[tt] remote blood washout in cryonics

[Eugen Leitl]

http://depressedmetabolism.com/

Remote blood washout in cryonics

One argument that is often raised in favor of “field vitrification” (or
vehicle based vitrification) is that it will reduce the time of (cold)
ischemia and eliminate the harmful effects of remote blood washout and
transport of a patient on water ice to a cryonics facility. A related
argument is that field vitrification will eliminate stabilization.

In fact, field vitrification will not eliminate the need for stabilization
because patients need to be protected from warm ischemic injury after cardiac
arrest until a location to carry out cryoprotectant perfusion has been
secured and surgical access to the patient’s vessels has been established (a
procedure that, in cryonics, takes at least fifteen minutes under the best of
circumstances). During that period the patient will still require prompt
cardiopulmonary support, induction of hypothermia, and administration of
anticoagulants and neuroprotective agents. As a consequence, stabilization
times should not differ between field vitrification or remote blood washout.
In light of the possibility that field vitrification will likely require more
demanding and time-consuming surgery, field vitrification might even
necessitate longer stabilization times. The only procedure that could reduce
or eliminate stabilization would be hospital-based vitrification.

Field vitrification will reduce the period between cardiac arrest and the
start of cryoprotective perfusion. But whether this is a clear advantage or
not depends on the question of whether remote blood washout and transport on
water ice introduces additional injury to the patient. Recent anecdotal
observations of cryoprotective perfusion of patients who have been washed out
in the field indicate that the procedure of blood washout itself may be
harmful. It is not clear, however, whether this is an intrinsic element of
remote blood washout and cold transport or the result of poor perfusion
techniques and flawed composition of the organ preservation solutions that
are used to replace the blood.

In cryonics, remote blood washout is done for at least three reasons: (1) to
eliminate the possibility of blood clotting and hypothermia-induced red cell
membrane rigidity, rouleaux formation, and cold agglutination; (2) to remove
ischemia-induced inflammatory products and endotoxins from the circulation;
and (3) to protect the patient from hypothermia-induced cell injury and edema
by substituting the blood with an organ preservation solution.

The organ preservation solution used today is called MHP-2. The original MHP
solution is a modification of RPS-2 (an organ preservation solution for
hypothermic kidney preservation created by Greg Fahy at the American Red
Cross) and stands for Mannitol-Hepes-Perfusate. It is designed as a so called
“intracellular” organ transplant solution. In order to reduce passive ion
exchange as a result of hypothermia-induced cell membrane pump inhibition,
its composition more closely resembles the composition of the solution inside
the cell rather than the interstitial fluid or blood plasma. MHP also
contains molecules to provide oncotic support, prevent acidosis, and reduce
free radical damage. In a series of groundbreaking experiments by Jerry Leaf
and Michael Darwin, MHP was successful in resuscitating dogs from up to 5
hours of asanguineous ultraprofound hypothermia. MHP-2 is a modification of
MHP that is believed to produce superior results.

A number of arguments have been put forward why remote blood substitution
with MHP-2 is not successful in securing viability of the brain during
transport, and may even produce adverse effects. The most obvious reason is
that MHP has been validated for up to 5 hours of ultraprofound hypothermia,
which is not the typical transport time of a cryonics patient. A related
problem is that MHP has not been validated in a model that reflects the
typical cryonics patient who experiences variable periods of hypoperfusion
and warm ischemia prior to and after cardiac arrest. And, unlike the canine
asanguineous ultraprofound hypothermia experiments, in cryonics MHP is used
as static cold preservation solution instead of being continuously perfused
at low flow rates. Although MHP can reportedly recover dogs from up to 3
hours of asanguineous circulatory arrest (clinical death), such a protocol
further reduces the time that viability of the brain can be maintained during
transport.

Although the MHP patent and the notebooks from the original washout
experiments are clear that MHP should be prepared as a hyper-osmolar
perfusate (~ 400 mOsm), it has been established that in recent years many
batches of MHP have not been mixed with hyper-osmolality as an endpoint, due
to a lack of osmometry quality controls. The exact effects of this are
unknown but have been hypothesized to explain why recent remote blood washout
has produced worse results than in the past, possibly by aggravating, or in
the case of a hypo-osmolar perfusate, producing edema. This problem, and the
confusion about the exact composition of MHP-2, is briefly discussed in the
Suspended Animation case report of Cryonics Institute patient CI-81.

Field vitrification is not the only solution to the limitations of remote
blood washout and transport on water ice. Another solution would be to
improve the composition of hypothermic organ preservation solutions and
perfusion protocols to secure extended periods of cerebral viability during
transport. Instead of substituting the patient’s blood with an organ
preservation solution, after which the patient is shipped on water ice, the
organ preservation solution can be continuously (or intermittently) perfused
at low flow rates, similar to machine perfusion in conventional organ
preservation, while the patient is being driven in a rescue vehicle to a
cryonics facility. This has a number of advantages, including the possibility
to sustain aerobic metabolism, improve microcirculation and administer
cytoprotective agents.

Although cerebral viability of the brain may be extended by improved organ
preservation solutions, there seems to be a fundamental limit to shipping
patients in hypothermic circulatory arrest because the remaining energy
demands of the brain will need to be satisfied by oxidative phosphorylation
(or other energy substrates) at some point. Although it is not known how far
these limits can be pushed by static use of organ preservation solutions, it
is likely that a protocol of continued hypothermic perfusion of remote
cryonics patients will exceed these limits. Like field vitrification, such a
protocol will present non-trivial technical and logistical challenges.

This still leaves the question of whether remote blood washout can aggravate
injury in ischemic patients unanswered. Since the original canine experiments
investigated MHP in healthy animals we do not know if some patients would be
better off without a blood washout. Dr. Southard, one of the inventors of
Viaspan (also called the University of Wisconsin solution in the scientific
literature), discussed similar concerns in a recent interview:

“In clinical organ preservation/transplantation, there are many unexplained
incidents of reperfusion injury. This is characterized by delayed graft
function in the liver and kidney. We do not see this in our animal models.
Thus, there are some differences between how experimental animals and human
donor organs respond to organ preservation. The difference may be related to
the fact that the UW solution was developed to preserve the “ideal organ.”
This is one taken from a relatively young and healthy lab animal donor and
transplanted into a healthy recipient. In the clinics, the donors are usually
brain-dead (brain trauma), remain in the ICU for periods up to a day or more,
are treated for hypotension, and come from an uncontrolled group of donors.
Therefore, we are now studying how UW solution preserves organs from the
“less-than-ideal” donor. We are simulating the clinical condition by inducing
warm ischemia or brain death in experimental animals to determine if UW
solution is suitable for these types of organs. If not, we will develop an
ideal method to preserve these less-than-ideal donor organs.” (quoted on the
old Viaspan website).

Similarly, organ preservation solutions used in cryonics need to be
investigated in models that better reflect the typical pre-mortem
pathophysiology and post-mortem procedures encountered in cryonics.
Developing stabilization technologies and procedures for “less than ideal
patients” is an important element in an approach known as “Evidence Based
Cryonics.”