31. January 2008 · Comments Off on Remote blood washout in cryonics · Categories: Cryonics · Tags: , , , ,

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.”