Clinical Pearl 78: Does Naloxone Really Cause Pulmonary Edema?

Case: 23 y/o male who is unresponsive found by his friends in an ally. Policearrive on scene first and find the patient to have a respiratory rate of four andpinpoint pupils. The decision is made to give 0.4 mg of intranasal Naloxone. The respiratory rate has improved to six per minute however his pupilsremain pinpoint and oxygen saturation is only 88% on room air. You administer an additional 0.4 mg IV and place the patient on a non-rebreather mask and shortly after the patient is alert and oriented to person, place, time, and situation. The patient becomes tachypneic to a rate of 30, is saturating at 90% on non-rebreather, is coughing up pink frothy sputum, has crackles diffusely on exam and is now in severe respiratory distress. The patient denies a history of hypertension, cardiac disease, or respiratory disease. Wha thappened?

The safety of naloxone has been questioned over many years however with its more controversial accessibility to non-medically trained personnel such as law enforcement officers and family members of potential victims one of the more life threatening questionable side effects has raised some concern. Does the administration of naloxone cause pulmonary edema?

A widely accepted mechanism of how naloxone causes pulmonary edema is adrenergic overload. The sudden reversal causes catecholamine release that increases stroke volume, blood pressure, pulse strength, cardiac index, and plasma concentrations of epinephrine. These catecholamines also result in increased pulmonary-capillary hydrostatic pressure causing increased permeability.

A confusing aspect of this is that opioids alone can cause pulmonary edema. Sir William Osler in 1880 noted in an autopsy of a patient who died of narcotic overdose had pulmonary edema which was much earlier than the development of naloxone. One proposed mechanism is that histamine release secondary to opioid use causes secretion of proteinaceous material from lung capillaries resulting in accumulation of fluid. A second is that with respiratory suppression there is a rapid increase in negative pulmonary pressure from the upper airway obstruction leading to the movement of fluid out of the pulmonary capillaries and into the interstitial and alveolar space.

So did the patient in our case have pulmonary edema as a result of using the opioid or naloxone was administered?

According to Boyer et al. naloxone has been mistakenly implicated as a cause of pulmonary edema. Boyer notes that studies have shown that pulmonary edema is not secondary to large doses of naloxone nor by means of continuous infusion as in a naloxone drip and that auscultatory signs of pulmonary edema, which are difficult to auscultate in an apneic patient, become apparent only after naloxone restores ventilation.

The development of non-cardiogenic pulmonary edema, more correctly identified as acute lung injury (ALI) is multifactorial and cannot be predicted. The overall incidence is low with rates ranging from 0.2% - 3.6% and studies suggest that patients who develop pulmonary edema following opiate overdose and naloxone administration usually do so within 4 hours however it has been seen in one case up to 8 hours.

So does Narcan cause pulmonary edema? There is no convincing evidence suggesting that it does. There is data and evidence supporting theories of the patient developing pulmonary edema because of using opioids as well as for naloxone potentiating a physiologic cascade of events that causes the edema. There have been may case reports of naloxone being suspected as causing non-cardiogenic pulmonary edema in both hospital and prehospital settings but to this date, there has been no trial published. Subsequently, naloxone induced pulmonary edema remains unproven.

1. Kienbaum P et al. Profound increase in epinephrine concentration in plasma and cardiovascular stimulation after mu-opioid receptor blockade in opioid-addicted patients during barbiturate-induced anesthesia for acute detoxification. Anesthesiology 1998;88(5):1154-61.

PubMed

2. Busti, A. J., Hinson, J., & Regan, L. (Eds.). (2015, August).

Mechanism for Naloxone-Related Pulmonary Edema in Opiate or Opioid

Overdose Reversal. Retrieved August 01, 2017, from

https://www.ebmconsult.com/articles/mechanism-naloxone-relatedpulmonary-

edema-opiate-opioid-overdose-reversal

3. Sporer, K. A., & Dorn, E. (2001). Heroin-Related Noncardiogenic Pulmonary Edema. Chest, 120(5), 1628-1632.

doi:10.1378/chest.120.5.1628

4. Bhaskar B, Fraser JF. Negative pressure pulmonary edemarevisited: Pathophysiology and review of management. Saudi J Anaesth.

2011;5(3):308-13

5. Boyer EW. Management of opioid analgesic overdose. N Engl J

Med. 2012;367(2): 146-55

6. Busti, A. J., Hinson, J., & Regan, L. (Eds.). (2015, August). Incidence of Naloxone-Related Pulmonary Edema After Reversal of Opioid Overdose. Retrieved August 1, 2017, from

https://www.ebmconsult.com/articles/incidence-naloxone-pulmonaryedema-

after-reversal-opioid-heroin-overdose

Clinical Pearl 77: Carbon Monoxide Poisoning: Is the RAD-57 Useful?

Currently, the standard for measuring Carbon Monoxide (CO) is CO-oximetry spectrophotometry via blood gas analysis. However the RAD-57 from Masimo, claims the ability to detect CO concentrations using a non-invasive instrument based on light spectrophotometry – a device similar to a pulse oximeter that measures CO. In fact, the device manufacturer claims the RAD-57 has the ability to measure functional O2-Hb as well as CO-Hb (SpCO). The question we ask is whether there is a role in the use of RAD-57 in the detection of CO in a prehospital setting or Emergency Department, and how reliable are these measurements? Can the RAD-57 readings be used clinical to truly risk stratify patients with CO poisoning?

Four prospective studies currently exist and the rest are case studies. These studies compared two variables; blood CO-Oximetry vs RAD-57 (SpCO) values, and were used to asses for % difference (bias), accuracy, and precision.

The first study, Barker et al, investigated the device in 10 healthy volunteers who were exposed to CO in a gas mixture until their CarboxyHb level reached 15%. The comparison revealed an uncertainty of +/- 2% from CO-Ox readings.

The prospective observational study by Suner et al used RAD-57 to measure CO levels for 10,856 patients from the ED. In the study 28 patients read positive with the RAD-57 of which 11 had no apparent clinical suspicion. Even though the study was able to show cases of occult CO poisoning, the data on the accuracy of those devices were not reported.

The third study Touger et al enrolled 120 patients with suspected CO toxicity based on history and was found to have an accuracy of 1.4% but had confidence intervals from -11.6 to 14.4 which demonstrates very poor accuracy of the device. Moreover the study revealed the RAD-57 only detected 11 out of the 23 patients that had COHb > 15%. Which means the preciseness of readings were also questionable due to the high false negative rate. This Annals of Emergency Paper concluded that Rad57 should not be used interchangeably with blood readings.

Roth et al. a prospective study actually found a positive outcome. This study measured the RAD-57 SpCO in 1278 ED pts in which 17 were positive, with a relatively low bias of 2.32% and precision of 4.01%. This study also revealed there as an increase in erroneous readings with increasing CO-Hb concentrations. The study might have suffered from selection bias, as not all patients that had SpCO readings had comparison CO-Hb results.

Nilson et al. demonstrated instances of elevated SpCO in the pre-hospital setting (n=1700). This initial elevated non-invasive reading did lead to faster blood CO-Hb measurement and time to hyperbaric therapy. It should be noted that that clinical outcomes were not measured. Case reports revealed when SpCO was used as a screening measure, all 5 cases that had a positive reading had a lower clinically acceptably level on CO-Ox (15% vs 10%). False positive results in such scenarios especially in the prehospital setting could lead to mismanagement of resources as well as add additional costs to the healthcare system.

Now how does SpCO stand up to concomitant hemoglobinopathies. Feiner et al. assessed the accuracy of SpCO reading with concomitant Methemglobenima, which revealed a linear increase in error with increasing MetHb levels, also questioning the reliability of SpCO readings.

From these limited studies we can infer that the use of the RAD-57 has significant limitations. Poor precision and sensitivity issues render that clinician unable to rule out CO poisoning in the field as well as the Emergency Department. Positive readings may guide triage however with the devices’ poor accuracy; the benefits might be overshadowed by the harm. Until improvements in device accuracy, we cannot recommend routine use of this device.

References:

Barker SJ, Curry J, Redford D. Measurement of carboxyhemo- globin and methemoglobin by pulseoximetry: a human vol- unteer study. Anesthesiology 2006;105:892–7

Suner S, Partridge R, Sucov A, Valente J, Chee K, Hughes A, Jay G. Non-invasive pulse CO-oximetry screening in the emergency department identifies occult carbon monoxide toxicity. J Emerg Med 2008;34:441–50

Touger M, Birnbaum A, Wang J, Chou K, Pearson D, Bijur P. Performance of the Rad-57 pulse COoximeter compared with standard laboratory carboxyhemoglobin measurement. Ann Emerg Med 2010;56:382– 8

Feiner JR, Bickler PE, Mannheimer PD. Accuracy of methemoglobin detection by pulse CO-oximetry during hypoxia. Anesth Analg 2010;111:143– 8

Roth D, Herkner H, Schreiber W, Hubmann N, Gamper G, Laggner AN, Havel C. Accuracy of noninvasive multiwave pulse oximetry compared with carboxyhemoglobin from blood gas analysis in unselected emergency department patients. Ann Emerg Med 2011;58:74 –9

Nilson D, Partridge R, Suner S, Jay G. Non-invasive carboxy- hemoglobin monitoring: screening emergency medical services patients for carbon monoxide exposure. Prehosp Disaster Med 2010;25:253– 6

O’Malley GF. Non-invasive carbon monoxide measurement is not accurate. Ann Emerg Med 2006;48:477– 8

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