Tag: Reperfusion Injury

Induction of hypothermia before CPR improves survival

It is difficult to match concerns about reperfusion injury during cardiopulmonary resuscitation (CPR) with specific proposals for alternative interventions. After all, no matter how harmful the effects of oxygenation may be, not restoring circulation in a patient in cardiac arrest is hardly a credible option. One alternative would be to restore circulation but withhold oxygen (or ventilate with room air). Another alternative would be to induce hypothermia during circulatory arrest before restoring circulation.

A recent paper in Resuscitation investigated the latter option and reports that delaying reperfusion  in mice until induction of mild hypothermia has been achieved can improve hemodynamics, survival and neurological outcome.  The time to drop the temperature from 37 degrees Celsius to 30 degrees Celsius was 90 seconds in mice. As the authors note, “this is not currently feasible in humans and it is likely that much longer resuscitation delays in the clinical setting might counteract the benefit of cooling before ROSC (return of spontaneous circulation)”.

Rapid partial cooling (as the authors suggest) may solve this problem but restoring circulation will result in moving warm blood to the very organs (such as the heart and the brain) that just had been cooled. Such an intervention will only work if some of the protective mechanisms of hypothermia, such as altered gene expression, are (partially) retained during subsequent rewarming.

One treatment modality that the authors did not research, but warrants investigation, would be to “mimic” intra-arrest hypothermia by restoring circulation and giving a cocktail of neuroprotective agents prior to restoring oxygenation. Such an approach may not eliminate all free radical injury upon restoring circulation, or eliminate other elements of reperfusion injury such as calcium overload and inflammatory responses, but it might be an interesting treatment to compare with induction of intra-arrest hypothermia and delayed CPR.

Incomplete ischemia during cardiopulmonary support

One concern about prolonged cardiopulmonary support in cryonics is that its decreasing effectiveness may not be able to meet cerebral oxygen demand, and may even become detrimental. Some investigators have  observed that severely reduced flow (cerebral blood flow less than 10% of control) to the brain may actually be more harmful than no flow at all.  Explanations of why incomplete (“trickle flow”) ischemia may be worse than complete ischemia include aggregation of slow moving blood cells,  glucose-induced excessive lactate production, and oxygen-induced free radical damage to membranes.

In contrast, a study by Steen et al. concluded that some blood flow is better than no flow at all. The authors found that dogs could sustain only 8 to 9 minutes of complete ischemia but 10 to 12 minutes of incomplete ischemia (cerebral blood flow less than 10% of control) without neurological impairment. These results are at odds with the findings of Hossmann et al. who found better electrophysiological recovery in cats and monkeys after complete ischemia, and studies by Nordstrom et al. who observed increased metabolic recovery in rats after complete ischemia.

The authors speculate that these differences may reflect the different durations of (in)complete ischemia. Hossmann et al. studied 60 minutes of ischemia and Nordstrom studied 30 minutes of ischemia. The authors note that the durations they studied (8-14 minutes) are more clinically relevant because neurological recovery with contemporary technologies is not possible after 30 or 60 minutes of cerebral ischemia. Although these findings provide support for restoration of any kind of cerebral circulation after cardiac arrest, it does not offer much guidance in evaluating the practice of prolonged cardiopulmonary support in cryonics.

The authors also draw awareness to the difficulty of correlating electrophysiological and metabolic recovery to neurological recovery. They quote a study by Salford et al. who observed some return of metabolism even though histological abnormalities had already been developed. Such studies warrant caution about using return of electrophysiological activity as an indicator of cerebral viability because it is not likely that such viability can be sustained over the long term, let alone predict functional recovery of the brain.  It is doubtful that viability in the latter, stricter, sense can be maintained during stabilization of most, if any, cryonics patients. At best, the studies that demonstrate recovery of electrophysiological and metabolic activity after prolonged cerebral ischemia offer hope that such periods of circulatory arrest do not produce acute information-theoretic death.

No metabolic or histological evidence was found to support the implication of no-reflow, lactate accumulation, and free radical damage in incomplete ischemia.  Again, the authors speculate that no-reflow may be more pronounced during longer periods of incomplete ischemia, an observation that seems to be indirectly supported by Fisher et al. who observed progressive impairment of perfusion for longer periods of ischemia.

Cryonics patients often experience shock, blood coagulation abnormalities, and decreased cerebral perfusion prior to pronouncement of legal death and cardiopulmonary support.  An additional complicating factor in cryonics is that cardiopulmonary support is often supplemented by induction of hypothermia and administration of vasopressors and neuroprotective agents. Although the paper by Steen et al. addresses a lot of issues that are important to evaluate cryonics procedures, it is clear that for real empirical guidance regarding the wisdom of prolonged cardiopulmonary support specific cryonics research models are required.