Abstract
Objective
To evaluate the association between the interval doses of epinephrine and one-year survival and one-year neurological prognosis after pediatric in-hospital cardiac arrest (IHCA).
Methods
This observational retrospective cohort study included pediatric patients (0–18 years) who experienced IHCA and received at least two doses of epinephrine from January 2015 to December 2022. Data were collected following the Utstein style. The mean interval between epinephrine doses was categorized as 〈 3, 3–5, or > 5 min. Primary outcome was one-year survival; secondary outcomes were survival to hospital discharge and one-year neurological prognosis, assessed by the Pediatric Cerebral Performance Category.
Results
194 patients were eligible. In the univariate adjusted analysis, patients who received epinephrine at intervals shorter than 3 min had a 2.3-fold increased chance of one-year survival (OR 2.3; 95 % CI 1.0–5.5; p = 0.042), although this association was not sustained in the multivariable regression. Longer intervals between epinephrine doses (OR: 0.71; 95 % CI 0.52–0.71; p = 0.03), continuous vasoactive drugs infusion prearrest (OR 0.1; 95 % CI 0.1–0.4; p < 0.001), longer resuscitation duration (OR 0.8; 95 % CI 0.7–0.9; p = 0.028), epinephrine doses (OR 0.68; 95 % CI 0.56–0.81; p < 0.001) were associated with reduced one-year survival. Neurological deterioration was observed in 6 (16.6 %) of the 36 patients after one year (p = 0.001). No association was found between epinephrine dosing intervals (OR 0.72; 95 % CI 0.16–3.14; p = 0.65) and neurological outcomes.
Conclusion
Epinephrine dosing interval was not independently associated with one-year survival after adjusted analyses. These findings underscore the complexity of pediatric resuscitation and support further multicenter prospective studies.
Keywords: Epinephrine, Cardiopulmonary resuscitation, Child, In-hospital cardiac arrest, Pediatric
Introduction
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.
Material and methods
Study design and study location
This was a retrospective observational cohort study of pediatric patients who underwent CPR from January 2015 to December 2022 and received at least two doses of epinephrine. Data were obtained from the local institutional registry, which follows Utstein style [16]. The project was approved by the hospital's ethics committee. Due to the inability to obtain informed consent at the time of cardiac arrest, presumed consent was applied, consistent with the approach used in prior resuscitation studies. The study was approved with a waiver of informed consent by the local Ethics and Research Committee, under protocol number: 29,404,620.0.0000.0068, on March 5th, 2020, and was conducted in a public university hospital with tertiary and quaternary healthcare, which is located in a large urban center and specializes in treating pediatric patients with complex chronic diseases. Extracorporeal cardiopulmonary resuscitation (ECPR) was not used in any of the included cardiac arrest events.
Study participants
Patients aged 0 to 18 years who experienced IHCA, regardless of duration, and who received at least two doses of epinephrine were included. Patients with out-of-hospital cardiac arrest (OHCA), CA due to trauma, or those who received boluses of other vasoactive drugs (e.g. vasopressin) instead of epinephrine during CPR were excluded.
Primary and secondary outcomes
The variables of interest are presented in Table 1. The interval between epinephrine doses was the exposure and the independent variable of interest. The interval between doses was defined as the time between the first dose of epinephrine and the outcome of resuscitation (ROSC or death), divided by the total number of epinephrine doses administered after the first dose, and was categorized as < 3 min, 3–5 min, and > 5 min. In the event of doubts, inconsistencies, or unavailable data, medical records were analyzed, and interviews were conducted with healthcare professionals involved in patient care or with family members.
Table 1.
Patient characteristics.
| Variables | Epinephrine average dosing period | p-value2 | |||
|---|---|---|---|---|---|
| Overall, n = 1941 | < 3 min, n = 871 | 3–5 min, n = 901 | > 5 min, n = 171 | ||
| Time of day of arrest | 0.121 | ||||
| Day | 95 (48.97 %) | 48 (55.17 %) | 37 (41.11 %) | 10 (58.82 %) | |
| Night | 99 (51.03 %) | 39 (44.83 %) | 53 (58.89 %) | 7 (41.18 %) | |
| Time of week of arrest | 0.009 | ||||
| Weekend | 54 (27.84 %) | 15 (17.24 %) | 32 (35.56 %) | 7 (41.18 %) | |
| Weekday | 140 (72.16 %) | 72 (82.76 %) | 58 (64.44 %) | 10 (58.82 %) | |
| Sex | 0.595 | ||||
| Female | 98 (50.52 %) | 41 (47.13 %) | 49 (54.44 %) | 8 (47.06 %) | |
| Male | 96 (49.48 %) | 46 (52.87 %) | 41 (45.56 %) | 9 (52.94 %) | |
| Age group | 0.828 | ||||
| Neonate, < 1 mo | 51 (26.29 %) | 23 (26.44 %) | 23 (25.56 %) | 5 (29.41 %) | |
| Infant, 1–12 mo | 69 (35.57 %) | 32 (36.78 %) | 30 (33.33 %) | 7 (41.18 %) | |
| Child, 1–12 yo | 58 (29.90 %) | 27 (31.03 %) | 28 (31.11 %) | 3 (17.65 %) | |
| Adolescent, > 12 yo | 16 (8.25 %) | 5 (5.75 %) | 9 (10.00 %) | 2 (11.76 %) | |
| Preexisting conditions | 186 (95.88 %) | 83 (95.40 %) | 88 (97.78 %) | 15 (88.24 %) | 0.154 |
| Genetic | 94 (48.45 %) | 44 (50.57 %) | 45 (50.00 %) | 5 (29.41 %) | 0.258 |
| Hepatic | 45 (23.20 %) | 23 (26.44 %) | 18 (20.00 %) | 4 (23.53 %) | 0.624 |
| Neurologic | 31 (15.98 %) | 10 (11.49 %) | 18 (20.00 %) | 3 (17.65 %) | 0.282 |
| Other diseases | 81 (41.75 %) | 36 (41.38 %) | 39 (43.33 %) | 6 (35.29 %) | 0.823 |
| Location of arrest | 0.001 | ||||
| PICU | 160 (82.47 %) | 72 (82.76 %) | 74 (82.22 %) | 14 (82.35 %) | |
| OR | 10 (5.15 %) | 10 (11.49 %) | 0 (0.00 %) | 0 (0.00 %) | |
| Pedriatric Floor with telemetry | 5 (2.58 %) | 0 (0.00 %) | 4 (4.44 %) | 1 (5.88 %) | |
| Emergency department | 19 (9.79 %) | 5 (5.75 %) | 12 (13.33 %) | 2 (11.76 %) | |
| Arrest witnessed | 191 (98.45 %) | 86 (98.85 %) | 88 (97.78 %) | 17 (100.00 %) | >0.999 |
| Previous insertion of airway | 141 (72.68 %) | 74 (85.06 %) | 54 (60.00 %) | 13 (76.47 %) | <0.001 |
| Insertion of airway during CPR | 40 (20.62 %) | 10 (11.49 %) | 25 (27.78 %) | 5 (29.41 %) | 0.012 |
| Previous cardiac monitoring | 151 (77.84 %) | 75 (86.21 %) | 67 (74.44 %) | 9 (52.94 %) | 0.006 |
| Prearrest vasoactive infusion | 104 (53.61 %) | 51 (58.62 %) | 45 (50.00 %) | 8 (47.06 %) | 0.44 |
| Calcium during CPR | 80 (41.24 %) | 27 (31.03 %) | 46 (51.11 %) | 7 (41.18 %) | 0.025 |
| Bicarbonate during CPR | 125 (64.43 %) | 52 (59.77 %) | 66 (73.33 %) | 7 (41.18 %) | 0.019 |
| Immediate cause | |||||
| Respiratory decompensation | 83 (42.78 %) | 36 (41.38 %) | 40 (44.44 %) | 7 (41.18 %) | 0.91 |
| Metabolic decompensation | 22 (11.34 %) | 9 (10.34 %) | 12 (13.33 %) | 1 (5.88 %) | 0.743 |
| Shock | 83 (42.78 %) | 39 (44.83 %) | 37 (41.11 %) | 7 (41.18 %) | 0.874 |
| Initial rhythm | |||||
| Pulseless electrical activity | 51 (26.29 %) | 20 (22.99 %) | 27 (30.00 %) | 4 (23.53 %) | 0.556 |
| Asystole | 41 (21.13 %) | 16 (18.39 %) | 21 (23.33 %) | 4 (23.53 %) | 0.701 |
| Bradycardia* | 91 (46.91 %) | 46 (52.87 %) | 37 (41.11 %) | 8 (47.06 %) | 0.293 |
| VF/VT | 7 (3.61 %) | 3 (3.45 %) | 3 (3.33 %) | 1 (5.88 %) | 0.711 |
| Missing | 4 | 2 | 2 | 0 | |
| Duration of CPR, min | <0.001 | ||||
| Mean (SD) | 18.29 (15.24) | 9.67 (9.26) | 24.01 (14.21) | 32.12 (20.68) | |
| Median (IQR) | 14.50 (7.00, 25.00) | 6.00 (5.00, 11.00) | 20.00 (14.00, 30.00) | 26.00 (20.00, 35.00) | |
| Range | 0.00, 95.00 | 0.00, 60.00 | 7.00, 77.00 | 11.00, 95.00 | |
| Time to 1st epinephrine dose, min | <0.001 | ||||
| Mean (SD) | 1.71 (2.27) | 0.72 (1.13) | 2.11 (2.15) | 4.59 (3.78) | |
| Median (IQR) | 1.00 (0.00, 3.00) | 0.00 (0.00, 1.00) | 2.00 (0.00, 4.00) | 5.00 (3.00, 6.00) | |
| Range | 0.00, 13.00 | 0.00, 5.00 | 0.00, 12.00 | 0.00, 13.00 | |
| Epinephrine mean dosing period, min | <0.001 | ||||
| Mean (SD) | 3.23 (1.49) | 1.99 (0.73) | 3.87 (0.60) | 6.20 (1.36) | |
| Median (IQR) | 3.17 (2.00, 4.00) | 2.00 (1.50, 2.55) | 3.75 (3.35, 4.30) | 5.50 (5.20, 7.00) | |
| Range | 0.00, 9.00 | 0.00, 3.00 | 3.00, 5.00 | 5.00, 9.00 | |
| Total epinephrine doses | <0.001 | ||||
| Mean (SD) | 4.01 (2.21) | 3.21 (1.94) | 4.73 (2.23) | 4.29 (2.05) | |
| Median (IQR) | 3.00 (2.00, 5.00) | 2.00 (2.00, 4.00) | 4.00 (3.00, 6.00) | 4.00 (3.00, 5.00) | |
| Range | 2.00, 10.00 | 2.00, 10.00 | 2.00, 10.00 | 2.00, 10.00 | |
| ROSC | 109 (56.19 %) | 58 (66.67 %) | 43 (47.78 %) | 8 (47.06 %) | 0.03 |
| Survival to discharge | 35 (18.04 %) | 21 (24.14 %) | 12 (13.33 %) | 2 (11.76 %) | 0.156 |
| 30 days | 42 (21.65 %) | 25 (28.74 %) | 15 (16.67 %) | 2 (11.76 %) | 0.099 |
| 180 days | 33 (17.01 %) | 21 (24.14 %) | 11 (12.22 %) | 1 (5.88 %) | 0.054 |
| 1 year | 31 (16.06 %) | 20 (22.99 %) | 10 (11.24 %) | 1 (5.88 %) | 0.062 |
| Baseline PCPC | 0.324 | ||||
| 1 | 22 (61.11 %) | 14 (66.67 %) | 7 (50.00 %) | 1 (100.00 %) | |
| 2 | 9 (25.00 %) | 3 (14.29 %) | 6 (42.86 %) | 0 (0.00 %) | |
| 3 | 5 (13.89 %) | 4 (19.05 %) | 1 (7.14 %) | 0 (0.00 %) | |
| 4 | 0 (0.00 %) | 0 (0.00 %) | 0 (0.00 %) | 0 (0.00 %) | |
| One-year survival PCPC | 0.827 | ||||
| 1 | 15 (41.67 %) | 8 (38.10 %) | 6 (42.86 %) | 1 (100.00 %) | |
| 2 | 10 (27.78 %) | 7 (33.33 %) | 3 (21.43 %) | 0 (0.00 %) | |
| 3 | 10 (27.78 %) | 6 (28.57 %) | 4 (28.57 %) | 0 (0.00 %) | |
| 4 | 1 (2.78 %) | 0 (0.00 %) | 1 (7.14 %) | 0 (0.00 %) | |
| Categorization of Baseline PCPC | 0.679 | ||||
| 1 + 2 | 31 (86.11 %) | 17 (80.95 %) | 13 (92.86 %) | 1 (100.00 %) | |
| 3 + 4 | 5 (13.89 %) | 4 (19.05 %) | 1 (7.14 %) | 0 (0.00 %) | |
| Categorization of One-year survival PCPC | 0.806 | ||||
| 1 + 2 | 25 (69.44 %) | 15 (71.43 %) | 9 (64.29 %) | 1 (100.00 %) | |
| 3 + 4 | 11 (30.56 %) | 6 (28.57 %) | 5 (35.71 %) | 0 (0.00 %) | |
n ( %).
Pearson’s Chi-squared test; Fisher’s exact test; Kruskal-Wallis rank sum test; mo, month; yo, years old; PICU, pediatric intensive care unit; OR, operating room; CPR, Cardiopulmonary resuscitation; VF, ventricular fibrilatrion; VT, ventricular tachycardia; SD, Standard deviation; IQR, interquartile range; min, minutes; ROSC, return of spontaneous circulation; PCPC, Pediatric Cerebral Performance Category. (Baseline event characteristics by exposure to CPR and one-year survival). Data are shown as n ( %), mean (SD) or median (interquartile range). *Bradycardia with poor perfusion.
The primary outcome was one-year survival. Secondary outcomes were survival to hospital discharge and neurological status at one-year. Neurological status was assessed by the Pediatric Cerebral Performance Scale (PCPC) [17], following the P-COSCA recommendation [18], which defines favorable outcomes as a PCPC score of 1 or 2 and unfavorable outcomes (neurological disability, persistent vegetative state) as a PCPC score of 3, 4, or 5.
Statistical analysis
For qualitative variables, absolute frequencies (n) and relative frequencies ( %) were reported, whereas measures of central tendency and dispersion, including the mean, median, interquartile range, range, and standard deviation, were provided for quantitative variables. Associations between demographic and clinical variables (categorical variables) and outcomes (survival to discharge and one-year survival) were evaluated using Fisher’s exact test or the chi-square test, as appropriate. Comparisons of continuous variables between outcome groups were performed using Student’s t-test or the nonparametric Mann‒Whitney U test, depending on data distribution, which was assessed with the Shapiro‒Wilk test. McNemar’s test was applied to evaluate changes in the PCPC scale score pre-arrest and after one-year. To assess the effect of the average interval between doses on outcomes (hospital discharge and one-year survival), an univariable logistic regression model was fitted with results reported as odds ratios (ORs) and 95 % confidence intervals (CIs). Unadjusted ORs (uOR) were also estimated for demographic and clinical factors. Multivariable logistic regression models were fitted using the categorized dose interval (< 3 min, 3–5 min, > 5 min) and known risk factors and confounders, including total epinephrine doses, prearrest continuous vasoactive drug infusion, and CPR duration (in minutes). Data analyses were conducted using the R package version 4.4.1 with two-sided tests at a significant level of 0.05.
Results
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.
One-Year survival status
In the univariable analysis, a statistically significant association was observed between longer mean epinephrine intervals and one-year survival (OR: 0.71; 95 % CI 0.52–0.95; p = 0.02), as demonstrated in Table 2. Specifically, patients who received epinephrine at intervals of <3 min had a 2.3-fold higher chance of one-year survival compared to those with intervals of 3–5 min (OR: 2.36; 95 % CI 1.05–5.58; p = 0.042). Furthermore, a higher number of epinephrine doses OR: 0.67; 95 % CI 0.49–0.86; p = 0.006) as well as the administration of continuous vasoactive drugs prior CA and longer CPR duration were inversely associated with one-year survival (OR: 0.23; 95 % CI 0.09–0.54; p = 0.001; OR: 0.90; 95 % CI 0.85–0.95; p < 0.001, respectively). In the multivariable analysis, prearrest continuous vasoactive infusion (OR = 0.18; 95 % CI, 0.06–0.43; p < 0.001) and longer CPR duration (OR = 0.87; 95 % CI, 0.77–0.97; p = 0.02) were significantly associated with reduced one-year survival. In contrast, total epinephrine doses, the epinephrine mean dosing interval, and epinephrine dosing intervals (< 3 min, 3–5 min, > 5 min) were not significantly associated with one-year survival.
Table 2.
One-year survival univariable and multivariable analysis.
| One-year survival |
Univariable model |
Multivariable model |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall, n = 1931 | No, n = 1621 | Yes, n = 311 | p-value2 | n | OR3 | 95 % CI3 | p-value | OR3 | 95 % CI3 | p-value | |
| Total epinephrine doses | <0.001 | 193 | 0.673 | 0.490 - 0.867 | 0.006 | 1.076 | 0.672 - 1.677 | 0.752 | |||
| Mean (SD) | 4.02 (2.21) | 4.22 (2.23) | 2.97 (1.76) | ||||||||
| Median (IQR) | 3.00 (2.00 −5.00) | 3.50 (2.25 - 5.00) | 2.00 (2.00 - 3.00) | ||||||||
| Range | 2.00 - 10.00 | 2.00 - 10.00 | 2.00 - 10.00 | ||||||||
| Previous vasoactive infusion | <0.001 | 193 | |||||||||
| No | 89 (46.11 %) | 66 (40.74 %) | 23 (74.19 %) | Ref | Ref | ||||||
| Yes | 104 (53.89 %) | 96 (59.26 %) | 8 (25.81 %) | 0.239 | 0.095 - 0.547 | 0.001 | 0181 | 0.068 - 0.436 | <0.001 | ||
| Duration of CPR, min | <0.001 | 193 | 0.907 | 0.853 - 0.953 | <0.001 | 0879 | 0.776 - 0.975 | 0.028 | |||
| Mean (SD) | 18.32 (15.28) | 20.02 (15.78) | 9.42 (7.73) | ||||||||
| Median (IQR) | 15.00 (7.00 - 25.00) | 16.00 (9.00 - 27.00) | 7.00 (4.50 - 10.50) | ||||||||
| Range | 0.00 - 95.00 | 0.00 - 95.00 | 2.00 - 35.00 | ||||||||
| Epinephrine mean dosing interval, min | 0.013 | 193 | 0.714 | 0.521 - 0.952 | 0.028 | ||||||
| Mean (SD) | 3.22 (1.49) | 3.32 (1.43) | 2.68 (1.67) | ||||||||
| Median (IQR) | 3.14 (2.00, 4.00) | 3.31 (2.50, 4.11) | 2.25 (1.50 - 3.58) | ||||||||
| Range | 0.00 - 9.00 | 0.50 - 9.00 | 0.00 - 8.00 | ||||||||
| Categorization of epinephrine interval dosing | 0.062 | 193 | |||||||||
| 3–5min | 89 (46.11 %) | 79 (48.77 %) | 10 (32.26 %) | Ref | Ref | ||||||
| < 3min | 87 (45.08 %) | 67 (41.36 %) | 20 (64.52 %) | 2.358 | 1.053 - 5.581 | 0.042 | 0.726 | 0.219 - 2.406 | 0.598 | ||
| > 5min | 17 (8.81 %) | 16 (9.88 %) | 1 (3.23 %) | 0.494 | 0.026 - 2.861 | 0.515 | 0.833 | 0.039 - 6.489 | 0.878 | ||
n, population number ( %).
Pearson’s Chi-squared test; Fisher’s exact test; Wilcoxon rank sum test.
OR, Odds Ratio; CI, confidence interval; min, minutes; OR, odds ratio; CPR, cardiopulmonar resuscitation; SD, Standart deviation; IQR, interquartile range.
Survival to discharge
There were no statistically significant associations between epinephrine dose intervals (reference 3–5 min) and survival to hospital discharge in either the univariate or multivariate analysis (uOR: 0.56; 95 % CI 0.17–1.80; p = 0.33 and OR: 1.58; 95 % CI 0.19–9.42; p = 0.62, respectively). In the univariable analysis, patients who received a higher number of epinephrine doses had a lower likelihood of survival to hospital discharge (OR: 0.63; 95 % CI 0.46–0.82; p = 0.002). Another important finding was that the mean dose interval was not associated with survival to discharge (OR: 0.82; 95 % CI 0.62–1.06; p = 0.148) according to the univariable analysis. In the multivariable analysis, longer CPR duration was also statistically significantly associated with a reduced likelihood of survival to discharge (OR: 0.87; 95 % CI 0.77–0.96; p = 0.016), as well as continuous vasoactive drugs infusion prior to CPR (OR: 0.17; 95 % CI 0.06–0.40; p < 0.001) as demonstrated in Table 3.
Table 3.
Survival to discharge univariable and multivariable analysis.
| Survival to discharge |
Univariable model |
Multivariable model |
|||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall, n = 1941 | No, n = 1591 | Yes, n = 351 | p-value2 | n | OR3 | 95 % CI3 | p-value | OR3 | 95 % CI3 | p-value | |
| Total epinephrine doses | <0.001 | 194 | 0.634 | 0.460 - 0.820 | 0.002 | 1.014 | 0.639 - 1.560 | 0.95 | |||
| Mean (SD) | 4.01 (2.21) | 4.26 (2.24) | 2.89 (1.68) | ||||||||
| Median (IQR) | 3.00 (2.00 - 5.00) | 4.00 (3.00 - 5.00) | 2.00 (2.00 - 3.00) | ||||||||
| Range | 2.00 - 10.00 | 2.00 - 10.00 | 2.00 - 10.00 | ||||||||
| Previous vasoactive infusion | <0.001 | 194 | |||||||||
| No | 90 (46.39 %) | 64 (40.25 %) | 26 (74.29 %) | Ref | Ref | ||||||
| Yes | 104 (53.61 %) | 95 (59.75 %) | 9 (25.71 %) | 0.233 | 0.098 - 0.513 | 0.001 | 0.176 | 0.069 - 0.409 | <0.001 | ||
| Duration of CPR, min | <0.001 | 194 | 0.908 | 0.858 - 0.951 | <0.001 | 0.872 | 0.774 - 0.965 | 0.016 | |||
| Mean (SD) | 18.29 (15.24) | 20.20 (15.86) | 9.60 (7.48) | ||||||||
| Median (IQR) | 14.50 (7.00 - 25.00) | 16.00 (9.00 - 27.50) | 7.00 (4.50 - 11.50) | ||||||||
| Range | 0.00 - 95.00 | 0.00 - 95.00 | 2.00 - 35.00 | ||||||||
| Epinephrine mean dosing interval, min | 0.038 | 194 | 0.82 | 0.620 - 1.062 | 0.148 | ||||||
| Mean (SD) | 3.23 (1.49) | 3.30 (1.36) | 2.90 (1.96) | ||||||||
| Median (IQR) | 3.17 (2.00 - 4.00) | 3.29 (2.50 - 4.07) | 2.50 (1.50 - 3.71) | ||||||||
| Range | 0.00 - 9.00 | 0.50 - 8.50 | 0.00 - 9.00 | ||||||||
| Categorization of epinephrine dosing interval | 0.156 | 194 | |||||||||
| 3–5min | 90 (46.39 %) | 78 (49.06 %) | 12 (34.29 %) | Ref | Ref | ||||||
| < 3min | 87 (44.85 %) | 66 (41.51 %) | 21 (60.00 %) | 2.068 | 0.960 - 4.634 | 0.068 | 0.568 | 0.176 - 1.808 | 0.339 | ||
| > 5min | 17 (8.76 %) | 15 (9.43 %) | 2 (5.71 %) | 0.867 | 0.127 - 3.622 | 0.86 | 1.588 | 0.190 - 9.424 | 0.629 | ||
n, population number ( %).
Pearson’s Chi-squared test; Fisher’s exact test; Wilcoxon rank sum test.
OR, Odds Ratio; CI, confidence interval; min, minutes; OR, odds ratio; CPR, cardiopulmonar resuscitation; SD, Standart deviation; IQR, interquartile range.
One-year survival neurologic status outcome
Among the 36 patients who were alive after one-year CPR, the PCPC score of 6 patients changed from favorable (PCPC score of 1 or 2) to unfavorable (PCPC score of 3 or 4), indicating that only 16.6 % of survivors experienced worsened neurological status after one-year (p = 0.01). No association was found between the epinephrine doses and neurological prognosis at one year (Table 4), but an association was found between fewer epinephrine doses and favorable neurological outcomes at one year (OR: 2.79; 95 % CI 1.26–8.70; p = 0.02).
Table 4.
One-year survival neurological status outcome, univariable and multivariable analysis.
| One-year survival PCPC |
Univariable model |
Multivariable model |
||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall, n = 361 | 1 + 2, n = 251 | 3 + 4, n = 111 | p-value2 | n | OR3 | 95 % CI3 | p-value | n | OR3 | 95 % CI3 | p-value | |
| Previous vasoactive infusion | 0.4 | 36 | ||||||||||
| No | 29 (80.56 %) | 19 (76.00 %) | 10 (90.91 %) | — | — | Ref | — | — | ||||
| Yes | 7 (19.44 %) | 6 (24.00 %) | 1 (9.09 %) | 0.317 | 0.016 - 2.227 | 0.317 | 0.045 | 0,05 | 0.000, 0.914 | 0.125 | ||
| Total epinephrine doses | 0.487 | 36 | 1.445 | 0.966 - 2.440 | 0.102 | 2.907 | 2.793 | 1.260, 8.702 | 0.029 | |||
| Mean (SD) | 3.00 (1.79) | 2.64 (0.95) | 3.82 (2.82) | |||||||||
| Median (IQR) | 2.00 (2.00 - 3.00) | 2.00 (2.00 - 3.00) | 2.00 (2.00 - 5.00) | |||||||||
| Range | 2.00 - 10.00 | 2.00 - 5.00 | 2.00 - 10.00 | |||||||||
| Duration of CPR, min | 0.797 | 36 | 1.022 | 0.928 - 1.121 | 0.632 | 0.829 | 0.836 | 0.619, 1.044 | 0.158 | |||
| Mean (SD) | 10.08 (7.68) | 9.68 (6.71) | 11.00 (9.85) | |||||||||
| Median (IQR) | 7.50 (5.00 - 12.00) | 7.00 (5.00 - 12.00) | 8.00 (5.00 - 10.50) | |||||||||
| Range | 2.00 - 35.00 | 2.00 - 25.00 | 3.00 - 35.00 | |||||||||
| Time to first epinephrine dose | 0.053 | 36 | 0.542 | 0.204 - 0.964 | 0.105 | |||||||
| Mean (SD) | 1.28 (2.12) | 1.68 (2.38) | 0.36 (0.92) | |||||||||
| Median (IQR) | 0.00 (0.00 - 2.00) | 1.00 (0.00 - 3.00) | 0.00 (0.00 - 0.00) | |||||||||
| Range | 0.00 - 10.00 | 0.00 - 10.00 | 0.00 - 3.00 | |||||||||
| Epinephrine mean dosing interval, min | 0.705 | 36 | 0.874 | 0.513 - 1.381 | 0.582 | 1.051 | ||||||
| Mean (SD) | 2.82 (1.58) | 2.91 (1.68) | 2.60 (1.40) | |||||||||
| Median (IQR) | 2.50 (1.50 - 3.69) | 2.50 (1.50 - 3.75) | 2.50 (1.25 - 3.58) | |||||||||
| Range | 1.00 - 8.00 | 1.00 - 8.00 | 1.00 - 5.00 | |||||||||
| Categorization of epinephrine interval dosing | 14 (38.89 %) | 9 (36.00 %) | 5 (45.45 %) | 0.806 | 36 | |||||||
| 3–5min | 21 (58.33 %) | 15 (60.00 %) | 6 (54.55 %) | — | — | — | — | |||||
| < 3min | 1 (2.78 %) | 1 (4.00 %) | 0 (0.00 %) | 0.72 | 0.167 - 3.149 | 0.656 | 0.831 | 0.079, 8.815 | 0.874 | |||
| > 5min | NA | NA | ||||||||||
PCPC, Pediatric Cerebral Performance Category.
n, population number ( %).
Pearson’s Chi-squared test; Fisher’s exact test; Wilcoxon rank sum test.
OR, Odds Ratio, CI, confidence interval; min, minutes; OR, odds ratio; CPR, cardiopulmonar resuscitation; SD, Standart deviation; IQR, interquartile range.
Discussion
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.
Grant/Funding source
Without institutional involvement, all costs were borne by the authors.
Data availability
The data that support the findings of this study are available from the corresponding author.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
The authors report no acknowledgements.
Editor: R. Soibelmann Procianoy
Footnotes
Institution or service with which the work is associated for indexing in Index Medicus/MEDLINE: Study conducted at Universidade de São Paulo (USP), Faculdade de Medicina, Hospital das Clínicas, Pronto Socorro do Instituto da Criança e do Adolescente, São Paulo, SP, Brazil.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available from the corresponding author.