Anoxic CPS

Melody,

You have asked a very complex and difficult to answer question (congratulations). Right off I'll tell you that I know of no definitive answer and I suspect that a great deal more well designed and targeted animal research will have to be carried out in order to answer this question. This research will likely have to be conducted by and for cryonicists because, at least at this time, the circumstances under which cryopatients are acutely stabilized have little relevance to conventional medicine (more on this directly).

Another point that should be made at the start is that cryopatients are a very biomedically heterogeneous population; even more so than most classes of medical/surgical patients. Patients will vary in age, cause of arrest, co morbidities, fluid balance, peri-arrest hypoxia-ischemia, post-arrest hypoxia ischemia, and so on. Some patients will arrest under nearly ideal conditions with very little peri- or post-arrest ischemic insult and with excellent prospects for restoration of adequate perfusion and gas exchange. Other patients, due to sepsis, pulmonary edema, the post-arrest ischemic interval, or other factors will have no prospect for restoration of gas exchange, or in some cases, even perfusion.

Unfortunately, what is required is clinical acumen in order to determine how to treat each patient optimally. A one-size-fits-all stabilization protocol, such as is now is being used in cryonics is not tenable. Currently, critical care medicine is undergoing a revolution based on the growing awareness that standardized protocols for managing conditions such as sepsis, acute respiratory distress syndrome, and congestive heart failure simply do not work because the patients are very heterogeneous; not only are the details of their circumstances very different within the group (say septic patients), so are their genetics. This makes both treatment and statistical analysis of outcomes much more complicated and problematic than previously thought. Uniform fluid and ventilator management strategies are proving unworkable and very injurious to large sub-groups of critically ill patients (and are increasingly being abandoned by the best clinicians).

In short, there is no substitute for good clinical skill in managing patients, and cryopatients are no exception. In fact, their extreme condition (typically far more injured than "living" patients), demands even more clinical skill and good judgement.

One problem with foregoing ventilation during cardiopulmonary support (CPS) is that severe hypoxia has profound hemodynamic and hemo-rheological consequences. It is difficult to restore adequate mean arterial pressure (MAP) in the presence of hypoxia and acidosis (especially under the impoverished flow conditions of closed chest CPS). This problem is compounded by hypoxia and acidosis-induced changes in red cell fluidity (red cells become rigid when depleted of ATP), hypoxia-induced alterations in red cell aggregability, increased platelet and white blood cell adhesion, and alterations in the character of the glycocalyx (increased stickiness) which lines the capillaries all further compromise perfusion. In fact, these changes greatly impede restoration of any microscopic tissue perfusion. Similarly, within minutes of cardiac arrest, there is nearly universal edema of both the capillary endothelial cells and the tissue parenchyma due to collapse of ion regulation; the sodium/potassium pumps run out of energy and cease to operate. This phenomenon is particularly pronounced in the brain and is likely a major contributor to the no-reflow phenomenon (failed reperfusion of the microcirculation). Re-oxygenation and the restoration of metabolism and effective cellular ionic pumping is thus very attractive because (at least historically) it is the only approach that offers the prospect of restoring effective perfusion which is necessary both in order to cool rapidly and to distribute cerebroprotective medications (especially absent extracorporeal support).

Of course, this is mostly just theory based on gedanken experiments and very limited laboratory investigations. It is certainly true that some cryopatients unequivocally benefit from aggressive reperfusion with ventilation as evidenced by return of good tissue perfusion and even the return of neocortical electrical activity (and if un-medicated, return of consciousness). However, most cryopatients are far too seriously injured by peri- and post-arrest disease and hypoxia-ischemia to respond in this way. What is really needed is systematic research in truly relevant animal models (i.e., following cardiac arrest from sepsis, hypovolemia in the setting of systemic inflammation, prolonged hypoxia, and so on) to determine if anoxic (closed chest) CPS can be made workable or even superior to CPS with ventilation. Administration of a hypertonic solution to reverse flow-inhibiting edema and containing drugs which reverse blood cell and glycocalyx stickiness and raise perfusion pressure to acceptable levels (without the need for ventilation) is a very attractive idea since it offers the prospect of side-stepping oxygen radical mediated reperfusion injury.

In the past, the only pressors in the resuscitation armamentarium were alpha adrenergic agonist drugs typified by epinephrine. None of these drugs are useable in the presence of acidosis because the alpha adrenergic receptors do not function in acidosis. With the advent of the use of vasopressin and related V1 receptor agonists in resuscitation and critical care medicine it is now possible to raise MAP in the presence of acidosis. Recent research has also made it abundantly clear that epinephrine (and at least some other alpha adrenergic agonists) impair cerebral blood flow during CPR, compromise the microcirculation, and undesirably increase cerebral metabolism (for these reasons epinephrine should no longer be used as a pressor in cryopatient CPS). What is not known is whether vasopressin and anoxic CPS will provide adequate perfusion and superior cytoprotection as opposed to CPS with ventilation. The only way to answer this question is to do the necessary experiments.

Finally, even if the answer to this and related questions is discovered, the current dismal level of cryopatient "care" would make application problematic; anoxic CPS presents its own formidable technical challenges and is conceivably more difficult to implement properly than is conventional CPS with ventilation. There have recently been many powerful advances in critical care and resuscitation medicine (both research and clinical) which cry out for application in cryonics. However, this is not possible (and should arguably not even be attempted) until competence is first achieved in the application of the most basic (and long understood) elements of patient care.

Mike Darwin