The PROTECT-HIE Pilot Trial (PROTECT-HIE)

The PROTECT-HIE Pilot Trial: Prophylactic Therapy to Enhance Cardiovascular Treatment in Neonatal Hypoxemic Ischemic Encephalopathy

Some babies experience a lack of oxygen and blood flow around the time of birth. This can lead to a serious condition called hypoxic-ischemic encephalopathy (HIE), which can injure the brain and other organs, including the heart. To reduce brain injury, babies with HIE are treated with therapeutic hypothermia, a standard treatment in which the baby's body temperature is carefully lowered for several days. While cooling helps protect the brain, many babies with HIE still develop heart problems and low blood flow, which may worsen outcomes.

Doctors often use medications to support the heart and circulation in these babies, but there is no clear agreement on which medication works best or when it should be started. One commonly used medication is dobutamine, which helps the heart pump more effectively. Dobutamine is already used in newborn intensive care units when babies show signs of heart weakness, but it is usually started only after problems develop.

The PROTECT-HIE trial aims to find out whether it is possible and safe to start dobutamine early, before clear signs of heart failure appear, in newborns with HIE who are receiving therapeutic hypothermia. The idea is that early support of the heart may improve blood flow to vital organs, including the brain, and potentially reduce injury.

In this study, 40 newborns with HIE will take part at a single neonatal intensive care unit. Babies will be randomly assigned to one of two groups. One group will receive a low, preventative dose of dobutamine within the first four hours after cooling begins. The other group will receive a placebo (an inactive fluid that looks the same). Neither the families nor the medical team assessing outcomes will know which treatment the baby received.

The main goal of this study is to determine feasibility-that is, whether starting dobutamine early during cooling can be done reliably and safely in this setting. Researchers will also collect information on important health outcomes, such as signs of brain injury on MRI, seizures, need for additional heart medications, heart function on ultrasound, recovery of blood markers, urine output, length of hospital stay, and survival.

Because HIE is an emergency condition and treatment must start very soon after birth, parents will be approached for consent after the baby has been stabilized. This approach is commonly used in neonatal emergency research and has been approved in similar studies.

The results of this study will help determine whether a larger trial should be done in the future. Ultimately, this research aims to improve care and outcomes for babies affected by HIE by optimizing support for the heart during a critical period after birth.

Study Overview

• Status: Not yet recruiting
• Conditions: Hypoxic-ischemic Encephalopathy (HIE)
• Intervention / Treatment: Drug: Dobutamine; Diagnostic test: TnECHO

Detailed Description

Purpose

The purpose of this study is to evaluate the feasibility and safety of initiating prophylactic dobutamine infusion in newborns with hypoxic-ischemic encephalopathy (HIE) who are undergoing therapeutic hypothermia (TH). Infants with HIE frequently experience cardiovascular instability during the early postnatal period, which may negatively affect cerebral perfusion and overall outcomes. This study aims to determine whether early, preventive cardiovascular support can be reliably implemented and whether it may be associated with improved short-term clinical outcomes.

Hypothesis

The primary hypothesis is that initiating prophylactic dobutamine infusion within the first four hours of therapeutic hypothermia in newborns with HIE is feasible and safe.

The secondary hypothesis is that early dobutamine prophylaxis may be associated with improved short-term in-hospital outcomes, including reduced severity of brain injury, improved cardiac function, and reduced need for escalation of cardiovascular support.

Justification

HIE remains a major cause of neonatal mortality and long-term neurodevelopmental impairment despite the widespread use of therapeutic hypothermia. Up to 80% of infants with HIE experience some degree of cardiovascular compromise, particularly involving right ventricular dysfunction, which has been associated with worse neurological outcomes and increased mortality.

Although vasoactive medications are frequently used in this population, there is no standardized or evidence-based approach regarding the optimal agent or timing of initiation. Dobutamine is a commonly used inotropic agent in neonates, with a favorable physiological profile that enhances cardiac contractility without significant increases in heart rate or systemic vascular resistance. Preliminary observational data suggest that dobutamine improves cardiac output in infants with HIE undergoing hypothermia.

Currently, dobutamine is typically initiated only after cardiovascular compromise becomes clinically apparent. A prophylactic approach, initiated early during therapeutic hypothermia, may help stabilize cardiac function, optimize systemic and cerebral perfusion, and potentially reduce secondary brain injury. Before a definitive efficacy trial can be conducted, it is necessary to establish the feasibility, safety, and protocol adherence of such an intervention. This pilot randomized controlled trial is designed to address that critical knowledge gap.

Objectives

Primary Objective

To determine the feasibility of initiating prophylactic dobutamine infusion within the first four hours of starting therapeutic hypothermia in newborns with HIE.

Secondary Objectives

To explore whether prophylactic dobutamine is associated with improved short-term clinical outcomes, including:

Presence and severity of brain injury on MRI Mortality Seizure activity (clinical or electrographic) Need for escalation of inotropic or vasoactive support Echocardiographic measures of cardiac function and pulmonary hemodynamics Time to normalization of lactate Duration of inhaled nitric oxide therapy, if required Urine output at 24, 48, and 72 hours Length of hospital stay until discharge or death Research Method / Procedures

This study is a single-center, double-blinded, randomized controlled feasibility trial conducted in a tertiary neonatal intensive care unit.

Eligible participants are newborns diagnosed with hypoxic-ischemic encephalopathy who are receiving therapeutic hypothermia. Infants will be excluded if they have congenital anomalies, contraindications to dobutamine, significant arrhythmias, or if they have already been started on inotropic support prior to randomization.

Participants will be randomized in a 1:1 ratio to either:

Intervention group: Prophylactic dobutamine infusion at 10 mcg/kg/min Control group: Placebo infusion (dextrose 5%) identical in appearance and administration Randomization will be computer-generated, with allocation concealment ensured through a secure REDCap system. The study will be double-blinded; parents, clinical staff, outcome assessors, and data analysts will remain unaware of group assignment until completion of the final analysis.

The assigned infusion (dobutamine or placebo) will be initiated within four hours of starting therapeutic hypothermia and continued until clinical improvement, escalation of cardiovascular support, or weaning at the discretion of the clinical team.

All participants will undergo standardized targeted neonatal echocardiography at two predefined time points during the first 48 hours. Clinical data will be collected throughout hospitalization, including laboratory results, imaging findings, medication use, adverse events, and outcomes.

Due to the emergency nature of HIE and the need for timely initiation of treatment, a deferred consent model will be used. Parents of surviving infants will be approached for written consent as soon as feasible after stabilization and prior to discharge. For infants who die before consent can be obtained, a waiver of consent will be requested for collection of minimal anonymized data.

Plan for Data Analysis

The primary analysis will focus on feasibility outcomes, including:

Proportion of eligible infants successfully receiving the intervention within four hours of initiating therapeutic hypothermia Protocol adherence rate The study will be considered feasible if more than 60% of eligible infants are recruited and more than 75% of randomized infants receive the assigned intervention without major protocol deviations.

Secondary clinical outcomes will be analyzed descriptively, as this pilot study is not powered to detect definitive efficacy differences. Continuous variables will be summarized using means, standard deviations, medians, and interquartile ranges as appropriate. Categorical variables will be reported as frequencies and percentages.

Comparisons between groups will be conducted using:

Student's t-test or Mann-Whitney U test for continuous variables Chi-square test for categorical variables All analyses will follow the intention-to-treat principle. Statistical significance will be defined as a two-sided p-value <0.05. Analyses will be performed using IBM SPSS and SAS statistical software after database lock and unblinding.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Aimann Surak, MD FRCPC; Phone Number: 780-735-4647; Email: aimann@ualberta.ca

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada
      • Royal Alexandra Hospital
      • Contact: Aimann Surak, MD FRCPC; Phone Number: 7807354647; Email: aimann@ualberta.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newborns with hypoxemic ischemic encephalopathy (HIE) receiving therapeutic hypothermia (TH).

Exclusion Criteria:

1. Congenital abnormality

2. known contraindication of dobutamine

   • Left ventricular outflow tract dynamic obstruction
   • Hypersensitivity to dobutamine
   • Uncorrected tachyarrhythmias or ventricular fibrillation
3. Newborns who are already started on inotropes at the time of randomization.
4. Parental refusal to consent to participate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dobutamine group; If randomized to the prophylaxis/dobutamine arm, dobutamine will be administered at a dose of 10 mcg/kg/min via intravenous access within 4 hours of initiating TH. As a part of standard care for HIE, a central umbilical venous access is routinely acquired whenever possible. We will use the dobutamine concentration of 2000 mcg/ml. The infusion will be prepared in dextrose 5% solution in 50 mL bags. Dobutamine monograph is attached to the protocol as well (Appendix F). The infusion will be continued until either weaned by the clinical team, escalation of inotropic support, or improvement of clinical situation to allow weaning of dobutamine.	Drug: Dobutamine; If randomized to the prophylaxis/dobutamine arm, dobutamine will be administered at a dose of 10 mcg/kg/min via intravenous access within 4 hours of initiating TH. As a part of standard care for HIE, a central umbilical venous access is routinely acquired whenever possible. We will use the dobutamine concentration of 2000 mcg/ml. The infusion will be prepared in dextrose 5% solution in 50 mL bags. Dobutamine monograph is attached to the protocol as well (Appendix F). The infusion will be continued until either weaned by the clinical team, escalation of inotropic support, or improvement of clinical situation to allow weaning of dobutamine.; Diagnostic test: TnECHO; In both groups, 2 TnECHOs will be performed. TnECHO T1 will be performed within the 24 hours of randomization, and TnECHO T2 will be performed within 24-48 hours after TnECHO T1. All echocardiographic assessments are done by physicians trained in TnECHO or by pediatric cardiology team. Echocardiographic assessment will be performed as per the American Society or Echocardiography guidelines(63-66). Details of the standardised echo views and measurements are outlined in Appendix B.
Placebo Comparator: Control group; Infants randomized to the placebo arm will receive an inert preparation containing no active pharmacologic agent. The placebo will be identical in appearance, volume, and method of administration to the active intervention and will be administered according to the same dosing schedule and duration. We will use dextrose 5% (as placebo), which will be started within 4 hours of initiating TH. The infusion will be continued until either weaned by the clinical team, escalation of inotropic support, or improvement of clinical situation to allow weaning of dobutamine.	Diagnostic test: TnECHO; In both groups, 2 TnECHOs will be performed. TnECHO T1 will be performed within the 24 hours of randomization, and TnECHO T2 will be performed within 24-48 hours after TnECHO T1. All echocardiographic assessments are done by physicians trained in TnECHO or by pediatric cardiology team. Echocardiographic assessment will be performed as per the American Society or Echocardiography guidelines(63-66). Details of the standardised echo views and measurements are outlined in Appendix B.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Feasibility/Safety	Proportion of eligible infants receiving the intervention (or placebo) within 4 hours of initiating TH	At 24 hours of age

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brain injury	Brain injury on MRI (normal/abnormal)	through study completion, an average of 1 month
Severity and type of brain injury	Severity and type of brain injury on head MRI [as per reference # 72 in the uploaded protocol, Mohammad K, et al. Consensus Approach for Standardization of the Timin]	through study completion, an average of 1 month
Mortality	Death (yes/no)	through study completion, an average of 1 month
Seizure activity	Presence of seizure activity either clinically or on EEG (yes/no)	through study completion, an average of 1 month
Need for escalation the inotropic support	Need for escalation the inotropic support (beyond the above-mentioned infusions) (yes/no)	through study completion, an average of 1 month
TAPSE in mm	Echocardiographic parameter	through study completion, an average of 1 month
RV FAC in %	Echocardiographic parameter	through study completion, an average of 1 month
LV EF in %	Echocardiographic parameter	through study completion, an average of 1 month
Time to normalizing lactate in hours	Time to normalizing lactate reported in hours (the cutoff for normal lactate is 3 as per local laboratory values)	through study completion, an average of 1 month
Duration of inhaled nitric oxide in hours	Duration of inhaled nitric oxide if needed reported in hours from the time of initiation to time of discontinuation	through study completion, an average of 1 month
Urine output in cc/k/hour	Urine output reported at 24, 48, and 72 hours reported in cc/k/hour	through study completion, an average of 1 month
Length of hospital stay in days	Length of stay in hospital in days defined from the date of birth till the date of discharge/death	through study completion, an average of 1 month

Collaborators and Investigators

• Sponsor: University of Alberta

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): April 30, 2029
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: January 29, 2026
• First Submitted That Met QC Criteria: February 10, 2026
• First Posted (Actual): February 12, 2026

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 2, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: dobutamine; therapeutic hypothermia; Hypoxic-ischemic encephalopathy; feasibility RCT; neonatal cardiac dysfunction; prophylactic inotrope; neonatal HIE
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Brain Ischemia; Signs and Symptoms, Respiratory; Hypoxia, Brain; Hypoxia; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Hypoxia-Ischemia, Brain; Organic Chemicals; Hydrocarbons; Hydrocarbons, Cyclic; Hydrocarbons, Aromatic; Amines; Catechols; Phenols; Benzene Derivatives; Phenethylamines; Ethylamines; Catecholamines; Dobutamine
• Other Study ID Numbers: Pro00162062

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD will not be shared to protect patient confidentiality. However, this could be re-considered if ethics approval is obtained from the requesting researcher and also the source ethics board.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No