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When efforts to resuscitate a child after cardiac arrest are unsuccessful despite the administration of an initial dose of epinephrine, it is unclear whether the next dose of epinephrine (i.e., the rescue dose) should be the same (standard) dose or a higher dose.
We performed a prospective, randomized, double-blind trial to compare high-dose epinep...
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The Nationwide Inpa...
Citations
... et al. (2015) included the following example provided byPerondi et al. (2004): "Children who remain in cardiac arrest after cardiopulmonary resuscitation are administered with an initial standard dose of epinephrine. If resuscitation is unsuccessful, should the next dose be the same dose or a higher dose?" ...
It is commonly necessary to perform inferences on the difference, ratio, and odds ratio of two proportions p1 and p2 based on two independent samples. For this purpose, the most common asymptotic statistics are based on the score statistics (S-type statistics). As these do not correct the bias of the estimator of the product pi (1-pi), Miettinen and Nurminen proposed the MN-type statistics, which consist of multiplying the statistics S by (N-1)/N, where N is the sum of the two sample sizes. This paper demonstrates that the factor (N-1)/N is only correct in the case of the test of equality of two proportions, providing the estimation of the correct factor (AU-type statistics) and the minimum value of the same (AUM-type statistics). Moreover, this paper assesses the performance of the four-type statistics mentioned (S, MN, AU and AUM) in one and two-tailed tests, and for each of the three parameters cited (d, R and OR). We found that the AUM-type statistics are the best, followed by the MN type (whose performance was most similar to that of AU-type). Finally, this paper also provides the correct factors when the data from a multinomial distribution, with the novelty that the MN and AU statistics are similar in the case of the test for the odds ratio.
... As another illustration, consider Fagerland, Lydersen, and Laake (2015), where the authors compare two survival rates, 1 p and 2 p , of children who undergo a "standard" dose or "high" dose of epinephrine after an initial standard dose of epinephrine seems to be ineffective for children who remain in cardiac arrest. Perondi et al. (2004) conducted the original experiment, from which was observed 7 of 34 patients who survived at 24 hours after a standard dose, and also observed 1 of 34 who survived at 24 hours after a high dose. Of main interest for these two articles was the direct comparison of 1 p with 2 p , whose point estimates are 0.21 and 0.03. ...
Interval estimation of a binomial proportion has had a consistent presence in the statistical literature through the years. Many interval procedures have been developed for a single proportion as well as for the difference of two proportions. However, little work has been conducted on the joint estimation of two binomial proportions. In this paper, we construct four confidence regions for two binomial proportions based on three statistics: the Wald (W), adjusted Wald (W*), score (S), and likelihood ratio (LR) statistics. Once the regions have been established, we compare their coverage probabilities and average areas for different parameter and sample size configurations. For small-to-moderate sample sizes, this paper finds that the three regions based on the W*, S, and LR statistics have good coverage properties, with the score region usually having the smallest average area. Finally, we apply these four confidence regions to some real data in veterinary science and medicine for the joint estimation of important proportions.
... Only 3 pediatric studies were included in the review, with a survival to hospital discharge ranging from 0 to 20% in the HDE group to 0 to 12% in the SDE group (10). These 3 randomized studies found that HDE therapy did not show any benefit over SDE therapy, either during IHCA or in the emergency department after failed prehospital resuscitation (7,8). Despite the need to follow guidelines during pediatric OHCA, no multicenter study has determined the proportion of patients receiving HDE during OHCA and no study has compared patients receiving HDE and SDE in a prehospital setting. ...
... P = 0.08). None of the 34 patients in the HDE group were alive at hospital discharge as compared with the 4 in the SDE group (7), and the main cause of arrest was respiratory. In our study, 10 (2.5%) patients from the HDE group and 14 (3.9%) from the SDE group were alive at D30 or hospital discharge. ...
Objectives:
The pediatric resuscitation guidelines recommend the use of 0. 01 mg kg-1 epinephrine during a cardiac arrest; an epinephrine dose higher than that is not recommended. The first aim of this study was to determine the administration rate of high epinephrine dose during pediatric out-of-hospital cardiac arrest. The second aim was to compare the survival status in patients who received high or standard doses of epinephrine.
Methods:
This was a multicenter comparative post-hoc study conducted between January 2011 and July 2021 based on the French National Cardiac Arrest Registry data. All prepubescent (boys < 12 years old, girls < 10 years old) victims of an out-of-hospital cardiac arrest were included. To compare survival status and control bias, patients who received a high epinephrine dose were matched with those who received a standard epinephrine dose using propensity score matching.
Results:
The analysis included 755 patients; 400 (53%) received a high dose and 355 (47%) received a standard dose of epinephrine. The median dose (mg kg-1) per bolus was higher in the high-dose group than that in the standard dose group (0.04 vs. 0.01 mg kg-1, P < 0.001). Before matching, there was no between-group difference in the 30-day survival rate or survival status at hospital discharge. Matching yielded 288 pairs; there was no between-group difference in the 30-day survival rate or survival at hospital discharge (High dose, n = 5; standard dose, n = 12; Odds ratios: 2.40, 95% confidence interval: 0.85-6.81). Only 2 patients in the standard dose group had a good neurological outcome.
Conclusion:
More than 50% of the patients did not receive the recommended epinephrine dose during resuscitation. There was no association between patients receiving a high dose or standard dose of epinephrine with the 30-day survival or survival status at hospital discharge. Collaboration across multiple cardiac arrest registries is needed to study the application of pediatric guidelines.
... we use the example in Table 2 in Fagerland, Lydersen, and Laake (2015), see Table 3. The data come from the randomized controlled trials (RCT) of epinephrine in children with cardiac arrest (Perondi et al. 2004). The results are shown in Table 4 and our new method has a shorter confidence interval. ...
Confidence interval (CI) for a proportion has been a topic discussed repeatedly in the literature because of its omnipresence in applications. A wide variety of CIs have been proposed since the Wald CI for a proportion performs quite poorly. Among them, the Wilson score interval is widely recommended. However, the Wilson score method suffers from the so-called "downward spikes" when the proportion is close to 0 or 1. Except for the exact methods which ensure the coverage probability be at least the nominal size, the performances of existing proposed methods are similar to the Wilson score CI or its slightly improved version at the cost of increased interval width or computational complexity. In this study, we propose a simple CI which has very good performance in the coverage probability, confidence width, and the location. Especially when the proportion is <20% or >80% the CI proposed has a shorter confidence width than the Wilson score method. In combination our new method with the Newcombe's hybrid way to construct CI for the difference of two independent proportions, we also get a better CI. ARTICLE HISTORY
... on According to current AHA guidelines, pediatric epinephrine IV dosing is 0.01 mg/kg of bodyweight for pediatric CA. 39 A study investigating the survival rate at 24 hours after CA using either high-dose epinephrine (0.1 mg/kg) or standard dose epinephrine (0.01 mg/kg) in pediatric patients found that high-dose IV epinephrine did not provide any benefits and may lead to worse outcomes compared with standard dose therapy. 40 However, this study only examined IV administration of epinephrine and not IO administration. Due to the alteration with bone marrow blood flow and the possible prolonged exposure to COMT and MAO, a higher dose of epinephrine may be necessary to improve resuscitative outcomes, when using IO epinephrine in the hypovolemic pediatric CA porcine model. ...
Background
Aims of the study were to determine the effects of humerus intraosseous (HIO) versus intravenous (IV) administration of epinephrine in a hypovolemic, pediatric pig model. We compared concentration maximum (Cmax), time to maximum concentration (Tmax), mean concentration (MC) over time and return of spontaneous circulation (ROSC).
Methods
Pediatric pig were randomly assigned to each group (HIO (n=7); IV (n=7); cardiopulmonary resuscitation (CPR)+defibrillation (defib) (n=7) and CPR-only group (n=5)). The pig were anesthetized; 35% of the blood volume was exsanguinated. pigs were in arrest for 2 min, and then CPR was performed for 2 min. Epinephrine 0.01 mg/kg was administered 4 min postarrest by either route. Samples were collected over 5 min. After sample collection, epinephrine was administered every 4 min or until ROSC. The Cmax and MC were analyzed using high-performance liquid chromatography. Defibrillation began at 3 min postarrest and administered every 2 min or until ROSC or endpoint at 20 min after initiation of CPR.
Results
Analysis indicated that the Cmax was significantly higher in the IV versus HIO group (p=0.001). Tmax was shorter in the IV group but was not significantly different (p=0.789). The MC was significantly greater in the IV versus HIO groups at 90 and 120 s (p<0.05). The IV versus HIO had a significantly higher MC (p=0.001). χ ² indicated the IV group (5 out of 7) had significantly higher rate of ROSC than the HIO group (1 out of 7) (p=0.031). One subject in the CPR+defib and no subjects in the CPR-only groups achieved ROSC.
Discussion
Based on the results of our study, the IV route is more effective than the HIO route.
... Studies have shown that higher doses of epinephrine lead to several adverse effects. Besides an association with higher mortality in an animal model (12), high dose epinephrine has been shown to cause severe rebound tachycardia, hypertension and ventricular arrhythmias following ROSC (13). The presence of fetal lung fluid and high pulmonary vascular resistance with low pulmonary blood flow may impair absorption of ET epinephrine at birth (14). ...
Background:
Distressed infants in the delivery room and those that have completed postnatal transition are both resuscitated according to established neonatal resuscitation guidelines, often with endotracheal (ET) epinephrine at the same dose. We hypothesized that ET epinephrine would have higher bioavailability in a post-transitional compared to transitioning newborn model due to absence of fetal lung liquid and intra-cardiac shunts.
Methods:
15 term fetal (transitioning newborn) and 6 postnatal lambs were asphyxiated by umbilical cord and ET tube occlusion respectively. Lambs were resuscitated after 5 min of asystole. ET epinephrine (0.1 mg/kg) was administered after 1 min of positive pressure ventilation (PPV) and chest compressions, and repeated 3 min later, followed by intravenous (IV) epinephrine (0.03 mg/kg) every 3 min until return of spontaneous circulation (ROSC). Serial plasma epinephrine concentrations were measured.
Results:
Peak plasma epinephrine concentrations were lower in transitioning newborns as compared to postnatal lambs: after a single ET dose (145.36 ± 135.5 ng/ml vs 553.54 ± 215 ng/ml, p < 0.01) and after two ET doses (443 ± 192.49 ng/ml vs 1406 ± 420.8 ng/ml, p < 0.01). The rates of ROSC with a single ET dose were similar in both groups (40% vs 50% in newborn and postnatal respectively, p > 0.99). There was a higher incidence of post-ROSC tachycardia and increased carotid blood flow in the postnatal group.
Conclusions:
In the postnatal period, ET epinephrine at currently recommended doses resulted in higher peak epinephrine concentrations, post-ROSC tachycardia and cerebral reperfusion without significant differences in incidence of ROSC. Further studies evaluating the optimal dose of ET epinephrine during the postnatal period are warranted.
... Especially in paediatric patients there is a higher risk of administering an improperly dosed drug [8]. A calculation error does not necessarily mean clinical harm, but medication errors in children often include a factor of 10 or more [9][10][11] which can be fatal as shown in the case of adrenaline dosing [12]. The emergency tapes or rulers are physically positioned parallel to the child and depending on child's length, an ordinal length category is determined, which consecutively recommends medication dosing, equipment size and a child's weight range accordingly. ...
The aim of this study was to test the feasibility and accuracy of a smartphone application to measure the body length of children using the integrated camera and to evaluate the subsequent weight estimates. A prospective clinical trial of children aged 0-<13 years admitted to the emergency department of the University Children's Hospital Zurich. The primary outcome was to validate the length measurement by the smartphone application «Optisizer». The secondary outcome was to correlate the virtually calculated ordinal categories based on the length measured by the app to the categories based on the real length. The third and independent outcome was the comparison of the different weight estimations by physicians, nurses, parents and the app. For all 627 children, the Bland Altman analysis showed a bias of -0.1% (95% CI -0.3-0.2%) comparing real length and length measured by the app. Ordinal categories of real length were in excellent agreement with categories virtually calculated based upon app length (kappa = 0.83, 95% CI 0.79-0.86). Children's real weight was underestimated by physicians (-3.3, 95% CI -4.4 to -2.2%, p < 0.001), nurses (-2.6, 95% CI -3.8 to -1.5%, p < 0.001) and parents (-1.3, 95% CI -1.9 to -0.6%, p < 0.001) but overestimated by categories based upon app length (1.6, 95% CI 0.3-2.8%, p = 0.02) and categories based upon real length (2.3, 95% CI 1.1-3.5%, p < 0.001). Absolute weight differences were lowest, if estimated by the parents (5.4, 95% CI 4.9-5.9%, p < 0.001). This study showed the accuracy of length measurement of children by a smartphone application: body length determined by the smartphone application is in good agreement with the real patient length. Ordinal length categories derived from app-measured length are in excellent agreement with the ordinal length categories based upon the real patient length. The body weight estimations based upon length corresponded to known data and limitations. Precision of body weight estimations by paediatric physicians and nurses were comparable and not different to length based estimations. In this non-emergency setting, parental weight estimation was significantly better than all other means of estimation (paediatric physicians and nurses, length based estimations) in terms of precision and absolute difference.
... atric cardiac arrest and noted a paucity of supporting evidence. 84,85 For pediatric IHCA, the use of high-dose epinephrine has been shown to be harmful compared with standard-dose epinephrine, 97 but there are no placebo-controlled studies. A recent retrospective registry study of time to epinephrine in pediatric IHCA for patients with nonshockable rhythms showed that delay to epinephrine administration was associated with reduced ROSC, survival to discharge, and favorable neurological outcome. ...
Despite significant advances in the field of resuscitation science, important knowledge gaps persist. Current guidelines for resuscitation are based on the International Liaison Committee on Resuscitation 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, which includes treatment recommendations supported by the available evidence. The writing group developed this consensus statement with the goal of focusing future research by addressing the knowledge gaps identified during and after the 2015 International Liaison Committee on Resuscitation evidence evaluation process. Key publications since the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations are referenced, along with known ongoing clinical trials that are likely to affect future guidelines.
... A pediatric prospective, randomized, double-blind, controlled trial comparing high-dose (0.1 mg/kg) versus standard dose (0.01 mg/kg) epinephrine for in-hospital cardiac arrest demonstrated that high-dose epinephrine was associated with worse 24-hour survival. 413 Epinephrine produces undesirable dose-related effects, such as increased myocardial oxygen consumption, so the goal of therapy is use of the lowest effective dose. If epinephrine does not produce improved hemodynamic function and the patient is thought to be an ECLS candidate, then the focus of the resuscitation should be the delivery of high-quality CPR and rapid activation of ECLS, rather than the administration of repetitive doses of epinephrine. ...
... In addition, potential reperfusion brain injury can be made worse by therapies aimed at myocardial support. 413,642,643 Myocardial Management ...
... 651 However, epinephrine leads to high afterload and increased myocardial oxygen consumption in the initial post-cardiac arrest phase at the time when the myocardium is most vulnerable to increased oxygen demands and imbalance of oxygen supply versus delivery. 413,652 This concern for increasing myocardial work at a time of myocardial vulnerability has led to the evaluation of alternative vasoactive agents such as vasopressin and other agents in resuscitation. 653,654 Myocardial Support Hemodynamic instability is common after cardiac arrest, and pharmacological support is often needed. ...
Cardiac arrest occurs at a higher rate in children with heart disease than in healthy children. Pediatric basic life support and advanced life support guidelines focus on delivering high-quality resuscitation in children with normal hearts. The complexity and variability in pediatric heart disease pose unique challenges during resuscitation. A writing group appointed by the American Heart Association reviewed the literature addressing resuscitation in children with heart disease. MEDLINE and Google Scholar databases were searched from 1966 to 2015, cross-referencing pediatric heart disease with pertinent resuscitation search terms. The American College of Cardiology/American Heart Association classification of recommendations and levels of evidence for practice guidelines were used. The recommendations in this statement concur with the critical components of the 2015 American Heart Association pediatric basic life support and pediatric advanced life support guidelines and are meant to serve as a resuscitation supplement. This statement is meant for caregivers of children with heart disease in the prehospital and in-hospital settings. Understanding the anatomy and physiology of the high-risk pediatric cardiac population will promote early recognition and treatment of decompensation to prevent cardiac arrest, increase survival from cardiac arrest by providing high-quality resuscitations, and improve outcomes with postresuscitation care.
... on According to current AHA guidelines, pediatric epinephrine IV dosing is 0.01 mg/kg of bodyweight for pediatric CA. 39 A study investigating the survival rate at 24 hours after CA using either high-dose epinephrine (0.1 mg/kg) or standard dose epinephrine (0.01 mg/kg) in pediatric patients found that high-dose IV epinephrine did not provide any benefits and may lead to worse outcomes compared with standard dose therapy. 40 However, this study only examined IV administration of epinephrine and not IO administration. Due to the alteration with bone marrow blood flow and the possible prolonged exposure to COMT and MAO, a higher dose of epinephrine may be necessary to improve resuscitative outcomes, when using IO epinephrine in the hypovolemic pediatric CA porcine model. ...
Objective:
Compare the maximum concentration (Cmax), time to maximum concentration (Tmax), mean concentration, rate of return of spontaneous circulation (ROSC), time to ROSC, and odds of ROSC when epinephrine is administered by humerus intraosseous (HIO) compared to intravenous (IV) routes in both a hypovolemic and normovolemic cardiac arrest model.
Design:
Prospective, between subjects, randomized experimental study.
Setting:
TriService Facility.
Subjects:
Twenty-eight adult Yorkshire Swine were randomly assigned to four groups: HIO normovolemia; HIO hypovolemia; IV normovolemia; and IV hypovolemia.
Intervention:
Swine were anesthetized. The hypovolemic group was exsanguinated 31 percent of their blood volume. Subjects were placed into arrest. After 2 minutes, cardiopulmonary resuscitation (CPR) was initiated. After another 2 minutes, 1 mg epinephrine was given by IV or HIO routes; blood samples were collected over 4 minutes. Hypovolemic groups received 500 mL of 5 percent albumin following blood sampling. CPR continued until ROSC or for 30 minutes.
Main outcome measures:
ROSC, time to ROSC, Cmax, Tmax, mean concentrations over time, odds of ROSC.
Results:
Cmax was significantly higher, the Tmax, and the time to ROSC were significantly faster in the HIO normovolemic compared to the HIO hypovolemic group (p < 0.05). All seven in the HIO normovolemic group achieved ROSC compared to three of the HIO hypovolemic group. Odds of ROSC were 19.2 times greater in the HIO normovolemic compared the HIO hypovolemic group.
Conclusion:
The HIO is an effective route in a normovolemic model. However, the findings indicate that sufficient blood volume is essential for ROSC in a hypovolemic scenario.
