Restoring cell and organ function after the heart stops

Pig kidneys after 3 hours of perfusion with a conventional heart-lung perfusion machine (top) and OrganEx (bottom). The black shows where fluid has reached. Andrijevic et al., Nature

Without a steady supply of oxygen from the blood, processes leading to cell death in mammals begin within minutes. Recent studies have shown that cells can still recover even hours after interrupting blood flow. But such recovery has so far only been demonstrated in isolated organs.

An NIH-funded team of researchers led by Dr. Nenad Sestan at Yale School of Medicine developed a system to promote cellular recovery and preserve tissue integrity in the intact body after loss of blood flow. The system, called OrganEx, is based on the team’s previous work restoring circulation and cell function in a pig brain that was removed after the animal’s death.

OrganEx uses a device like the heart-lung machines that take over the functions of the heart and lungs during surgery. The device pumps a mix of the pig’s own blood and a protective fluid throughout the body’s blood vessels in a process called perfusion. This fluid contains oxygen and a synthetic form of hemoglobin—the oxygen-carrying protein in red blood cells. It also contains electrolytes and compounds designed to protect cells and prevent blood clots.

The researchers tested OrganEx in pigs undergoing cardiac arrest. Perfusion of pigs began one hour after cardiac arrest and continued for another six hours. Results appeared in Nature on August 3, 2022.

OrganEx was able to circulate the fluid throughout the body and deliver adequate oxygen to tissues. It also prevented electrolyte imbalances that normally occur when blood flow stops. The researchers compared OrganEx with a conventional heart-lung perfusion machine that pumped the pig’s own blood back through its body.

OrganEx perfusion for six hours preserved cell and tissue integrity and reduced cell death in various organs. These included the brain, heart, liver, and kidneys. In the brain, OrganEx preserved all three major cell types: neurons, astrocytes, and microglia. Cells in the heart, liver, and kidneys had less damage than corresponding cells after treatment with the standard device. 

The researchers also found signs of restored organ function in the perfused pigs. They observed glucose uptake in brain, heart, and kidneys. They found electrical activity and contraction in the heart, and protein synthesis in the liver and brain. Several organs activated genes associated with cellular repair processes and preventing cell death.

These findings suggest the potential for organs to recover up to an hour after blood flow stops. OrganEx technology could leverage this potential to prolong the life of human donor organs. This could make more organs available for transplants. It might also help damaged organs to recover following heart attacks or strokes. Yet the researchers stress that further research will be needed. It remains to be seen how much organ function can be recovered and how long it can be maintained. Because of the ethical implications of brain recovery after death, this and future work will continue to require rigorous ethical review.

“There are numerous potential applications of this exciting new technology,” says study co-author Dr. Stephen Latham, director of the Yale Interdisciplinary Center for Bioethics. “However, we need to maintain careful oversight of all future studies, particularly any that include perfusion of the brain.”

—by Brian Doctrow, Ph.D.