Oximetry-Guided Reoxygenation Improves Neurological Outcome After Experimental Cardiac Arrest

Department of Surgery, University of Maryland, Baltimore, Baltimore, Maryland, United States
Stroke (Impact Factor: 6.02). 01/2007; 37(12):3008-13. DOI: 10.1161/01.STR.0000248455.73785.b1
Source: PubMed

ABSTRACT Current guidelines suggest that cardiac arrest (CA) survivors should be ventilated with 100% O(2) after resuscitation. Breathing 100% O(2) may worsen neurological outcome after experimental CA. This study tested the hypothesis that graded reoxygenation, with oximetry guidance, can safely reduce FiO(2) after resuscitation, avoiding hypoxia while promoting neurological recovery.
Mature dogs underwent 10 minutes of CA and restoration of spontaneous circulation with 100% O(2.) Animals were randomized to 1-hour additional ventilation on 100% FiO(2) or to rapid lowering of arterial O(2) saturation to <96% but >94% with pulse oximeter guidance. Animals were awakened at hour 23, and the neurological deficit score (0=normal; 100=brain-dead) was measured. Reanesthetized animals were perfusion-fixed and the brains removed for histopathology.
The neurological deficit score was significantly better in oximetry (O) dogs. O dogs appeared aware of their surroundings, whereas most hyperoxic (H) animals were stuporous (neurological deficit score=43.0+/-5.9 [O] versus 61.0+/-4.2 [H]; n=8, P<0.05). Stereological analysis revealed fewer injured CA1 neurons in O animals (cresyl violet: 35.5+/-4.3% [O] versus 60.5+/-3.3% [H]; P<0.05). There were also fewer fluoro-Jade B-stained degenerating CA1 neurons in O animals (3320+/-267 [O] versus 6633+/-356 [H] per 0.1 mm(3); P<0.001).
A clinically applicable protocol designed to reduce postresuscitative hyperoxia after CA results in significant neuroprotection. Clinical trials of controlled normoxia after CA/restoration of spontaneous circulation should strongly be considered.

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    • "An example of how avoiding hyperoxia can provide neuroprotection comes from studies comparing neurochemical and neurologic outcomes after experimental cardiac arrest, for animals artificially ventilated using either 100% O 2 or 21% to 30% O 2 during the first hour of reperfusion . Compared with animals receiving normoxic resuscitation, those receiving hyperoxic ventilation display elevated markers of oxidative stress, e.g., nitrotyrosine, impaired mitochondrial respiration, inhibited pyruvate dehydrogenase enzyme activity, decreased cerebral aerobic energy metabolism, increased hippocampal neuronal death, and worse neurologic outcome (Vereczki et al, 2005; Balan et al, 2006; Richards et al, 2007; Fiskum et al, 2008). These findings illustrate the concept that simple avoidance of unnecessarily high levels of O 2 can defend against oxidative stress-induced mitochondrial bioenergetic dysfunction and provide neuroprotection in a clinically relevant model of acute brain injury. "
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    ABSTRACT: Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca(2+) overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O(2) and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca(2+)-activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.
    Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 03/2012; 32(7):1362-76. DOI:10.1038/jcbfm.2012.32 · 5.34 Impact Factor
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    • "Recently, higher survival rates have been reported for patients treated with therapeutic hypothermia after successful resuscitation from cardiac arrest [2] [3], confirming that patient outcome is determined not only by the time of circulation recovery but also by the pathophysiologic processes triggered by cardiac arrest. Other treatments, such as early hemodynamic optimization [1], controlled reoxygenation [4], supportive care, and disease-specific interventions guided by the patients' conditions, have potential benefit for patients with post– cardiac arrest syndrome. One possible benefit of the above treatments is the prevention of an increase in the oxygen debt and a decrease in the systemic and cerebral metabolic rates of oxygen consumption [5]. "
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    ABSTRACT: BACKGROUND: The hemoglobin (Hb) level is an essential determinant of oxygen delivery. The restoration of blood perfusion to vital organs and the capacity for oxygen delivery may be associated with ischemia and reperfusion injuries during cardiac arrest and after cardiac arrest. However, whether the Hb level is associated with neurologic outcome in post-cardiac arrest patients remains unclear. METHODS: Emergency medical service information and clinical demographics were compiled for witnessed out-of-hospital cardiac arrest patients with coma after the restoration of spontaneous circulation. The study end point was defined as a favorable neurologic outcome at 28 days. We evaluated the relationship between the Hb level at the time of hospital arrival and the neurologic outcome using univariate analyses and a multivariate logistic regression analysis. RESULTS: There were 137 witnessed cardiac arrest patients: 49 (35.7%) survived and 34 (24.8%) achieved a favorable neurologic outcome. Univariate analyses showed that the favorable outcome group was characterized as having a higher Hb level, a younger age, a higher percentage of male patients, and ventricular fibrillation as the initial cardiac rhythm. In a multivariate analysis adjusting for potential confounding factors, the Hb level at the time of hospital arrival (odds ratio, 1.26; 95% confidence interval, 1.00-1.58) was an independent predictor of a favorable neurologic outcome. CONCLUSION: A higher Hb level at the time of hospital arrival was associated with a favorable short-term neurologic outcome among post-cardiac arrest patients with a presumed cardiac etiology.
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    • "While normoxia appeared to reduce white matter damage in gerbils at 14 days of reperfusion , this finding was not quantified (Mickel et al., 1990). A highly quantitative and non-biased stereologic approach was used to demonstrate reduced hippocampal neuronal death in the clinically more relevant canine cardiac arrest model (Balan et al., 2006; Liu et al., 1998; Vereczki et al., 2006); however, these results were obtained at 24 h of reperfusion, while cell death continues for days to weeks following transient global cerebral ischemia. To test for the potential long-term benefits of normoxic resuscitation after global cerebral ischemia in an additional species, we examined longer-term hippocampal neuronal survival (at 7 and 30 days), and behavioral outcomes (at 23–30 days), using a rat model of transient global cerebral ischemia. "
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    ABSTRACT: In this study we tested the hypothesis that long-term neuropathological outcome is worsened by hyperoxic compared to normoxic reperfusion in a rat global cerebral ischemia model. Adult male rats were anesthetized and subjected to bilateral carotid arterial occlusion plus bleeding hypotension for 10 min. The rats were randomized to one of four protocols: ischemia/normoxia (21% oxygen for 1 h), ischemia/hyperoxia (100% oxygen for 1 h), sham/normoxia, and sham/hyperoxia. Hippocampal CA1 neuronal survival and activation of microglia and astrocytes were measured in the hippocampi of the animals at 7 and 30 days post-ischemia. Morris water maze testing of memory was performed on days 23-30. Compared to normoxic reperfusion, hyperoxic ventilation resulted in a significant decrease in normal-appearing neurons at 7 and 30 days, and increased activation of microglia and astrocytes at 7, but not at 30, days of reperfusion. Behavioral deficits were also observed following hyperoxic, but not normoxic, reperfusion. We conclude that early post-ischemic hyperoxic reperfusion is followed by greater hippocampal neuronal death and cellular inflammatory reactions compared to normoxic reperfusion. The results of these long-term outcome studies, taken together with previously published results from short-term experiments performed with large animals, support the hypothesis that neurological outcome can be improved by avoiding hyperoxic resuscitation after global cerebral ischemia such as that which accompanies cardiac arrest.
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