Epinephrine in the Pediatric Intensive Care Unit: A Dose-Effect Trial

Study Overview
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Brief Summary
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The use of peri-arrest bolus epinephrine (PBE) has emerged as a rescue strategy for life-threatening hypotension in pediatric intensive care units (ICU) despite scant published data supporting its use in this setting. As optimal dosing of PBE in this population is unclear, we aim to determine if an initial dose of 0.5 mcg/kg versus 1.0 mcg/kg yields differences in hemodynamic outcomes. The EPI Dose Study is a single-center, prospective, randomized, double-blind, dose-effect trial measuring systolic blood pressure (SBP) before and after PBE is given. We hypothesize that the 1.0 mcg/kg group will have more robust increases in SBP.

Detailed Description
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In order to test the hypothesis that PBE doses of 1.0 mcg/kg will have more robust increases in SBP as compared to 0.5 mcg/kg in critically ill children and young adults with acute hypotension, we plan to conduct a Phase II, single-center, prospective, randomized, double-blind, dose-effect trial. Children and young adults <26 years of age who, at the discretion of the clinical team, require rescue PBE for life-threatening hypotension and meet inclusion/exclusion criteria will be enrolled. Prior to randomization, our pharmacy team will prepare treatment packets with 3 pre-mixed PBE which will be stocked in the ICUs with either 5 mcg/mL or 10 mcg/mL of epinephrine. Clinicians will be instructed to use 0.1 mL/kg of the experimental syringe for the initial dose, resulting in target doses of 0.5 mcg/kg (Arm 1) or 1 mcg/kg (Arm 2), respectively. Treatment packs will be labeled according to the randomization scheme, and only the pharmacy team will have knowledge of the concentration of epinephrine in each package. Nurses will be instructed to record the exact time of the experimental dose, around which all time-sensitive data will be collected. The clinicians, patients and research team will be blinded to the intervention. We will not restrict any other interventions chosen by the clinical team. Unblinded interim analyses will be performed after the first 6 months of enrollment, and every 12 months thereafter through study completion and reported to the Data and Safety Monitoring Board (DSMB).

Official Title
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Epinephrine in the Pediatric Intensive Care Unit: A Dose-Effect Trial (EPI Dose)

Conditions
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Hypotension

Intervention / Treatment
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* Drug: Epinephrine 0.5 mcg/kg
* Drug: Epinephrine 1 mcg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female less than 26 years of age. Admitted to BCH and receiving care in a participating ICU. Is prescribed BDE for acute hypotension deemed to be life-threatening in the judgement of the treating clinician. Exclusion Criteria: Has opted out of the study prior to enrollment. Has orders in place which limit resuscitation efforts. Is actively receiving chest compressions while PBE is administered. Is receiving care in the neonatal intensive care unit. Is receiving care outside of the ICU at the time PBE is administered (i.e procedural areas). Is pregnant or breastfeeding. Is a prisoner. Is a ward if the state (DCF custody).

Ages Eligible for Study
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Maximum Age: 25 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 0.5 mcg/kg Dose<br>Providers use 0.1 mL/kg of 5 mcg/mL epinephrine for target dose 0.5 mcg/kg | Drug: Epinephrine 0.5 mcg/kg<br>* Syringe with 5 mcg/mL epinephrine<br>* Other names: Peri-Arrest Bolus Epinephrine;|
| Active Comparator: 1.0 mcg/kg Dose<br>Providers use 0.1 mL/kg of 10 mcg/mL epinephrine for target dose of 1.0 mcg/kg | Drug: Epinephrine 1 mcg/kg<br>* Syringe with 10 mcg/mL epinephrine<br>* Other names: Peri-Arrest Bolus Epinephrine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Systolic Blood Pressure | The lowest systolic blood pressure value in the 5 minutes prior to or up to 1 minute after the documented time of PBE administration (nadir) subtracted from the highest systolic blood pressure in the 5 minutes following PBE (must be subsequent to the nadir). If an additional dose of PBE was administered within 5 minutes of the initial dose, the peak SBP will be the highest value recorded prior to the subsequent dose. Primary analysis will be performed with an intention-to-treat approach based on the concentration of study drug received. An exploratory analysis will be performed per protocol based on the actual volume of study drug the patient received on first administration being within 20% of the intended volume. Patients who received ≥0.4 to ≤0.6 mcg/kg will be considered in the 0.5 mcg/kg group whereas patients who received ≥0.8 to ≤1.2 mcg/kg will be considered in the 1 mcg/kg group. | 10 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Severe (Stage II) Hypertension | The proportion of patients whose peak systolic blood pressure (determined as per the primary outcome) is greater than or equal to the 95th percentile plus 12 mmHg or greater than or equal to 140 mmHg, whichever is lower. | 5 minutes |