Naloxone administration by emergency medical services may be associated with improved rates of return of spontaneous circulation and survival to hospital discharge in patients who experienced out-of-hospital cardiac arrests, according to a large retrospective cohort study.

In the study, published in JAMA Network Open, investigators included 8,195 patients who experienced out-of-hospital cardiac arrests (OHCA) treated in three Northern California counties between 2015 and 2023.

The investigators found that naloxone administration was associated with an 11.8–percentage point absolute increase in return of spontaneous circulation (ROSC) and a 3.9–percentage point absolute increase in survival to hospital discharge. This translated to a number needed to treat (NNT) of 9 for ROSC and 26 for survival to hospital discharge.

The investigators used propensity score-based models to analyze the data from emergency medical services (EMS)-treated patients aged 18 years or older who received treatment for nontraumatic OHCA. The primary outcome was survival to hospital discharge, with sustained ROSC as a secondary outcome.

Among the 8,195 patients (median age = 65 years, 67.6% male), 715 (8.7%) were believed by treating physicians to have drug-related OHCA. The study population included 1,304 Asian, Native Hawaiian, or Pacific Islander patients (15.9%), 1,119 Black patients (13.7%), 2,538 White patients (31.0%), and 663 Hispanic/Latino patients (8.1%). Naloxone was administered to 1,165 patients (14.2%).

Cardiac arrest characteristics revealed that 6,707 patients (81.8%) had nonshockable cardiac rhythms, while 1,488 (18.2%) had shockable rhythms. Witnessed cardiac arrests accounted for 4,481 cases (54.7%), with 3,714 cases (45.3%) being unwitnessed. Regarding location, 6,037 cardiac arrests (73.7%) occurred at home or in a living facility, 1,201 (14.7%) on the street, and 595 (7.3%) in public or commercial buildings.

Comorbidities were common among patients, with 1,323 (16.1%) having diabetes, 1,221 (14.9%) cardiovascular disease, 1,794 (21.9%) hypertension, and 505 (6.2%) respiratory disease.

EMS interventions included epinephrine administration in 7,124 patients (86.9%) and airway placement in the field for 1,969 patients (24.0%).

Using nearest neighbor propensity matching, naloxone was associated with increased ROSC (absolute risk difference [ARD] = 15.2%, 95% confidence interval [CI] = 9.9%–20.6%) and increased survival to hospital discharge (ARD = 6.2%, 95% CI = 2.3%–10.0%). Similar results were found using inverse propensity-weighted regression adjustment.

In the naloxone group, 34.5% of patients achieved ROSC compared with 22.9% in the non-naloxone group. Survival to hospital discharge was 15.9% in the naloxone group vs 9.7% in the non-naloxone group.

Risk ratios from inverse probability-weighted regression adjustment models showed:

• ROSC: risk ratio [RR] = 1.55 (95% CI = 1.36–1.77)
• Survival to hospital discharge: RR = 1.51 (95% CI = 1.22–1.87).

The treatment effect in the treated (ATET) analysis yielded even stronger associations:

• ROSC: ARD = 15.5% (95% CI = 11.7%–19.2%), RR = 1.80 (95% CI = 1.73–1.88)
• Survival to hospital discharge: ARD = 7.8% (95% CI = 5.1%–10.4%), RR = 1.89 (95% CI = 1.77–2.01).

In a regression model assessing effect modification between naloxone and presumed drug-related OHCA, naloxone was associated with improved survival to hospital discharge in both presumed drug-related OHCA (odds ratio [OR] = 2.48, 95% CI = 1.34–4.58) and non–drug-related OHCA groups (OR = 1.35, 95% CI = 1.04–1.77).

The investigators also found that patients with presumed drug-related OHCA (OR = 8.40, 95% CI = 6.93–10.10) and those with nonshockable cardiac rhythms (OR = 1.59, 95% CI = 1.30–1.96) had a higher risk of receiving naloxone. Conversely, older patient age and the presence of comorbidities (OR = 0.63, 95% CI = 0.53–0.76) were associated with a lower risk of receiving naloxone.

Adjusted logistic regression models revealed:

• Age 65 to 78 years: OR for ROSC = 1.30 (95% CI = 1.11–1.54), OR for survival = 0.79 (95% CI = 0.63–0.99)
• Age ≥ 79 years: OR for ROSC = 1.27 (95% CI = 1.07–1.51), OR for survival = 0.30 (95% CI = 0.23–0.41)
• Male sex: OR for ROSC = 0.81 (95% CI = 0.73–0.91)
• Nonshockable rhythm: OR for ROSC = 0.57 (95% CI = 0.50–0.65), OR for survival = 0.18 (95% CI = 0.15–0.21)
• Unwitnessed arrest: OR for ROSC = 0.47 (95% CI = 0.42–0.53), OR for survival = 0.36 (95% CI = 0.30–0.43).

The study involved multiple EMS agencies, with San Francisco Fire Department handling the most cases (4,028, 49.2%), followed by Sacramento City Fire Department (2,061, 25.2%), and Global Medical Response, Yolo (903, 11.0%).

Methodologically, the investigators employed propensity score–based nearest neighbor matching and inverse probability-weighted regression analysis techniques to account for potential biases and confounding factors. They also conducted additional analyses examining the average treatment effect on the treated group and included interaction terms in their models.

The study had several limitations, including its observational nature, which may have introduced potential for bias. The investigators were unable to differentiate routes of naloxone administration or account for naloxone administered by bystanders or non-EMS first responders. Additionally, the cohort was limited to a single area of the country, which may have limited generalizability.

Despite these limitations, the study represented one of the first large-scale evaluations of the association of naloxone with OHCA outcomes in clinical practice. The findings supported further evaluation of naloxone as a potential component of cardiac arrest care, particularly given the increasing incidence of opioid-associated OHCA in recent years.

The investigators concluded that additional work may be needed to examine the association between naloxone and OHCA outcomes, including prospective interventional studies of naloxone in cardiac arrest care.

One author reported receiving grants from the Substance Abuse and Mental Health Services Administration outside the submitted work. No other disclosures were reported.