Cardiac Arrest, Extracorporeal Membrane Oxygenation, Reperfusion Injury
Conditions
Brief summary
The purpose of this project is to test the feasibility and safety of inhaled hydrogen gas (H2) administration as a rescue therapy during cardiac arrest requiring extracorporeal cardiopulmonary resuscitation (ECPR, i.e. mechanical circulatory support). Under exemption from informed consent, patients undergoing refractory cardiac arrest in the cardiac ICU at a participating center will be randomized to standard therapy with or without the administration of 2% hydrogen in gases administered via the ventilator and ECMO membrane for 72 hours.
Detailed description
The purpose of this project is to test the feasibility and safety of inhaled hydrogen gas (H2) administration as a rescue therapy during cardiac arrest requiring extracorporeal cardiopulmonary resuscitation (ECPR, i.e. mechanical circulatory support). Each year, 500,000 patients in the US suffer a cardiac arrest and a growing number of them are resuscitated using ECPR. However, neurologic and renal injury remain important resulting comorbidities. The pathophysiology of these often-devastating injuries is ischemia (inadequacy of blood flow, at times compounded by hypoxemia) followed by an abrupt reperfusion (ECMO flow initiation). Among patients with congenital heart disease (CHD) receiving ECPR, 52% either die prior to discharge or suffer severe neurologic impairment. Diatomic hydrogen (H2) administration during and following ECPR may chemically reduce the toxic mediators that directly damage cellular structures and improve neurologically intact survival. Preclinical data. Several groups have described that H2 inhalation decreases injury when administered following ischemic stroke, myocardial infarction, and cardiac arrest in rodents. Our group demonstrated that inhalation of 2.4% H2 for 24 hours following an experimental swine ischemia-reperfusion injury (as occurs in ECPR) improved neurologic scores, decreased seizures, diminished T2 white matter injury volume by 65%, and improved serum creatinine. Safety study in healthy participants. Under an investigator-initiated IND, we exposed 8 healthy adult participants to up to 72 hours of 2.4% H2 inhalation via high flow nasal cannula, finding no adverse effects on markers of hepatic, renal, cardiac or pulmonary function and no clinically significant symptoms reported. Having received a favorable pre-IND review from the FDA, we propose a two-center early phase study of H2 administration in patients with CHD receiving ECPR. Study overview. We propose an early-phase randomized trial entitled the 'Hydrogen FAST Trial' (Hydrogen's Feasibility And Safety as a Therapeutic agent). The trial will have a 3-patient vanguard phase and 53 patients with CHD experiencing ECPR randomly assigned in a 3:2 (32/21) ratio to either usual care plus 2% H2 gas for 72 hours or to usual care. Patients will be recruited from two sites. We will primarily examine feasibility and safety (severe adverse events, independently adjudicated), as well as some indicators of efficacy. Hypotheses. Primary feasibility endpoint: We hypothesize that H2 gas will be administered for a mean of \>90% of the first 72 consecutive post-arrest hours in patients so-assigned. Primary safety endpoint: We hypothesize that compared with patients receiving usual post-arrest care, patients receiving H2 will not exceed the treatment-related SAE rate of the usual care group by \>12.5% in the 30 days following randomization. Secondary feasibility endpoint: We hypothesize that H2 gas will be administered for a mean of \>90% of the first 72 consecutive hours post-H2 initiation in patients so-assigned.
Interventions
DRUGHydrogen
Hydrogen gas (2%) in air or oxygen administered for 72 hours via ventilator and ECMO membrane. Oxygen concentration titrated per clinical team.
OTHERUsual care
Usual care post-ECPR event, including targeted temperature management.
Sponsors
Boston Children's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Intervention model description
Randomized to usual care with or without treatment
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 1. Patients admitted to a cardiac intensive care unit at a participating site with cardiac comorbidity, including congenital heart disease, myocarditis, cardiac arrhythmia, or rejection of a transplanted heart. 2. Patients are anticipated to be between birth to 18 years of age, although occasionally a patient over the age of 18 may be enrolled. 3. Patient experiencing a refractory cardiac arrest \>5 minutes and receiving ongoing CPR in the ICU, cardiac catheterization lab, or cardiac operating room. 4. The decision made by the clinical team to resuscitate from ongoing, refractory cardiac arrest using ECPR due to a lack of other available options.
Exclusion criteria
Meeting any of the following criterion renders the patient ineligible for the trial: 1. Enrollment in the opt-out program. 2. Patients known to be pregnant. 3. Patients who are prisoners. 4. Prior ECPR episode during admission (whether or not they were enrolled in the trial). 5. Enrollment does not occur within 6 hours of the decision to resuscitate using ECPR. Note that ECMO cannulation without preceding CPR does not qualify as ECPR and such patients will not be included.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of hydrogen administration (primary) | 72 hours | Percentage of the first 72 consecutive post-arrest hours (starting at the time of first CPR initiation) in which H2 gas was administered via all of the applicable pathways (e.g. mechanical ventilator and ECMO membrane). |
| Safety of hydrogen administration | 30 days | Incidence rate of SAEs of interest per day during the first 30 days post-randomization that have been classified as treatment-related or possibly treatment-related. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Hospital length of stay | From date of randomization until the date of hospital discharge or date of death from any cause, whichever came first, assessed up to 12 months | Duration of hospital stay until first hospital discharge |
| Survival to hospital discharge | From date of randomization until the date of hospital discharge or date of death from any cause, whichever came first, assessed up to 12 months | Survival to hospital discharge |
| Feasibility of hydrogen administration (secondary) | 72 hours | Percentage of the first 72 consecutive hours post-H2 initiation in which H2 gas was administered via all of the applicable pathways (e.g. mechanical ventilator and ECMO membrane). |
| Functional status score | Calculated on admission to the hospital, at 24 h before cardiac arrest, at hospital discharge, and at 6 months post-randomization | Functional status score computed based on a detailed review of neurology notes, primary team notes, nursing notes and physical exam documentation by two independent investigators. |
| ICU length of stay | From date of randomization until the date of first ICU discharge or date of death from any cause, whichever came first, assessed up to 12 months | Duration of ICU stay until first transfer out of ICU |
Countries
United States
Contacts
Primary ContactJohn N Kheir, MD
Backup ContactVictoria Habet, DO
Outcome results
None listed