by Brent Olson, NRP & Hashim Zaidi, MD
Clinical Scenario
You answer a call for on-line medical control for a 28-year-old male patient refusing transport to the hospital. The paramedics report that he was initially cyanotic with pinpoint pupils and snoring, shallow respirations. The paramedics administered a single dose of 2 mg intranasal naloxone. The patient subsequently became alert, oriented, conversant, and admitted to opioid use approximately half an hour prior. His physical exam is unremarkable without signs of trauma, a normal set of vitals including pulse oximetry, and a normal blood glucose level. They have been on scene for 15 minutes and are requesting input as the patient is adamant that they do not want to be transported to the hospital. Can you safely allow the patient to refuse care on scene? Are there other factors that may be assessed to help mitigate risk or prompt transportation for further care?
Many EMS Systems Are Evaluating Ways to Mitigate the Risks of Refusal in Post Naloxone Patients
Literature Review
Numerous studies have evaluated the safety of patient refusal after naloxone resuscitation and have found extremely low mortality rates, ranging from 0-0.48% in the 24-28 hours after refusal.[1-7] In these studies, patients who passed the EMS system’s refusal criteria were allowed to decline transport to the hospital. Although the studies used different criteria to determine whether a patient is eligible to refuse, they all similarly cross-checked patient records with medical examiner records in the area during the designated time frame. Many of these studies chose to narrow their focus by reviewing only the records of deaths deemed solely secondary to heroin or morphine metabolites.[1-3]Another study that compared the patients’ GCS upon arrival to the ED against their mortality outcome found zero deaths and low rates of repeat naloxone dosing in patients with a GCS 14 in comparison to those with a GCS < 14.[8] While this study does not comment on the initial field GCS that EMS crews evaluated immediately post resuscitation, we can cautiously extrapolate the data to presume that higher GCS scores in the field will also be predictive of better patient outcomes.
Another critical aspect examined in the literature is the post naloxone resuscitation time frame in which adverse events have been shown to occur. Early studies have reported adverse effects, such as delayed respiratory depression, over a wide range of up to 120 minutes. [9] More recent studies have shown this window can be narrowed to within 1 hour for evaluating for signification complications.[3,10]Unsurprisingly, longer acting opioids such as methadone often led to delayed respiratory depression.[9] Another literature reported complication feared to be due to naloxone is noncardiogenic pulmonary edema. Sporer and colleagues found this to be an extremely rare finding (0.9%) and one that, after a field overdose reversal, was evident with hypoxia upon arrival to the ED. In applying this to the prehospital world, signs of respiratory depression and pulmonary edema will likely present while EMS crews are still on scene and any patients that begin to show signs of sustained or rebound hypoxia after a resuscitation should be transported to the Emergency Department. Refusing patients and their caretakers should be educated on the risk of adverse respiratory effects within the next hour, and advised to call 911 if they begin to experience shortness of breath or respiratory depression after EMS crews leave the scene.
Methadone and Other Long Acting Opioid Agonists Are High Risk for Delayed Respiratory Depression
More recent studies have attempted to create a validated set of objective criteria that allows ED physicians to combine physical exam findings with clinical gestalt to make a decision about patient discharge at the 1-hour mark. The components of the criteria include 1) patient can mobilize as usual 2) SpO2 on room air : 92% or above, 3) respiratory rate >10 breaths/min and <20 breaths/min, 4) temperature >35°C and <37.5°C, 5) heart rate >50bpm and <100bpm, and 6) GCS of 15.[11-13] Together, these criteria makes up the St. Paul’s Early Discharge Rule. A validation study in 2017 done by Clemency and colleagues found that combining these rules with clinical gestalt resulted in missing adverse effects in only 1.8% of resuscitated overdoses.[13] But what about EMS? With these recent studies, there is adequate research demonstrating that allowing certain naloxone resuscitated opioid overdoses to refuse care by EMS on scene results in few adverse events. These adverse events are rare, and often evident within 1-2 hours for respiratory depression or immediately, as in the case of pulmonary edema. Patients have best outcomes when presenting as alert and oriented with a GCS of 15, with normal vital signs including blood sugar, and without oral or long acting opioid agents on board.
Hospital Observation Upon Reversal (HOUR) Criteria13
Evidence suggests that patients who have overdosed on short-acting opiates and have been reversed with naloxone have a very low rate of adverse outcomes. While this suggests that refusal of transport is therefore reasonable, there are a number of additional measures that should be considered to ensure a safe refusal. While there is a low level of documented evidence to support some of these factors, the combination of these in the low risk patient may help to reduce adverse events in this patient population. The first is to ensure that the patient is going to be released to a caregiver. Ideally, this would occur in a setting when both the patient and their caregiver will be awake for the next few hours. In one study evaluating rates of rebound toxicity deaths, all were due to patients going to sleep after being released by EMS and subsequently being found deceased in the morning.[7] The magnitude of the dose required for a naloxone response has also been a factor considered in the safety of a refusal. Although with limited data, doses larger than 0.4 mg could point to more potent synthetic agents having caused the overdose and may need extended observation.[14] In addition to dose, route of administration must also be considered with the IN route being most commonly utilized in the validation study of the St. Paul’s Early Discharge Rule.[13] It has also been shown to maintain higher blood concentration than IV over a 120-minute time frame.[15] McDonald and colleagues showed that the “2 mg IN dose produced speed of onset and early exposure comparable to 0.4 mg IM, while maintaining plasma levels for the next 2 hours at twice the level of the IM reference.”[16] Depending on the dosing, this helps to categorize IV and IM dosing as potentially being more at risk for adverse events as higher analogous concentrations required for resuscitation may be underlying more potent opioid toxicities. Ideally many of these opioid toxicities would have predictable pharmacokinetics. Therefore, patients that are resuscitated with low doses of IN naloxone are potentially at lower risk of rebound toxicity.
Pure IV Heroin Overdose Reversal Has the Most Predictable Pharmacokinetics; More Potent and Mixed Opioid Overdose Reversals Display More Unpredictable Pharmacokinetics
In ideal circumstances, post resuscitation field refusals would apply strictly to IV heroin overdoses, as this is what much of the data that we have available from the late 90s and early 2000s evaluated. When we venture outside of this realm into other drugs, co-ingestions, and alternate routes of ingestion, the pharmacokinetics get more difficult to predict. Watson and colleagues’ study showed that higher rates of recurrent toxicity occurred with long-acting opioids such as methadone, sustained-release morphine, and propoxyphene.[9] Similarly, almost half of the opioid toxicity recurrence “misses” that occurred after applying the St. Paul’s Early Discharge Rule and clinical judgment in the HOUR study were due to oral ingestions, such as methadone.[13] Since many of the earliest studies excluded co-ingestions and the pharmacokinetic alterations they could cause, it seems to be in the provider’s best interest to consider these patients for further evaluation. Obviously, it is often extremely difficult to determine the source of the overdose or intoxication while on scene with the patient. The decision will have to be made by asking the patient the substance and route they have used, evaluation of the scene, known history of the patient, and clinical evaluation of the patient. In support of this, recent studies have found the largest predictors of death in the months after an overdose-related ED visit to be patients using opioid agonist therapy or benzodiazepines in the past 12 months, opioid abuse plus another substance abuse disorder, a previous nonfatal heroin overdose, and 3 previous nonfatal overdoses.[17,18] Therefore, we encourage providers to attempt to transport patients with drug abuse histories that meet these criteria to the ED for possible early intervention. If patients are deemed appropriate to allow for on-scene refusal, adverse effects can be minimized when the overdose was due to IV heroin use without co-ingestions, when the resuscitation did not require more than 0.4 mg of IV/IM naloxone or preferably its 2 mg IN equivalent, and when the patient and their caretaker are advised to remain awake for the next few hours.
Although we have strong evidence to suggest that it is safe to allow for on-scene refusals post naloxone administration, much of the current research is still with limitations. A large barrier that EMS providers and ED physicians currently face is the recent surge in synthetic agents. Much of the research that was done on this topic came from the late 90s or early 2000s, before synthetics had hit the market yet. These studies that were able to look purely at heroin seem to have reliably reproducible results. The synthetic agents that are sometimes found in today’s drug pool make pharmacokinetics much more difficult to predict. Most of the data we have covered also is looking specifically at mortality and not morbidity. This means we are excluding any sort of health complications that do not result in death, i.e. anoxic brain injuries or pulmonary complications. The research method of cross-checking patient information from EMS refusals with death records from the medical examiner’s office that we have previously described is also not a perfect system. Patients could easily cross geographical borders and their death would not be recorded at that coroner’s office, for example. Additionally, we are missing opportunities for addiction interventions. Getting the patient to the ED could be the first step in a chain of events that could lead to recovery, consisting of social work consultations, medication assisted treatment e.g. buprenorphine, rehabilitation centers, or providing resources and patient education. There are some EMS systems who have initiated linking patients to addiction/recovery programs in the field to address this very issue. As discussed, much of the recent data reported originates from the ED setting, looking at when a patient can be safely discharged. Unfortunately, EMS time and personal constraints make it impractical to observe the patient on scene for an hour. These clinical decision rules still require validation in the prehospital world.
Case Conclusion
Let’s return to our paramedic crew on scene with the 28-year-old male patient. He was resuscitated with one dose of 2 mg IN naloxone. He is now alert and oriented, all of his vital signs are within normal limits, and he is not showing any signs of recurrent hypoxia. His sober partner is also on scene and agrees to watch over him for the rest of the afternoon, making sure he stays awake. He admitted to injecting IV heroin, but states he is not under the influence of any other drugs or alcohol. He denies having any medical history, taking any medications including benzodiazepines, and has not had any previous overdoses requiring resuscitation or hospitalization. You ask your EMS crew to explain all risks of refusing transport up to and including death, to advise the patient and caregiver to call 911 if he begins to experience any recurrence of respiratory depression or adverse symptoms such as shortness of breath, and you accept the refusal as medical control. The EMS crew completes the refusal of transport paperwork, but leaves behind a flyer outlining substance-abuse/addiction resources that are available in the local area.
References
1. Vilke GM: Assessment for Deaths in Out-of-hospital Heroin Overdose Patients Treated with Naloxone Who Refuse Transport. Academic Emergency Medicine. 2003;August 1;10(8):893–6.
2. Vilke GM, Buchanan J, Dunford JV, et al.: Are heroin overdose deaths related to patient release after prehospital treatment with naloxone? Prehospital Emergency Care. 1999;January;3(3):183–6.
3. Boyd JJ, Kuisma MJ, Alaspää AO, et al.: Recurrent opioid toxicity after pre-hospital care of presumed heroin overdose patients. Acta Anaesthesiologica Scandinavica. 2006;November;50(10):1266–70.
4. Heyerdahl F, Hovda KE, Bjornaas MA, et al.: Pre-hospital treatment of acute poisonings in Oslo. BMC Emerg Med. 2008;December;8(1):15.
5. Wampler DA, Molina DK, McManus J, et al.: No Deaths Associated with Patient Refusal of Transport After Naloxone-Reversed Opioid Overdose. Prehospital Emergency Care. 2011;June 8;15(3):320–4.
6. Levine M, Sanko S, Eckstein M: Assessing the Risk of Prehospital Administration of Naloxone with Subsequent Refusal of Care. Prehospital Emergency Care. 2016;September 2;20(5):566–9.
7. Rudolph SS, Jehu G, Nielsen SL, et al.: Prehospital treatment of opioid overdose in Copenhagen—Is it safe to discharge on-scene? Resuscitation. 2011;November;82(11):1414–8.
8. Fidacaro GA, Patel P, Carroll G, et al.: Do Patients Require Emergency Department Interventions After Prehospital Naloxone?: Journal of Addiction Medicine. doi: 10.1097/ADM.0000000000000563 (Epub ahead of print).
9. Watson WA, Steele MT, Muelleman RL, et al.: Opioid Toxicity Recurrence After an Initial Response to Naloxone. Journal of Toxicology: Clinical Toxicology. 1998;January;36(1–2):11–7.
10. Smith DA, Leake L, Loflin JR, et al.: Is admission after intravenous heroin overdose necessary? Annals of Emergency Medicine. 1992;November;21(11):1326–30.
11. Willman MW, Liss DB, Schwarz ES, et al.: Do heroin overdose patients require observation after receiving naloxone? Clinical Toxicology (15563650). 2017;February;55(2):81–7.
12. Christenson J, Etherington J, Grafstein E, et al.: Early Discharge of Patients with Presumed Opioid Overdose: Development of a Clinical Prediction Rule. Academic Emergency Medicine. 2000;7(10):1110–8.
13. Clemency BM, Eggleston W, Shaw EW, et al.: Hospital Observation Upon Reversal (HOUR) With Naloxone: A Prospective Clinical Prediction Rule Validation Study. Academic Emergency Medicine. 2019;26(1):7–15.
14. Cole JB, Nelson LS: Controversies and carfentanil: We have much to learn about the present state of opioid poisoning. The American Journal of Emergency Medicine. 2017;November 1;35(11):1743–5.
15. Clemency BM, Eggleston W, Lindstrom HA: Pharmacokinetics and Pharmacodynamics of Naloxone. Academic Emergency Medicine. 2019;26(10):1203–4.
16. McDonald R, Lorch U, Woodward J, et al.: Pharmacokinetics of concentrated naloxone nasal spray for opioid overdose reversal: Phase I healthy volunteer study. Addiction. 2018;March;113(3):484–93.
17. Leece P, Chen C, Manson H, et al.: One-Year Mortality After Emergency Department Visit for Nonfatal Opioid Poisoning: A Population-Based Analysis. Annals of Emergency Medicine. 2020;January;75(1):20–8.
18. Krawczyk N, Eisenberg M, Schneider KE, et al.: Predictors of Overdose Death Among High-Risk Emergency Department Patients With Substance-Related Encounters: A Data Linkage Cohort Study. Annals of Emergency Medicine. 2020;January;75(1):1–12.
Edited by Maia Dorsett, MD PhD, @maiadorsett
All photographs are unlicensed and copyright free from pixabay.