SCCM Resource Library-Epinephrine Dosing Intervals Are Associated With Pediatric Cardiac Arrest Outcomes

Video Transcription

Hi, everyone. My name is Martha Kinsley, and I am a junior faculty member in the Division of Critical Care Medicine at the Children's Hospital of Philadelphia.  I will be talking to you today about epinephrine dosing intervals and outcomes from pediatric in-hospital cardiac arrest.  I will first briefly review some background on the topic of epinephrine and cardiac arrest, including the recent study that informed this current work.  I will discuss my objectives and hypothesis, and then review methods, results, conclusions and offer some future directions. Epinephrine during CPR.  What can I say other than it's complicated? You are all well aware that data to support its use are limited and variable.  Most studies are retrospective and observational, and as cardiac arrest is heterogeneous and complex, it is a challenging event to study. What about dosing interval?  Both PALS and ACLS recommend giving epinephrine boluses every three to five minutes, but data to support this interval are, again, lacking.  In fact, recent large registry studies in pediatric and adult in-hospital cardiac arrest  have shown an association between the recommended interval of three to five minutes and worse outcomes compared to longer intervals.  In a pediatric study using the Get With The Guidelines registry, investigators compared one to five, five to eight, and eight to ten minute dosing intervals.  Importantly, patients with one to three minute intervals had similar outcomes to PALS recommended three to five minute intervals, and so those patients were combined.  While unadjusted odds ratios showed worse survival for longer intervals, after adjustment  for a priori confounders, including CPR duration, they actually found increased odds of event survival and survival to hospital discharge with intervals greater than five minutes.  These findings got us thinking. First, as actual administration times were not available, the intervals were estimated  and likely to overestimate the dosing interval because of how they were necessarily calculated.  CPR duration after the first dose of epinephrine was divided by the remaining doses of epinephrine.  This incorporates time between the final dose and Rosker death, which is not part of a true interval.  In a single center study, with code documentation available, we could calculate the actual intervals and partially overcome this limitation.  Second, does CPR duration confound the relationship between interval and outcome or mediate it?  We hypothesized that children given epinephrine more frequently than recommended by PALS would  lead to better diastolic blood pressure earlier in the arrest, faster Rosk, and thus better survival.  Thus, we conducted a single center retrospective cohort study of 125 index in hospital cardiac arrests.  We hand calculated epinephrine dosing intervals based on documented times on bedside code sheets rounded to the nearest minute and created an event level average for each patient,  which we refer to as calculated dosing interval. Adjusting for a priori confounders, we created logistic and linear regression models to explore  the association between dosing intervals of less than or equal to two minutes versus greater than two minutes and survival outcomes.  We called epinephrine given at least every two minutes frequent epi. We picked two minutes as the cutoff based on pharmacologic studies of epinephrine during  cardiac arrest in animal models, which suggests that a shorter dosing interval than currently recommended may be beneficial.  We found that epinephrine dosing intervals less than or equal to two minutes, aka frequent  epinephrine, were associated with our primary outcome of survival to discharge with a favorable neurologic status.  Frequent epinephrine was also associated with improved odds of survival to discharge and Rosk and shorter CPR duration by 15 minutes.  In a subset of patients with arterial lines, we showed that patients exposed to frequent epi see a significant increase in their diastolic blood pressure following a second dose of  epinephrine, providing a plausible mechanism for faster Rosk, less low flow time, and better neurologic survival.  With the recent conclusion of the ICU recess trial, we next sought to investigate frequent epinephrine using multicenter data.  The ICU recess trial was a prospective multicenter cluster randomized trial of a novel patient-centric  resuscitation care improvement bundle involving 18 US pediatric ICUs across 10 clinical sites.  Patients were included if they were greater than or equal to 37 weeks corrected gestational age and less than or equal to 18 years of age and had CPR of any duration.  Patients were excluded if they had a documented lack of commitment to aggressive ICU therapies, were brain dead, or had an out-of-hospital cardiac arrest associated with the current  hospitalization. Importantly, unlike in the single-center study, most ICU recess patients had data available  only for determining an estimated dosing interval, much like the Get With The Guidelines study I referenced earlier.  However, with the high-fidelity data collection of a multicenter trial, we felt some of the limitations of the large registry studies could be surmounted.  We explored the relationship between estimated and calculated dosing intervals in those patients  who had sufficient information available to determine both, about a quarter of subjects. On the y-axis is the estimated interval, the interval susceptible to overestimation.  On the x-axis is the calculated interval, which is the event-level average of actual intervals. You can see that the estimated interval is indeed higher than the calculated interval  in many cases, a mean of about 1 minute higher and a median of about 0.7 minutes higher. Thus, instead of a 2-minute cutoff, as in our single-center study, we chose a 3-minute  cutoff to best test our hypothesis using this data. We hypothesized that epinephrine given at intervals of less than 3 minutes would be  associated with improved survival-to-hospital discharge with a favorable neurobehavioral outcome compared to dosing intervals of greater than or equal to 3 minutes.  Our primary outcome was survival-to-hospital discharge with a favorable neurologic outcome defined as a PCPC score of 1 to 2 or no change from the patient's baseline.  Secondary outcomes were ROSC, survival-to-discharge, and CPR duration. We included indexed arrests from the ICU recess trial.  We excluded patients with fewer than two doses of epinephrine, those who underwent eCPR, and those with greater than 8-minute dosing intervals, which were presumed to reflect  intermittent return of circulation during the arrest. To examine the association between our exposure and outcomes, we used ordinary linear regression  or Poisson regression with robust error estimates and adjusted for a priori covariates, including  hospital and others associated with outcomes in pediatric cardiac arrest literature. There were 1,129 indexed arrests amongst ICU recess subjects.  After sequential exclusions, there were 382 arrests available for analysis. Among the final cohort, 286 received epinephrine at intervals of at least 3 minutes.  Ninety-six received epinephrine at intervals less than 3 minutes. I have collapsed some of the categorical variables for simplicity.  There was no significant association between dosing interval and the listed patient characteristics on univariate analysis.  This table shows pre-event characteristics, including PRISM score, presence of a vasoactive infusion at the start of the arrest, and VIS score.  Again, there were no associations between dosing interval and these covariates on univariate analysis.  Moving on to event characteristics, median CPR duration in minutes was significantly shorter for those receiving epinephrine at intervals less than 3 minutes on univariate analysis.  The same was true for CPR duration as a categorical variable. This table provides pharmacologic interventions by exposure group.  Both groups had the same median time to first epinephrine dose, and the less than 3 group received a half dose more, though it was not statistically significant.  The median dosing interval for the greater-than-or-equal-to-3-minute group was 4.5 minutes, compared to 2 minutes for the less than 3 group.  There were no differences among groups in other inter-arrest medications, but sodium bicarbonate did approach significance. This table shows a summary of outcomes.  The ROSC rates generally were very good, as well as neurologic outcomes amongst survivors. Patients with more frequent epinephrine had a higher rate of ROSC.  This table shows the results of our regression modeling of the association between dosing intervals and outcomes, both for the full cohort and then stratified by the presence  of a vasoactive infusion in place at the time of arrest. For our primary outcome, patients on a vasoactive infusion at the time of their arrest had a  significantly increased risk of good neurologic outcome when exposed to epinephrine at intervals of less than 3 minutes.  This was also seen for ROSC, but in the entire cohort, as well as those on a vasoactive infusion.  There was no difference in relative risk of survival-to-hospital discharge between groups, though results approached significance for those on a vasoactive infusion.  Lastly, in the linear regression model of the association of intervals with CPR duration, patients receiving epinephrine at less than 3-minute intervals had 9 fewer minutes of  CPR in the full cohort and 11 fewer minutes in the cohort of patients on a vasoactive infusion.  CPR duration for those not on a vasoactive infusion approached but did not reach significance for shorter CPR duration.  Estimated epinephrine dosing intervals of less than 3 minutes among indexed cardiac arrests in the ICU recess trial were associated with improved survival-to-hospital discharge  with a favorable neurobehavioral outcome in patients on a vasoactive infusion at the time of arrest.  These shorter intervals were also associated with improved ROSC and shorter CPR duration, and those findings were driven primarily by those on a vasoactive infusion at the time  of arrest. This is in contrast to our single-center study, which found the most robust survival benefit among patients not on a vasoactive infusion at the time of arrest.  These results challenged the current AHA-recommended dosing interval of 3-5 minutes, but randomized control trials are needed.  A trial could compare different intervals or a PALS-compliant versus patient-centric approach, meaning giving epinephrine only when intra-arrest blood pressure is low.  It is likely that one epinephrine dosing regimen does not suit every patient, and some likely do not need epinephrine at all.  A better understanding of this widely-used drug will allow us to maximize benefits in the right patients while minimizing toxicities in survivors of pediatric and hospital cardiac  arrest. I'd like to thank my primary mentors, Bobby Sutton, Ryan Morgan, and Bob Berg, as well as the rest of the co-authors on the project.  I'd like to thank Ron Reeder from University of Utah for statistical support, as well as all of the ICU-resusked investigators and research and clinical support.  Lastly, I'd like to thank SCCM for the opportunity to share my work through a star research presentation.  Thank you all so much for your time, and I hope to see you in person next year.

Video Summary

Dr. Martha Kinsley discusses the use of epinephrine in pediatric in-hospital cardiac arrest. She highlights the limited and variable data available regarding its effectiveness. Most studies have been retrospective and observational, making it difficult to determine optimal dosing intervals. A recent study found an association between shorter dosing intervals (less than or equal to 2 minutes) and better survival outcomes. Another multicenter study using the ICU recess trial data further supported these findings. Dr. Kinsley suggests that randomized controlled trials are needed to determine the most effective dosing regimen for epinephrine in pediatric cardiac arrest.

Asset Subtitle

Resuscitation, Pharmacology, Pediatrics, 2022

Asset Caption

INTRODUCTION: In a single-center observational study, epinephrine administered more frequently than recommended by the American Heart Association (≤2 minutes) was associated with improved outcomes from pediatric in-hospital cardiac arrest (p-IHCA). The objective of this study was to evaluate the association between epinephrine dosing intervals and outcomes in a multicenter study. We hypothesized that dosing intervals ≤2 minutes would be associated with survival compared to >2 minutes. METHODS: Subjects were children ≤18 years old and ≥37 weeks corrected gestational age who had an index cardiac arrest while admitted to one of the 18 participating ICUs of The ICU-RESUScitation Project (NCT028374497), a multicenter, cluster randomized interventional trial. Patients who received < 2 doses of epinephrine, received extracorporeal cardiopulmonary resuscitation (ECPR) or had a dosing interval >8 minutes were excluded (presumed intermittent return of spontaneous circulation [ROSC]). Frequent epinephrine was defined as an interval ≤2 minutes. Regression models evaluated the association between frequent epinephrine and 1) outcomes and 2) CPR duration. The primary outcome was survival with favorable neurobehavioral outcome (Pediatric Cerebral Performance Category score 1-3 or no change from baseline). RESULTS: Among 383 patients meeting inclusion and exclusion criteria, 200 (52%) were less than 1 year of age, 168 (44%) survived to hospital discharge and 157 (41%) survived with favorable neurobehavioral outcome. Fifty-four (14%) received frequent epinephrine. After adjustment for illness category, age, first documented rhythm, weekday vs night/weekend, clinical site, time to first epinephrine dose and Pediatric Risk of Mortality (PRISM) score, frequent epinephrine was not associated with survival with favorable neurobehavioral outcome (aOR 1.23, 95CI 0.92, 1.69, p = 0.18) or survival to discharge (aOR 1.19, CI95 0.89, 1.59, p = 0.26) but was associated with higher rates of ROSC (aOR 1.32, CI95 1.18, 1.48, p < 0.01) and shorter CPR duration (adjusted effect estimate -15.1 minutes, CI95 -20.9, -9.35, p < 0.01). CONCLUSIONS: In patients receiving at least two doses of epinephrine, frequent epinephrine was not associated with improved neurobehavioral outcome but was associated with improved odds of ROSC and shorter CPR duration.

Meta Tag

Content Type Presentation

Knowledge Area Resuscitation

Knowledge Area Pharmacology

Knowledge Area Pediatrics

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Cardiac Arrest

Tag Pharmacology

Tag Pediatrics

Tag Cardiopulmonary Resuscitation CPR

Year 2022

Keywords

epinephrine

pediatric in-hospital cardiac arrest

effectiveness

dosing intervals

survival outcomes

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