fit for transport” based on the following criteria:

1. Poor oxygenation prior to movement of patient to stretcher
2. Flight crew unable to “rescue” patient with ventilator manipulation or bagging
3. Transport was 45 to 60 minutes by ground
4. Accepting physician no longer felt patient an Extra Corporeal (ECMO) candidate due to prolonged down time.

This patient was transported to the Medical ICU at the referring hospital. iNO was weaned in a “step-down” fashion to off. Follow-up was challenging as patient was managed at an outside facility. However, a call to the ICU the following day found the patient on 60% FiO₂, following commands, and aggressively treated with diuretics with no further pulmonary edema appreciated.

Another Case to Consider

A 22-year-old male with a history of ADHD, anxiety, depression, hallucinations, and substance abuse. The patient’s grandmother reports that he was gone all day and returned home around 2245 “not acting like himself” and “like he does when he’s on something”. The patient was heard with loud snoring respirations from his room a few minutes later and was found to be unresponsive by his grandparents who immediately called 911 and began chest compressions.

EMS arrived to find patient with a GCS of 11. There were no reports of emesis on clothing or face. EMS administered 6mg of Narcan, placed 2 peripheral intravenous catheters (IV), and an iGel, and transported to a local hospital. While en route, the patient woke up and ripped out his IV’s, the iGel then became unresponsive again. EMS completed the transport utilizing bag and mask (BVM) ventilations. Upon arrival, he was noted to have pulse oximetry readings (SpO₂) in the of 30-40% range. He was administered another 4mg of Narcan IM (total of 10mg of Narcan given). He was immediately intubated for airway protection. Intubation was reportedly “long and complicated” with immediate flash pulmonary edema noted with endotracheal (ETT) tube placement. He received 100% oxygen as well as Flolan at 9ml/hr. This resulted in a slow return in SpO₂ to 89-91%. The patient’s pre-intubation PaO₂ was noted at 28 mmHg with a rise to 58 mmHg noted after intubation. His pupils were noted to be 7mm and sluggish. His blood pressure spiked to 200’s/100’s necessitating the initiation of a nitroglycerin infusion that was eventually stopped and replaced with norepinephrine and vasopressin following acute refractory hypotension.

The transport team arrived and chemically paralyzed the patient in an effort to decrease oxygen demand, placed him on Pressure-Controlled Mechanical Ventilation (PCV) and 10 ppm of iNO. Assessment findings were significant for 7mm minimally responsive pupils and excessive diaphoresis. An ABG just prior to transport team arrival was: 7.193/68.9/59/83%. The ABG following the aforementioned interventions was: 7.18/47.6/83/93%. The patient was transported to tertiary care and continued on norepinephrine, vasopressin, PCV, and iNO by the accepting ICU.  His admission chest x-ray (CXR) is below. Note the Diffuse bilateral patchy alveolar opacities compatible with ARDS/pulmonary edema/multifocal pneumonia.

On day 1 of admission, the norepinephrine as well as the iNO were weaned to off and his oxygen (FiO₂) requirement was down to 90%. On day 4 of admission, he was extubated to Heated High-Flow Nasal Cannula (HHFNC). No further pulmonary edema was appreciated.

So let’s talk Narcan

Narcan is a mu-opioid-receptor antagonist developed in the 1960’s (Patti et al., 2020) that is used for reversal of opioid effects (Jiwa, Sheth, & Silverman, 2018). It is currently approved for administration IM, IV, or IN (intranasal) (Patti et al., 2020). Given the praises it has recently received, it may be easy to overlook the adverse side effects of the medication that include hypotension, arrhythmias, seizures, and rarely flash noncardiogenic pulmonary edema (NCPE) (Patti et al., 2020). Narcan-induced NCPE is estimated to occur in 0.2-3.6% of patients (Jiwa et al., 2018).

While the exact etiology is unclear, narcan-induced NCPE is believed to be caused by an adrenergic response from a large increase in centrally mediated catecholamines following naloxone administration. When naloxone is given to a patient, a catecholamine-mediated response is elicited. The effect of those catecholamines results in hypertension, tachycardia, and diaphoresis. Additionally, the increased catecholamines cause a shift of blood flow into pulmonary vasculature, leading to severe pulmonary vasoconstriction and pulmonary hypertension. An exact dose or the route of administration at which naloxone causes acute pulmonary edema is still debatable (Patti et al., 2020). Timely securing the airway, adjusting PEEP to assist oxygenation, and administering diuresis are the key to successful management of such patients (Patti et al., 2020).

While very few cases of narcan-induced NCPE have been reported in the literature, it is nonetheless a phenomenon to be aware of when working with overdose patients. Other causes of hypoxia and respiratory failure such as aspiration pneumonia should be considered as a differential and aggressively treated until it can be ruled out.

Take-Home Points

1. Are these patients to safe for transport? There is no “always” or black and white answer to that question. Each transport crew needs to evaluate the situation and decide for themselves if it is safe to proceed with transport. Reasons for not transporting the first patient are listed above. The second patient was transported based on the following information:
   1. His PaO₂ has increased to 83 mmHg on PCV without excessive pressures and iNO at 10ppm
   1. We were traveling by ground with an out-of-hospital time of <15 minutes
   1. He could be “rescued” with manual ventilations using a BVM and a PEEP valve
2. How should transport and EMS personnel treat narcan-induced NCPE? The resounding answer is simply to be aware of it. Administer narcan in appropriate doses and titrate to positively affect responsiveness and resist giving subsequent doses if no response is noted. If you suspect NCPE, administer diuretics while en route if the patient’s blood pressure can tolerate it, but consult medical control prior to administration. Promptly secure the airway, titrate PEEP as the blood pressure tolerates to augment oxygenation, and treat with 100% FiO2.
3. Remember that NCPE is not well-documented in the literature and a lot of research is still needed to determine dose correlation, patient-specifics, timeline of illness, and most appropriate treatment approaches. You will likely receive some push-back or resistance to a discussion related to narcan-induced NCPE, but press on and keep it as one of your working differentials until it is ruled out or a more definitive cause of the pulmonary edema and refractory hypoxia can be identified.

References

Jiwa, N., Sheth, H., & Silverman, R. (2018). Naloxone-Induced Non-Cardiogenic Pulmonary Edema: A Case
Report. https://doi.org/10.1007/s40800-018-0088-x

Patti, R., Ponnusamy, V., Somal, N., Sinha, A., Sharma, S., Yoon, T., & Kupfer, Y. (2020). Naloxone-Induced
Noncardiogenic Pulmonary Edema. American Journal of Therapeutics, 27(6), 672-673.
https://doi.org/10.1097/MJT.0000000000001037