Intramuscular epinephrine in cardiac arrest: A systematic review

Background: Epinephrine administered by intravenous (IV) or intraosseous (IO) route is the first-line medication for cardiac arrest and is associated with improved survival. Intramuscular (IM) epinephrine is currently not indicated for cardiac arrest but may be faster and easier to administer and may result in improved patient outcomes. Aim: To evaluate the evidence for IM epinephrine compared to IV or IO epinephrine in, and animals with cardiac arrest. Methods: This systematic review followed the PRISMA guidelines and was registered in PROSPERO (CRD42021259729). Databases were searched for studies comparing IV, IO, and IM epinephrine administration in cardiac arrest up to June 2, 2025. Studies in children, adults, and animals with cardiac arrest were included. Studies involving neonates and unpublished studies (such as conference abstracts and trial protocols) were excluded. Two investigators reviewed studies for relevance, extracted data and assessed bias of individual studies using the ROBINS-I and OHAT tools. Certainty of evidence was evaluated using GRADE methodology. Results: One observational adult out-of-hospital cardiac arrest (OHCA) study, five animal studies, and one narrative review were included. For all studies, the risk of bias was moderate and certainty of evidence was low. In the one human before-and-after study of 1405 adults with OHCA, IM epinephrine was associated with improved survival (11.0 % vs 7.0 %; aOR 1.73, 95 % CI 1.10-2.71) and neurologically favourable survival (9.8 % vs 6.2 %; aOR, 1.72, 95 % CI 1.07-2.76) compared to IV/IO epinephrine. Animal studies in both adults and children had heterogeneous methods and results were mixed. Conclusion: A limited number of studies have compared IM epinephrine to IV/IO or no epinephrine in cardiac arrest, including one human trial which showed improved neurological survival for IM epinephrine. Further studies, particularly randomized controlled trials in humans, to explore IM epinephrine for cardiac arrest are justified.