From: kqb@cbnewsl.cb.att.com (kevin.q.brown)
Subject: Re: Possible thawing process
Organization: AT&T Bell Laboratories
Date: Fri, 28 Aug 1992 15:55:58 GMT
X-Crossposted-To: cryonics mailing list

    ------------------------ Forwarded Message ------------------------

>Message-Subject: CRYONICS Gas/Liquid phase cooling
>From: edgar@spectrx.saigon.com (Edgar W. Swank)
>Date: Mon, 24 Aug 92 19:05:04 PDT

OK for sci.cryonics
OK for Cryonics Digest
 
In response to my posting about gas phase freeze/thaw technique,
designed to keep an open circulatory system at all times
(Msg # 1112),
 
Rich Schroeppel  rcs@cs.arizona.edu
 
has sent me several E-mail messages directly commenting and offering
suggestions. With his permission, I'll now share a summary of our
exchanges with you.
 
Rich (Aug 7):
 
There are a fair number of fluids that remain liquid well below
the temperature of freezing water.  Your heat-transfer fluid
doesn't have to stay liquid all the way down to LN2, just far
enough that the cells are shut down.
 
Edgar (Aug 14):
 
No, the main benefit of using a gas coolant was to have the
circulatory system free for the benefit of whoever attempts a revival.
A coolant liquid at LN2 might be OK, but not a solid. Another benefit
of fluid down to LN2 would be more uniform cooling/rewarming which
might reduce some of the thermal stresses which now cause gross cracks
to appear.
 
Rich (Aug 7):
 
Ordinary alcohol is liquid down to some surprising temperature,
I think well below dry ice.  It's probably out for chemical
reasons, though.  Freons would be an obvious candidate for
the early cooling; maybe CF4 or CH2F2.  For the later cooling,
Xe or Kr, or maybe Ar; I'm not sure what the liquid ranges of
these are, but they can be increased through modest high
pressure.  N2 might be the last coolant, although boiling
could be a problem.
 
Edgar (Aug 14):
 
>From an old Handbook of C & Ph.
             B.P.         M.P.  Deg C
N2          -195.8      -209.86
Kr          -152.9      -156.6
Xe          -107.1      -112
Ar          -185.7      -189.2
 
So you can see all the noble gases don't have sufficient
liquid range.
 
My old handbook didn't have any info on Freon or other CF's,
but I like your idea for early cooling. This might be a good
candidate for a transition fluid from liquid to gas. The problem
is, each liquid used in the procedure must mix fairly well with
the liquid which proceeds it so that it can flush it out. I think
I remember hearing that Freon is pretty non-toxic.
 
On the other hand, alcohol mixes very well with water as well as
reducing the freezing point. But alcohol is pretty toxic, but maybe
not too much below 0 deg C?
 
Rich (Aug 17):
 
I spent a few minutes last night poking through my Handbook of
Chemistry & Physics, and the Merck Manual.  Some candidate fluids,
with wide liquid ranges, are NF3, C2H6, CF4, CF2Cl2, C3H8, and
CHFClBr.  They are generally described as "inert", not much
solubility in water, not explosive, fairly wide liquid ranges.
Typical toxicity is "simple asphyxiant", which I take to mean
"safe" in our context.
 
I have two reservations with gasses as coolants:  the first is
that the heat capacity is small, on a volume basis, so lots of
gas is needed to transfer a little bit of heat.  The second is
hard to quantify, but my feeling is that the fluid should have
roughly the same viscosity as blood: if it's too much greater,
it can't get through the capillaries (without a damaging head
of pressure further back in the arteries); if it's too much
less, I'd expect it to find some pathway through the system
and ignore the rest of it.
 
I'm assuming that liquids are better for these reasons.
There are a lot of liquids available, so if the ones I've
suggested don't work out, there are alternatives.  Propane (C3H8)
is somewhat magic, in that its boiling point varies a lot
with pressure; if we can pressurize the patient to ~30 atm,
then it's liquid at 37C.  There are flammability problems
though.  Also, any air spaces in the patient would be crushed;
the ones that come to mind are the middle ear, the sinuses if
blocked, and the GI tract.  The lungs could also be a problem.
 
The choice is a bit cramped at the LN2 temperature range,
although I suppose LN2 itself is a candidate.
 
There's a lot of nuisance with using multiple cooling fluids, etc.
to work out; but simply freezing a rat & reviving it would be
a big step forward; the descent to LN2 temperatures could be
a second experiment.  One of the freons would be the ideal
liquid for the simple freezing experiment.  Maybe CF2Cl2.
 
Edgar (Aug 20):
 
Re the fluids you mention, all the characteristics sound good
EXCEPT "not much solubility in water".  We need a transition liquid
miscible in both water and NF3, etc.  Do your handbooks offer any
possibilities?  Alcohol still looks good except for toxicity which
may not be a problem below 0 C.  Do NF3... mix well with alcohol?
 
Rich (Aug 20):
 
I think "not soluble in water" is *good*.  It means that the fluid acts
solely as a heat transfer agent, and not chemically.  This should be
helpful in preventing toxicity.  It also means that the fluid won't
diffuse into the patient, so we can get it all back out.  Propane worries
me a bit in this respect; the recovering patient might retain quite a
bit of propane.  If it acts solely as a dissolved-gas anesthetic, then
the patient should recover as it gradually diffuses out.
 
I think alcohol is bad:  It will be chemically active well below 0C,
and it will lower the freezing point of any water it mixes with.  It
will probably diffuse into the patients cells and screw them up badly.
 
Edgar (Aug 23):
 
While I agree that non-soluble in water also tends to mean inert and
non-toxic, there is still the problem of washing out the water-based
blood or currently used cryo-protective blood substitutes.  I'm afraid
that trying to wash out a water-based liquid with something else that
won't mix with water will get the same result as trying to wash out
a liquid with a gas. "Bubbles" of one liquid within the other and
an incomplete removal of the water-based liquid, leading to
solidification and clogging of the circulatory system at lower temps.
 
By the time alcohol is introduced, temperature should be far enough
below zero C that cell interiors are frozen solid. Hopefully that
should limit diffusion of alcohol into the cells.  We still may have
to worry about alcohol attacking or dissolving the cell walls it
contacts.
 
Both of these concerns are easily tested experimentally. Make a
(simplified) glass model of the circulatory system including many
capillary-sized glass tubes in parallel. Fill the system with water.
Try to wash out the system by pouring in Freon, etc. See how many
of the capillaries still contain water.  Try the same thing on a
hamster; once pure Freon is the effluent, dissect & see how much
water was left.
 
Take various tissue samples at (say) -5 deg C. Immerse in alcohol
pre-cooled to -5 C. Remove, wash, and examine microscopically for
damage.  Or try live cultures that survive a round trip from -5 C and
see how many stay alive after immersion in alcohol, washing &
re-warming.
 
Edgar (Aug 20):
 
I don't think low heat transfer of gas is a concern.  Current practice
is to cool patients from dry ice temperature (with ice clogged
circulatory system) to LN2 by dangling them *in vapor phase* above
boiling LN2.
 
Rich (Aug 20):
 
I'll concede this point.  I'll note that handling liquids is somewhat
easier than handling gasses, but that the difference in convenience
would be outranked by any substantial benefit to the patient.
 
Edgar (Aug 20):
 
I agree that viscosity much higher than blood (or containing
particulates much larger than blood cells) is a concern, but I don't
see the concern for less viscosity.  Helium, especially, is likely
to find new pathways even finer than the capillaries, but I don't
see the harm. A large leak or "short circuit" in the circulatory
system will be a problem with high or low viscosity. A small leak
should still allow some pressure differential across the capillaries.
However, it's been a long time since I had basic fluid dynamics in
College, much less anything advanced.
 
Rich (Aug 20):
 
I'm only going on gut feeling here; I've never had any fluid dynamics
training.  My worry is that the He (or other low viscosity fluid) will
find a few easy paths through the circulation, and ignore the rest.
The patient will remain mostly full of blood, defeating your goal.
Live people must have some active system controlling vascular resistance
locally, to let the right amount of blood through.
 
Edgar (Aug 20):
 
Re using propane & 30 atm.  I don't think it would be a big problem
to catheterize the air spaces you mention in advance of starting
perfusion.  The main danger seems to be to the perfusion team (and
patient!) from fire and explosion. Certainly the patient needs to be
completely enclosed and all oxygen flushed out before introducing
propane. We have to flush out the propane (with helium?) before LN2
anyway so this is not an ongoing hazard.
 
Rich (Aug 20):
 
Well, people do successfully handle propane every day, so it must be a
solved problem.  A few percent oxygen is okay, as long as it's below the
explosion threshold.  A "no ignition sources" rule might be a real
nuisance, implying sealed motors, all metal objects grounded, who knows
what.  We need information from someone with handling experience.
 
Rich (Aug 19):
 
I did a bit more bookwork, with the Merck Manual.
 
LN2 boils at 77K = -196C.
 
NF3:  melts -208.5, boils -129.  (All Centigrade, of course.)
Insoluble in water, rather inert chemically.
Toxicity:  Prolonged exposure may cause mottling of teeth,
skeletal changes; see Chronic Effects of NaF.
[I'm proposing short term, intimate, acute exposure at low
temperatures.  I'll hope that it's harmless.  Their data is
presumably for the gas.]
 
CCl2F2 (Freon12) melts -158, boils -30.  At 10 atm pressure, boils 42.
Insoluble in water.
Toxicity:  Zip.
 
C5H12 (normal pentane) melts -130, boils 36.
Slightly soluble in water.  Flammable.
Toxicity:  Narcotic at high concentrations.
[I assume this is due to the solubility, and maybe to lack of O2.
I hope that short term exposure to the liquid is harmless.]
 
 
It looks like pentane & NF3 are a plausible pair of cooling fluids.
Freon12 could be a bridge if the overlap between -129 & -130 is
uncomfortable; or a mixture of pentane + Freon12 should have a
slightly lower melting point, without lowering the boiling point
too much.
Pentane is imperfect.
The Merck doesn't have all the different possible combinations of
alkyl halogen compounds; there may be a freon that has a suitable
liquid range, is not water soluble, and not flammable.  I'd want
to examine fully substituted propanes, maybe half F & half Cl;
say C3Cl4F4.
 
Edgar (Aug 21):
 
It certainly looks like you have found a good set of fluids that
together encompass a liquid range from above zero C to below LN2.
It seems we have an option to store at LN2 with either gaseous
Helium or liquid NF3 (which may also prevent tooth decay! (:) ).
 
As I said in my previous msg, the problem is lack of a transition
fluid that IS soluble both in water and the organic fluids you suggest.
I can't think of anything better than alcohol offhand.

--
edgar@spectrx.saigon.com (Edgar W. Swank)
SPECTROX SYSTEMS +1.408.252.1005  Silicon Valley, Ca
Newsgroups: sci.cryonics