Cardiac arrest (CA) is a significant cause of morbidity and mortality in the pediatric population worldwide [1]. Increasing survival rates of in-hospital pediatric CA patients have been reported in high-income countries [2,3], and this trend has also been demonstrated in a limited number of studies in middle-income countries [4,5,6]. The population experiencing in-hospital cardiac arrest (IHCA) consists mainly of patients with severe comorbidities, representing 71 % to 90.9 % of cases [4,7,8]. Although the prognosis of in-hospital pediatric cardiopulmonary resuscitation (CPR) can be influenced by many factors [6], the role of epinephrine remains highly debated. Epinephrine administration during CPR increases coronary and cerebral perfusion [9], but it also stimulates cardiac adrenergic receptors, potentially leading to harmful effects on the heart during the ischemia and reperfusion phases [10]. The interval of epinephrine administration may play a crucial role in balancing its desirable and adverse effects, thus impacting outcomes. The International Liaison Committee on Resuscitation (ILCOR) 2023[11] recommends administering epinephrine at 3- to 5-minute intervals; however, recent literature[12,13] challenges this recommendation, suggesting that intervals shorter than 3 min are associated with increased chances of return of spontaneous circulation (ROSC) and survival to hospital discharge.

There remains an inconsistency in the literature regarding the epinephrine dose interval and CPR prognosis. Hoyme et al. (2017)[1] in a multicenter retrospective cohort study demonstrated that, in adjusted analyses, administering epinephrine at intervals longer than 5 min was significantly associated with improved hospital survival. In contrast, Kienzle et al. (2021)[12] in a single-center retrospective cohort study reported that epinephrine doses at intervals <2 min were associated with increased chances of survival and better neurological outcomes. A recent multicenter cohort study by Kienzle et al. (2024)[13] concluded that shorter dose intervals (<3 min) led to increased ROSC but were not associated with favorable neurological outcomes. Studies in adults have also shown inconsistent results regarding the epinephrine dose interval[14,15] and CPR prognosis [15].

Most pediatric CPR studies have been conducted in high income countries [1,12,13], with few scientific studies in middle[4, 6]income nations. Studies from middle-income countries are needed to better understand the epinephrine dosing during CPR, as there are gaps in the scientific evidence supporting current guidelines. Another important aspect is the lack of pediatric studies evaluating the role of epinephrine in long-term survival and neurological outcomes.

The hypothesis for this study was that shorter epinephrine dose intervals than currently recommended are associated with better pediatric CPR outcomes. Therefore, the objective of this study was to evaluate the associations of the interval between epinephrine doses administered during in-hospital pediatric CPR and one-year survival and one-year neurological prognosis.

A total of 599 patients were included in the CPR registry, and after applying the exclusion criteria, a final sample of 194 eligible patients was obtained (Figure 1). The descriptive events analysis is presented in Table 1. CPR events occurred almost equally by sex (female 50.52 %) and the predominant age group was 1–12 months (35.57 %). Most patients had a preexisting condition (95.88 %). The most observed initial rhythm was bradycardia (47.89 %) and more than half of the population was receiving continuous vasoactive drug infusion prearrest (53.6 %). The mean interval between epinephrine doses administered during CPR was 3.23 min, 46.39 % of patients received epinephrine at an interval of 3–5 min. The mean epinephrine doses were 2.69, the mean CPR duration was 18.29 min. In terms of outcomes, ROSC occurred in 56.19 % of patients, 18.04 % were discharged, and 16.06 % were alive at one-year.

Fig. 1.

Patient flowchart for study. CA, cardiac arrest; OHCA, out of hospital cardiac arrest.

This study evaluated the association between epinephrine dosing intervals during pediatric in-hospital cardiopulmonary resuscitation and one-year survival, survival to hospital discharge, and one-year neurological outcomes. Current resuscitation guidelines recommend epinephrine administration every 3–5 min during CPR11. In the studied cohort, although shorter dosing intervals (< 3 min) were associated with higher one-year survival in univariate analyses, this association was not sustained after adjustment for relevant confounders. No association was identified between epinephrine dosing intervals and neurological outcomes.

The association between epinephrine dosing interval and outcomes must be interpreted in the context of cardiopulmonary resuscitation duration. As resuscitation efforts become prolonged, the spacing between epinephrine doses naturally increases, making the dosing interval a partial surrogate for CPR length. This phenomenon has been described in pediatric resuscitation studies, including those by Hoyme et al. (2017)[1] and Ortmann et al. (2023) [19], both of which demonstrated a strong correlation between longer dosing intervals and longer CPR duration.

This study population has a profile similar to other in-hospital pediatric CPR studies conducted in major centers[20] allowing for comparison of the results. The population came from a single quaternary care center in a middle-income country, specialized in treating critically ill pediatric patients, predominantly with complex chronic conditions (95.6 %), who were under CPR and had survived. Survival rates to hospital discharge in children with IHCA have improved over the last decade[2], and higher rates of favorable neurological prognosis among survivors have also been reported [21], as shown in a study by Shimoda-Sakano et al. (2020) [22].

Kienzly et al. (2021) [13], in a retrospective study at a single pediatric center, reported that administering epinephrine at intervals of 2 min or less was associated with increased diastolic pressure during CPR, shorter CPR duration, increased ROSC, and better discharge outcomes with good neurological prognosis. In contrast, in this study, no association was observed with hospital discharge, nor with a favorable neurological outcome at discharge.

Recently, in a multicenter observational study, Kienzly et al. (2024)[12] reported that patients who received at least two doses of epinephrine with intervals of <3 min were not associated with better neurological outcomes; however, they were associated with sustained ROSC and a shorter CPR duration, as shown in the present study, which also did not find an association with neurological outcomes, but with one year survival.

In contrast, Hoyme et al. (2017) [1], in a multicenter retrospective study, demonstrated that administering epinephrine during pediatric IHCA at intervals greater than five minutes was associated with higher in-hospital survival when adjusted for CPR duration [OR = 1.81 (95 % CI 1.26–2.59) and 2.64 (95 % CI 1.53–4.55) for intervals of > 5–8 min and 8–10 min, respectively]. Unlike the unadjusted findings, in which shorter epinephrine intervals were initially associated with improved one-year survival, this association was not sustained after multivariable adjustment. This attenuation likely reflects the strong influence of CPR duration on outcomes, reinforcing the concept that epinephrine dosing interval and resuscitation length are intrinsically interrelated variables. The discrepancy can be attributed to the differences in the study's design, such as the number of cases included, single vs multicenter study, and the different intervals of epinephrine doses. Epinephrine interval doses on pediatric CPR outcomes is complex and challenging to study, which is why this topic remains controversial.

There are also studies in the adult population that have attempted to better clarify the association between epinephrine dosing intervals and outcomes during CPR. For example, a recent meta-analysis[23] on adult CPR did not demonstrate a significant association between epinephrine dose intervals and survival with better hospital outcomes and favorable neurological outcomes. In contrast, the present study found that shorter epinephrine administration intervals were associated with increased one-year survival rates.

Epinephrine is a potent inotropic, chronotropic, and vasopressor agent widely used in CPR [24]. However, the deleterious and cumulative effects of epinephrine, such as arrhythmias and tissue hypoperfusion culminating in neurological damage, seem to be related to the greater number of epinephrine doses, as demonstrated in previous studies [8,10]. In a situation of circulatory collapse, such as CA, distinguishing between beneficial and harmful effects becomes challenging. The development of continuous monitoring methods to guide interventions during CA is crucial. For example, invasive blood pressure measurement is already used in many centers for this purpose. In the present study, however, this parameter could not be analyzed as it is not yet included in the institutional CPR registry.

Although in the present study the CPR outcomes were not adjusted with CA rhythms, this topic remains of interest in resuscitation studies and is related to patient prognosis and outcomes [25]. There is a trend in the literature to analyze symptomatic bradycardia apart from asystole and pulseless electrical activity, as the physiological response of patients with bradycardia and poor perfusion[3] receiving epinephrine can be different. In bradycardia, the precise mechanisms driving ROSC outcomes are not fully understood, but the hemodynamic response during CPR has been speculated, perhaps because CPR is initiated at an earlier stage of the cardiorespiratory collapse process. It is worth noting that bradycardia was the initial rhythm observed in 47.89 % of the cases in this study; therefore, the interpretation of the results should take this aspect into account.

The present study also evaluated other parameters known to interfere with in-hospital CPR prognosis, such as prearrest continuous vasoactive drugs infusion, the number of epinephrine doses, the initial rhythm, and the duration of CPR. Importantly, although these variables were included in the adjusted analyses, their role in the results obtained when studying epinephrine cannot be completely ruled out. Administration of prearrest continuous vasoactive drugs infusion was associated with a lower chance of discharge (OR: 0.17; 95 % CI 0.06–0.40; p < 0.001) and lower one-year survival (OR: 0.18; 95 % CI 0.06–0.43; p < 0.001), corroborating with other studies that also reported lower survival to hospital discharge [22,26,27,28].

Another relevant topic in CPR is the number of epinephrine doses. A narrative review addressing the use of epinephrine in pediatric CPR[29] revealed an inverse relationship between the number of epinephrine doses and survival, as did other studies [30]. This study revealed the same associations for both survival to discharge and one-year survival (OR: 0.63; 95 % CI 0.46–0.82; p = 0.002 and OR: 0.67; 95 % CI 0.49–0.86; p = 0.006). Regarding CPR duration, an inverse association was also found, with shorter CPR times associated with a greater chance of survival to discharge (OR 0.87; 95 % CI 0.77–0.96; p = 0.01) and one-year survival (OR 0.88; 95 % CI 0.77–0.97; p = 0.03). Another point attempted to elucidate the factors associated with longer CPR duration in children with IHCA without success. Understanding the factors that influence the duration of CPR and its relationship with pediatric survival, taking into account the patient’s profile and the hospital environment, can be essential to improve outcomes.

Neurological outcome has been a current topic of investigation [2,4,6,20], and an association with factors such as CPR duration, baseline PCPC, number of epinephrine doses, and prearrest continuous vasoactive drugs infusion has been demonstrated. In the present study, neurological status worsened at one-year survival in 16.6 % of the patients (p = 0.01), and no significant association was found with the epinephrine dose interval. Kienzle et al. (2024)[13] obtained similar results related to survival to discharge. In another study, Kienzle et al. (2021)[12] reported favorable discharge outcomes with good neurological prognoses associated with epinephrine intervals. This inconsistency among studies demonstrates the difficulty and complexity in analyzing neurological prognosis after CPR in relation to epinephrine.

It is important to point out that there is currently no adequate tool for assessing neurological prognosis after CPR. Although most studies use the PCPC, there is a movement within the scientific community to find better parameters for evaluating neurological status [18]. This is also a concern of ILCOR in its latest update in 2023 [11].

It is crucial to highlight some limitations of this study. Most limitations are inherent to the observational nature of the study, where causation cannot be established. On the other hand, observational studies are feasible and closely approximate reality, whereas randomized clinical studies in pediatric CPR are challenging, lengthy, expensive, and have limited clinical applicability owing to the rigid exclusion criteria. Another possible limitation is the lack of invasive blood pressure data and the absence of quality CPR parameters. An important aspect to consider is that the study was conducted in a single center, making it difficult to generalize the results, but on the other hand, it has high internal validity and contributes to improvements in CPR within the institution. The population consists almost entirely of patients with preexisting serious conditions, which could be considered a limitation, but, from another point of view, this is precisely the growing profile of hospitalized children. Overall, the present findings should be interpreted as hypothesis-generating rather than definitive, reinforcing the need for cautious interpretation of univariate associations in resuscitation research.

In conclusion, in this cohort, epinephrine dosing interval was not independently associated with one-year survival after adjustment for relevant confounders. The findings underscore the complexity of resuscitation processes and support further investigation in larger, multicenter studies. No relationship was observed between the epinephrine dose interval and one-year neurological prognosis.

Without institutional involvement, all costs were borne by the authors.

The data that support the findings of this study are available from the corresponding author.