Critical cooling rate to prevent ischemic brain injury
Induction of hypothermia can reduce injury to the brain when it is deprived of oxygen. How fast do we need to cool a patient during cardiac arrest or stroke to prevent irreversible injury to the brain?
It is an established fact that induction of hypothermia prior, during, or after circulatory arrest can reduce brain injury. As a general rule, the lower the temperature is dropped, the longer the brain can tolerate circulatory arrest. The neuroprotective effects of hypothermia are often expressed using the Q10 rule which says that for every 10 degrees Celsius drop in temperature metabolic rate decreases by 50%. Or to put it differently, the Q10 rule states that ischemic damage susceptibility is decreased by a factor of 2 for every 10 degrees Celsius temperature drop. Q10 may vary between species and in different organs and cells. For example, different temperature sensitivities were observed for release of the neurotransmitters glutamate, aspartate, glycine, and GABA during cerebral ischemia by Nakashima et al. Because even very modest reductions of brain temperature can have profound neuroprotective effects, the Q10 rule may not tell the complete story.
Other things being equal, it would be very useful to have a measure of brain injury when hypothermia is induced prior and/or during cardiac arrest. At least two authors have made an attempt to produce such a measure of ischemic exposure. In Cryonics Magazine (2nd Quarter, 1996), Michael Perry started initial work on this in an article called “Toward a Measure of Ischemic Exposure” (PDF). Perry’s Measure of Ischemic Exposure (MIX) calculates how long the patient has been at a given temperature, with a higher weighting used for higher temperatures. A related measure has been proposed be Steve Harris called the E-HIT. E-HIT stands for Equivalent Homeothermic Ischemic Time. In his (unpublished) manuscript, Harris uses the E-HIT formula to calculate the equivalent normothermic ischemic time for different cryonics case scenarios and real cases. Clearly, the availability of such a measure (and its routine calculation in case reports) would constitute a major contribution to cryonics as evidence based medicine. It could aid in deciding if viability of the brain was maintained during cryonics procedures by estimating the equivalent warm ischemic time.
What makes such a measure complicated during cardiopulmonary resuscitation (CPR), or cardiopulmonary support (CPS) in cryonics stabilization procedures is that hypothermia may only constitute one intervention to mitigate brain injury. In an ideal cryonics case, pronouncement of legal death is followed by rapid restoration of oxygenated blood flow to the brain by (mechanical) cardiopulmonary support, administration of neuroprotective drugs and induction of hypothermia. Such a combination of interventions might avoid any injury to the brain, reducing the equivalent warm ischemic time to zero. A more realistic scenario is that such a combination of interventions may reduce the extent of ischemic injury compared to cooling only. Another complicating factor is that oxygenation in combination with low perfusion pressures might produce more injury than “anoxic cardiopulmonary support” (chest compressions without ventilation). It is clear that calculating a measure of equivalent ischemic time for real cryonics cases can become very complicated.
It would be interesting to know the cooling rate that would be necessary to stay ahead of brain injury, using contemporary medical criteria, during circulatory arrest. For this purpose we use some very simplifying assumptions:
1.The patient is not ischemic prior to pronouncement of legal death.
2. Cooling is initiated immediately after pronouncement of legal death.
3. There is no cardiopulmonary support or administration of neuroprotective agents.
4. Brain injury starts at 5 minutes of warm ischemia.
5. Q10 is 2.0: for every 10 degrees Celsius we decrease the temperature , metabolism is dropped 50% , which doubles the time a patient can tolerate ischemia.
6. No other forms of injury occur other than ischemic injury.
7. Ischemic injury is completely eliminated at the glass transition temperature of the vitrification agent M22 (-123.3°C).
8. A constant cooling rate is assumed.
Using these assumptions, Alcor’s Mike Perry calculates that a cooling rate of 2.89 degrees Celsius per minute is necessary to stay ahead of the equivalent of 5 minutes of warm ischemia.
Let Ehit = total ischemic time limit in hours, 1/12 corresponding to 5 min
Q10 = factor of decrease in metabolism per 10 degrees
Tdrop = desired temperature drop, from 37 degrees (body temp) down to -123.3= 160.3 degrees Celsius
ch=desired cooling rate in deg/hour
cm=desired cooling rate in deg/min = ch/60
ch = 10*(1-exp(-Tdrop*ln(Q10)/10))/(Ehit*ln(Q10))
For Q10=2, Tdrop = 160.3, cm = 2.89 deg/min
If some of the assumptions are slightly changed we find the following for Q10=2.2
For Q10=2.2, Tdrop = 160.3, cm = 2.54 deg/min
If we assume negligible ischemic insult below 0 Celsius and only worry about cooling down to that temperature, so Tdrop is only 37 rather than 160.3, it doesn’t change these amounts drastically:
For Q10=2, Tdrop = 37, cm = 2.66 deg/min
For Q10=2.2, Tdrop = 37, cm = 2.40 deg/min
Clearly, such high cooling rates cannot be achieved during either conventional cardiopulmonary resuscitation or cardiopulmonary support in cryonics. The cooling rates we can hope for during the initial stages of cryonics procedures may exceed 1.0 degrees Celsius per minute at best. It is therefore not realistic to assume that cooling alone may be able to limit brain injury to a degree that allows resuscitation without adverse neurological effects using contemporary medical criteria. This should strengthen the case for the use of other interventions such as administration of neuroprotective agents and oxygenation of the patient. Although the latter intervention may produce adverse effects on the brain itself, the calculations above indicate that anoxic cardiopulmonary support is not compatible with maintaining viability of the brain as the objective of cryonics stabilization procedures. The case for rapid stabilization of cryonics patients remains strong.