Clinical Characteristics of Pediatric Patients With Carbon Monoxide Poisoning.

OBJECTIVES: Carbon monoxide (CO) poisoning is a common and deadly form of poisoning that is often treated with hyperbaric oxygen. The characteristics of children exposed to CO and then treated with hyperbaric oxygen have not been delineated. The purpose of this study was to describe the clinical characteristics of children treated with hyperbaric oxygen therapy for CO poisoning at a regional hyperbaric referral center. METHODS: The study is based on a retrospective review of data extracted from the medical records of children (age <19 years) who were referred to our center for hyperbaric oxygen therapy for CO poisoning between 2008 and 2013. Inferential analyses were used to compare demographic characteristics, serum carboxyhemoglobin (COHb) levels, and presenting symptoms. RESULTS: Forty-seven children met our study criteria. Their mean age was 8.9 years, and their mean COHb level was 14.3% (range, 3.4%-30.1%). Severity of symptoms did not correlate with serum COHb levels; however, neurologic symptoms at presentation were more common in patients with a COHb level greater than 25%. There was a correlation between increasing age and higher COHb levels and between COHb and lactate levels. CONCLUSIONS: Our retrospective review of patients' records showed no correlation of serum COHb levels with symptoms on presentation; however, a correlation was found between increasing age and COHb level as well as lactate level and COHb level.

Carbon monoxide and ST-elevation myocardial infarction: case reports.

We describe two cases of myocardial infarction with ST-segment elevation on electrocardiogram associated with carbon monoxide (CO) poisoning, a condition rarely reported in the literature. The first was a 62-year-old woman who experienced chest pain in the emergency department (ED) while being assessed for exposure to carbon monoxide in her home. The second was an 80-year-old man who fainted at home and was found to have ST elevation during the ED workup. After hospitalization, he returned home and soon thereafter had difficulty walking and speaking. The responding paramedics detected a very high CO level in the home. Both patients received hyperbaric oxygen therapy within the first several hours of presentation. For this combination of conditions, it is difficult to derive evidence-based management recommendations, given the paucity of cases reported to date. We conclude that rapid consultation with interventional cardiology and consideration of angioplasty or stenting are appropriate, especially when electrocardiographic findings and echocardiography point to a specific coronary distribution. Hyperbaric oxygen therapy might have a role in the treatment, based on its effects on myocardial ischemia and injury in other models.

Air-Evacuation-Relevant Hypobaria Following Traumatic Brain Injury Plus Hemorrhagic Shock in Rats Increases Mortality and Injury to the Gut, Lungs, and Kidneys.

ABSTRACT: Rats exposed to hypobaria equivalent to what occurs during aeromedical evacuation within a few days after isolated traumatic brain injury exhibit greater neurologic injury than those remaining at sea level. Moreover, administration of excessive supplemental O2 during hypobaria further exacerbates brain injury. This study tested the hypothesis that exposure of rats to hypobaria following controlled cortical impact (CCI)-induced brain injury plus mild hemorrhagic shock worsens multiple organ inflammation and associated mortality. In this study, at 24 h after CCI plus hemorrhagic shock, rats were exposed to either normobaria (sea level) or hypobaria (=8,000 ft altitude) for 6 h under normoxic or hyperoxic conditions. Injured rats exhibited mortality ranging from 30% for those maintained under normobaria and normoxia to 60% for those exposed to 6 h under hypobaric and hyperoxia. Lung histopathology and neutrophil infiltration at 2 days postinjury were exacerbated by hypobaria and hyperoxia. Gut and kidney inflammation at 30 days postinjury were also worsened by hypobaric hyperoxia. In conclusion, exposure of rats after brain injury and hemorrhagic shock to hypobaria or hyperoxia results in increased mortality. Based on gut, lung, and kidney histopathology at 2 to 30 days postinjury, increased mortality is consistent with multi-organ inflammation. These findings support epidemiological studies indicating that increasing aircraft cabin pressures to 4,000 ft altitude (compared with standard 8,000 ft) and limiting excessive oxygen administration will decrease critical complications during and following aeromedical transport.

Transcriptional activation of antioxidant gene expression by Nrf2 protects against mitochondrial dysfunction and neuronal death associated with acute and chronic neurodegeneration.

Mitochondria are both a primary source of reactive oxygen species (ROS) and a sensitive target of oxidative stress; damage to mitochondria can result in bioenergetic dysfunction and both necrotic and apoptotic cell death. These relationships between mitochondria and cell death are particularly strong in both acute and chronic neurodegenerative disorders. ROS levels are affected by both the production of superoxide and its toxic metabolites and by antioxidant defense mechanisms. Mitochondrial antioxidant activities include superoxide dismutase 2, glutathione peroxidase and reductase, and intramitochondrial glutathione. When intracellular conditions disrupt the homeostatic balance between ROS production and detoxification, a net increase in ROS and an oxidized shift in cellular redox state ensues. Cells respond to this imbalance by increasing the expression of genes that code for proteins that protect against oxidative stress and inhibit cytotoxic oxidation of proteins, DNA, and lipids. If, however, the genomic response to mitochondrial oxidative stress is insufficient to maintain homeostasis, mitochondrial bioenergetic dysfunction and release of pro-apoptotic mitochondrial proteins into the cytosol initiate a variety of cell death pathways, ultimately resulting in potentially lethal damage to vital organs, including the brain. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a translational activating protein that enters the nucleus in response to oxidative stress, resulting in increased expression of numerous cytoprotective genes, including genes coding for mitochondrial and non-mitochondrial antioxidant proteins. Many experimental and some FDA-approved drugs promote this process. Since mitochondria are targets of ROS, it follows that protection against mitochondrial oxidative stress by the Nrf2 pathway of gene expression contributes to neuroprotection by these drugs. This document reviews the evidence that Nrf2 activation increases mitochondrial antioxidants, thereby protecting mitochondria from dysfunction and protecting neural cells from damage and death. New experimental results are provided demonstrating that post-ischemic administration of the Nrf2 activator sulforaphane protects against hippocampal neuronal death and neurologic injury in a clinically-relevant animal model of cardiac arrest and resuscitation.

Oximetry-Guided normoxic resuscitation following canine cardiac arrest reduces cerebellar Purkinje neuronal damage.

BACKGROUND: Animal studies indicate that maintaining physiologic O2 levels (normoxia) immediately after restoration of spontaneous circulation (ROSC) from cardiac arrest (CA) results in less hippocampal neuronal death compared to animals ventilated with 100% O2. This study tested the hypothesis that beneficial effects of avoiding hyperoxia following CA are apparent in the cerebellum and therefore not limited to one brain region. METHODS: Adult beagles were anesthetized and mechanically ventilated. Ventricular fibrillation CA was induced by electrical myocardial stimulation and cessation of ventilation. Ten min later, dogs were ventilated with 100% O2 and resuscitated using 3 min of open chest CPR followed by defibrillation. Dogs were ventilated for 1 h with either 100% O2 or with O2 titrated rapidly to maintain hemoglobin O2 saturation at 94-96%. FiO2 was adjusted in both groups between one and 24 h post-arrest to maintain normoxic PaO2 of 80-120 mm Hg. Following 24 h critical care, dogs were euthanized and cerebellum analyzed for histochemical measures of neuronal damage and inflammation. RESULTS AND CONCLUSIONS: Hyperoxic resuscitation increased the number of injured Purkinje cells by 278% and the number of activated microglia/macrophages by 18% compared to normoxic resuscitation. These results indicate that normoxic resuscitation promotes favorable histopathologic outcomes in the cerebellum (in addition to hippocampus) following CA/ROSC. These findings emphasize the importance of avoiding unnecessary hyperoxia following CA/ROSC.

Calcium uptake and cytochrome c release from normal and ischemic brain mitochondria.

At abnormally elevated levels of intracellular Ca2+, mitochondrial Ca2+ uptake may compromise mitochondrial electron transport activities and trigger membrane permeability changes that allow for release of cytochrome c and other mitochondrial apoptotic proteins into the cytosol. In this study, a clinically relevant canine cardiac arrest model was used to assess the effects of global cerebral ischemia and reperfusion on mitochondrial Ca2+ uptake capacity, Ca2+ uptake-mediated inhibition of respiration, and Ca2+-induced cytochrome c release, as measured in vitro in a K+-based medium in the presence of Mg2+, ATP, and NADH-linked oxidizable substrates. Maximum Ca2+ uptake by frontal cortex mitochondria was significantly lower following 10 min cardiac arrest compared to non-ischemic controls. Mitochondria from ischemic brains were also more sensitive to the respiratory inhibition associated with accumulation of large levels of Ca2+. Cytochrome c was released from brain mitochondria in vitro in a Ca2+-dose-dependent manner and was more pronounced following both 10 min of ischemia alone and following 24 h reperfusion, in comparison to mitochondria from non-ischemic Shams. These effects of ischemia and reperfusion on brain mitochondria could compromise intracellular Ca2+ homeostasis, decrease aerobic and increase anaerobic cerebral energy metabolism, and potentiate the cytochrome c-dependent induction of apoptosis, when re-oxygenated mitochondria are exposed to abnormally high levels of intracellular Ca2+.

Hyperoxic reperfusion after global ischemia decreases hippocampal energy metabolism.

BACKGROUND AND PURPOSE: Previous reports indicate that compared with normoxia, 100% ventilatory O(2) during early reperfusion after global cerebral ischemia decreases hippocampal pyruvate dehydrogenase activity and increases neuronal death. However, current standards of care after cardiac arrest encourage the use of 100% O(2) during resuscitation and for an undefined period thereafter. Using a clinically relevant canine cardiac arrest model, in this study we tested the hypothesis that hyperoxic reperfusion decreases hippocampal glucose metabolism and glutamate synthesis. METHODS: After 10 minutes of cardiac arrest, animals were resuscitated and ventilated for 1 hour with 100% O(2) (hyperoxic) or 21% to 30% O(2) (normoxic). At 30 minutes reperfusion, [1-(13)C]glucose was infused, and at 2 hours, brains were rapidly removed and frozen. Extracted metabolites were analyzed by (13)C nuclear magnetic resonance spectroscopy. RESULTS: Compared with nonischemic controls, the hippocampi from hyperoxic animals had elevated levels of unmetabolized (13)C-glucose and decreased incorporation of (13)C into all isotope isomers of glutamate. These findings indicate impaired neuronal metabolism via the pyruvate dehydrogenase pathway for carbon entry into the tricarboxylic acid cycle and impaired glucose metabolism via the astrocytic pyruvate carboxylase pathway. No differences were observed in the cortex, indicating that the hippocampus is more vulnerable to metabolic changes induced by hyperoxic reperfusion. CONCLUSIONS: These results represent the first direct evidence that hyperoxia after cardiac arrest impairs hippocampal oxidative energy metabolism in the brain and challenge the rationale for using excessively high resuscitative ventilatory O(2).

Ultrasound-diagnosed cardiac tamponade after blunt abdominal trauma-treated with emergent thoracotomy.

Ultrasound imaging enhances the physician's ability to evaluate, diagnose, and treat emergency department (ED) patients. Because ultrasound imaging is often time-dependent in the acutely ill or injured patient, the emergency physician is in an ideal position to use this technology. Focused ultrasound examinations provide immediate information and can answer specific questions about the patient's physical condition. We report a case in which blunt trauma to the abdomen and pre-existing pericardial fluid, due to human immunodeficiency virus (HIV), caused pericardial tamponade, diagnosed by bedside ultrasonography, and subsequent cardiac arrest. An ED thoracotomy released this tamponade, and spontaneous cardiac activity returned. The indications for and efficacy of ED thoracotomy have been debated for many years. Multiple studies have shown that patients with isolated penetrating chest trauma have the best outcome and that patients with blunt trauma without signs of life at the scene or in the ED have the poorest. We demonstrate the importance of ultrasound use by emergency physicians to assess trauma patients with pulseless electrical activity and suggest that in specific clinical situations after blunt trauma, an ED thoracotomy can be life saving.

Aeromedical evacuation-relevant hypobaria worsens axonal and neurologic injury in rats after underbody blast-induced hyperacceleration.

BACKGROUND: Occupants of military vehicles targeted by explosive devices often suffer from traumatic brain injury (TBI) and are typically transported by the aeromedical evacuation (AE) system to a military medical center within a few days. This study tested the hypothesis that exposure of rats to AE-relevant hypobaria worsens cerebral axonal injury and neurologic impairment caused by underbody blasts. METHODS: Anesthetized adult male rats were secured within cylinders attached to a metal plate, simulating the hull of an armored vehicle. An explosive located under the plate was detonated, resulting in a peak vertical acceleration force on the plate and occupant rats of 100G. Rats remained under normobaria or were exposed to hypobaria equal to 8,000 feet in an altitude chamber for 6 hours, starting at 6 hours to 6 days after blast. At 7 days, rats were tested for vestibulomotor function using the balance beam walking task and euthanized by perfusion. The brains were then analyzed for axonal fiber injury. RESULTS: The number of internal capsule silver-stained axonal fibers was greater in animals exposed to 100G blast than in shams. Animals exposed to hypobaria starting at 6 hours to 6 days after blast exhibited more silver-stained fibers than those not exposed to hypobaria. Rats exposed to 100% oxygen (O2) during hypobaria at 24 hours postblast displayed greater silver staining and more balance beam foot-faults, in comparison with rats exposed to hypobaria under 21% O2. CONCLUSION: Exposure of rats to blast-induced acceleration of 100G increases cerebral axonal injury, which is significantly exacerbated by exposure to hypobaria as early as 6 hours and as late as 6 days postblast. Rats exposed to underbody blasts and then to hypobaria under 100% O2 exhibit increased axonal damage and impaired motor function compared to those subjected to blast and hypobaria under 21% O2. These findings raise concern about the effects of AE-related hypobaria on TBI victims, the timing of AE after TBI, and whether these effects can be mitigated by supplemental oxygen.

Oximetry-guided reoxygenation improves neurological outcome after experimental cardiac arrest.

BACKGROUND AND PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death.

Resuscitation and prolonged ventilation using 100% oxygen after cardiac arrest is standard clinical practice despite evidence from animal models indicating that neurologic outcome is improved using normoxic compared with hyperoxic resuscitation. This study tested the hypothesis that normoxic ventilation during the first hour after cardiac arrest in dogs protects against prelethal oxidative stress to proteins, loss of the critical metabolic enzyme pyruvate dehydrogenase complex (PDHC), and minimizes subsequent neuronal death in the hippocampus. Anesthetized beagles underwent 10 mins ventricular fibrillation cardiac arrest, followed by defibrillation and ventilation with either 21% or 100% O2. At 1 h after resuscitation, the ventilator was adjusted to maintain normal blood gas levels in both groups. Brains were perfusion-fixed at 2 h reperfusion and used for immunohistochemical measurements of hippocampal nitrotyrosine, a product of protein oxidation, and the E1alpha subunit of PDHC. In hyperoxic dogs, PDHC immunostaining diminished by approximately 90% compared with sham-operated dogs, while staining in normoxic animals was not significantly different from nonischemic dogs. Protein nitration in the hippocampal neurons of hyperoxic animals was 2-3 times greater than either sham-operated or normoxic resuscitated animals at 2 h reperfusion. Stereologic quantification of neuronal death at 24 h reperfusion showed a 40% reduction using normoxic compared with hyperoxic resuscitation. These results indicate that postischemic hyperoxic ventilation promotes oxidative stress that exacerbates prelethal loss of pyruvate dehydrogenase and delayed hippocampal neuronal cell death. Moreover, these findings indicate the need for clinical trials comparing the effects of different ventilatory oxygen levels on neurologic outcome after cardiac arrest.

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity.

The pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate and represents the sole bridge between anaerobic and aerobic cerebral energy metabolism. Previous studies demonstrating loss of PDHC enzyme activity and immunoreactivity during reperfusion after cerebral ischemia suggest that oxidative modifications are involved. This study tested the hypothesis that hyperoxic reperfusion exacerbates loss of PDHC enzyme activity, possibly due to tyrosine nitration or S-nitrosation. We used a clinically relevant canine ventricular fibrillation cardiac arrest model in which, after resuscitation and ventilation on either 100% O2 (hyperoxic) or 21-30% O2 (normoxic), animals were sacrificed at 2 h reperfusion and the brains removed for enzyme activity and immunoreactivity measurements. Animals resuscitated under hyperoxic conditions exhibited decreased PDHC activity and elevated 3-nitrotyrosine immunoreactivity in the hippocampus but not the cortex, compared to nonischemic controls. These measures were unchanged in normoxic animals. In vitro exposure of purified PDHC to peroxynitrite resulted in a dose-dependent loss of activity and increased nitrotyrosine immunoreactivity. These results support the hypothesis that oxidative stress contributes to loss of hippocampal PDHC activity during cerebral ischemia and reperfusion and suggest that PDHC is a target of peroxynitrite.

Mechanisms of ischemic neuroprotection by acetyl-L-carnitine.

Acetyl-L-carnitine is a naturally occurring substance that, when administered at supraphysiologic concentrations, is neuroprotective in several animal models of global and focal cerebral ischemia. Three primary mechanisms of action are supported by neurochemical outcome measures performed with these models and with in vitro models of acute neuronal cell death. The metabolic hypothesis is based on the oxidative metabolism of the acetyl component of acetyl-L-carnitine and is a simple explanation for the reduction in postischemic brain lactate levels and elevation of ATP seen with drug administration. The antioxidant mechanism is supported by reduction of oxidative stress markers, for example, protein oxidation, in both brain tissue and cerebrospinal fluid. The relatively uncharacterized mechanism of inhibiting excitotoxicity could be extremely important in both acute brain injury and chronic neurodegenerative disorders. New experiments performed with primary cultures of rat cortical neurons indicate that the presence of acetyl-L-carnitine significantly inhibits both acute and delayed cell death following exposure to NMDA, an excitotoxic glutamate antagonist. Finally, several other mechanisms of action are possible, including a neurotrophic effect of acetyl-L-carnitine and inhibition of mitochondrial permeability transition. While the multiple potential mechanisms of neuroprotection by acetyl-L-carnitine limit an accurate designation of the most important mode of action, they are compatible with the concept that several brain injury pathways must be inhibited to optimize therapeutic efficacy.

Delayed therapy of experimental global cerebral ischemia with acetyl-L-carnitine in dogs.

Acetyl-L-carnitine (ALCAR), when administered immediately following restoration of spontaneous circulation (ROSC) from experimental cardiac arrest (CA) has previously been demonstrated to promote normalization of brain energy metabolism and neurologic recovery following 10 min CA. In order to determine ultimate efficacy for this or other drugs, clinical trials must be performed in human subjects. In several human clinical trials, though, drug administration has been significantly delayed following resuscitation from CA. These experiments test the hypothesis that post-resuscitative delay in ALCAR administration will impair the ability of this drug to promote neurologic recovery. Neurological deficit scoring (23 h) as well as frontal cortex lactate levels (2 and 24 h) were compared following resuscitation from 10 min CA in dogs receiving either ALCAR or drug vehicle 30 min following ROSC. Dogs treated with ALCAR 30 min following ROSC from 10 min CA exhibited more normal cerebral cortex lactate levels than did vehicle control animals. There was no difference, however, in neurologic deficit scores between groups, with all animals demonstrating moderate to severe clinical neurologic impairment at 23 h following ROSC. A 30-min delay in ALCAR administration following ROSC from 10 min CA impairs the ability of this drug to promote neurologic recovery despite apparent normalization of brain lactate levels.

Hyperoxic resuscitation improves survival but worsens neurologic outcome in a rat polytrauma model of traumatic brain injury plus hemorrhagic shock.

BACKGROUND: Many traumatic brain injury (TBI) patients experience additional injuries, including those that result in hemorrhagic shock (HS). Interactions between HS and TBI can include reduced brain O2 delivery, resulting in partial cerebral ischemia and worse neurologic outcome. This study tested the hypothesis that inspiration of 100% O2 during resuscitation following TBI and HS improves survival, reduces brain lesion volume, and improves neurologic outcome compared with resuscitation in the absence of supplemental O2. METHODS: The adult male rat polytrauma model consisted of controlled cortical impact-induced TBI followed by 30 minutes of HS (mean arterial pressure, 35-40 mm Hg) induced by blood withdrawal. The HS phase was followed by a 1-hour "prehospital" Hextend fluid resuscitation phase and then a 1-hour "hospital phase" when shed blood was reinfused. Rats were randomized on the day of surgery to three groups with 10 per group: sham, polytrauma normoxic, and polytrauma hyperoxic. Normoxic animals inspired room air, and hyperoxic animals inspired 100% O2 during both resuscitation phases. Neurobehavioral tests were conducted weekly until the rats were perfused with fixative at 30 days after injury. Brain sections were stained with Fluoro Jade B and used for quantification of contusion, penumbral, and healthy cortical volumes. RESULTS: Survival was greater following hyperoxic compared with normoxic resuscitation. Composite neuroscores obtained at 2 weeks to 4 weeks following hyperoxic resuscitation were lower than those of shams. Balance beam foot faults measured at 2 weeks after injury were greater following hyperoxic resuscitation compared with normoxic resuscitation and those of shams. There was no significant difference in cerebrocortical pathology between the normoxic and hyperoxic polytrauma groups. CONCLUSION: The survival of rats following controlled cortical impact plus HS was greater following hyperoxic resuscitation. In contrast, neurologic outcomes were better following normoxic resuscitation.

Hyperbaric oxygen reduces neuronal death and improves neurological outcome after canine cardiac arrest.

BACKGROUND AND PURPOSE: Studies suggest that hyperbaric oxygen (HBO) is neuroprotective after experimental cerebral ischemia, but the mechanism is unknown. This study tested the hypotheses that postischemic HBO affords clinical and histopathological neuroprotection after experimental cardiac arrest and resuscitation (A/R) and that this neuroprotection results from improved cerebral oxygen metabolism after A/R. METHODS: Anesthetized adult female beagles underwent A/R and randomization to HBO (2.7-atm absolute [ATA] for 60 minutes, 1 hour after A/R) or control (Po2=80 to 100 mm Hg; 1 ATA). Animals underwent neurological deficit scoring (NDS) 23 hours after A/R. After euthanasia at 24 hours, neuronal death (necrotic and apoptotic) in representative animals was determined stereologically in hippocampus and cerebral neocortex. In experiment 2, arterial and sagittal sinus oxygenation and cerebral blood flow (CBF) were measured. Cerebral oxygen extraction ratio (ERc), oxygen delivery (Do2c), and metabolic rate for oxygen (CMRo2) were calculated (baseline and 2, 30, 60, 120, 180, 240, 300, and 360 minutes after restoration of spontaneous circulation). RESULTS: NDS improved after A/R in HBO animals (HBO, 35+/-14; controls, 54+/-15; P=0.028). Histopathological examination revealed significantly fewer dying neurons in HBO animals; the magnitude of neuronal injury correlated well with NDS. HBO corrected elevations in ERc (peak, 60+/-14% for controls, 26+/-4% for HBO) but did not increase Do2c or CMRo2, which decreased approximately 50% after A/R in both groups. CONCLUSIONS: HBO inhibits neuronal death and improves neurological outcome after A/R; the mechanism of HBO neuroprotection is not due to stimulation of oxidative cerebral energy metabolism.

Neuroprotective effects of hyperbaric oxygen treatment in experimental focal cerebral ischemia are associated with reduced brain leukocyte myeloperoxidase activity.

OBJECTIVE: Hyperbaric oxygen (HBO) reduces cerebral infarct size after middle cerebral artery occlusion (MCAO) in rats through an unknown mechanism. In other forms of injury, cellular protection with HBO is associated with diminished infiltration of polymorphonuclear neutrophils (PMN). We hypothesized that HBO given prior to or after MCAO reduces PMN infiltration into the brain, and that decreased PMN infiltration is associated with improved functional and anatomic outcome. METHODS: Forty rats underwent MCAO and were randomized to pretreatment with HBO (3 ATA) immediately prior to (n=13), or posttreatment immediately after surgery (n=12), or to control (air 1 ATA) (n=15). Five rats underwent sham surgery. Neurologic outcome was measured at 24 h in all animals. Brain myeloperoxidase (MPO) activity (n=22) and infarct volume (n=23) were determined. RESULTS: MPO activity was significantly higher in controls (mean 0.28, 95% C.I. 0.17-0.38) than in the HBO pretreatment group (0.12, 0.08-0.16), HBO posttreatment group (0.16, 0.13-0.19), and the sham group (0.02, -0.02 to 0.05). HBO treated animals also had better neurologic outcomes (pretreatment 1.5, 0.9-2.1, posttreatment 2.6, 2.0-3.2) and smaller infarcts (pretreatment 27%, 18-37%, posttreatment 28%, 19-37%) than controls (neurologic outcome 3.7, 3.1-4.4, infarct volume 39%, 30-48%). Neurologic outcomes correlate better with MPO activity (R(2)=0.75) than with infarct volume (R(2)=0.25). CONCLUSION: These data confirm the neuroprotective effects of HBO in cerebral ischemia and suggest that the mechanism of this action may involve inhibition of PMN infiltration in the injured brain.

Hyperoxic reperfusion after global cerebral ischemia promotes inflammation and long-term hippocampal neuronal death.

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.

Postischemic oxidative stress promotes mitochondrial metabolic failure in neurons and astrocytes.

Oxidative stress and mitochondrial dysfunction have been closely associated in many subcellular, cellular, animal, and human studies of both acute brain injury and neurodegenerative diseases. Our animal models of brain injury caused by cardiac arrest illustrate this relationship and demonstrate that both oxidative molecular modifications and mitochondrial metabolic impairment are exacerbated by reoxygenation of the brain using 100% ventilatory O(2) compared to lower levels that maintain normoxemia. Numerous molecular mechanisms may be responsible for mitochondrial dysfunction caused by oxidative stress, including oxidation and inactivation of mitochondrial proteins, promotion of the mitochondrial membrane permeability transition, and consumption of metabolic cofactors and intermediates, for example, NAD(H). Moreover, the relative contribution of these mechanisms to cell injury and death is likely different among different types of brain cells, for example, neurons and astrocytes. In order to better understand these oxidative stress mechanisms and their relevance to neurologic disorders, we have undertaken studies with primary cultures of astrocytes and neurons exposed to O(2) and glucose deprivation and reoxygenation and compared the results of these studies to those using a rat model of neonatal asphyxic brain injury. These results support the hypothesis that release and or consumption of mitochondrial NAD(H) is at least partially responsible for respiratory inhibition, particularly in neurons.