From: Eugene Leitl (
Date: Mon Apr 30 2001 - 05:54:37 MDT

(((Sorry for crossposting this to all and sundry -- actually I'm
   not, since below piece contains large amounts of clueful bits,
   succinctly shedding light on a highly relevant and often-enough
   overlooked problem set)))

CryoNet Message #16156
Date: Sun, 29 Apr 2001 20:18:47 EDT


By Mike Darwin, CEO Kryos, Inc.


Ischemia is the pathologic interruption of the delivery of adequate blood
flow to tissues. Unlike anoxia where only oxygen delivery is compromised,
ischemia constitutes a complete disruption of the normal functions of
blood flow: delivery of oxygen and nutrients and other molecules essential
to cellular survival as well as the removal of harmful byproducts of
metabolism. Ischemia can either be partial or complete, regional (as in
stroke), or global as in cardiac arrest.


In order to understand the implications of ischemia in the human
cryopreservation patient it is first desirable to understand ischemia in
the context of contemporary medicine. Heart attack and stroke are likely
to be the pathologies that most clinicians cite as the principal cause of
ischemia. In fact, ischemia is the major underlying cause of most
mortality and morbidity in the critical care setting (ICU and Emergency
Department) in the Western world. Closed head injury, blunt force trauma,
shock and sepsis all have ischemia as the fundamental underlying common
pathway. All of these illnesses have their lessons to teach about the
pathophysiology mechanisms of ischemia.

However, for purposes of clarity and relevance I will focus on global
ischemia secondary to cardiac arrest as a result of heart attack or
exsanguinating trauma. Of most immediate relevance to the cryopreservation
patient is ischemia secondary to sudden cardiac death (SCD) and the events
which follow failed or morbid resuscitation.


Each year in the United States there are 540,000 deaths from myocardial
infarction (MI) [1] (with 350,000 of these deaths occurring before the
patient reaches the hospital) as a result of a non-perfusing arrhythmia,
principally ventricular fibrillation [2]. This mode of sudden cardiac
death (SCD) is also responsible for the majority of the 190,000
in-hospital deaths from MI, which typically occur within the first 24
hours following admission. [3]. Especially tragic is that 50% of these
deaths occur in persons ~50 years of age or less [4]. An estimated
additional 20,000 incidents of SCD occur as a result of asphyxiation,
drowning, electrocution, and genetic or developmental predisposition to
lethal arrhythmias (Wolf-Parkinson's White Syndrome, congenital thickening
of the intraventricular septum, and idiopathic arrhythmic disease) and
other non-atherosclerosis causes. This later category of SCD typically
occurs in individuals whose mean age is less than 25 [5]. At this time
the principal treatments for SCD consist of initiation of manual,
"bystander" cardiopulmonary resuscitation, so-called Basic Cardiac Life
Support (BCLS) followed by "definitive" treatment of the arrhythmia
beginning with defibrillation and the application of Advanced Cardiac Life
Support (ACLS) [6].

ACLS consists of the application of an algorithm of manual CPR, electrical
defibrillation and pharmacologic therapy aimed at restoring a perfusing
cardiac rhythm and adequate blood pressure and cardiac output to sustain
life until definitive treatment of the underlying cause of the cardiac
arrest can be achieved (e.g., coronary revascularization, implantation of
an automatic defibrillator, or life-long anti-arrhythmic therapy) [6].

The time to survival without neurological deficit following cardiac arrest
in the absence of BCLS declines rapidly following a sigmoid curve with
survival without neurological deficit being ~95% following 1 minute of
arrest time, and 0% following 9 minutes of arrest [7]. Put another way,
50% of patients will experience significant morbidity or death following 4
minutes of circulatory arrest.

What is not shown in this table is that the effect of immediate bystander
CPR on survival is negligible in most studies [8, 9], with the primary
benefit being observed in patients who's time from the initiation of BCLS
to successful cardiac resuscitation was greater than 8 minutes [10]. There
is evidence in the literature that morbidity is improved with prompt
bystander CPR [11] providing that EMS response is also rapid, although
this remains controversial [10, 12]. A corollary of this is that the
overall survival rate following SCD, with, or without, serious
neurological morbidity ranges between 1% (New York City, NY) [13] to 17%
(Seattle, WA) [14]. The mean survival (defined as survival to discharge
from the hospital) in the United States as a whole is generally agreed to
be at best 15% [15] with ~70% of these patients experiencing lasting
neurological morbidity (ranging from "mild" cognitive impairment to total
incapacitation in the Persistent Vegetative State (PVS) [16-18].

The primary cause of non-survival in patients experiencing SCD is failed
cardiac or cerebral resuscitation. Arguably, it is failed cerebral
resuscitation, since most underlying causes of refractory cardiac arrest
could be treated by "bridging" supportive technologies such as emergency
femoral-femoral cardiopulmonary bypass (CPB) until myocardial
revascularization and hemodynamic stabilization is achieved [19]. When
this technology is applied to patients who are candidates for good
neurological outcome, the survival rate is increased [20-22]. These
technologies are not typically used on patients who are unsuccessfully
resuscitated (restoration of adequate cardiac rhythm and perfusion)
because of the justified perception that irreversible brain damage would
have occurred during the prolonged period of cardiac arrest or CPR/ACLS
[20]. Similarly, it is for this reason that most attempts to achieve
cardiopulmonary resuscitation in-hospital in patients who are not
hypothermic, or intoxicated with sedative drug are terminated following 15
minutes [23, 24].

It is noteworthy that both past and current ACLS protocols contain no
drugs aimed at treating the primary cause of failed or morbid
resuscitation from SCD: principally post-ischemia-reperfusion
encephalopathy (Textbook of Advanced Cardiac Life Support, Second Edition,

Over the past 15 years a vast number of therapeutic interventions have
shown great promise in animal models in the laboratory [25-28]. However,
none of these has been successfully applied clinically despite numerous
attempts [29, 30]. These reasons include: a) the inappropriateness of
animal models being used to validate pharmacologic or other means of
therapeutic intervention, b) failure to address the multifactorial nature
of the pathophysiology of ischemia-reperfusion injury, and c) the
inability to rapidly induce mild systemic hypothermia which, arguably, has
been shown to be one of the most potent interventions in achieving
improved outcome from prolonged periods of cardiac arrest and the
resulting normothermic systemic and, particularly, cerebral ischemia.

In 1994, Critical Care Research, Inc. (Critical Care Research, then called
21st Century Medicine) of Rancho Cucamonga, CA began a program of research
to investigate the used of multimodal drug therapy combined with mild,
post resuscitative hypothermia (33 C-34 C). By Early 1996 Critical Care
Research was achieving routine recovery of dogs from ~17 minutes of
normothermic ischemia with 75% overall long term survival (<3 months) with
less than 75% detectable neurological deficit in survivors. These
extraordinary results were achieved by a multimodal drug approach using a
slightly modified version of Safar, et al.'s model of CPB with
hemodilution and prompt institution of hypothermia to achieve initial
restoration of circulation and oxygenation [31-33].

Neurobehavioral and histological evaluation of randomly selected survivors
from this study demonstrated no detectable deficits in 75% of the
surviving animals (exceptions were some neuronal loss in the cerebellum,
which was not associated with any demonstrable long-term disability, or
motor deficit).

It is noteworthy that no other investigators have come close to
demonstrating these kinds of survival times following whole body
normothermic cardiac arrest in dogs with such low levels of neurological

Mortality Secondary to Massive Exsanguinating Trauma Resulting Cardiac
Arrest Before Tertiary Care Is Accessible

Closely related in pathophysiology to prolonged normothermic ischemia
secondary to SCD is cardiac arrest secondary to exsanguinating trauma. It
is estimated that ~20,000 US civilians a year die as result of hemorrhage
from abdominal and thoracic injuries [36], or from poly-trauma. In
developing nations this problem is even more severe as a disproportionate
amount of trauma occurs in rural settings remote from tertiary care
facilities and with no helicopter or other airlift infrastructure
available to shorten this interval.

Similarly, approximately 90% of the battlefield casualties who fail to
reach tertiary care facilities die from intractable hemorrhage during
transport. The US military under the auspices of DARPA is currently
funding a multimillion project to achieve ~30 minutes of battlefield
"suspended animation" using chilled, drug containing crystalloid
solutions, to solve this serious cause of war-related mortality [37].

Cardiac arrest secondary to exsanguinating trauma offers a unique
opportunity for intervention in the pathophysiological cascade of
normothermic cardiac arrest. Because blood loss and deterioration of the
patient to the agonal state occur over a time course of minutes to an hour
or longer, it is possible to begin administration of systemic and
cerebroprotective drugs, inhibit the clotting cascade, and induce modest
hypothermia via the infusion of large quantities of chilled
volume-replacement solutions. Typically, 3-4 liters of crystalloid are
administered for each liter of blood lost. In situations where
exsanguination will result in cardiac arrest, such as fracture of the
liver, rupture of the spleen, and laceration of major vascular structures,
60% to 70% of the patient's blood volume will have been replaced with
crystalloid at a ratio of 3:1 prior to cardiac arrest. For a typical 70 kg
adult this would represent a volume of ~10 liters, which, if administered
chilled to 2 -4 C could be expected to reduce systemic (core) temperature
by ~3 -4 C, thus providing additional ischemic protection, transport time,
and time for surgical repair of the hemorrhagic lesion(s).

The ability to administer large volumes of parenteral products of defined
electrolyte composition, containing multiple drugs, cellular edema
inhibiting polymers, and hemorheologic agents prior to the occurrence of
the insult (systemic ischemia) offers the opportunity to prevent many of
the foreseeable irreversible pathological events which occur during
ischemia as a result of SCD.

Many of the therapeutic drugs which have proven effective in Critical Care
Research's pilot study of sudden cardiac arrest (prolonged systemic
ischemia) are likely to be far more effective if administered prior to the
insult, rather than after a prolonged period of ischemia. The ability to
induce a maximally effective degree of post-resuscitation hypothermia
during the insult period is yet another added advantage of this mode of
cardiac arrest.

Thus, prolonged ischemic insult from either SCD or hemorrhagic cardiac
arrest are interrelated and lend themselves to integration into a single
protocol for investigation.

[References are available upon request]

End Part I

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