Overdose-related cardiac arrest has dramatically risen in recent years, due primarily to the rise in the opioid epidemic. In 2000, the Joint Commission issued a statement establishing pain measurers as a required element of each hospital visit, introducing the concept of pain as the fifth vital sign . This prioritization of categorizing pain, coupled with recent literature supporting the use of novel opioids in treating noncancer-based pain due to the perception that there was a reduced risk of tolerance/misuse and dependence brought about the rise in opioid-related overdose deaths secondary to prescribed opioids. Shortly thereafter, in 2010, heroin use made a rapid increase resulting in second peak in opioid related deaths. The introduction of synthetic opioids, such as fentanyl in 2013 brought about a significant peak in overdose related death. Finally, in 2023 overdose related deaths peaked due to the inclusion of synthetic opioids as primary drugs of misuse and adulterants in the drug supply resulted in maximal incidence of death. Fortunately, 2024 has projected declines in overdose related deaths.

Per the Centers for Disease Control and Prevention (CDC) National Vital Statistics System, drug-related death incidence in the United States is decelerating as of 2024. Provisional data, which includes reported counts and predictive modeling from counties available at the time of analysis, indicates a reduction in drug overdose-related fatalities. As of October 2024, recorded overdose deaths were 82,020, closely aligned with the predicted figure of 84,076, reflecting a 25.5% decrease compared to October 2023, when there were 109,703 recorded (112,910 predicted) deaths. This current rate is comparable to the figures recorded in May 2020, early in both the coronavirus disease 2019 (COVID-19) pandemic and the initial emergence of fentanyl as a prevalent adulterant in the illicit drug supply. Despite the overall decline, fentanyl-laced substances continue to significantly contribute to overdose mortality, reflecting ongoing challenges in public awareness and substance identification.

While national overdose rates have decreased, notable regional disparities persist. States including North Carolina, Virginia, Delaware, Michigan, New Hampshire, West Virginia, South Carolina, Ohio, New Jersey, Wisconsin, and Pennsylvania have all experienced provisional declines in overdose deaths exceeding 30%. Conversely, states such as Utah, Nevada, and Alaska have recorded concerning increases in overdose deaths, reporting rises of 6.7%, 7.8%, and 16.4%, respectively.

Demographic analysis also highlights disparities in overdose mortality. In 2023, CDC’s State Unintentional Drug Overdose Reporting System (SUDORS) data indicated a substantial gender disparity, with males representing 71.6% of overdose deaths, compared to 28.4% in females. Additionally, while non-Hispanic white individuals continue to represent most drug-related fatalities, overdose death rates among Black and Hispanic populations have risen significantly since 2020, identifying these demographics as increasingly vulnerable.

While national data on drug overdose deaths are readily available, capturing the true incidence of OD-OHCA has been difficult. Previous studies have demonstrated that clinical bedside estimations regarding the etiology of cardiac arrest are often unreliable, with subsequent autopsy data frequently identifying overdose as the true cause, even when a different initial etiology was presumed. Consequently, OD-OHCA may be significantly underreported within cardiac arrest registries.

Registries such as the Cardiac Arrest Registry to Enhance Survival (CARES) and the Resuscitation Outcomes Consortium, 2 extensive databases dedicated to OHCA outcomes, identify cases of overdose-related cardiac arrest based on criteria including positive toxicology screens at hospital admission, documented presence of drug paraphernalia, empty medication containers, tourniquet application, or clear historical evidence of active substance use. Observable scene evidence and hospital-based toxicologic confirmation presents inherent limitations. Specifically, overdose-related cases may be inadvertently misclassified or omitted entirely if toxicology tests are not performed systematically or if crucial evidence at the scene is overlooked or undocumented. Thus, there is considerable risk of underreporting and misclassification, complicating efforts to understand the full impact of OD-OHCA events.

Despite these challenges, investigations have sought to establish OD-OHCA incidence trends. Research from the University of California San Francisco revealed an increase in the proportion of OHCA attributed to overdoses from 1% in 2015 to 17.6% in 2023 ( P -value for trend = 0.0001), correlating with a 30% annual increase in OHCA treated by emergency medical services (EMS) over the same period. Similar trends were observed in the CARES registry, where an analysis of 367,573 OHCA incidents with EMS resuscitation attempts identified 29,500 (8.0%) as OD-OHCA. The annual incidence significantly increased from 14.0% in 2017 to 28.4% in 2021.

Demographically, the OD-OHCA population differs markedly from the general OHCA cohort. Individuals experiencing OD-OHCA tend to be significantly younger in age, have fewer comorbidities and are less likely to experience witnessed arrests or receive bystander-initiated resuscitative efforts. ^, A recent descriptive study from CARES found that overdose OD-OHCA patients were younger in age (OD: 39.0±12.6 year old vs non-OD: 63.6±16.3 year old, P <.001), reported significantly fewer comorbidities, were much less likely to experience a witnessed arrest (OD: 21.7% vs non-OD: 46.1%, P <.001), and had lower rates of shockable initial arrest rhythms (OD: 5.1% vs non-OD: 20.9%, P <.001).

While some OD-OHCA events result from a single agent, most involve polysubstances, including those unknowingly consumed. According to 2023 data from SUDORS, opioids were involved in approximately 81.4% of overdose deaths, with illegally manufactured fentanyl (IMF) alone accounting for 75.2%. Five substance combinations were most frequently implicated, contributing to 73.5% of all deaths:

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  IMF alone (25.0%)

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  IMF with cocaine (19.2%)

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  IMF with methamphetamine (15.1%)

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  Methamphetamine alone (8.5%)

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  Cocaine alone (5.7%)

Over time, trends show a sharp increase in fentanyl-related deaths since the onset of the COVID-19 pandemic, alongside a notable decline in heroin involvement. The rise in fentanyl-stimulant couse, particularly with cocaine and methamphetamine, has contributed significantly to recent overdose deaths.

The predominant mechanism by which opioid overdose leads to cardiac arrest is central respiratory depression , typically culminating in pulseless electrical activity (PEA) or asystole . This occurs through activation of mu-opioid receptors, a subtype of G protein-coupled receptors, within critical respiratory centers in the brainstem, particularly the pre-Bötzinger complex in the medulla and the Kölliker-Fuse nucleus in the pons. The resulting decrease in respiratory rate, tidal volume, and ventilatory response to hypoxia and hypercapnia ultimately leads to hypoxic respiratory arrest. Compared to natural opioids (eg, morphine and heroin), synthetic opioids such as fentanyl and its analogs exhibit significantly higher potency and rapid onset of action, resulting in faster and more profound respiratory suppression. This contributes to a higher risk of sudden and severe hypoxemia, even with small doses. ^,

An additional opioid-induced mechanism, Wooden Chest Syndrome , (WCS) is characterized by rapid laryngospasm, and muscle rigidity of the chest wall and diaphragm after fentanyl (and other synthetic opioids) ingestion results in rapid hypoventilation and hypoxemia. Unlike classic respiratory depression, WCS involves nonopioid pathways, including activation of vagal C-fibers , noradrenergic and cholinergic receptors. The incidence of WCS in OA-OHCA is unknown; however, muscle rigidity was noted to be the most common atypical presentation of an overdose in a single-center retrospective cohort study.

The increasing prevalence of opioid-stimulant combination overdoses adds complexity to the pathophysiology of overdose-related cardiac arrest. Between 2010 and 2021, the proportion of overdose deaths involving both fentanyl and stimulants (such as cocaine or methamphetamine) rose from 0.6% to 32.3%. Stimulants exert adrenergic, dopaminergic, and serotonergic effects–including tachycardia, hypertension, agitation, and hyperthermia, which may initially mask signs of opioid-induced respiratory depression. Animal studies suggest a dose-dependent interaction between fentanyl and amphetamines, in which low-dose stimulants exacerbate respiratory suppression, while higher doses may paradoxically reverse it. Further, opioid-stimulant combination overdoses appear to have increased mortality risk. Clinically, opioid-stimulant overdoses are associated with higher fatality rates and lower effectiveness of naloxone. Patients with combined opioid-stimulant OHCA demonstrate lower survival to hospital discharge compared to those with opioid-only OHCA (10% vs 22%). Additionally, naloxone administration was less frequent and less effective in opioid-stimulant overdoses, contributing to higher fatality rates.

Several additional substances, commonly coingested with opioids, exacerbate the risk of overdose-induced cardiac arrest.

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  Alcohol intensifies respiratory depression through multiple mechanisms, including A2A receptor agonism, GABA_A receptor potentiation, and NMDA receptor inhibition. ^, Alcohol is implicated in over 22% of opioid pain relief-related deaths.

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  Benzodiazepines potentiate GABA_A receptor activity leading to Central Nervous System and respiratory depression. Among US veterans prescribed opioids, 27% were also prescribed benzodiazepines and found to have a 4 times higher risk of overdose death.

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  Xylazine, a veterinary sedative, and α-2 adrenergic agonist has been identified in 23% of seized fentanyl powder. The α-2 adrenergic effects of xylazine sedation, analgesia, muscle relaxation, respiratory depression, and hypotension. Among Philadelphia, Maryland, and Connecticut, a 2023 study showed that xylazine was present in 25.8%, 19.3%, and 10.2% of overdose deaths, respectively.

OA-OHCA differs from non-OA OHCA in both etiology and clinical presentation. In contrast to arrests due to acute coronary syndromes or arrhythmias, OA-OHCA is primarily asphyxial, caused by hypoxia from respiratory depression. These arrests are more likely to present with nonshockable rhythms, such as PEA or asystole, rather than ventricular fibrillation or pulseless ventricular tachycardia. ^, OA-OHCA cases often involve longer no-flow intervals, attributed to delayed recognition of arrest. The resulting cerebral hypoxia and global ischemia increase the risk of oxidative stress and early neurologic injury, and are more likely to develop severe cerebral edema, and brain death. Electroencephalogram (EEG) monitoring in these patients frequently reveals generalized periodic discharges and electrographic seizures, reflecting a more severe neurologic insult compared to primary cardiac causes of arrest.

Timely recognition of opioid overdose is critical. Because effective reversal measures are available, early intervention can prevent progression to cardiac arrest. Informal practices such as spotting , where individuals observe others using drugs and respond if an overdose occurs, can be employed to prevent progression to cardiac arrest. Smartphone-based overdose detection apps have contributed to successful reversals in nearly 96% of overdose events and often preceded EMS arrival by more than 5 minutes.

Distinguishing respiratory depression from sleep or agonal breathing is challenging for untrained bystanders. If a person is unresponsive to verbal or painful stimuli, cardiac arrest should be presumed and EMS activated immediately. Good Samaritan laws, legal protection for those who willingly and in good faith provide emergency aid, play a crucial role in encouraging layperson intervention during emergencies. ^,, These laws provide legal protection for layperson intervention in overdose in 41 states. States with this additional legal protection have a 15% lower incidence of opioid overdose mortality. Increasing awareness and trust in these legal protections remains a public health priority. ^,,,,,

Naloxone, a mu-opioid antagonist, displaces opioids, may reverse respiratory depression, and may prevent OA-OHCA. While naloxone was initially only used by health care workers and EMS clinicians, its use has expanded in the community as harm reduction efforts have focused on making naloxone more accessible, equipping laypersons and first responders like law enforcement. ^,, For the layperson, preventing OA-OHCA and restoring spontaneous breathing is the goal. Lay people can provide 2 mg intranasal or intramuscular naloxone. For those patients who are revived from opioid overdose with naloxone, paramedic-initiated buprenorphine is an emerging therapy that has been shown to be safe. ^,

If a patient deteriorates to OA-OHCA, high-quality resuscitation of OHCA with layperson cardiopulmonary resuscitation (CPR) and AED use should be initiated. Unlike OHCA associated with cardiac etiologies, OA-OHCA results from respiratory failure and may involve airway obstruction, making rescue breathing a critical adjunct for trained responders. Basic airway maneuvers, such as jaw thrust or head-tilt chin-lift, followed by mouth-to-mouth ventilation or use of barrier devices and visualization of good chest rise, can enhance oxygenation during resuscitation. ^, Rescue breathing should be emphasized in layperson education alongside chest compressions, especially among populations at high risk for opioid overdose.

EMS providers play a central role in either reversing opioid toxicity before arrest or managing resuscitation once arrest has occurred. For patients with respiratory depression but intact pulses, naloxone and assisted ventilation remain first-line interventions. Advanced airway management, via bag-valve-mask (BVM) ventilation, supraglottic airways, or endotracheal intubation, may be required depending on patient status and provider expertise.

While no studies have directly evaluated the efficacy of supraglottic airways compared to endotracheal intubation in OA-OHCA, 3 recent randomized controlled trials that sought to address the use of airway management during OHCA suggest that outcomes are similar between patients in OHCA where a supraglottic airway was used compared to an endotracheal intubation. ^,, An airway device should be selected based on local standards and EMS clinician skill level for patients in OA-OHCA. Given high failure rates of intubation in OHCA (up to 44%), proficiency in BVM ventilation remains foundational. ^,

If layperson are not available to provide naloxone or their provision of naloxone is ineffective, EMS clinicians may escalate doses of naloxone to prevent OA-OHCA. If the patient has progressed to cardiac arrest, standard high-quality CPR should be initiated. While naloxone may still be administered, it should not delay or distract from core resuscitative efforts (eg, CPR, basic life support, advanced cardiac life support) as its impact on OA-OHCA outcomes is uncertain. Recent retrospective evidence suggests potential benefit from naloxone if given early, particularly before vascular access attempts, but further prospective data are needed. Wang and colleagues and Dillon and colleagues found that provision of naloxone in OA-OHCA increased survival to hospital discharge (odds ratio [OR], 2.48; 95% confidence interval [CI] [1.34–4.58]). ^, Another study found that patients with an OHCA and an initial nonshockable rhythm who were given naloxone before attempting vascular access attempts were more likely to survive hospital discharge (OR, 4.41; 95%CI [1.78–10.97]).

Postresuscitation care begins in the field. Patients who respond to naloxone without requiring CPR represent a critical opportunity for secondary prevention. EMS clinicians should consider initiating harm reduction strategies including.

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  Distribution of take-home naloxone kits

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  Referral to addiction treatment programs

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  Counseling on high-potency opioid risks (eg, fentanyl and xylazine)

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  Initiating buprenorphine in the field, an option post naloxone rescue for those with Clinical Opiate Withdrawal Scale score of 5 or more, and no reported methadone use for 5 days. Published observational studies have shown this practice to be feasible and safe.

Patients with capacity can refuse ambulance transportation to the hospital, a practice that has demonstrated safety, ^,,,, although EMS clinicians should monitor closely for recurrent hypoventilation and oxygenation via continuous end-tidal CO2 and pulse oximetry monitoring and provide education before discharge. Notably, these studies occurred before the increased presence of highly potent opioids like fentanyl, which may change a patient’s response to naloxone treatment. If a patient refuses transport to the hospital, EMS clinicians should provide treatment resources, spanning from take-home naloxone to connecting patients to additional resources for harm reduction. Noting variability regarding transport timing, and unknown impact on OD-OHCA outcomes, on-scene resuscitation of patients with OHCA is associated with survival compared to intra-arrest transport, or transport of patients during their OHCA. ^,,

Targeted temperature management (TTM) aims to minimize neurologic damage caused by ischemia-reperfusion injury following cardiac arrest. OD-OHCA patients who are comatose should be considered for TTM, and maintain a temperature between 32°C and 36°C for at least 24 hours per current American Heart Association guidelines. Recent results from the TTM-2 trial have questioned the neuroprotective effects of TTM ; however, importantly, a strategy of fever prevention targeting 37.8 F was used as the control arm. Notably, patients with OD-OHCA were not included in this trial of temperature control, and it is unclear how the results of TTM2 translate to a noncardiac etiology of cardiac arrest. In retrospective studies, hyperthermia/fever is associated with worse neurologic outcomes. ^,,

Although data on TTM in OD-OHCA are limited, retrospective analyses suggest potential benefits. One study involving 121 OD-OHCA cases found that TTM was associated with increased odds of survival to hospital discharge (OR 11.3, 95% CI 2.8–46.3, P <.001), although neurologically intact survival did not significantly improve. Given the heightened risk of early cerebral hypoxia in opioid-related arrests, the role of TTM and fever prevention in improving neurologic recovery remains a key research area.

Monitoring for opioid withdrawal syndrome (OWS) is essential in the postarrest period, especially in patients who have received naloxone or have chronic opioid exposure. Common OWS features include increased arousal/agitation, tachycardia, hypertension, piloerection, yawning, nausea, vomiting, and diarrhea. Autonomic instability can also result in hypotension, which may confound the PCAS clinical picture. Although validated withdrawal scales are lacking in this population, a structured approach to sedation assessments (eg, Richmond Agitation-Sedation Scale) and clinical assessments may provide indirect markers given the interventions such as mechanical ventilation and sedation may complicate the clinical picture.

High sedation and/or analgesia requirements, perhaps in the setting of increased arousal/agitation, could be signs of withdrawal. ^, Features such as ventilator asynchrony (eg high peak-pressure alarms, inappropriate tidal volumes, and double triggering) may indicate OWS. Unique to naloxone reversal for opioid use is the development of acute pulmonary edema and hypoxemia. This responds well to positive pressure ventilation, and in the setting of mechanical ventilation may be reflected by high peak and plateau pressures in the context of worsening lung compliance.

OWS (and other withdrawal syndromes) can result in seizures, which in the context of postarrest neurologic insult has the potential to confound the overall clinical picture. A thorough assessment of substance use and likelihood of severe withdrawal should be weighed against the possibility of postcardiac arrest neurologic injury resulting in seizures. Regardless of etiology, if seizures are of concern–EEG monitoring should be implemented and treatment should be initiated with benzodiazepines, followed by other antiseizure medications (such as levetiracetam, phenytoin, valproate, propofol among others).

If physical or physiologic features suggest the patient is experiencing OWS, full opioid-agonists (eg, fentanyl and hydromorphone) can be administered for both treatment of withdrawal, as well as an analgosedation approach in mechanically ventilated patients. In addition to full opioid agonism, adjunctive treatments can be used such as benzodiazepines, α2-adrenergic agonists (clonidine, dexmedetomidine), and antiemetics (ondansetron). Ketamine can be considered for cases not responding to other treatments. ^, Caution should be applied when interpreting awakening and neurologic recovery in patients requiring additional treatments for OWS.

Given the rising prevalence of polysubstance overdose, multiple withdrawal syndromes may coexist, including alcohol and benzodiazepine withdrawal, which should be treated accordingly. Benzodiazepines and phenobarbital remain the mainstays of therapy in such cases.

Toxicology screening can aid in identifying coingestants but should be interpreted with caution due to limitations in assay sensitivity. False negatives are common with synthetic opioids and novel agents. One recent retrospective study found that urine drug screening was unreliable for predicting postmortem serum 6-acetylmorphine, benzodiazepines, fentanyl, and opiates. For general opioid and fentanyl detection, urine drug screen sensitivity can be as low as 66.7% and 57.5%, respectively. While toxicology screening tests may yield valuable insight, their results and interpretation should be approached with caution.

In the setting of coingestion with stimulants, patients should be closely monitored via telemetry for evidence of arrythmia. QTc and QRS abnormalities should be identified and Toxicology consultation considered for complex cases in which potential for sodium or potassium channel blockading effects occur. Electrolytes (eg, potassium and magnesium) should be monitored and repleted to minimize risk of arrythmia.

Medications for Opioid Use Disorder (MOUD, including methadone; a full mu-opioid agonist, buprenorphine; a partial mu-opioid agonist) are increasingly prescribed amidst the ongoing opioid epidemic. With intensive care unit (ICU) admissions associated with opioid overdoses increasing from 44 to 59 per 10,000 admissions over the past decade, many OA-OHCA patients may likely have an existing MOUD prescription. There are no guidelines and very limited evidence regarding MOUD during critical illness and close Addiction medicine consultation, if available, is recommended. In general, continuation of methadone and buprenorphine can be considered.

Despite notable differences in the demographic and arrest characteristics of OD and OA-OHCA patients versus those who experience cardiac arrest due to other causes, survival outcomes are often similar. While considering the misclassification concerns, multiple prior studies have examined survival to hospital discharge as well as survival with good neurologic recovery.

A 2019 meta-analysis of 12 studies reported improved survival to discharge among OD-OHCA patients (pooled OR 2.2, 95% CI: 1.7–2.7; I ² = 0%; P =.45). However, outcomes varied across studies depending on geographic region and evolving drug use patterns. For instance, an analysis of King County, Washington EMS data found no difference in unadjusted survival rates between OD-OHCA and non-OD-OHCA patients (20% [138 of 702] vs 18% [1095 of 6088]). Yet, in adjusted analyses stratified by drug profile, survival differed significantly. Patients with combined opioid-stimulant arrests had the lowest survival to discharge (10% [21 of 205]) compared to those with stimulant-only OHCA (22% [29 of 129]) or OHCA due to other substances (26% [19 of 73]). In a statewide study from Arizona, the survival to hospital discharge for OD-OHCA was 18.6%, compared to 11.9% ( P <.0001) for cardiac etiology arrests. The adjusted odds ratio for survival in OA-OHCA was 2.1.

Another observational study reported unadjusted survival rates of 20% for OD-OHCA versus 18% for nonoverdose OHCA, although patients with combined opioid-stimulant OHCA had notably lower survival (10%). Further insights from the CARES registry demonstrated that among patients with shockable initial rhythms, rates of good neurologic recovery, defined as a Cerebral Performance Category of 1 or 2, were similar between overdose and nonoverdose OHCA cases. However, for those with nonshockable initial rhythms, OD-OHCA patients experienced significantly better neurologic recovery (OD: 9.6% vs non-OD: 3.1%, P <.001).

Neurologic prognostication should not be performed prematurely. Current guidelines recommend delaying prognostic assessments until at least 72 hours after ROSC or normothermia, noting that initially, comatose patients may regain consciousness after this period. This delay allows for clearance of sedative agents, resolution of confounding metabolic disturbances, and a more reliable clinical examination.

It is unknown if, and/or to what extent, OD-OCHA may have delayed awakening compared to non-OD-OHCA. However, several factors may contribute to prolonged unconsciousness beyond typical timelines.

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  Residual effects of long-acting opioids or high-potency agents such as fentanyl and its analogs.

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  Coingestants like benzodiazepines, alcohol, or xylazine, which may exert synergistic or cumulative central nervous system depression.

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  Hepatic or renal impairment, which slows drug metabolism and clearance.

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  Sedative accumulation from in-hospital interventions or prearrest exposures.

These overlapping factors can mask neurologic recovery potential and increase the risk of misclassifying patients as neurologically devastated. While specific data on time to awakening in OD-OHCA is limited, clinical experience and pharmacologic reasoning suggest that delayed recovery of consciousness is not uncommon and does not necessarily portend a poor outcome.

Clinicians should remain vigilant against prematurely withdrawing life-sustaining therapy in this population. Serial neurologic examinations, multimodal neuroprognostication tools (eg, EEG, pupillometry, and somatosensory evoked potentials), and a structured, time-based approach remain critical to guiding decisions.