RIC in HIE: A Safety and Feasibility Trial

Study Overview
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Brief Summary
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Remote Ischemic Conditioning has never been studied in neonates with HIE. However, RIC has been studied in animal models of perinatal asphyxia and has shown encouraging results. In neonatal rats with HIE, RIC is associated with reduced sensory motor deficits compared to non-RIC, and repeated cycles in three consecutive days is superior to a single treatment. In piglets, four cycles of 10 minutes of bilateral hindlimb ischemia immediately after bilateral common carotid occlusion results in reduced cell death in the periventricular white matter and internal capsule. These preclinical studies support the hypothesis that RIC may be beneficial in infants with HIE.

Detailed Description
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Hypoxic-ischemic encephalopathy (HIE) is a devastating condition in which newborn infants are deprived of oxygen in the peripartum period, resulting in brain injury. HIE is a leading cause of infant morbidity and mortality worldwide. Within the last 15 years, the introduction of hypothermia as a therapy for HIE has revolutionized our care of these vulnerable infants, but despite these improvements, nearly 50% of infants die or have major disability at 18 months. Therefore, there is a significant need to develop novel adjunctive therapies for HIE. Remote ischemic conditioning (RIC) is a procedure that involves the application of brief cycles of non-lethal ischemia and reperfusion to a remote site, with the goal of protecting distant organs exposed to ischemic injury. RIC has been extensively studied in experimental models and applied clinically in adults, children, and neonates. In neonates, there have been trials exploring its potential role before cardiac surgery and necrotizing enterocolitis. Most of these studies performed up to 4 cycles of 5 minutes of ischemia in a single day and found RIC to be feasible and safe. Experimental studies suggest that RIC, acting through three inter-related mechanisms (neural, humoral, and systemic pathways) is associated with increased cerebral blood flow, decreased inflammation, and enhanced cell survival. RIC has been studied as a potential treatment in adult stroke, and while the evidence to date is inconclusive, preliminary data suggest that RIC may reduce the size and the severity of the stroke lesion, as well as improve cognitive outcomes. RIC has been studied in animal models of perinatal asphyxia and has shown encouraging results. In neonatal rats with HIE, RIC is associated with reduced sensory motor deficits compared to non-RIC, and repeated cycles in three consecutive days is superior to a single treatment. In piglets, four cycles of 10 minutes of bilateral hindlimb ischemia immediately after bilateral common carotid occlusion results in reduced cell death in the periventricular white matter and internal capsule. These preclinical studies support the hypothesis that RIC may be beneficial in infants with HIE. In this proposal, we outline a carefully designed and conducted early phase study of RIC in neonates with HIE.

Official Title
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Remote Ischemic Conditioning in Hypoxic-Ischemic Encephalopathy: A Safety and Feasibility Trial

Conditions
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Hypoxic-Ischemic Encephalopathy

Intervention / Treatment
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* Device: Remote Ischemic Conditioning


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Qualifying for therapeutic hypothermia according to the primary care team based on the current SickKids HIE Protocol Exclusion Criteria: Gestational age <35 weeks Known central nervous system malformations Known chromosomal or genetic anomalies Confirmed or suspected inborn error of metabolism Parental decision for withdrawal of life-sustaining treatment (comfort care). If this decision is made after enrollment but before completion of RIC intervention, no further study-related intervention will be performed. Patients requiring significant hemodynamic support (two or more agents for blood pressure support, >0.05mcg/kg/min epinephrine infusion, or >0.1 mU/kg/min vasopressin) for the four hour period prior to RIC Patients requiring inhaled nitric oxide or fraction of inspired oxygen (FiO2) >50% for the four-hour period prior to RIC
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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Arm - Remote Ischemic Conditioning<br>Remote Ischemic Conditioning | Device: Remote Ischemic Conditioning<br>* Patients randomized to the RIC arm, cohorts of 4 consecutive patients will receive escalating therapy: A. 4 consecutive patients will undergo 4 cycles of 3 minutes ischemia, followed by 5 minutes reperfusion, on Day 1 of therapeutic hypothermia B. Observing no safety events (see below) from patients in group A, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Day 1 of therapeutic hypothermia. C. Observing no safety events from patients in group B, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Days 1 and 2 of therapeutic hypothermia. D. Observing no safety events from patients in group C, 4 consecutive patients will undergo 4 cycles of 5 minutes ischemia, followed by 5 minutes reperfusion, on Days 1, 2, and 3 of therapeutic hypothermia. All infants will have an extra 1ml of blood collected.<br>|
| No Intervention: Control Arm - No Remote Ischemic Conditioning<br>No intervention. A blood pressure cuff will be placed on the infant's arm but will not be inflated. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RIC cycles administered as planned (Y/N) | Designated RIC cycles are administered as planned (dichotomous variable) | 72 hours | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Frequency of limb ischemia, incidence of RIC interruption and rescue intervention, incidence of subcutaneous fat necrosis, incidence of acute kidney injury, mortality | 72 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with cutaneous injury | New-onset of skin breakdown, bruising, ecchymosis or petechiae, within 24 hours after the end of the maneuver (comparing to the previous baseline assessment) | 24 hours | 
| Number of patients with transient and persistent pain defined as a premature infant pain profile (PIPP) score >7 | Pain measured by PIPP score > 7 will be considered as an episode of pain. A patient will be considered to have persistent pain if PIPP score is higher than the baseline score 6 hours after the maneuver. | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypoxic-Ischemic Encephalopathy