X-Message-Number: 9781
Date: Tue, 26 May 1998 14:03:54 -0400
From: Michael Darwin <>
Subject: Safar's Limits

Thomas Donaldson (whom, generally,  I respect greatly) writes with his
usual degree of assurance (:-)):

>To Mr (?) Leitl: The article you quote is now behind the times, and
>it is not even cryonics research which has produced that. The current
>public limit to revivability after heart stoppage is now 10 minutes,
>as done by Peter Safar and his coworkers in research towards means 
>to lengthen that period. 

This is not so.  Peter and his group have achieved good functional
neurological recovery (Overall Performance Catergory or OPC= 1) (OPC=5
brain death or coma) after *12 minutes of normothermic ischemia* in about
20-30% of their dogs. This is OLD news, at least 5 years old and has been
published in _Stroke_ and _Critical Care Medicine_. (Sorry, I'm home and
have neither the cites nor a spell checker on this machine.)  When Safar,
et al. began using their model of hypothermic hemodilution with
hypertension (i.e., heart-lung machine assisted resuscitation, as opposed
to CPR and defibrillation) about 30 years ago they got consistent
OPC=1recovery after about 9 minutes of normothermic cardiac arrest.  After
hundreds of dogs and three decades of tireless work they have extended this
time to 12 minutes, or, as Peter wistfully says himself, "That's about a
minute a decade!"

One of the reasons I've not communicated much with Thomas on matters like
this is that I've noticed disturbing inaaccuracies in his reporting of
research results in areas where I am conversant with the work.  For
instance, both Thomas and I attended lectures by Peter Safar of the Safar
International Research Institute and Paul Segall of BioTime.  There were
serious inaccuracies in Thomas' reporting on both these presentations.  As
a case in point, Peter presented both his best dog OPC and Neurological
Scoring data during his talk and his numbers were clearly better than 10
minutes.  Leonov and Safar have achieved at least 1 OPC=1 dog after 17
minutes of normothermic ischemia.  Statistically we do far better with 75%
of dogs reaching OPC=1 after 15 minutes. Leonov's and Safar's studies are
long ago published in the open literature.

Further, any comparison betwenn between Peter's work and ours requires
important qualifications.  They get apparently faster acute neurological
recovery and follow their animals only to 72 or 96 hours.  They have fewer
iatrogenic deaths and are using a simpler protocol.  Their controls do
better than ours even though our experimentals do better than their
experimentals.  Our models differs from Safar's in a couple of important
ways: one being their use of of intra-aortic levophed to facilitate
post-ischemic reperfusion (delivered by a catheter threaded up the aorta
from the groin; a maneuver we believe is not clinically feasible in the
field and is injurious to the heart.  I could go on and list other points. 
It is, however, fair to say that we are using a very close approximation of
the Safar model of systemic normothermic cardiac arrest in the dog. 

My special thanks to Peter for his many tips and frank coversation which
made this possible!

Thomas goes on to say:

>Mike Darwin and (funding by) Saul Kent claim to have significantly
>lengthened even this period, to 15 minutes or longer. So far as I know,
>they haven't published their methods. Whether you believe them depends
>on whether you trust them when they make such statements; I know both
>men and would trust them, but still hope that they can publish their
>results ASAP. Details are critical in such things.

This statement is one which is very true:  The part about disclosure and
details, that is!  Claims made in a vacuum of information mean little, even
if you DO trust the people involved.  Even good investigators can be misled
by their own work.  As I always say, one of the EASIEST people to fool is
yourself; everybody else is then fooled (if they are not demanding of
rigor) as a matter of course and often with greater ease!

Thomas can get ALL the details on the techniques used at 21CM by signing a
nondisclosure agreement.  He is also welcome to watch a CRS experiment in
progress and see the outcome.  But, even this is no substitute for
peer-reviewed full disclosure.  I will say the following about the 21CM
resuscitation work which may help to clarify matters:

1) Patents take an enormous amount of time and the delay time to
publication is usually 3-4 years if international coverage is desired
(which is especially the case here). I find this immensely frustrating and
damaging to scientific progress.  However, both Greg Fahy and I have made
other people rich beyond our wildest imaginings (and probably their too!)
with not a penny to show for it ourselves by being generous with our
intellectual property.  This has been painful, not only because of the
personal effects (relative poverty), but because it has prevented us from
furthering our own further *research* at the pace we'd like in the way we'd
like with our *own* money.

2) The technology for cerebral resuscitation 21CM has developed is not very
clinically applicable at the moment (except, ironically, to ideal cryonics
cases!).  It requires currently bulky hardware, cranky drug preparations,
and a large staff to implement.  Automation and AI software will be
critical to clinical application, as will top-notch biomedical engineering
to allow for packaging and minaturization of sensor and control
technologies.  We are actively seeking collaborators in this area, and,
gratifyingly, are having some luck!

3) Perfluorochemical (PFC) liquid ventilation for rapid induction of
hypothermia is far further along (we are beginning our stastistical run on
this technology and have an excellent collaborator for EM and
histopathology on the lungs).  Our patents will soon issue on this (one has
already), we have a large volume of data, the experiments are "easy" to do,
and we expect to be submitting abstracts and preparing publications soon. 
PFC ventilation is critical to the cerebral resuscitation technology
because a key element of this technology (to which we owe a deep debt to
Peter Safar) is the absolute requirement that hypothermia of 33-34 degrees
C be induced within the first 10 to 15 minutes of post-ischemic
reperfusion.  If this is to be achieved in the field, it must be done
simply and without recourse to vascular acccess (i.e., bypass or
intracarotid perfusion), at least in our opinion. 

As I have said before, I think 21CM's near-term profit centers are going to
be in cryobiology, not critical care.  Evaluations on fundamentally new
CPAs for use in traditional cryobiological settings are underway, and we
have a goal of shipping product by the end of this year or the middle of
next year.  The first three abstracts of data on these novel agents have
been submitted for peer-reviewed publication.  Papers are in preparation
now, and there is a wealth of novel and exciting data.

So, while the cerebral resuscitation work is impressive and exciting, it is
also very costly, very demanding, and fraught with regulatory hurdles.  It
is a testament to the the company's stupidity er, I mean foresight ;-),
that they continue to pursue these demanding areas when products and
profits for the taking are so abundant elsewhere in the company's stable of
intellectual property.  For this far-sighted and courageous stance I wish
to thank both Saul Kent and Bill Falloon; otherwise I'd be unemployed!


Mike Darwin

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