In
mammals, blood carries oxygen and nutrients to the body's organs and
cells. But if blood flow stops, these cells will quickly die and organs
are injured.
This
death can be slowed in organs and tissues removed from the body, buying
time for organ transplantation. However, preserving entire organ
systems minutes after the heart stops pumping can be a challenge.
Existing methods include what's known as an extracorporeal membrane oxygenation system (ECMO),
which pumps blood into a machine that removes carbon dioxide from it,
while adding oxygen. While it serves the purpose of balancing gases,
every minute of delay allows the damage to build.
To
address the problem, a new system has been shown to restore some organ,
cellular, and molecular function in dead pigs, and to preserve their
tissues, even when the treatment is only initiated one hour after
cardiac arrest.
The researchers adapted an existing technology called BrainEx, which has been shown to restore some function in isolated pig brains hours after death.
Their new system, called OrganEx, is intended for whole-body use in large mammals.
OrganEx has two components: a machine, and a fluid.
The
machine is connected to the circulatory system. It creates a pulse
similar to a heartbeat and oxygenates the fluid, similar to an ECMO.
Where it stands apart is in the way it adds drugs to aid circulation and
prevent clotting.
The
machine also includes a number of sensors for important features of
circulation like metabolism, hemoglobin, pressure, and flow.
It
pumps synthetic fluid, mixed with the animal's own blood at a 1:1
ratio, through the dead animal's whole body. This fluid, unlike blood,
is not made up of cells, although it is designed to protect cells from
harm, and carry oxygen and drugs throughout the body.
(David Andrijevic, Zvonimir Vrselja, Taras Lysyy, Shupei Zhang; Sestan Laboratory; Yale School of Medicine)
Above: Representative
images of electrocardiogram tracings in the heart (top),
immunostainings for albumin in the liver (middle), and actin in the
kidney (bottom). The images on the left side represent the organs
subjected to a control perfusion, while the images on the right
represent the organs subjected to perfusion with the OrganEx technology.
The
system was tested in pigs one hour after cardiac arrest, as well as
control groups in which organ functions were tested immediately after
cessation of blood flow, as well as one hour and seven hours later. Kept
at body temperature, tissues continued to process fuel and generate
waste at a controlled rate.
One hundred pigs (Susscrofa domesticus) were used overall, including those used to develop the system prior to the published experiments.
The
researchers found OrganEx can preserve the integrity of tissue, reduce
cell death, and revive certain molecular and cellular processes across
vital organs like the heart, brain, liver, and kidneys.
OrganEx
out-performed ECMO across the board. Organs treated by the new system
were less affected by hemorrhage or tissue swelling, and the researchers
observed gene expression patterns specific to repair processes within
certain organs and cell types.
The team also checked the architecture of cells in the brain, which usually suffer damage from ischemia.
Brain
cell numbers had diminished in all treatment groups, except for
OrganEx, where, in some sections of the brain, minimal damage had
occurred, and in the prefrontal cortex, cells had been recovered to
similar levels as the group that had not been exposed to warm ischemia.
A major test of the experiment's success was the recovery of organ function.
Brain
function was measured using continuous EEG. The scientists were adamant
to distinguish between the brain functions they detected and electrical
activity which would indicate some level of 'life' (as brain death is the main definition of death in clinical settings).
While
brain death persisted in the OrganEx group, the bodies showed some head
and neck movement after contrast injection – used to help show more
detail in imaging – into the carotid artery in the neck, which delivers blood to the brain and head. This movement did not occur in living sedated animals, or in the ECMO group.
"Thoughtful
evaluation is needed to elucidate why head and neck movements occurred
after contrast injection only in the OrganEx group," the researchers write.
They are unsure why this occurred, but say it shows motor function output had been preserved, at least in the "spinal cervical cord or its roots."
In
the heart, some spontaneous activity was detected via ECG and some
contractions in the left ventricle cells were seen in the OrganEx group
that were not seen in the ECMO group.
Other organs, such as the liver and kidneys, also showed some key signs of recovery in their functionality.
While
tests of this system in humans are still far off, the researchers
believe OrganEx has huge potential for human organ transplants. They
hope it will improve the time an organ intended for transplant can be
preserved, which, for instance, could allow organs to be transported
further distances, to recipients in need.
"The
findings highlight a previously unappreciated capacity of the mammalian
body to partially recover after an interruption to blood flow, which
could increase organ availability for transplantation," the researchers write.
However, the team says that further studies are needed "to fully understand the potential of
OrganEx to aid cellular recovery after death or interrupted blood
circulation".
The research was published in Nature.