X-Message-Number: 16156
From: 
Date: Sun, 29 Apr 2001 20:18:47 EDT
Subject: ISCHEMIA: AN INTRODUCTION, Part I

GLOBAL ISCHEMIA: A COMPREHENSIVE INTRODUCTION, PART I

By Mike Darwin, CEO Kryos, Inc.

WHAT IS ISCHEMIA

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.

BACKGROUND

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.

EPIDEMIOLOGY

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, AHA,1996).

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 deficit.

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

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=16156