Updates in Pediatric Cardiac Arrest

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Pediatric cardiac arrests are, potentially, some of the most challenging patients for an emergency physician to care for. Cognitively, emotionally; these patients push us to our very limits. In this journal club recap, we cover 3 recently published articles looking at the care of these patients. Should survivors be cooled? Is Epi any good? Which is better amiodarone or lidocaine?

We recap 3 recently published articles that look at various aspects of caring for pediatric cardiac arrest patients. Is Epi helpful? Therapeutic hypothermia or normothermia - which is better? Is old school lidocaine better than amiodarone?


Moler, F., Silverstein, F., Holubkov, R., Slomine, B., Christensen, J., Nadkarni, V., Meert, K., Clark, A., Browning, B., Pemberton, V., Page, K., Shankaran, S., Hutchison, J., Newth, C., Bennett, K., Berger, J., Topjian, A., Pineda, J., Koch, J., Schleien, C., Dalton, H., Ofori-Amanfo, G., Goodman, D., Fink, E., McQuillen, P., Zimmerman, J., Thomas, N., Jagt, E., Porter, M., Meyer, M., Harrison, R., Pham, N., Schwarz, A., Nowak, J., Alten, J., Wheeler, D., Bhalala, U., Lidsky, K., Lloyd, E., Mathur, M., Shah, S., Wu, T., Theodorou, A., Sanders, R., Dean, J. (2015). Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children The New England Journal of Medicine 372(20), 1898-1908. https://dx.doi.org/10.1056/nejmoa1411480

Goal: Determine if therapeutic hypothermia confers a survival with good functional outcome benefit over therapeutic normothermia in pediatric out of hospital cardiac arrest.

Methods:

  • Prospective, randomized, multi-center (38 PICUs) trial enrolling N=295 patients

  • Inclusion: Children (age 48 hours - 18 years), cardiac arrest (chest compressions for >2 min), ROSC attained, required mechanical ventilation after ROSC

  • Exclusion (not exhaustive): GCS 5 or 6, major trauma or bleeding, terminal illness, hypothermia as cause of arrest, also 208 were excluded “had a clinical team that decided to withhold aggressive treatment”

  • Protocol

    • Arm 1: 33 degrees for 48 hours

    • Arm 2: 36.8 degrees for 48 hours

    • After initial 48 hours ALL PATIENTS were then kept at 36.8 degrees for another 72 hours


Primary Outcomes (*NONE of the following demonstrated statistical significance)

  • Survival at 1 year: 38% hypothermia, 29% normothermia

  • Survival at 1 year with VABS-II >70: 20% hypothermia, 12% normothermia

    • VABS-II is an age-adjusted multi-variable score that attempts to quantify neurologic function (points given for things like communication, motor function, social skills, etc.); 0 is bad, 100 is good.


Secondary Outcomes (*NONE of the following demonstrated statistical significance)

  • Need for blood transfusion: 54% both groups

  • Serious arrhythmia: 11% hypothermia, 9% normothermia

  • Culture-proven infections: 46% hypothermia, 39% normothermia


Discussion

  • Difficult to say whether study was underpowered to detect a difference in the primary outcome or if no difference exists

    • Sample size was set to detect an absolute effect size of 15-20% (8% demonstrated in the trial)

    • Neonatal and adult data suggests a benefit for hypothermia

    • Possibility that benefit is derived from prevention of fever, and not hypothermia itself, as other trials with control group = no temperature regulation seem to have an easier time demonstrating benefit vs trials with control group = targeted normothermia.

    • No consensus here from AHA: 'reasonable to cool these patients or do targeted normothermia'

    • No consensus from major pediatric centers, either

  • What we do know is that aberrant physiology is usually harmful to the vulnerable brain (post-ROSC, TBI, etc.)

    • Aim to avoid fever, hypoxia, hyperoxia, hypocapnia, hypotension, seizures, elevated ICP


Matsuyama, T., Komukai, S., Izawa, J., Gibo, K., Okubo, M., Kiyohara, K., Kiguchi, T., Iwami, T., Ohta, B., Kitamura, T.(2020). Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac ArrestJournal of the American College of Cardiology 75(2), 194-204. https://dx.doi.org/10.1016/j.jacc.2019.10.052

This study was a population based observational study that looked at prehospital administration of epinephrine in pediatric out-of-hospital cardiac arrest. This study was performed in Japan and used a national registry to collect data from January 2007 to December 2016 on pediatric patients 8 to 17 years old that suffered cardiac arrest in the pre-hospital setting. They want to address resuscitation time bias where longer resuscitation attempts are likely to have more interventions and these interventions may lean towards harm given worse prognosis in longer arrests. To accomplish this, they used time-dependent propensity score-sequential matching where patients that had received epinephrine were matched to patients that were at risk of receiving epinephrine at that same time point but had not yet received epinephrine.  They only had 306 patients that received epinephrine and matched 608 patients. They found that epinephrine lead to a significant difference in pre-hospital ROSC. However, there was no significant difference in 1-month survival and 1-month survival with favorable neurological outcomes.

This study is valuable in that it provides further knowledge where little evidence had previously existed. However, it might be underpowered that find statistical differences for 1-month survival and survival with favorable neurological outcomes with only 306 patients that had received epinephrine. Furthermore, this study was performed in Japan and there are differences in the Japanese EMS system such as epi is not given to patients younger than 8, IO access cannot be obtained in the field, and only specialized technicians are allowed to administer IV medications. And finally, propensity score matching may introduce further bias because only observable confounders are taken into account. 

Holmberg, M., Ross, C., Atkins, D., Valdes, S., Donnino, M., Andersen, L., Guerguerian, A., Foglia, E., Fink, E., Lasa, J., Roberts, J., Duval-Arnould, J., Bembea, M., Gaies, M., Kleinman, M., Gupta, P., Sutton, R., Sawyer, T. (2020). Lidocaine versus Amiodarone for Pediatric In-Hospital Cardiac Arrest: An Observational Study Resuscitation 149(), 191-201. https://dx.doi.org/10.1016/j.resuscitation.2019.12.033

Background

In-hospital cardiac arrest occurs in thousands of children each year in the United States, with a mortality rate of up to 60%. Ventricular fibrillation and pulseless ventricular tachycardia, although not the most common presenting rhythms in pediatric cardiac arrests, may present in a shock-refractory state and confer high mortality rates if unable to be treated. There is a paucity of pediatric literature assessing patient outcomes with use of any particular antiarrhythmic in shock-refractory cases, with the majority of updated recommendations in pediatric advance life support (PALS) based on small case series or adult studies. Thus, Holmberg et.al. sought to compare outcomes in pediatric cardiac arrest patients receiving amiodarone or lidocaine for shock-refractory ventricular fibrillation or ventricular tachycardia.

Study Design

  • Prospective, observational cohort study of pediatric patients who suffered from an in-hospital cardiac arrest with an initial or subsequent shockable rhythm between 2000-2018 with data available through the Get With the Guidelines – Resuscitation registry.

  • Inclusion criteria: age less than 18, initial or subsequent shockable rhythm, and administration of amiodarone or lidocaine at any time during arrest

  • Exclusion criteria: return of spontaneous circulation (ROSC) within 2 minutes of arrest, administration of both amiodarone and lidocaine, or any missing data on covariates or primary outcome (excluded from primary analysis)

  • 471 patients identified with patient demographics and event characteristics (first pulseless rhythm, time to epinephrine, time to intubation, time to initiation of chest compressions) available

  • Primary outcome: sustained ROSC

  • Secondary outcomes: survival to 24 hours, survival to hospital discharge, survival to hospital discharge with a favorable neurological outcome 

Analysis

  • Primary analysis: complete case analysis with propensity score matching (amiodarone (N=90) and lidocaine (N=90))

  •  Secondary analyses: 

    • Subgroup analysis for age group, year in which cardiac arrest took place, sequence of shockable rhythm, illness category

    • Sensitivity analysis to account for 106 missing patient data

Results

There was no statistical difference in ROSC, survival to 24 hours, survival to hospital discharge, or survival to hospital discharge with a favorable neurological outcome in the primary analysis, subgroup analysis, or sensitivity analysis.

Limitations

  • Despite the robust amount of patient and event characteristics available to the authors, there was no data on timing or dosage of the antiarrhythmic administered – this could very well lead to concern for confounding factors

  • The overall sample size after propensity score matching (from an initial identified patient population of 471 to 180) was small, and likely underpowered the study to detect any true difference in patient outcome between the lidocaine and amiodarone groups

  • There were a large number of patients with one or more missing variables, leading to selection bias and possible underlying confounding

Conclusion

Although the numerous iterations of analysis and propensity score matching techniques resulted in no significant difference in clinical outcomes when using amiodarone versus lidocaine in in-hospital pediatric cardiac arrests with shockable rhythms, the small sample size, missing patient variables, and lack of antiarrhythmic timing and dosing characteristics likely led to underpowering of the study and introduced confounding factors. Further research is likely warranted to further assess patient outcomes with use of lidocaine versus amiodarone in pediatric cardiac arrest with shock-refractory ventricular arrhythmias.

References

  1. Matsuyama, T., Komukai, S., Izawa, J., Gibo, K., Okubo, M., Kiyohara, K., Kiguchi, T., Iwami, T., Ohta, B., Kitamura, T.(2020). Pre-Hospital Administration of Epinephrine in Pediatric Patients With Out-of-Hospital Cardiac ArrestJournal of the American College of Cardiology 75(2), 194-204. https://dx.doi.org/10.1016/j.jacc.2019.10.052

  2. Moler, F., Silverstein, F., Holubkov, R., Slomine, B., Christensen, J., Nadkarni, V., Meert, K., Clark, A., Browning, B., Pemberton, V., Page, K., Shankaran, S., Hutchison, J., Newth, C., Bennett, K., Berger, J., Topjian, A., Pineda, J., Koch, J., Schleien, C., Dalton, H., Ofori-Amanfo, G., Goodman, D., Fink, E., McQuillen, P., Zimmerman, J., Thomas, N., Jagt, E., Porter, M., Meyer, M., Harrison, R., Pham, N., Schwarz, A., Nowak, J., Alten, J., Wheeler, D., Bhalala, U., Lidsky, K., Lloyd, E., Mathur, M., Shah, S., Wu, T., Theodorou, A., Sanders, R., Dean, J. (2015). Therapeutic Hypothermia after Out-of-Hospital Cardiac Arrest in Children The New England Journal of Medicine 372(20), 1898-1908. https://dx.doi.org/10.1056/nejmoa1411480

  3. Holmberg, M., Ross, C., Atkins, D., Valdes, S., Donnino, M., Andersen, L., Guerguerian, A., Foglia, E., Fink, E., Lasa, J., Roberts, J., Duval-Arnould, J., Bembea, M., Gaies, M., Kleinman, M., Gupta, P., Sutton, R., Sawyer, T. (2020). Lidocaine versus Amiodarone for Pediatric In-Hospital Cardiac Arrest: An Observational Study Resuscitation 149(), 191-201. https://dx.doi.org/10.1016/j.resuscitation.2019.12.033

Authorship

  • Moler et al - Jim Makinen, MD, PGY-3, University of Cincinnati Department of Emergency Medicine

  • Matsuyama et al - Eileen Hall, MD, PGY-3, University of Cincinnati Department of Emergency Medicine

  • Holmberg et al - Sim Mand, MD, PGY-3, University of Cincinnati Department of Emergency Medicine

  • Posting and Editing - Jeffery Hill, MD MEd