Editor’s note: Paramedics take a great deal of pride in their ability to perform complex resuscitations in the field; to bring hospital level care to wherever the patient may need it. But is your practice based in dogma or research? Watch the EMS1 on-demand webinar, Pharmacotherapy’s role in resuscitation, to learn about the strength of the evidence regarding commonly used drugs in resuscitation.
Top takeaways on IM epinephrine
- There is a growing body of evidence that the timing of epinephrine/adrenaline may influence outcomes in cardiac arrest. In the prehospital environment, the potential for IM administration may increase the numbers of responders who can administer adrenaline as well as decrease the time to administration.
- Pre-post studies represent a form of non-randomised experimental research that cannot reliably determine cause and effect.
- While this study is not rigorous enough to be conclusive, the study describes an absolute increase in survival to discharge of 4% and a 50% relative increase in survival with favourable neurological status. The possibilities of IM adrenaline are too exciting to ignore and will undoubtable be the subject of further research.
Research study: Palatinus HN, Johnson MA, Wang HE, Hoareau GL, Youngquist ST. Early intramuscular adrenaline administration is associated with improved survival from out-of-hospital cardiac arrest. Resuscitation. 2024 Jun 9;201:110266. doi: 10.1016/j.resuscitation.2024.110266.
The population. 1,405 adult, non-traumatic out of hospital cardiac arrest patients meeting the criteria for adrenaline use.
The intervention. The experimental group (420 patients) received adrenaline 5 mg, then usual care.
The comparator. The control group (985 patients) received usual care.
The outcome. The purpose was to conduct a before and after study early first dose adrenaline in adult OHCA. The primary outcomes was:
- Survival to hospital discharge
The secondary outcomes were:
- Time from EMS arrival to first dose of adrenaline
- Survival to hospital admission
- Favourable neurological function at discharge
Memorable quotes
“IM adrenaline was associated with improved survival to hospital admission, survival to discharge and functional survival.”
“… the study pooled subgroups and did not stratify based on initial rhythm, type of vascular access or bystander CPR.”
“Given the limitations … these results should be interpreted with caution.”
Results
IM adrenaline was associated with improved survival to discharge (11% vs 7%; aOR 1.73, 95% CI 1.10 – 2.71)
- Time to adrenaline was faster in IM cohort (median 4.3 [IQR 3.0-6.0] vs. 7.8 min [IQR 5.8 – 10.4])
- IM adrenaline was associated with improved survival to hospital (37.1% vs 31.6%; aOR 1.37, 95% CI 1.06 – 1.77).
- IM adrenaline was associated with improved frequency of favourable neurologic status (9.8% vs 6.2%; aOR 1.72, 95% CI 1.07 – 2.76)
IM epinephrine: Discussion
Adrenaline (epinephrine) has been a mainstay of pharmacological management of cardiac arrest for some time. Conceptually, vasoconstriction helps support perfusion (especially coronary perfusion) during CPR and promotes return of circulation. Recently, the early administration has been associated with improved ROSC rates.
The authors assumed that IM administration would be faster than IV or IO, and were testing if this impacted patient outcomes.
Interpreting the study is complicated by a number of factors. First, there were important difference in the study populations. The experimental group was younger by a mean of 3 years (56.5 vs. 59.5 years).
More importantly, there was a difference in bystander CPR rates, the experimental group having 69.8%, while the control group had only 56%. The authors reported an absolute increase in survival of 4% in the experimental group, leaving the question of whether the difference was a result of the adrenaline IM or to a nearly 14% increase in bystander CPR. In fact, the authors report a doubling in survival to hospital discharge with the presence of bystander CPR across both groups.
Furthermore, the study timelines also complicate interpretation of the results. The experimental group spanned the 5 years after 2019, meaning, that the COVID-19 pandemic occurred only during the experiment group. The authors address this issue, discussing the possible consequence of the pandemic and social distancing on bystander CPR rates. This seems somewhat contradictory in the face of increased CPR rates during the experimental period. The authors acknowledge the increase in deaths related to the pandemic, but are unable to account for how that may influence the survival rates.
Additionally, there have been many changes in resuscitation in the decade and a half since the beginning of the study, including:
- CPR feedback devices
- Mechanical CPR
- The introduction of modalities (e.g., vector change or double sequential defibrillation, which were not discussed in the study)
- ECMO
- Dispatch-assisted CPR (which changed how bystander CPR rates were captured)
The pre-intervention group was recruited between 2010 and 2019, while the post-intervention group was monitored from 2019 to 2024. This means the majority of the pre-intervention group were managed under 2010 or 2015 American Heart Association Emergency Cardiac Care (ECC) guidelines, while the majority of the post-intervention group was managed under 2020 guidelines.
The authors used a number of statistical techniques, including per protocol and intention to treat analysis, but the (relatively) low number of participants limited more nuanced analysis, so the influence of this remains unanswered.
| MORE: Reimagining Resuscitation - Epinephrine in the order of interventions
There are also questions surrounding the issue of drug dose and performance via the IM route. IM injections generally result in longer time to peak onset versus IV administration. It is possible that even with earlier administration of adrenaline via the IM route, that equivalent blood levels may not be reached earlier. However, to my knowledge, the adrenaline data regarding these differences comes from animal or neonatal models, which may not reflect its behaviour in adults or cardiac arrest states. Even the selection of 5 mg as a dose was based on the practical considerations involved with IM drug administration and not specific research. The author argue that this should be equivalent to 0.5 mg IV dose, which introduces the possibility that the benefit to patients may have come lower doses instead of earlier administration.
The study is important because of its potential. Despite real questions about the strength of the relationship between outcome and IM adrenaline, it represents a potentially new tool in prehospital cardiac arrest management that has real-world consequences. It bridges the gap between animal studies, hypothetical models and patient care.
If early IM adrenaline could improve survival, it opens up adrenaline to a whole group of responders who can’t start IVs. It could be as widespread as bystander CPR and public access defibrillation, being available to anybody who knows how to use an epi-pen.
In isolation, this article is not rigorous enough to be practice changing. The chances of it reaching clinical practice are increased by the potential survival benefit, the ease of implementation and the relative familiarity of the drug to those involved. What is lacking is an examination of the risks or potential downsides of the intervention. Despite the limitations, this research is valuable because previous studies were comprised of animal and hypothetical models; as a first human trial, it paves the way for more rigorous research.
