Opioid-specific advanced life support therapies for cardiac arrest : ALS 3451; TF SR

Conflict of Interest Declaration

The ILCOR Continuous Evidence Evaluation process is guided by a rigorous ILCOR Conflict of Interest policy. The following Task Force members and other authors were recused from the discussion as they declared a conflict of interest: None

The following Task Force members and other authors declared an intellectual conflict of interest and this was acknowledged and managed by the Task Force Chairs and Conflict of Interest committees: None

CoSTR Citation

Grunau B, O’Neil B, Giustini D, Drennan IA, Lavonas EJ. on behalf of the International Liaison Committee on Resuscitation Advanced Life Support Task Force. Opioid-Specific Advanced Life Support Therapies for Cardiac Arrest Consensus on Science with Treatment Recommendations [Internet] Brussels, Belgium: International Liaison Committee on Resuscitation (ILCOR) Advanced Life Support Task Force, 2024 Nov 1. Available from: http://ilcor.org

Authors: Grunau B (Brian.Grunau@ubc.ca), O’Neil B (boneil@med.wayne.edu), Giustini D (dean.giustini@ubc.ca), Drennan I (ian.drennan@sunnybrook.ca), Lavonas E (Eric.Lavonas@dhha.org)

Collaborators: All ALS Task Force Members

Methodological Preamble and Link to Published Systematic Review

This is the first Consensus on Science with Treatment Recommendations (CoSTR) on this topic.

Systematic Review

Not published currently.

PICOST

The PICOST (Population, Intervention, Comparator, Outcome, Study Designs and Timeframe)

Population: Adults and children in any setting (in-hospital or out-of-hospital) with cardiac arrest secondary to suspected opioid poisoning

Intervention: Any opioid-specific advanced life support (ALS)-level therapy (e.g., intra-arrest naloxone or other drugs, or other intra-arrest ALS-level interventions) for cardiac arrest resuscitation

Comparators: Standard Basic Life Support (BLS) and/or Advanced Cardiovascular Life Support (ACLS) management

Outcomes: We classified favourable neurological outcomes and survival at hospital discharge, 30-days, and longer follow-up as critical outcomes; and return of spontaneous circulation (ROSC) as an important outcome.

Study Designs: We included randomized controlled trials (RCTs) and comparative non-randomized studies (non-randomized controlled trials, interrupted time series, controlled before-and-after studies, cohort studies). We included published studies and conference abstracts.

Timeframe: All years and all languages were included as long as there was an English abstract. Literature search performed Sept. 14, 2024.

PROSPERO Registration CRD42024596637

Consensus on Science

We performed a systematic review to identify all studies which compared any opioid-specific advanced life support therapy to standard resuscitative management. We found studies pertaining to naloxone and bicarbonate.

Intra-Arrest Naloxone

For the critical outcome of favourable neurological outcome at hospital discharge, we identified very low-certainty evidence (downgraded for risk of bias and indirectness) from 3 observational studies. One study (Strong, 2023 [conference abstract]) of 218 adult out-of-hospital cardiac arrests (OHCA) due to presumed overdose (not specific to opioids), reported that naloxone (given prior to ROSC) was not associated with favourable neurological outcomes (adjusted odds ration [AOR] 1.99, 95% CI 0.34-11.55).¹ A subsequent analysis of the same overall dataset (Strong 2024) examined 1807 EMS-unwitnessed cases with initial non-shockable rhythms, and reported that naloxone (given prior to vascular access) was associated with an increased odds of favourable neurological outcomes (adjusted OR 4.61, 95% CI 1.74–12.19).² A third study (Love 2023 [conference abstract]) of 164 adult OHCAs presenting to the emergency department with a history of overdose or substance use (not specific to opioids) reported that favourable neurological outcomes were not more common among patients treated with naloxone than those without (26% vs 27%, p=0.915).³

For the critical outcome of survival to hospital discharge, we identified very low-certainty evidence (downgraded for risk of bias and indirectness) from 4 observational studies. One study of 8195 undifferentiated OHCAs (Dhillon 2024) reported that naloxone was associated with increased survival to hospital discharge (risk difference 6.2%, 95% CI 2.3-10.0%).⁴ Another study of undifferentiated OHCAs (Quinn 2024) matched 159 cases treated with naloxone to 159 cases who were not, and reported that naloxone was not associated with survival to hospital discharge (adjusted OR 1.01, 95% CI 0.46-2.21).⁵ Similar to the findings for the outcome of favourable neurological outcome, Strong 2024² reported an association between naloxone and improved survival (AOR 4.41, 95% CI 1.78-10.97) among EMS-unwitnessed OHCAs with initial non-shockable rhythms, whereas Strong 2023¹ did not detect an association (AOR 1.99, 95% CI 0.39-10.30) among OHCAs due to presumed overdose.

For the important outcome of ROSC, we identified very low-certainty evidence (downgraded for risk of bias and indirectness) from 3 observational studies. Similar to the above findings, Dhillon 2024⁴ (risk difference 15.2%, 95% CI 9.9-20.6%) and Strong 2024² (AOR 2.14, 95% CI 1.20–3.81) reported that naloxone was associated with an improved odds of ROSC among undifferentiated OHCAs and EMS-unwitnessed cases with initial non-shockable rhythms, respectively. Quinn 2024 did not detect an association (AOR 0.43, 95% CI 0.16 - 1.2) among undifferentiated OHCAs.^5.

EtD: ALS 3451 Et D Naloxone 30 OCT 2024

Intra-Arrest Bicarbonate

For the critical outcome of favourable neurological outcome at hospital discharge we identified no studies.

For the critical outcome of survival to hospital discharge we have identified very low-certainty evidence (downgraded for risk of bias and indirectness) from 1 observational study (Alqahtani 2019), which examined an 18-year period of 1545 EMS-treated OHCAs with suspected drug overdose, defined as evidence of deliberate or accidental overdose of prescribed or unprescribed drugs, or ethanol.⁶ Authors analyzed multiple factors associated with survival to hospital discharge, and reported that bicarbonate (compared to no sodium bicarbonate treatment) was associated with a decreased odds of survival to hospital discharge (AOR 0.16, 95% CI 0.08-0.31).

For the important outcome of ROSC we identified no studies

EtD: ALS 3451 Et D Bicarbonate 30 OCT 2024

Treatment Recommendations

During advanced life support for cardiac arrest due to opioid poisoning, there is insufficient evidence to recommend any additional opioid-specific therapies (e.g., naloxone), beyond standard resuscitation care.

If rescuers are uncertain whether a patient with suspected opioid poisoning is actually in cardiac arrest, administration of an opioid antagonist (e.g., naloxone) is warranted (Good Practice Statement).

Justification and Evidence to Decision Framework Highlights

• We acknowledged that cardiac arrest resuscitations are time-sensitive task-saturated endeavors with multiple competing priorities.⁷ We did not believe that the very low certainty evidence regarding the benefit of any opioid-specific ALS intervention was sufficient to recommend, given the risk of interfering with other evidence-based interventions. In making this recommendation we place a higher value on not adding yet unproven therapies (outside of a controlled research setting), which may interfere with other interventions known to confer benefit. Given the uncertain state of the evidence, there is also a possible risk of harm.
• Our aim was to evaluate the evidence of advanced treatments (e.g., intravenous naloxone) that may confer benefit for those with opioid toxicity and confirmed cardiac arrest. This recommendation is directed at providers of ALS,⁷ i.e., clinicians able to distinguish respiratory depression/apnea from cardiac arrest. However, if there is uncertainty regarding whether a patient is indeed in cardiac arrest, implementing the recommended treatments for respiratory depression/apnea (i.e. naloxone) is warranted, along with other cardiac arrest interventions.
• This recommendation is not intended to inform care by individuals without training to ascertain pulselessness. For these rescuers, when attending to patients with opioid toxicity it may be difficult or impossible to distinguish between a patient with respiratory depression/apnea vs. cardiac arrest. In these scenarios, please refer to the ILCOR CoSTR “Resuscitation care for suspected opioid-associated emergencies (BLS #811)”.⁸
• This topic was deemed a priority given the current large number of deaths due to opioid toxicity. Current evidence suggests that opioids may be responsible for up to 10% of OHCA’s in some jurisdictions.^9,10
• Opioids suppress the respiratory drive, leading to hypoxia and subsequent cardiac arrest. Naloxone is an effective reversal agent for opioid-induced respiratory depression, however its effectiveness in cardiac arrest is unclear, particularly when artificial respiration is provided.¹¹ Animal models have shown that naloxone may improve the probability of ROSC over standard resuscitation (even in the absence of opioids),^12–14 however other data suggests opioid-reversal may worsen cerebral injury.^15,16
• We identified several observational studies in our systematic review, however which were limited by serious risk of bias and indirectness.
• Indirectness: There were no studies which actually examined the population of interest for this recommendation, i.e., those with opioid-associated OHCA. Some studies included undifferentiated OHCAs,^2,4,5 and others limited to those with suspected drug-overdose^1,3,6 (including a wide array of prescription and non-prescription drugs). In addition, there were no studies examining in-hospital cardiac arrest or pediatrics cases, and thus for these populations the evidence is very indirect.
• Bias: Previous studies have shown that drug-related OHCA is associated with improved outcomes compared to undifferentiated OHCA^17,18, and that opioid-related OHCA is associated with improved outcomes compared to other drug-related OHCAs¹⁹. Drug-related cases are more likely to be treated with naloxone than undifferentiated OHCA,⁴ and opioid-related OHCA are more likely to be treated with naloxone than other drug-related cases.¹⁹ Thus, treatment with naloxone may simply be a marker of opioid toxicity and its apparent superior prognosis, rather than providing any actual benefit. In addition, existing studies did not account for the specific timing of naloxone or bicarbonate administration in analyses, and thus are limited by resuscitation time bias.²⁰

Knowledge Gaps

• There were no randomized controlled trials that evaluated standard care with and without naloxone or other opioid-antagonists in suspected opioid-associated cardiac arrest, for which further investigative work is needed.
• There was no evidence available for in-hospital cardiac arrest or pediatric cardiac arrest

References

1. Strong N, Daya M, Neth M, Noble M, Jui J, Lupton J. The Association Between Naloxone Administration and Outcomes for Out-of-Hospital Cardiac Arrest Due to Suspected Overdose. Circulation. 2023;148(Suppl 1).

2. Strong NH, Daya MR, Neth MR, Noble M, Sahni R, Jui J, Lupton JR. The association of early naloxone use with outcomes in non-shockable out-of-hospital cardiac arrest. Resuscitation. 2024;201. doi:10.1016/j.resuscitation.2024.110263.

3. Love C, Boivin Z, Doko D, Duignan K, She T. Does Naloxone Improve Outcomes in Cardiac Arrests Related to Opiate Overdose? Academic Emergency Medicine. 2023;Suppl 1(30):260. doi:10.1111/acem.14718.

4. Dillon DG, Montoy JCC, Nishijima DK, Niederberger S, Menegazzi JJ, Lacocque J, Rodriguez RM, Wang RC. Naloxone and Patient Outcomes in Out-of-Hospital Cardiac Arrests in California. JAMA Netw Open. 2024:e2429154. doi:10.1001/jamanetworkopen.2024.29154.

5. Quinn E, Murphy E, Du Pont D, Comber P, Blood M, Shah A, Kuc A, Hunter K, Carroll G. Outcomes of Out-of-Hospital Cardiac Arrest Patients Who Received Naloxone in an Emergency Medical Services System With a High Prevalence Of Opioid Overdose. Journal of Emergency Medicine. 2024;67(3):e249-e258. doi:10.1016/j.jemermed.2024.03.038.

6. Alqahtani S, Nehme Z, Williams B, Bernard S, Smith K. Long-term trends in the epidemiology of out-of-hospital cardiac arrest precipitated by suspected drug overdose. Resuscitation. 2019;144:17-24. doi:10.1016/j.resuscitation.2019.08.036.

7. Panchal AR, Bartos JA, Cabañas JG, Donnino MW, Drennan IR, Hirsch KG, Kudenchuk PJ, Kurz MC, Lavonas EJ, Morley PT, O’Neil BJ, Peberdy MA, Rittenberger JC, Rodriguez AJ, Sawyer KN, Berg KM. Part 3: Adult Basic and Advanced Life Support: 2020 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Circulation. 2020;142(16 2):S366-S468. doi:10.1161/CIR.0000000000000916.

8. Castren M, Perkins G, Kudenchuk P, Mancini MB, Avis B, Brooks S, Chung S, Considine J, Hatanaka T, Nishiyama C, Ristagno G, Semeraro F, Smith C, Smyth M, Morley P, Olasveengen TM. Resuscitation care for suspected opioid-associated emergencies Consensus on Science with Treatment Recommendations. International Liaison Committee on Resuscitation (ILCOR) Basic Life Support Task Force. https://costr.ilcor.org/docume.... Published February 11, 2020. Accessed October 13, 2024.

9. Mok V, Brebner C, Yap J, Asamoah-Boaheng M, Hutton J, Haines M, Scheuermeyer F, Kawano T, Christenson J, Grunau B. Non-prescription drug-associated out-of-hospital cardiac arrest: Changes in incidence over time and the odds of receiving resuscitation. Resuscitation. 2024;195:110107. doi:10.1016/j.resuscitation.2023.110107.

10. Yogeswaran V, Drucker C, Kume K, Poel A, Yarid N, Leyde S, Rea TD, Chatterjee NA. Presentation and Outcomes of Adults With Overdose-Related Out-of-Hospital Cardiac Arrest. JAMA Netw Open. 2023;6(11):e2341921. doi:10.1001/jamanetworkopen.2023.41921.

11. Dezfulian C, Orkin AM, Maron BA, Elmer J, Girotra S, Gladwin MT, Merchant RM, Panchal AR, Perman SM, Starks MA, van Diepen S, Lavonas EJ. Opioid-Associated Out-of-Hospital Cardiac Arrest: Distinctive Clinical Features and Implications for Health Care and Public Responses: A Scientific Statement From the American Heart Association. Circulation. 2021;143(16). doi:10.1161/CIR.0000000000000958.

12. Wang Y, Gao L, Meng L. Small-dose naloxone combined with epinephrine improves the resuscitation of cardiopulmonary arrest. Am J Emerg Med. 2008;26(8):898-901. doi:10.1016/j.ajem.2008.04.017.

13. Chen M ‐H., Xie L, Liu T ‐W., Song F ‐Q., He T. Naloxone and epinephrine are equally effective for cardiopulmonary resuscitation in a rat asphyxia model. Acta Anaesthesiol Scand. 2006;50(9):1125-1130. doi:10.1111/j.1399-6576.2006.01141.x.

14. Wang Y, Gao L, Meng L. Naloxone Combined with Epinephrine Decreases Cerebral Injury in Cardiopulmonary Resuscitation. J Emerg Med. 2010;39(3):296-300. doi:10.1016/j.jemermed.2008.10.014.

15. Islam MR, Yang L, Lee YS, Hruby VJ, Karamyan VT, Abbruscato TJ. Enkephalin-Fentanyl Multifunctional Opioids as Potential Neuroprotectants for Ischemic Stroke Treatment. Curr Pharm Des. 2016;22(42):6459-6468. doi:10.2174/1381612822666160720170124.

16. Chao D, Donnelly DF, Feng Y, Bazzy-Asaad A, Xia Y. Cortical δ-Opioid Receptors Potentiate K ⁺ Homeostasis During Anoxia and Oxygen–Glucose Deprivation. Journal of Cerebral Blood Flow & Metabolism. 2007;27(2):356-368. doi:10.1038/sj.jcbfm.9600352.

17. Shekhar AC, Nathanson BH, Mader TJ, Coute RA. Cardiac Arrest Following Drug Overdose in the United States: An Analysis of the Cardiac Arrest Registry to Enhance Survival. J Am Heart Assoc. 2024;13(3). doi:10.1161/JAHA.123.031245.

18. Koller AC, Salcido DD, Callaway CW, Menegazzi JJ. Resuscitation characteristics and outcomes in suspected drug overdose-related out-of-hospital cardiac arrest. Resuscitation. 2014;85(10):1375-1379. doi:10.1016/j.resuscitation.2014.05.036.

19. Yogeswaran V, Drucker C, Kume K, Poel A, Yarid N, Leyde S, Rea TD, Chatterjee NA. Presentation and Outcomes of Adults With Overdose-Related Out-of-Hospital Cardiac Arrest. JAMA Netw Open. 2023;6(11):e2341921. doi:10.1001/jamanetworkopen.2023.41921.

20. Andersen LW, Grossestreuer A V, Donnino MW. “Resuscitation time bias”-A unique challenge for observational cardiac arrest research. Resuscitation. 2018;125:79-82. doi:10.1016/j.resuscitation.2018.02.006.