The results of this study validate and expand the results previously reported in our clinically relevant model of CA/ROSC. We have demonstrated significant clinical10
as well as histological9
neuroprotection afforded to animals resuscitated with room air after 10 minutes of CA compared with similar animals resuscitated with 100% O2
for as little as 1 hour. In addition, normoxic animals showed significantly less protein oxidation in the selectively vulnerable hippocampal CA1 region. In particular, animals resuscitated with room air showed significantly greater enzyme activity and immunoreactivity for pyruvate dehydrogenase,9,23
a key enzyme of metabolism that may contribute to cerebral metabolic derangements for 24 hours or longer after CA/ROSC.24,25
The goal of any preclinical translational trial, however, must be to provide the background information necessary to develop safe, human clinical trials with a reasonable expectation of positive outcomes. Although our earlier studies have been extremely promising and although our large-animal model closely mimics the clinical scenario of human CA/ROSC, the protocol used in those studies would not easily translate to human trials. The animals used were healthy at baseline; as such, we were able to successfully resuscitate all animals without supplemental O2 and then provide minimal O2 support in the postresuscitative phase. In contrast, most humans undergoing CA have underlying cardiopulmonary disease, which would make initial resuscitation difficult, if not impossible, in the absence of supplemental O2.
We thus attempted to design a clinical paradigm whereby supplemental O2
would be provided to all CA victims during CPR in an attempt to maximize initial resuscitation, followed by rapid pulse oximetry-guided lowering of inspired O2
to physiological levels, thus simultaneously avoiding the potentially damaging extremes of both hyperoxia and hypoxia. Although this protocol has proven experimentally feasible, we were concerned at the outset that even a short exposure to supplemental O2
would worsen neurological outcomes because of the well-described respiratory burst of O2
free radicals that occurs almost immediately on reperfusion after complete global ischemia.26
We chose to use pulse oximetry to guide O2
titration rather than ABGs because of its ease of use as well widespread availability in both prehospital and hospital settings. With pulse oximetry guidance, we were able to safely and rapidly lower inspired O2
after resuscitation, reaching physiological levels of arterial O2
within 12 minutes. Animals receiving O2
titration in this manner demonstrated improved clinical as well as histological outcomes. The utility of pulse oximetry in the critical patient is sometimes questioned, with early studies showing a disparity between pulse oximeter-measured O2
saturations and blood gas values.27,28
New pulse oximeter technology,29
however, as well as alternative probe sampling sites,30
have been shown to greatly increase the utility of pulse oximetry in the critically ill patient, making translation of these study results to human trials clinically feasible.
Several limitations of this study should be noted. We used only healthy adult female animals to study CA, a condition that occurs in humans of both sexes with advanced cardiopulmonary disease. The implications of studying cerebral ischemia in female animals only must be considered, especially in light of mounting evidence for the role of sex-defining steroids in the modulation of cerebral ischemic injury.31
Although a similar model of CA/ROSC found no sex-related differences in clinical neurological outcome at 24 hours,32
trials are planned to extend these experiments to male dogs in an attempt to demonstrate neuroprotection independent of sex. We also examined neurological deficit and histological damage at only 1 time point, 24 hours. Although significant neuroprotection was demonstrated at 24 hours, the question must be raised whether oximetry-guided normoxia provides permanent neuroprotection or whether this treatment protocol merely delays the onset of further neurological injury. In an attempt to answer this question, studies are ongoing in our laboratory in an established rat model of complete global ischemia to examine the long-term implications of normoxic versus hyperoxic resuscitation.