X-Message-Number: 9621
Date: Tue, 5 May 1998 02:24:29 -0400
From: Mike Darwin <>
Subject: 21CM Cerebral Resuscitation

Saul Kent has asked me to briefly outline the cerebral resuscitation and
critical care medicine research 21st Century Medicine  (21CM) is doing.  I
do not think this is the appropriate venue for detailed disclosures and, as
we are pursuing both patent protection and peer-reviewed publication of
this work, I will keep my remarks general.

A few days ago anyone not living under a freeway underpass in the United
States became aware that the FDA had approved a pill to treat impotence
(Viagra) which appears to be highly effective and which in pre-launch
studies, of which the FDA was aware,appeared to facilitate intercourse in
most post-pubertal males_and females_ (not just in the target population of
50+ yr old males). Viagra now accounts for 2 of every 3 prescriptions being
written in the US. Yesterday, Bob Ettinger posted a summary of a
news-service story describing the incredible success of angiostatin and
endostanin in "curing" virtually all solid tumors in rodents and quoted the
researchers as having even more optimistic data than has yet been
published.  To my knowledge this true; this drug combination has worked in
three species so far and has shown minimal side effects and virtually
complete efficacy against all solid tumors on which it has been tried
(adenocarcinomas, sarcomas, osteosarcomas and several others).  To put this
into perspective, adenocarcinomas alone constitute the vast majority of
solid tumors of clinical relevance and human terror: cancers of the lung,
breast, mouth, stomach colon, anus/rectum, and pancreas.  Similarly, the
statin-drugs (such Lovastatin) have been shown to cut cardiovascular
morbidity and mortality by 50% if started in persons at risk of a heart
attack even in middle age and to similarly reduce mortality in patients who
have suffered a first heart attack (i.e., reducing their likelihood of
dying of a second heart attack).  Finally, the protease inhibitors and
combination antiviral therapy have emptied out hospices and closed down
virtually every AIDS unit in Southern California in the space of 18 months.
All this and Prozac too!

The purpose of the above rather lengthily paragraph is to point out that we
live in interesting times and that the century ahead (if we don't destroy
ourselves) will be the century of biology, as this, the 20th century has
been the century of physics and engineering.

One of my primary reasons for becoming involved in human cryopreservation
as a 13-year-old was a desire to defeat death and to be a part of the
emerging control over every aspect of human biology.  In beginning my
career in cryonics I began at the beginning: which was the problem of how
to maintain the newly "dead" patient in a viable condition, or at least to
minimize injury from ischemia as much as possible until definitive
stabilization (freezing) could be brought to bear.  I naively thought this
would be a relatively easy task since extended CPR seemed to fit the bill
for what was needed and a few problems such as cold-agglutination, acidosis
and anticoagulation could be easily overcome. Now, 30 years later,  I have
a far different perception.

I learned, much to my horror, on the first patient I had the opportunity to
begin immediate machine assisted CPR on under ideal conditions (i.e., in
hospital within seconds of pronouncement and with an intact circulatory
system which had not been ravaged by hours of pre-mortem shock or
multi-system organ failure) that closed chest CPR didn't work.  My patient
went into rigor mortis within a few hours despite excellent mechanical CPR,
buffering, anticoagulation, and what was then thought to be adequate
external cooling with ice bags.

That patient taught me a lot.  His name can be disclosed  now: it was
Willie DeMar. Because I collected enormous amounts of data from that
patient and subsequent ones I was able to determine that there were many
problems, not the least of which was that it took him nearly 8-hours to
cool to just about room temperature!  Most of that time I was moving
essentially no blood, the patient having gone into rigor within 2 hours
after the start of "transport."

Watching cryopatients die up-close and personal and having the added
opportunity to work in hospital in a critical care setting for the better
part of a decade taught me a great deal more.  Until recently however, all
of the efforts I've exerted have resulted in incremental advances or
improvements in the front-end of care (cardiopulmonary-cerebral
resuscitation) of patients as opposed to dramatic advances in capability. 
I learned how to cool patients more rapidly by direct contact with ice and
and water and invented the PIB, and with Jerry Leaf, became expert at
developing systems that allowed for rapid (by cryonics standards), in-field
heart-lung machine facilitated cooling and oxygenation of cryopatients as
well as blood washout with extended recovery and survival as a routine
expectation (using a dog model for validation).

Periodically we would apply our growing insights and technology to
ostensibly reversible animal models of sudden cardiac death trying to
recover dogs from periods of _normothermic_ cerebral ischemia of 10 to 12
minutes' duration, but with no success.

The last 5 years has seen an explosion in our understanding in the
pathophysiology of ischemic injury:  We are now beginning to understand the
critical biochemical and biophysical events that cause injury and prevent
long-term recovery of dogs (and people) after periods of cardiac arrest of
much greater than 6 minutes duration. Equally important, via the modality
of liquid perfluorochemical ventilation I have learned how to _rapidly_
cool patients  by the crtitical 2 degrees necessary to facilitate cerebral
preservation upon reperfusion (restart of blood circulation).

Just as importantly, a virtual cornucopia of drugs and bio-regulatory
molecules are becoming available to us to block many if not all of the
critical damaging reactions that occur during both ischemia and upon
reperfusion.  At 21CM we early on adopted a philosophy that cerebral
ischemia-reperfusion injury was complex, multifactorial and that a single
magic bullet mon-drug or approach was unlikely to work.  We carefully
studied the literature and observed that with few exceptions, virtually all
of the work being done in this area was done using small animal models with
a mono-therapeutic approach.  The reasons for this are many and I will list
but a few:

*Drug combinations are rarely, if ever approved by the U.S. FDA.
*Most institutional research is aimed at unraveling the mechanics of a
particular aspect of the pathology with the endpoint being a measured
biochemical, physiological, or behavioral parameter.  For example, a single
free radical blocking drug might be given to determine the importance of
free radicals in ischemic injury of a high specialized kind with the
measured end-point being detection of free radical inhibition in brain
tissue upon reperfusion by a measurement such as chemiluminesence.
*Multi-modal therapeutic research is costly and difficult to conduct and
creates great problems in determining exactly _what_ part of the protocol
is working.
*The few multimodal trials done to date have usually shown a net negative
benefit to combining drugs.
*For the above reasons it is difficult to publish papers using such
approaches in peer-reviewed journals which focus on "clean" science with a
strong emphasis on understanding small parts of the problem definitively.
*Most of this work is done by people who get rewarded for a "nice" piece of
science rather than a definitive clinical endpoint.

This last point is very important, and I'll get to it directly.  At 21CM
our goal was not _primarily_ to further understanding into the mechanics of
injury in ischemia, but rather to overcome ischemic injury.  Our endpoint
was not reducing the evidence of histological damage, or the level of key
biochemical markers of injury, but  rather to achieve integrated, long term
survival of animals _without neurological deficit_ in a model directly
relevant to humans.

We spent a great deal of time and money choosing, developing, and
validating the model.  We also spent a great deal of time and energy trying
to sift through the enormous literature on cerebral ischemia-reperfusion
injury and come to some conclusions about what were the most important
mechanisms and pathways of injury to treat or block and which were the
best, least expensive, most readily available drugs to achieve these ends
with.

Our sole mission was to get dogs back with reasonable consistency after 15
to 20 minutes of normothermic cardiac arrest (whole body ischemia at 37.5
C) and _without neurological deficit._  In others words; the dogs had to
survive, recover fully, and show retention of memory as well as the ability
to learn and interact socially with humans normally.  (The latter is a
dauntingly complex task requiring full conservation of mentation).

The structure of this kind of research approach is technologically oriented
rather than academic.  It is a "moonshot" mentality rather than a "doctoral
dissertation" mentality.  This is _not_ to slight the thousands of toiling
scientists working on mono-modal treatments and teasing out basic
biological pathways of injury: these people made our work possible.  And,
quite podssibly, some of them _will_ discover magic bullet drugs with
enormous payoff.

What we have done is to use a complex, multi-drug cocktail to treat
cerebral ischemia-reperfusion injury.  We have further learned that in
addition to drugs there must be artificial, _automated_  re-imposition of
physiological "homeostasis," or regulation of the animal's internal
environment for a period of some hours following resuscitation.  We have
further discovered that the complexity and possible adverse interaction of
the drugs used in the protocol requires computer driven AI algorithms to
control timing, sequence, and the amount of various drugs delivered.  In
short, drugs alone are not enough, an integrated system which measures
multiple critical physiological parameters inside the animal and then
_adjusts_ them optimally with both pharmacological and mechanical
interventions is critical to success.

Using this approach we have achieved in the pilot canine cerebral
resuscitation experimental group:

100% acute neurological recovery following 15 to 17 minutes of total body
cardiac arrest at 37.5 C.
75% long term-survival of animals (i.e., great than 1 month) with normal
kennel behavior (i.e., motor function, grooming, reproduction, etc).
50% of survival animals have no detectable neurological deficit with
complex behavioral evaluation (including learning and memory).
50% survival of animals with _mild_ neurological deficit: subtle changes in
ability to learn or remember or behavior changes such decreased inhibition
and loss of social interactivity with humans.

There has been 100% mortality in the control group.  
There has been 100% lack of acute neurological recovery in our historical
controls using the typical American Heart Association Advanced Cardiac Life
Support (ACLS) Protocol.
The longest we have recovered a dog from normothermic cardiac arrest is 17
minutes, with normal mentation at 3 months post-procedure.

We are now in the process of locking our protocol into place and beginning
a fully blinded statistical run with a standardized insult  time of 15
minutes of cardiac arrest. 

The relevance of this work to contemporary medicine is potentially
enormous.  In the United States approximately 350,000 people die each year
from failed cerebral resuscitation.

Many others die or suffer lasting disability from head trauma, and one
thing we have learned at 21CM is much of the pathophysiology of blunt force
head trauma overlaps that of ischemia-reperfusion injury.

The company has no plans to directly market this technology, but rather to
pursue licensing in order to generate revenues. The company also has no
plans to conduct clinical trials in the U.S. or to introduce this
technology to the U.S. marketplace, even though the U.S. constitutes 2/3rds
of the world's overall drug market.

It is also fair to say that this work is in its infancy with enormous
amounts of hardware and software development needed to facilitate optimum
application of our protocol.  

Some of the drugs used in our protocol are novel and patentable and will be
of direct, and we believe, potent therapeutic utility as stand- alone
molecules used to treat specific critical illnesses such as shock,
malignant hyperthermia, heat stroke, and post-traumatic respiratory
distress syndrome. Others are the products of other pharmaceutical
companies.

One of the frustrating and exciting things about this work is that we have
scarcely scratched the surface of the possibilities.  We are achieving what
we believe to be astonishing results now, and yet we have over 40 novel
compounds which we currently do not have the resources to evaluate, but
which offer the promise of even better results both in terms of outcomes at
the current time limit of 17 minutes, and in terms of allowing recovery
from longer arrest periods, perhaps out to as long as 30 to (in selected
cases) 60 minutes of clinical death at normothermia without neurological
deficit.

Recently Bob Ettinger and the Cryonics Institute criticized the 21CM
cerebral resuscitation research program stating:

>some of us have problems with infliction of suffering on dogs or
>other animals, even if the eventual goal is to save human life. Certainly
this
>is a gray area, but I want it on the record, again, that Cryonics
Institute
>does no experiments on live animals. When they are killed for our
research, it
>is either routinely at a slaughterhouse where it would have happened in
any
>event, or by euthanasia under the supervision of a veterinarian, and not
on CI
>premises in any case.

I will have more to say on this soon. It is sufficient to say now that
animals in our laboratory are managed for pain and discomfort using the
best available pharmaceutical technology with cost as no barrier, including
the use of drugs such as Propofol which allow for titration of sedation
and, when coupled with morphine and or Fentanyl, (we have a DEA license)
allow for very tight control over pain and agitation.  It is certainly the
case that our our animals are managed for post-operative pain and
discomfort better than the millions of companion animals (pets) who undergo
painful surgical procedures and then are caged or sent home with their
owners with NO pain management whatsoever.

In summary, we believe that our work has the potential to improve the
quality and length of both human and companion animal life and we feel our
work is very worthwhile.  We see the company's prospects for financial
rewards in this area with caution.  There are many obstacles to successful
clinical application of this technology.  Personally, I believe the real
profit centers at 21CM are likely to be vastly improved cryopreservation
methods with application not just to transplantation but to engineered
tissues and to conventional cryopreservation technologies, perhaps
allowing, for instance, stable dry ice temperature storage of viable cells
and tissues such sperm, ova, embryos and blood: thus eliminating the need
for costly and dangerous technologies such as liquid nitrogen storage and
superinsulated dewars for transportation of cryopreserved biologicals.

Nevertheless, the company maintains a strong commitment to critical care
medicine and some of the first human clinical applications of 21CM
technology seem likely to come from that division of the company. 

Mike Darwin, Director of Research
21st Century Medicine

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