Blood flow during CPR and reperfusion injury

An important objective during stabilization of cryonics patients is restoring circulation of blood to the brain. In ideal cases, this can be achieved by aggressive mechanical cardiopulmonary support, hemodilution ,and administration of vasoactive medications. In not-so-ideal cases, one or more of these interventions are omitted or delayed. This raises the question if low flow perfusion scenarios can be detrimental to the brain because of increased reperfusion injury.  In a previous post, a paper was reviewed that found that (very) low cerebral blood flow was better than no flow at all, allowing a wider therapeutic window for successful resuscitation. Why do the low flows generated during manual cardiopulmonary resuscitation (or cardiopulmonary support in cryonics) improve the likelihood of successful neurological recovery?

In a recent paper (2008) in Resuscitation, Rea, Cook and Hallstrom propose that the low flow state generated by manual CPR simultaneously protects against ischemic injury and limits reperfusion injury. They speculate that low flow during CPR “arrests” ischemia and induces post-ischemic conditioning, which reduces exposure to peak values of oxidative stress and increases resistance to reperfusion injury when normal flow is restored:

If full flow was restored early on after collapse, the accumulation of stress mediators would be relatively modest and so the cell could tolerate reperfusion injury without moderating the peak level of oxidative substrate or priming the cell’s protective pathways. However as the duration of no flow increases, stress mediators accumulate to a level where full or near-full flow would produce oxidative injury that would overwhelm the cell unless peak oxidative stress levels are mitigated and protective pathways are preemptively up-regulated, as might occur with graded flow.

The authors even speculate that in some scenarios manual CPR might be superior to newer devices and techniques (such as  automated vest CPR or active compression-decompression CPR) that can restore blood to physiological levels because manual closed chest CPR protects the heart and brain from peak levels of stress mediators.

As the authors note, if this hypothesis is correct, treatment of cardiac arrest would require a highly individualized approach “whereby certain physiologic states would be best served by different levels of circulation and hence distinct doses of CPR.” Such treatment modalities will require complicated monitoring and resuscitation efforts, such as automated control over perfusion pressure and ventilation during CPR.

Although this model makes sense from a theoretical level, it seems to be at odds with the discovery that low flow perfusion cannot reverse the “no-reflow” phenomenon. If blood flow cannot be restored to some parts of the brain, it is not likely that ischemic injury can be “arrested” in those areas. It also seems to be at odds with the work of other resuscitation researchers who found that increased perfusion pressures and hemodilution can increase the time that resuscitation from normothermic ischemia is possible. And because low flow perfusion limits the rate of external and internal cooling, such graded resuscitation strategies decrease cooling rates if resuscitation is complemented with induction of hypothermia. Perhaps the authors could also improve on their own model by allowing aggressive reperfusion but without oxygen (or just room air) during the early stages of reperfusion.

Because rapid induction of hypothermia is the most fundamental intervention in human cryonics preservation, the relevance of this model may be limited. However, in cryonics stabilization circulation is usually restored before any significant temperature decreases are possible.  Cryonics patients often have distinctly different pathophysiological characteristics, which makes straightforward application of such models, if practical at all, extremely challenging. As has been reiterated before, without the creation of realistic cryonics research models and serious efforts at monitoring cryonics patients during transport, it will be hard to evaluate the relevance of recent insights in resuscitation medicine and extrapolate its findings.