Half a century after the initial 1905 canine experiments of Crile and Dolley, Pearson and Redding aimed to optimize the efficacy of adrenaline by refining its dosage and administration route. Building upon Crile’s groundwork, they conducted similar investigations involving repeated administration of 1 mg of adrenaline in dogs following induced cardiac arrest. As noted in their findings, “return of spontaneous circulation (ROSC) occurred in 1 of 10 animals without epinephrine and 9 of 10 animals with epinephrine,” leading them to the conclusion that “epinephrine is of great benefit in restoring spontaneous circulation” (1).

Their research unfolded during a critical juncture in resuscitation science. The successful replication of Crile’s and Dolley’s research played a pivotal role in establishing adrenaline as a fundamental pharmacological intervention in resuscitation. So, their experimental techniques were nearly verbatim incorporated into the initial edition of the Advanced Cardiovascular Life Support (ACLS) guidelines in 1974 and have remained largely unchanged in subsequent updates (2). The dosage of 1 mg, initially selected by Crile and Dolley over a century ago, became the standard for resuscitation in adults experiencing cardiac arrest without further refinement. It continues mostly unchanged holding prominence in contemporary resuscitation practices (3) up to recent times.

Almost from the beginning of its use, a number of issues remain unresolved. In the initial experiments, it was already clear that high and repeated adrenaline doses led to myocardial failure and worse neurologic prognosis (3).

The indication in shockable rhythms is still uncertain. The utilization of adrenaline in individuals experiencing a shockable cardiac arrest, often attributed to a primary cardiac cause like acute myocardial infarction, can lead to adverse effects. It can potentially heighten the demand for myocardial oxygen due to its positive inotropic and chronotropic effects. This increased demand, coupled with reduced blood flow to other organs, could be linked to unfavorable outcomes in such patients.

So, for individuals experiencing ventricular fibrillation or pulseless ventricular tachycardia, expeditious defibrillation (within 2 min) is recommended. Even though shockable rhythms comprise less than 20% of all in-hospital cardiac arrests (IHCAs), the likelihood of survival in patients with a shockable rhythm is three- to four-fold higher than for patients with a nonshockable rhythm, especially when defibrillation treatment can be provided without delay.

Only in cases where these rhythms persist after two defibrillations, the American Guidelines advise for administration of epinephrine (4). United Kingdom and European Resuscitation Guidelines even suggest waiting for up to three unsuccessful defibrillation attempts (5). The use of adrenaline in this context remains a subject of debate, and it is not endorsed as a primary treatment for shockable rhythms, as immediate defibrillation is highly effective in achieving the ROSC in the majority of these patients and has become the standard of care.

In this issue of Critical Care Medicine, Stewart et al (6) analyze data of an observational cohort of 37,668 adult patients with an IHCA due to an initial shockable rhythm from 513 U.S. hospitals included in Get With The Guidelines-Resuscitation (GWTG-R) registry during a 20-year period (2000–2019). In the study, they try to determine hospital variation rates in adrenaline administration before defibrillation and its association with IHCA risk-adjusted survival.

The median rate of administering epinephrine before defibrillation in hospitals was as high as 18.8%, with a shocking number of 7061 patients (almost one of five) receiving adrenaline before defibrillation, reaching almost 70% in some hospitals. Also, a considerable variability across different hospitals (ranging from 0% to 68.8%) was displayed. The odds of two identical patients receiving epinephrine before defibrillation varied by 54% at two randomly selected hospitals, indicating notable disparities.

Using multivariable hierarchical regression, major teaching status and the annual volume of IHCA cases were identified as factors associated with the hospital rate of epinephrine administration before defibrillation. So, odds for epinephrine was higher at major teaching status hospitals, and lower at sites with higher annual rates of cardiac arrest events, but these structural variables did not meaningfully explain the extent of hospital practice variation.

When compared with hospitals in the lowest quartile (Q1) of epinephrine administration before defibrillation, there was a significant consistent decline in risk-adjusted survival at hospitals with higher rates of 4.0% (Q1: 44.3%, Q2: 43.4%; Q3: 41.9%; Q4: 40.3%; p for trend < 0.001) and also for favorable neurologic survival of 5.1% (Q1 38.9% vs. Q4 33.8%; p < 0.001). Although delays in defibrillation were more common in the highest quartile, both associations with lower survival and lower favorable neurologic survival, remained significant after adjusting for time to defibrillation.

The authors interpret the results as a possible spillover effect since nonshockable rhythms account for almost 90% of IHCA. This would also explain why prior administration of adrenaline is more frequent in major teaching hospitals, where trainees often preform resuscitation, and in hospitals with fewer IHCA events, and, therefore, with less institutional experience.

The study faces the limitations of using data from a registry, with a potential for unmeasured confounding, and without being able to ascribe causal inferences. The fact that teaching hospitals exhibit lower compliance is a priori surprising, and it cannot be ruled out that the administration of epinephrine before defibrillation could be a marker of other aspects of resuscitation care (e.g., quality of resuscitation maneuvers). The substantial variation in hospital rate of epinephrine administration remained largely unchanged after adjustment of hospital variables, suggesting that they play only a limited role. Additional research is needed to identify hospital processes that underline such large fluctuation in epinephrine administration.

As participation in the registry is voluntary, generalizability of findings may be limited.

The authors conclude that the practice of administering epinephrine before defibrillation in cases of shockable IHCA is prevalent and exhibits significant variation among U.S. hospitals. Furthermore, higher rates of epinephrine administration before defibrillation were associated with a stepwise reduction in risk-adjusted survival rates. Urgent efforts are needed to prioritize immediate defibrillation for patients with shockable IHCA and to discourage early epinephrine administration.

The study by Stewart et al (6) deepens knowledge gained from several previous articles on registry data that have shown that deviations from ACLS guidelines are pervasive.

A first study published in 2016 in the New England Journal of Medicine showed that delayed defibrillation occurred in more than 30% of the patients and was associated with a significantly lower probability of survival (22.2% vs. 39.3%). A graded association was observed, indicating that with each additional minute of delay in defibrillation, there was a corresponding decrease in rates of survival to hospital discharge (p for trend < 0.001) (7).

Another study conducted under the GWTG-R initiative, revealed also a notable divergence from guidelines, wherein 51% of patients experiencing an initial shockable rhythm refractory to the first defibrillation within 2 minutes received epinephrine before the second defibrillation. This practice, inconsistent with current recommendations, was associated with a 30% lower likelihood of survival (8).

In a third study including almost 35,000 patients of the GWTG-R registry, more than 20% of the patients were given adrenaline before defibrillation. This practice was associated with lower odds of survival to discharge (22.4% vs. 29.7%; p < 0.001), favorable neurologic survival, and survival after acute resuscitation. Data were analyzed at a patient-level basis (9).

The current article by Stewart et al (6) addresses a crucial topic, drawing data from a 20-year span of the GWTG-R registry, encompassing over 37,000 patients. The well-executed study, employing a thoughtful statistical approach, reveals a shocking level of noncompliance with guidelines, particularly in larger teaching hospitals. The implications extend beyond the evident impact on survival rates and favorable neurologic outcomes.

It makes a significant contribution by revealing substantial variations among hospitals, suggesting that the sequence of administering epinephrine before defibrillation is not merely a random phenomenon. Notably, this rate surpassed 25% in a quarter of the hospitals, underscoring the potential modifiability of this practice. Implementing hospital interventions that prioritize immediate defibrillation, steering away from an epinephrine-first strategy, in these cases, holds promise for substantial improvements in overall IHCA survival rates.

This serves as a noteworthy reminder amidst our technologically advanced medical landscape that, despite exploring intricate aspects like the metabolic response to arrest, personalized tailored strategies, and prognostic factors, we must not overlook the fundamental importance of ensuring adherence to cardiopulmonary resuscitation (CPR) guidelines.

Perhaps we need to take a step back and return to basics, addressing the fundamental question posed by the study by Stewart et al (6): What factors contribute to the notably low adherence to basic guidelines, and what proactive measures can be implemented to mitigate this issue? The substantial variation among hospitals emphasizes the opportunity to reshape established care patterns and enhance the management of patients experiencing shockable IHCA, a subgroup with the highest potential for survival. Before further complicating the handling, perhaps we should address the need to be perfectionists in complying with the guidelines and to perform excellent CPR maneuvers, that is, to go back to the basics. Perhaps American and European guidelines could be unified, and strategies could be sought and generalized to meet the current evidence as we expand knowledge beyond the canine experiments of more than 100 years ago.

1. Pearson J, Redding J: The role of epinephrine in cardiac resuscitation. Anesth Analg. 1963; 42:599–606 2. Standards for cardiopulmonary resuscitation (CPR) and emergency cardiac care (ECC). I. Introduction. JAMA. 1974; 227:837–840 3. Kasha B, Brit L, Alessandra Della P, et al.: After a century, epinephrine’s role in cardiac arrest resuscitation remains controversial. Am J Emerg Med. 2021; 39:168–172 4. Panchal AR, Bartos JA, Caba.as JG, et al.: Adult basic and advanced life support writing group. Part 3: Adult basic and advanced life support: 2020 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020; 142(16_Suppl_2):S366–S468 5. Soar J, Nolan JP, B.ttiger BW, et al.; Adult advanced life support section Collaborators: European Resuscitation Council guidelines for resuscitation 2015: Section 3. Adult advanced life support. Resuscitation. 2015; 95:100–147 6. Stewart C, Chan PS, Kennedy K, et al.; American Heart Association’s Get With The Guidelines (GWTG) Resuscitation Investigators: Hospital Variation in Epinephrine Administration Before Defibrillation for Cardiac Arrest Due to Shockable Rhythm. Crit Care Med. 2024; 52:878–886 7. Chan PS, Krumholz HM, Nichol G, et al.: Delayed time to defibrillation after in-hospital cardiac arrest. N Engl J Med. 2016; 358:9–17 8. Andersen LW, Kurth T, Chase M, et al.; American Heart Association’s Get With The Guidelines-Resuscitation Investigators: Early administration of epinephrine (adrenaline) in patients with cardiac arrest with initial shockable rhythm in hospital: Propensity score matched analysis. BMJ. 2016; 353:i1577 9. Evans E, Swanson MB, Mohr N, et al.; American Heart Association’s Get With The Guidelines-Resuscitation investigators: Epinephrine before defibrillation in patients with shockable in-hospital cardiac arrest: Propensity matched analysis. BMJ. 2021; 375:e066534