Newborns with life-threatening congenital heart disease often undergo open-heart surgery with cardiopulmonary bypass, which carries a risk of damaging the brain. Critically ill newborns who are placed on ECMO are at even higher risk for brain injury. Hypothermia, or cooling the body, can improve neurologic outcomes, but has limitations.
A new study in a large animal model suggests that adding a dash of hydrogen to the usual mix of respiratory gases could further protect babies’ brains.
When oxygen goes rogue
When infants are placed on bypass or ECMO, blood flow is interrupted, causing temporary hypoxia, or low-oxygen conditions. The brain, a heavy oxygen user, suffers the most from oxygen deprivation. But it’s when blood flow is restored and oxygen is reintroduced that the real damage occurs. Formerly oxygen-deprived cells respond to the sudden influx by forming toxic chemicals known as reactive oxygen species, which damages DNA and cell membranes.
“During the reperfusion process, the cell mitochondria overreact and end up using oxygen to injure themselves,” explains John Kheir, MD, a cardiologist in Boston Children’s Hospital’s Cardiac Intensive Care Unit.
The body tries to scavenge these chemicals, but they can overwhelm the scavenging system and injure the tissue. When this occurs in the brain, it can cause neurologic impairment.
That’s where inhaled hydrogen gas (H2) comes in. The inert gas enters cells easily and reacts harmlessly with oxygen molecules, forming water. Kheir had read a landmark paper from Japan showing that hydrogen is a potent antioxidant; in rats, H2 buffered the effects of the reactive oxygen species, markedly suppressing brain injury when oxygen supply was cut and then reintroduced.
The American Heart Association and Children’s Heart Foundation gave Kheir’s team a grant to test the idea of providing extra hydrogen, together with hypothermia, in piglets undergoing cardiopulmonary bypass. As described today in the journal JACC: Basic to Translational Medicine, the team added 2.4 percent hydrogen gas to the animals’ usual ventilation gases during and after arrested blood flow and hypoxia. Compared with controls, the treated animals did significantly better on neurologic evaluations. They had fewer seizures, smaller areas of tissue injury on brain MRI and decreased chemical markers of brain and kidney injury in their blood.
Moving inhaled hydrogen to patients
Kheir, also an associate professor at Harvard Medical School, is gearing up to test hydrogen gas in a clinical trial. Since patients can inhale H2 through conventional ventilators, it can easily be incorporated into clinical workflows. And it has already been tested in stroke patients in Japan. Kheir believes many patients at risk for brain hypoxia could potentially benefit from hydrogen, including infants undergoing congenital heart surgery or those suffering a stroke, cardiac arrest or pneumonia.
What we want to do is create an ancillary therapy that is cheap and easy to do that can mitigate injury in survivors.
The first planned step is a small safety trial in eight healthy adult volunteers at Boston Children’s. Paid participants will inhale a hydrogen-containing mixture for escalating periods of time under close monitoring. Assuming the treatment is safe, Kheir then plans to expand to a Phase II trial with several other U.S. medical centers, involving patients undergoing cardiopulmonary resuscitation (CPR) who are then placed on ECMO.
“We’ve gotten better at resuscitating patients and getting the heart to start beating, and even some emergency departments are putting patients onto ECMO,” he says. “But during that time, the brain may be deprived of oxygen. What we want to do is create an ancillary therapy that is cheap and easy to do that can mitigate injury in survivors.”
Alexis R. Cole, BS, was first author on the JACC paper. The study was supported by the American Heart Association (15GRNT25700161), the Hess Family Cardiac Innovation Fund, the Furber Family Innovative Therapies Fund and donor Lindsay Bartels.