Rapid Cooling in Cryonics

The protocols regarding the rate of cooling have been debated amongst prominent researchers interested in hypothermic techniques, for many decades, with no clear answer. What is known is that rapid cooling and/or warming can lead to gaseous emboli, and that maintaining a temperature gradient of 10°C, or less, during the cooling of human patients provides a proven margin of safety. Cardiac surgeons truly hate the time spent waiting for the patient to be cooled and rewarmed. If they could shorten this time by using rapid cooling, they certainly would, yet the 10°C safety margin is adhered to in heart surgery, all around the world.

I employed hypothermic techniques on an almost-daily basis, for many years, cooling most patients to 28 - 32°C. I also participated in a significant number of profound hypothermia cases, where our patients were cooled to below 18°C and then exsanguinated. I saw the vast majority of our patients wake up, neurologically intact. Some of them had minor neurological deficits that turned out to be transient. Would they have had any benefit from being cooled more rapidly? It's doubtful. Would they have suffered greater cerebral injury if cooled rapidly. I believe that's probable.

Yes, the risk of micro-air emboli is greater with rapid warming than rapid cooling, but warming and cooling always take place at the same time. While the heat exchanger in the perfusion circuit is cooling the patient, the patient functions as a heat exchanger, warming the perfusate that comes to the body, and vice versa.

In Dr. Harris' June 22, 2007 "Great Expectations" post on the Cold Filter Forum, he stated, "I do not believe you will find any support in the literature for your contention that too-rapid cooling is to be avoided while on bypass. But I could be wrong, so show me."

For Dr. Harris to have not ever seen any literature supporting the avoidance of too-rapid cooling on bypass, he must not have looked, at all. It's out there, and it's plentiful. Here are just a few examples:

The Manual of Clinical Perfusion
Second Edition Updated
By Bryan V. Lich, CCP and D. Mark Brown, CCP

If cooling is used a temperature gradient less than 10°C between the arterial and venous blood is maintained. This prevents the formation of microbubbles. (Page 75.)

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University of Michigan Medical Center
C.S. Mott Children’s Hospital
Protocols and Guidelines for Pediatric Perfusion

Upon initiation of CPB, the perfusionist cools the patient maintaining an 8 - 12°C temperature gradient between the perfusate and rectal and/or nasopharyngeal temperature whichever is highest. This technique avoids the generation of gaseous emboli when the solubility in the blood of atmospheric gases is lowered by excessive rewarming of the perfusate in the tissue.
http://www.amsect.org/pediatric/protocols/mott.pdf (Page 59)

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Myocardial Protection and Cardiopulmonary Bypass
CARDIOPULMONARY BYPASS

1. The Circulatory Environment

B. Heat exchanger· The cooling or warming gradient is usually within 10-14 degrees of the patient’s temperature· This minimizes the tendency for gas to come out of solution and risk of air embolism· Mixed blood temperature should be less than or equal to 38.5C· The water bath should stay between 15 and 42C to prevent organ damage (too cold) and hemolysis (too warm)
Maintain a gradient of 4-6C, as rapid cooling produces uneven cerebral cooling
http://www.ctsnet.org/doc/2220

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From Ben Best’s Website:

Cell survival generally drops to zero for cooling rates that are either too rapid or too slow, giving an "inverted U curve". Excessively fast cooling rates kill cells by osmotic damage to membranes caused by pressure & friction from the exiting water molecules. Or excessively fast cooling allows for formation of ice inside cells -- which is far more damaging than extracellular ice. There is evidence that plasma membrane damage due to excessive osmotic pressure creates holes in the membrane allowing ice to form intracellularly [BIOPHYSICAL JOURNAL; Muldrew,K; 66(2 Pt 1):532-541 (1994)]. If cooling is too slow, however, cells will be killed either by prolonged exposure to the toxic concentrations of electrolytes that form outside the cell or by mechanical crushing from extracellular ice.
http://www.benbest.com/cryonics/cooling.html (Note: The link to the Muldrew paper is incorrect; here’s a new link to that article: http://www.biophysj.org/cgi/reprint/66/2_Pt_1/532 )

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Cerebral consequences of hypothermic circulatory arrest in adults.
EB Griepp, RB GrieppDepartment of Cardiothoracic Surgery, Mount Sinai Medical Center, New York, New York 10029.

“At present, risk factors associated with less favorable cerebral outcome after HCA include: prolonged duration of HCA (usually greater than 60 min); advanced patient age; rapid cooling…”
http://www.ionchannels.org/showabstract.php?pmid=1606366 (HCA = hypothermic circulatory arrest)

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Australia and New Zealand College of Perfusionists
Notes in Clinical Perfusion

Hypothermia & CPB
rate of cooling & warming and the effect on monitored temperatures

Temperature management entails 3 principles:
1) During both cooling & rewarming a maximum of 10°C is maintained between the water temperature (of the heater-cooler) and the blood temperature

a)Too rapid cooling may be associated with cerebral injury [eg cerebral vasoconstriction may be associated with reduced uniform cooling of brain)

b)Too rapid rewarming may be associated with the danger of gas bubble formation as gases become less soluble in blood as temperature increases + critical post ischaemic period characterised by high cerebrovascular resistance -impaired autoregulation & high cerebral metabolic demand for oxygen

2)Secondly, once the desired patient temperature has been reached, a further 10 minutes at least is required at this temperature to allow for uniform cooling of brain when cooling & uniform warming of body when rewarming

3) Once on HCA, must reduce rewarming-maintain hypothermia: use cooling blanket
· Is important to ensure cooling is not done too rapidly and once have reached target temperature a further interval of cooling is achieved prior to circulatory arrest to allow for uniform cooling of the brain and other vascular organs
http://www.perfusion.com.au/CCP/Details%20in%20perfusion%20technique/Hypothermia%20&%20CPB.htm

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The effect of cooling rate during perfusion on function and morphology of rabbit kidney grafts.
Jacobsen IA, Chemnitz J, Kemp E, Buhl MR.

"The effect of cooling of rabbit kidneys during the initial flush with Collins' solution for simple hypothermic storage was studied. After cooling at an average rate of 3.7 degrees C/min. graft function was found to be immediately life-sustaining, and renal morphology after perfusion as well as 30 min. and 24 hours posttransplant was found to be normal. Posttransplant function after cooling at a rate of 7.2 degrees C/min. was significantly lower, permitting survival of only 30% of recipient animals, and damage was seen in proximal tubular cells."
PMID: 7013052 [PubMed - indexed for MEDLINE]

(My note: In summary, faster cooling rates led to cellular damage and lowered survival rate.)

I understand that rapid cooling may be an "necessary evil," in regard to the vitrification process, as the solutions being used are more toxic at higher temperatures. However, I question the wisdom of rapid cooling during the washout procedure, while the patient has either blood or the biocompatible washout solution in their circulation. I've seen many patients wake up, neurologically intact, after being cooled to clinical death, below 18°C, and left that way for a period of time. I think it's reasonable to assume a patient could slowly be cooled to near zero, for the washout procedure, with the same amount of safety.

I may be wrong, but I don't believe it will ever be proven that rapid cooling to near zero C is as safe, or safer, than adhering to the proven safety guidelines that were established in surgical hypothermia protocols, long ago. I'm still concerned when I see Platt's statements about the cooling abilities of his "Liquid Ventilation" system on the Suspended Animation web site: “Typically a descent from 25 degrees Celsius (78 Fahrenheit) to 3 degrees celsius (37.4 Fahrenheit) takes less than five minutes. The system is then ready for use."

Does this mean they are applying this technique to a still warm patient when the liquid is at 3°C? Is it wise to flush fluid at 3°C into a patient at near 37°C, (using their lungs as a heat exchanger and greatly exceeding the 10°C safety gradient). There are studies that indicate rapid cooling may not be as damaging as it has been thought to be, but is it worth the risk at this point in time? Cardiac surgeons and perfusionists all around the world think it is not. Does Charles Platt even care? Or is he just interested in as many design and fabrication hours as he can get and taking credit for the design of new equipment, no matter how ill-advised?

I do think the idea of using lung lavage for initial cooling of cryonics patients could be of value when it is not possible to immediately place the patient on bypass. However, I think the cryonics protocols for cooling AND post-ischemic oxygenation, (another topic I will address, soon, on this blog), via lung lavage/liquid ventilation, should be more carefully examined.