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

UpToDate

Clinical Pearl 76: Ventilation Strategies in Cardiac Arrest

You have a patient in cardiac arrest who needs some sort of ventilation or oxygenation strategy.  Three choices exist:

1. 1Passive Oxygenation
2. Asynchronous Ventilation
3. Ventilation with interposed intermittent compression

Which do you choose?  First we should acknowledge a few things before we look at the science.

1.      For the noncardiac arrest patient, passive oxygenation is a great thing for patients who are breathing at least 4 times per minute and saturation is at least 93 percent.  If the patient is below these numbers you should bag until you get to these numbers and then go back to passive oxygenation (NRB with High-Flow Nasal Cannula or BVM with Peep Valve and High Flow Nasal Cannula Underneath WITHOUT squeezing the BVM or CPAP). For three minutes if the decision to intubate has been made

2.      CC-CPR (chest compression CPR is a great thing) for “Untrained Rescuers.”  When a layperson arrives at the scene the benefit of good compressions outweighs stopping compressions to ventilate.  This practice is proven in multiple studies.

3.      Bagging people can cause harm.  It decreases myocardial blood flow,  decreases cerebral blood flow, causes shunting by distending the alveoli and opens the Lower Esophageal Sphincter which results in gastric distention and aspiration from vomiting.  Additionally this makes it harder to intubate patients.

So now the science. .. First we should acknowledge that not breathing is a bad thing so if we are not going to ventilate cardiac arrest patients based on the science we better make absolutely sure the science is very very overwhelming for not ventilating.   This is because not ventilating/breathing results in increased PCO2, decreased oxygenation and leads to anoxic brain injury/brain death.  In lieu of great science (published papers) we need many expert societies to back us up that we are doing the correct thing. 

Luckily, this is one of the less controversial topics for us because we really only have one paper that the current recommendation is based on. ..that is correct one paper on what to do when EMTs or higher medical personnel oxygenate/ventilation in cardiac arrest.   The 2015 AHA guideline states “for witnessed cardiac arrest in a shockable rhythm, it may be reasonable for EMS systems with priority-based multi-tiered response to delay positive-pressure ventilation by using a strategy of up to three cycles of 200 continuous compressions with passive oxygenation insufflation and airway adjuncts”  was based on an older paper in 2009 by Dr. Bobrow which appeared in Annals of Emergency Medicine.  No further research research supports this position. 

Now guidelines are somewhat silly because by the time they come out more science exists or they are already outdateed because of a lack of other published articles.  Before we look at the sole paper this was based on, we should be clear what it states:

1. This practice may be reasonable which is hardly an endorsement
2. It is only for Witnessed cardiac arrests.  If you are doing this based on unwitnessed cardiac arrests…it is dangerous and not based on any science or recommendation furthermore and you are risking harm.
3.  It is only for initial shockable rhythms.  So if the initial rhythm is not VFIB or Pulseless VT, (or the AED fires)..there is no science or recommendation for any society and you are risking doing harm.

More importantly…lets look at this paper that this recommendation is based on……..a subgroup analysis of 200 patients.  In this subgroup analysis, patients who received up to 3 cycles of 200 compressions had better neurologically intact survival only in the witnessed group.  30 compressions is 18 seconds so 200 compressions is 120 seconds.  Therefore if you are doing passive oxygenation for more than 200 compressions (120 seconds), this is against the guideline as well.  So why was the recommendation only in Witnessed VF/Pulseless VT?  It is because all the other patients did WORSE when they got passive oxygenation.  Specifically:

1. Neurolocally Intact Survival in the Unwitnessed Cardiac Arrest group was  better in BVM group 13.8% vs 7.3%.  That is correct the chance of Neurologically intact survival was two times greater in the group who were bagged if they had an unwitnessed cardiac arrest.  If you are doing passive oxygenation in this group you are decreasing someones chance of neurologically intact survival.
2. Neurologically Intact Survival in nonshockable rhythms was better with BVM 3.7 vs. 1.3.  So you in this study three times more patients had neurologically intact survival if they had a BVM used vs. Passive oxygenation.  Again if you are doing passive oxygenation in this group you are decreasing someone change of survival!!!

So why did the one group do better when they had passive oxygenation…the answer may be very simple.  The study did not keep track of how fast EMS ventilated.  In studies you can show differences in two study groups by either the treatment group doing very good or the control group doing very bad.  It is quite possible since we know that excessive bagging is bad that patients in this study  were bagged too aggressively and that is why there was a difference between the intervention and control group.  The other major explanation is that patients who had witness cardiac arrests  required minimal need for ventilation since they were just breathing.  Remember they only did passive oxygenation for 2 minutes then they bagged them too!

Since there is really no evidence for this practice…are there any studies which demonstrate we should not be doing this?   The Annals of Emergency Medicine paper and current recommendation say we should not be doing this in unwittnessed arrests or nonshockable rhythms or greater 200 compressions.  Moreover all of the papers that show benefit and make recommendations for CC-CPR are for “untrained rescuers.” However all of the studies done with this were observational studies.  Finally a large EMS prehospital cardiac arrest trial was published in New England Journal of Medicine by Nichol in December 2015.  This major trial of 114 EMS agencies, 23,711 adult patients was done by the Resusciation Outcomes Consortium and actually supported complete ventilation!!!  It was statistically very superior to everything done and reinforced that some complete ventilations are necessary.  While its primary endpoint evaluation continuous compressions vs interrupted and found better outcomes with interrupted it showed that complete ventilation was better than asynchronous.  Although this study had a few problems…. it is the overwhelming the most well done study ever on the topic…  Finally in the last major review published by M. Chang April 2017 titled “The Past, Present and Future of Ventilation During CPR” in Current  Opinion in Critical Care Medicine discusses that ventilations of 8-10 are the best methods for cardiac arrest patients.   This author agrees!!!

Conclusions:

1. Based on one older and small paper, passive oxygenation for Witness Cardiac Arrests with Ventricular Fibrillation/Pulseless Ventricular Tachycardia (AED shockable rhythm) is not unreasonable however better literature suggests that even this practice is not best evidence.
2. Prolonged passive oxygenation by medical personal (greater than 200 compressions) has no evidence to support it and potentially can cause harm.
3. Passive oxygenation by medical personal for unwitnessed cardiac arrests or nonshockable rhythms is not supported in the literature and potentially can cause harm.