Does the Injection Site Matter During CPR? A Systematic Review and Meta-Analysis of Drug Pharmacokinetics and Pharmacodynamics

Abstract

Background: Cardiac arrest is a time-critical medical emergency during which prompt and effective drug delivery plays a key role in patient outcomes. Current resuscitation guidelines recommend intravenous (IV) access as the first-line route, with intraosseous (IO) access recommended as an alternative when IV access is delayed or not feasible. Although the endotracheal (ET) route was previously included in resuscitation protocols, it is no longer recommended. This study aims to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) effects of resuscitation drugs administered through different injection sites and under varying hemodynamic conditions in in vivo animal models. Methods: PubMed, CENTRAL and ClinicalTrials.gov were searched up to August 2025 for studies comparing different injection sites for the same drug (adrenaline/epinephrine, amiodarone, lidocaine and vasopressin) during CPR. Study selection, data extraction, and quality assessments were performed independently by two reviewers. Frequentist random-effects models were used to calculate mean differences and odds ratios (ORs) with 95% confidence intervals (CIs). Results: Fourteen prospective experimental studies (sample sizes ranging from 15 to 49 animals) conducted on swine were included. For epinephrine under normovolemia, humeral IO (HIO) access achieved significantly higher maximum concentrations (C_max; p = 0.0238) and a shorter time to the maximum concentration (T_max; p < 0.01) compared to IV, translating into faster return of spontaneous circulation (ROSC) (p = 0.0681). Under hypovolemia, IV access proved superiority over IO for epinephrine administration (MD = +382.80 ng/mL; p = 0.0022). The time to ROSC was significantly shorter with sternal IO (SIO) compared to tibial IO (TIO) (p = 0.0109). For amiodarone and vasopressin, no consistent or statistically significant differences were observed between administration routes, and in several cases, the findings were based on a single study. Conclusions: The injection site significantly influences the PK and PD of epinephrine during cardiac arrest. Proximal IO routes may offer advantages under normovolemic conditions, while IV access appears superior in cases of hypovolemic shock. Further research is needed to guide optimal drug delivery in varying hemodynamic conditions during cardiac arrest.

Keywords: cardiac arrest; cardiopulmonary resuscitation; injection site; meta-analysis; pharmacodynamics; pharmacokinetics; resuscitation drugs.

Figure 1

Flow diagram of the study (PRISMA flowchart).

Figure 2

Forest plots of pharmacokinetic parameters during CPR with epinephrine, amiodarone and vasopressin under normovolemic and hypovolemic conditions. Panels (a,b) show pooled mean difference in C_max and panels (c,d) present pooled mean difference in T_max. References appearing in the figure: [16,18,21,25,27,29,31,33,34].

Figure 3

Forest plots of pharmacodynamic outcomes during CPR with epinephrine, amiodarone and vasopressin under normovolemic and hypovolemic conditions. Panels (a,b) present the probability of ROSC and panels (c,d) illustrate time to ROSC. References appearing in the figure: [16,18,21,26,27,28,30,31,33,34].