The correct answer is:

As long as the patient is in cardio-respiratory arrest, standard resuscitation alone is indicated; naloxone is unlikely to be beneficial and may do harm.

Key Point:

In their March 2021 scientific statement on opioid-associated out-of-hospital cardiac-arrest (OA-OHCA), the AHA states: 

If the patient with OA-OHCA is definitely pulseless and receiving standard resuscitation, including assisted ventilation, naloxone is unlikely to be beneficial. Because there is a theoretical basis for harm, standard resuscitation alone is indicated.

Explanation:

Interestingly, only the recommendations in the accompanying text have changed; the AHA flow-charts for OA-OHCA have remained the same.

OA-OHCA flowchart from the March 2021 AHA scientific statement (arrows added for emphasis):

OA-OHCA flowcharts from the current online AHA guideline:

In both sources (current online AHA ACLS algorithms and current AHA scientific statement),the flowcharts mention naloxone as follows:

Layperson: 

1. Give naloxone if opioid-related overdose is suspected and the person is not breathing normally (assuming presence of naloxone kit).

2. Consider naloxone if opioid-related overdose is suspected in a patient with altered mental status and normal respirations. More specifically, the flowchart states to prevent deterioration by taping and shouting, repositioning, considering naloxone, and continuously observing until EMS arrives.

Health Care Professional: 

1. Give naloxone if opioid-related overdose is suspected in a patient with inadequate respirations and with pulse.

2. Consider naloxone if opioid-related overdose is suspected in a patient with altered mental status and with normal respirations. More specifically, the flowchart states to prevent deterioration by taping and shouting, opening the airway, and considering naloxone. 

3. Consider naloxone if opioid-related overdose is suspected in a patient with cardiorespiratory arrest. More specifically, the flowchart states to start CPR, use AED, consider naloxone, refer to BLS/ALS protocols.

However, the naloxone recommendations in the accompanying text diverge in a subtle but clinically important way:

March 2021 AHA Scientific Statement: 

If the patient is definitely pulseless and receiving standard resuscitation, including assisted ventilation, naloxone is unlikely to be beneficial. Because there is a theoretical basis for harm, standard resuscitation alone is indicated.

AHA Online 2021 ACLS Recommendation: 

For patients known or suspected to be in cardiac arrest, in the absence of a proven benefit from the use of naloxone, standard resuscitative measures should take priority over naloxone administration, with a focus on high-quality CPR (compressions plus ventilation”).

Why is this Subtle Change Clinically Important?

Ongoing research has established that the typical OA-OHCA with its characteristic hypoventilation is more similar to a drowning event (hypoxia precedes/causes cardiac arrest) than a sudden cardiac arrest due to arrhythmia (cardiac arrest occurs in non-hypoxic person). The important difference lies in the fact that in cardiac arrest induced by hypoxia, the brain experiences an increasingly hypoxic environment with continued blood flow and therefore also continued glucose supply. This situation causes ongoing, increasingly anaerobic brain metabolism, which renders the brain of patients with OA-OHCA significantly more acidotic (down to a pH of 6.0) and challenged by severe oxidative stress than the brain of patients experiencing sudden cardiac arrest with both glucose and oxygen supply ceasing at the same time. Opioids appear to be brain-protective from the increased free-radical stress in the severely acidotic brains of pulseless patients with OA-OHCA, which is why naloxone is not recommended in these situations. However, naloxone is recommended for preventing deterioration prior to cardiac arrest or re-deterioration after successful resuscitation from OA-OHCA.

Since lay people are not expected to differentiate a person with respiratory arrest with versus without a pulse, a lay person is always recommended to give naloxone to an unresponsive person with suspected opioid overdose and abnormal breathing.

Pearl: Methadone-induced cardiac arrest tends to be secondary QT prolongation-induced arrhythmias and therefore mimics a regular cardiac arrest (presenting as Torsades de Pointes or other form of ventricular fibrillation) rather than a hypoxia-induced cardiac arrest (which tends to present with asystole or pulseless electrical activity).

Following is a list of all recommendations in the March 2021 Scientific Statement:

List ALL Recommendations from AHA Scientific Statement of OA-OHCA:

1. The incidence of opioid-associated out-of-hospital cardiac arrest (OA-OHCA) is often underestimated because of limitations in prehospital registries and shows significant geographic variation. More than half of EMS-assessed OA-OHCA cases may not be recognized as OA or may not be counted in EMS databases because resuscitation was not attempted.

2. Different opioids bind to μ-opioid receptors with vastly differing potencies and cause analgesia, euphoria, and respiratory depression to different degrees; for this reason, the risk of OA-OHCA varies between opioids. Some opioids, particularly methadone, cause dysrhythmias. Opioid antagonists reverse respiratory depression but can precipitate withdrawal; while not directly lethal, withdrawal has important negative effects. Most OA-OHCA involves concomitant use of multiple sedatives. 

3. Long-term use of opioids, particularly when injected, can cause brain injury through hypoxemia, infection, inflammation, or embolism. Opioids may be neuroprotective after brain anoxia or ischemia/reperfusion. There is a theoretical reason to suspect harm from precipitating opioid withdrawal in the ischemic brain, but no human data demonstrate this effect. 

4. Methadone can prolong the QT and predispose to sudden cardiac death. Endocarditis rates are increasing in pace with the opioid epidemic. δ-Opioid receptor agonism protects the heart against ischemic damage in animal models. Some causes of OA-OHCA are not reversible with opioid antagonists and require other therapy. 

5. Long-term opioid use can cause or exacerbate pulmonary hypertension by direct and indirect mechanisms. 

6. OA-OHCA may be complicated by aspiration of gastric contents, noncardiogenic pulmonary edema, and rhabdomyolysis. Rapid opioid reversal can precipitate pulmonary edema and gastric aspiration. 

7. Fundamental differences exist between anoxic perfusion in OA-OHCA and sudden ischemia produced by cardiac causes of OHCA. Anoxic perfusion causes more severe brain injury during ischemia and reperfusion. 

8. Prehospital response to OA-OHCA is shaped by the training of the rescuer(s), which defines their roles (Tables 3 and 4) and ability to intervene (Figure 5). Optimizing outcomes after OA-OHCA requires appropriate training for those individuals likely to encounter individuals with opioid poisoning. 

9. First responders should presume OA-OHCA when individuals with suspected opioid poisoning do not respond to basic interventions and activate EMS while performing CPR. 

10. OA-OHCA requires attention to airway management and breathing, which are difficult skills to learn and retain. EMS professionals should select an airway device for OA-OHCA on a case-by-case basis, taking into consideration local standards, clinical context, and the provider training. 

11. Rescue breaths in addition to high-quality chest compressions (conventional CPR) are likely preferable in resuscitation of individuals with OA-OHCA. Conventional CPR requires adequate training and willingness on the part of the trained layperson. 

12. If the patient is definitely pulseless and receiving standard resuscitation, including assisted ventilation, naloxone is unlikely to be beneficial. Because there is a theoretical basis for harm, standard resuscitation alone is indicated. Opioid antagonism to prevent OA-OHCA in patients with OA central nervous system and respiratory depression is always reasonable and should be delivered along with CPR when it is uncertain whether the patient is pulseless. Dose titration of naloxone for patients with central nervous system and respiratory depression may be required when potent synthetic opioids have been used, but over antagonism has potential adverse events. 

13. Although most data support safety when individuals reversed from severe respiratory depression caused by opioid poisoning refuse EMS transport, this should be viewed with caution given increasingly common polypharmacy and long-acting opioids. Individuals with OA-OHCA requiring CPR should be transported to the hospital. 

14. Current guidelines support consideration of TTM use in patients with nonshockable initial rhythms, and there is no evidence to suggest harm in patients after OA-OHCA. 

15. Clinicians treating patients with OA-OHCA with shock should use a systematic approach to identify causes of shock. Reasonable initial resuscitation may include crystalloid to correct hypovolemia and norepinephrine to correct hypotension. 

16. ICUs that care for OA-OHCA should use validated sedation and pain assessment to titrate therapy to individual needs. 

17. Given the potential for delayed clearance of intoxicants after OA-OHCA, a stepwise approach to prognostication in most cases should delay decisions about withdrawal of life-sustaining therapy until (1) at least 72 hours after ROSC and normothermia, (2) initial intoxicants and their metabolites have cleared, and (3) ICU-administered sedatives and analgesics have cleared. 

18. We endorse existing critical care societal guide- lines intended to reduce complications such as ventilator-associated pneumonia, central line infection, delirium, enteral nutrition, and venous thrombosis in the management of patients with OA-OHCA.303,316,335,337,344–346 Patients with opioid use disorder (OUD) are more likely to have certain infections. 

19. OUD often results in overdose and OA-OHCA. Secondary prevention such as medications for opioid use disorder (MOUD), take-home-naloxone (THN), counseling, religious and spiritual services, and basic life support training to patients or family members and subsequent inpatient or outpatient therapy should be considered as part of discharge planning. 

20. Rescue breathing is challenging to teach and implement broadly. It is sensible to target the significant time and resources required to teach conventional CPR to those portions of the population most likely to attend to OA-OHCA (Table 5).

21. Telemetry-CPR (T-CPR) instructions to provide compression-only CPR in OHCA have strong support. The ability of dispatchers to correctly identify opioid poisoning is an area where improvement is possible. Such recognition could permit targeted instructions to administer naloxone or perform conventional CPR as appropriate. 

22. Improving public access to naloxone saves lives by preventing OA-OHCA, yet important questions remain on how to optimize strategies. 

23. Local and national efforts are underway to improve naloxone awareness among providers, high-risk patients, and the public. 

References:

Dezfulian C, et al.  American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation; Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Council on Clinical Cardiology. 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 Mar 8:CIR0000000000000958. doi: 10.1161/CIR.0000000000000958. Epub ahead of print. PMID: 33682423

American Heart Association. Web-based Integrated Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 3: Adult Basic and Advanced Life Support. (accessed on April 10, 2021)