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Ann Thorac Surg 1999;67:371-376
© 1999 The Society of Thoracic Surgeons

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Original Articles

Increased intracerebral excitatory amino acids and nitric oxide after hypothermic circulatory arrest

^a Division of Cardiac Surgery, Johns Hopkins Medical Institutions and Kennedy-Krieger Research Institute, Baltimore, Maryland, USA

Address reprint requests to Dr Baumgartner, Division of Cardiac Surgery, Johns Hopkins Hospital, Blalock 618, 600 North Wolfe St, Baltimore, MD 21287
e-mail: wbaumgar{at}welchlink.welch.jhu.edu

Presented at the Poster Session of the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA Jan 26–28, 1998.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Prolonged hypothermic circulatory arrest (HCA) results in neurologic injury, but the mechanism of this injury is unknown. This study was undertaken to measure quantitatively intracerebral excitatory amino acids and citrulline, an equal coproduct of nitric oxide, during HCA. We hypothesized that HCA resulted in higher levels of glutamate, aspartate, glycine, causing increased intracellular calcium, and therefore, nitric oxide and citrulline.

Methods. Ten dogs underwent intracerebral microdialysis and 2 hours of HCA at 18°C. Effluent was analyzed by high performance liquid chromatography with electrochemical detection. Five dogs each were sacrificed at 8 and 20 hours after HCA. Neuronal apoptosis was scored from 0 (no injury) to 100 (severe injury).

Results. Time course of HCA was divided into six periods. Peak levels of amino acids in each period were compared with those at baseline. Glutamate, coagonist glycine, and citrulline, an equal coproduct of nitric oxide, increased significantly over baseline during HCA, cardiopulmonary bypass, and 2 to 8 hours after HCA. Aspartate increased significantly during HCA and 8 to 20 hours after HCA. Apoptosis score was 65.56 ± 5.67 at 8 hours and 30.63 ± 14.96 at 20 hours after HCA.

Conclusions. Our results provide direct evidence that HCA causes increased intracerebral glutamate and aspartate, along with coagonist glycine. We conclude that HCA causes glutamate excitotoxicity with subsequent nitric oxide production resulting in neurologic injury, which begins during arrest and continues until 20 hours after hypothermic circulation arrest. To provide effective cerebral protection, pharmacologic strategies to reduce glutamate excitotoxicity require intervention beyond the initial ischemic insult.

	Introduction

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Hypothermic circulatory arrest (HCA) is a widely adopted technique in congenital heart operations and aortic arch and thoracic aortic procedures [1–5]. However, cerebral neurons are intolerant to ischemia, limiting the safe period of arrest. Morbidity and mortality increase substantially when the duration of arrest exceeds 45 minutes [4]. Clinical neurologic sequelae, including choreoathetosis, learning and memory deficits, seizures, and impaired intellectual development, occur in up to 15% of children and 18% of adults [4–7]. Neuronal cell death in the neocortex, hippocampus, basal ganglia, and cerebellum is the cause of this HCA-induced neurologic injury, but the mechanism of this injury is unknown.

In other neurologic disorders, including Huntington disease, neuropathic pain syndromes, stroke, cerebral ischemia, hypoxia, anoxia, and carbon monoxide poisoning, strong evidence suggests that injury to neurons might be caused by overstimulation of excitatory amino acid receptors, including glutamate and aspartate [8]. This excitotoxicity is predominantly mediated by calcium influx through ionic channels of activated glutamate receptors. Calcium triggers a cascade of intracellular reactions, including nitric oxide production, which results in neuronal degeneration and death.

Previous work in our laboratory also found glutamate excitotoxicity in HCA-induced neurologic injury [9–12]. We showed that glutamate receptor antagonists and inhibitors of neuronal nitric oxide synthase reduce neurologic injury after HCA. In the present in vivo study, we hypothesized that HCA results in increased extracellular glutamate, aspartate, and glycine, thereby activating glutamate receptors to trigger an influx of intracellular calcium. Calcium then activates nitric oxide synthase, producing nitric oxide, which results in cell death. We quantitatively examined changes in intracerebral levels of excitatory amino acids and nitric oxide in a canine model of hypothermic circulatory arrest.

	Material and methods

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Preparation
Our canine model of hypothermic circulatory arrest has been described previously [9–12]. Ten colony-bred heartworm-negative male hound dogs, 20 to 27 kg, 7 to 12 months old, were used. Anesthesia was induced with sodium thiopental (3.0 mg/kg intravenously) and maintained with 0.5% to 2.0% halothane. Bilateral tympanic membrane, nasopharyngeal, and rectal temperature probes were placed. Tympanic membrane temperature closely correlates with brain temperature. Electrocardiographic activity was monitored. A Swan-Ganz catheter via the left external jugular vein and arterial catheter in the left femoral artery were placed.

Cardiopulmonary bypass and hypothermic circulatory arrest
Cardiopulmonary bypass (CPB) circuit consisted of a Cobe membrane oxygenator (Cobe Laboratories, Inc, Lakewood, CO), a Sarns roller pump (Sarns Inc, Ann Arbor, MI), and a 40-µm inline arterial filter. The circuit was primed with 1.5 L of lactated Ringer’s solution with 50 mEq of sodium bicarbonate and 10 mEq of potassium chloride. After heparinization (300 U/kg intravenously), the right femoral artery was cannulated with a 12-F to 14-F arterial cannula and advanced into the descending aorta. Eighteen French to 20-F venous cannulas were advanced to the right atrium through the right external jugular and femoral veins.

Closed chest CPB was instituted; animals were surface cooled (ice bags around head and cooling blanket) and core (CPB) cooled to a tympanic membrane temperature of 18°C within 25 to 30 minutes. Mean arterial pressures were maintained at 50 to 60 mm Hg with pump flows of 80 to 100 mL/kg and reduced to 60 mL/kg when temperature was less than 32°C. Arterial blood gases were controlled using alpha-stat strategy. When the arterial pump was turned off, venous blood was drained by gravity into the reservoir. Circulatory arrest was maintained for 2 hours followed by reinstitution of CPB and rewarming. Sodium bicarbonate (50 mEq) and lasix (20 mg) were added to the reservoir. At normothermia (37°C), animals were weaned from CPB and decannulated.

Postoperatively, the dogs were ventilated and anesthetized with intravenous fentanyl (10–20 µg/kg) and midazolam (1 mg) as needed. Intensive care unit monitoring was used. At 8 and 20 hours after HCA five dogs each were sacrificed fully anesthetized by exsanguination and perfusion with ice cold saline or 4% paraformaldehyde for histopathology.

Intracerebral microdialysis
Positioned in a Kopf stereotactic device, animals had the right side of skull exposed. Burr holes were drilled 3 mm caudal to the coronal suture and 8 mm from the midsagittal axis. Dura was opened and microdialysis probes (CMA 10/4; Acton, MA) were placed stereotactically to a depth of 20 mm in the corpus striatum. Confirmation of proper placement was determined at sacrifice. Tissue was allowed to stabilize for 180 minutes after probe placement. Warmed artificial cerebrospinal fluid (mmol/L concentration: NaCl, 131.8; NaHCO₃, 24.6; CaCl₂, 2.0; KCl, 3.0; MgCl₂, 0.65; urea, 6.7; and dextrose, 3.7) was infused at 1 µL/minute. Effluent was collected serially every 30 minutes and immediately frozen at -70°C. Samples were then assayed by high performance liquid chromatography with electrochemical detection for extracellular amino acid concentrations, according to a method described previously [13, 14]. Citrulline concentration was used as a marker of nitric oxide production. All concentrations were not corrected for probe efficiency.

Histopathology
The right side of each brain was postfixed in 10% formalin, embedded in paraffin, and 8-µm sections were stained with hematoxylin and eosin or cresyl violet. The left side of each brain was sliced into 1-cm sections and immediately frozen on dry ice for biochemical studies. Apoptosis was scored from 0 (no injury) to 100 (severe injury) in the dentate gyrus of the hippocampus of paraffin-embedded tissue in a blinded fashion by a single neuropathologist. Apoptosis score was based on the percentage of apoptotic neurons present along the dentate gyrus. Normal untreated dogs have no apoptosis and have a 0 score.

Statistical analyses
All values are expressed in mean ± standard deviation of the population. Comparisons between groups were made by analysis of variance for repeated measures or Student’s t test where appropriate.

Animal care
All experimental protocols were preapproved by the Animal Care and Use Committee of the Johns Hopkins Medical Institutions. Animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH Publication No. 85-23, revised 1985).

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Physiologic variables
Cooling times on CPB ranged from 25 to 30 minutes. Tympanic membrane temperatures during cooling, arrest, rewarming, and recovery phases, are shown in Figure 1. Mean arterial pressures were significantly lower than baseline during cooling CPB, the initial phases of rewarming CPB, and at the end of CPB (Fig 2). Mean arterial pressures during recovery were similar to those at baseline. Cardiac output was decreased for 6 hours after CPB, before returning to baseline (Fig 3). No significant changes in arterial blood gases occurred with similar pH and partial pressure of carbon dioxide. Hyperglycemia occurred during reperfusion CPB but normalized during recovery. Hemodilution occurred during CPB, with an initial hemoconcentration until 4 hours after CPB when hemoglobin levels returned to baseline (Fig 4).

View larger version (20K): [in this window] [in a new window]   Fig 1. Tympanic membrane temperatures in degrees centigrade over time. All figure error bars represent standard deviation of the population. (CPB = cardiopulmonary bypass; HCA = hypothermic circulatory arrest.)

View larger version (21K): [in this window] [in a new window]   Fig 2. Mean arterial pressures (MAP) in mm Hg during cardiopulmonary bypass (CPB), hypothermic circulatory arrest (HCA), reperfusion CPB, and recovery.

View larger version (15K): [in this window] [in a new window]   Fig 3. Cardiac output (CO), L/minute, at baseline and during recovery.

View larger version (20K): [in this window] [in a new window]   Fig 4. Hemoglobin (Hgb) levels during cardiopulmonary bypass (CPB), hypothermic circulatory arrest (HCA), reperfusion, and recovery.

View larger version (14K): [in this window] [in a new window]   Fig 5. Intracerebral glutamate concentrations (micromoles) increased during hypothermic circulatory arrest (HCA), reperfusion cardiopulmonary bypass (CPB), and 2 to 8 hours after HCA. *p < 0.05. All amino acid concentrations have n = 10 for arrest, reperfusion CPB, and 2–8 hours after HCA, except for 8 to 20 hours after HCA has n = 5, because five dogs were sacrificed at 8 hours after HCA.

View larger version (14K): [in this window] [in a new window]   Fig 6. Intracerebral glycine levels (micromoles) increased during arrest, reperfusion cardiopulmonary bypass (CPB), and 2 to 8 hours after hypothermic circulatory arrest (HCA). *p < 0.05.

View larger version (12K): [in this window] [in a new window]   Fig 7. Intracerebral aspartate levels (micromoles) increased during arrest and 8 to 20 hours after hypothermic circulatory arrest (HCA). *p < 0.05. (CPB = cardiopulmonary bypass.)

View larger version (12K): [in this window] [in a new window]   Fig 8. Citrulline and nitric oxide were produced significantly during arrest, reperfusion cardiopulmonary bypass (CPB), and 2 to 8 hours after hypothermic circulatory arrest (HCA). *p < 0.05.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Hypothermic circulatory arrest is an important technique in aortic and congenital heart operations [1–5]. It provides a bloodless operative field unobstructed by vascular clamps and cannulas. However, the period of safe arrest is limited by the intolerance of cerebral neurons to ischemia. Neurologic injury caused by neuronal cell death occurs when the duration of arrest exceeds 45 minutes [4]. The clinical sequelae include choreoathetosis, seizures, learning and memory deficits, and impaired intellectual development [5–7]. In this study, we hypothesized that glutamate excitotoxicity mediates HCA-induced neuronal cell death.

Olney [15] first coined the term "excitotoxicity," which may constitute the final common pathway by which various neurologic insults result in neuronal cell degeneration and death. In excitotoxicity, neuronal injury is caused by overstimulation of excitatory amino acid receptors, including glutamate and aspartate [8]. Glutamate, the principal neurotransmitter of the brain, is responsible for many physiologic neurologic functions, including cognition, memory, movement, and sensation. Pathophysiologically, excessive extracellular excitatory amino acids, glutamate and aspartate, activate glutamate receptors. There are two types of glutamate receptors, metabotropic receptors coupled to G proteins and ionotropic receptors coupled directly to ion channels. Ionotropic receptors consist of three types: N-methyl-D-aspartate (NMDA), -amino-3-hydroxy-5-methyl-4-isoxazolepropionate, and kainate receptors; stimulation of these receptors results in membrane depolarization. Glutamate and coagonist glycine are required to activate the NMDA receptor, triggering the influx of calcium intracellularly. Calcium influx into the cell triggers a cascade of cellular reactions, activating proteases, endonucleases, protein kinases, phospholipases, and nitric oxide synthase. Nitric oxide synthase produces nitric oxide, which in reaction with superoxide anion forms peroxynitrite. Peroxynitrite then results in lipid peroxidation, DNA degradation, and neuronal cell death.

In this study, we quantitatively measured intracerebral amino acids during HCA using a microdialysis technique. Microdialysis enables in vivo measurement of changes in extracellular concentrations of amino acids over time [16]. Microdialysis probes were placed in the striatum, a region where significant neuronal injury occurs after HCA. Infused artificial cerebrospinal fluid equilibrated with the brain’s extracellular space through the dialysis membrane and amino acid levels were then determined by high performance liquid chromatography with electrochemical detection.

We found that the excitatory amino acids, glutamate and aspartate, increased significantly during the ischemic period of arrest. Glutamate remained substantially elevated during reperfusion CPB and 2 to 8 hours after HCA, whereas aspartate returned to baseline and peaked again late 8 to 20 hours after HCA. Changes in glycine, the coagonist of glutamate on the NMDA receptor, paralleled changes in glutamate. The nonexcitatory amino acids, glutamine and arginine, did not increase over time.

Because nitric oxide synthase is the only enzyme in the brain that produces citrulline, and citrulline is produced in stoichiometrically equivalent amounts with nitric oxide, citrulline levels were used as a marker for nitric oxide production. Because nitric oxide has such a short half-life, its production was quantified most accurately by measuring citrulline production. Despite its short half-life, nitric oxide’s pathophysiologic significance is due to its ability to form other toxic metabolites, including peroxynitrite, nitrogen dioxide, and hydroxyl radical. Nitric oxide was produced during the same time periods as glutamate and glycine, increasing significantly during arrest, reperfusion CPB, and 2 to 8 hours after HCA.

Although separate experiments with prolonged cardiopulmonary bypass were not performed with microdialysis, the levels of all amino acids were compared at baseline, at the end of cooling CPB alone, during HCA, reperfusion CPB, and recovery. Of note, glutamate and citrulline levels increased during cooling CPB, suggesting that CPB without HCA might have neurotoxic effects; however, these changes were not statistically significant. Whether prolonged CPB alone results in increased intracerebral excitatory amino acids and neurotoxicity is not known. In the present study, no significant differences were found in any amino acid concentrations from baseline to the end of cooling CPB alone without HCA. We concluded that the changes in amino acid concentrations were the effect of HCA. Although hyperglycemia and reduced cardiac output during recovery might have damaging neurologic effects and might affect intracerebral amino acid levels, these conditions represented pathophysiologic derangements caused by HCA. Therefore, whether hyperglycemia or reduced cardiac output directly contributes to further increases in neurotoxic amino acids was not determined, but provided evidence of the damaging effects of HCA.

The increased levels of glutamate, aspartate, glycine, and nitric oxide did correspond with neurologic injury, because 2 hours of HCA produced apoptotic neuronal cell death 8 and 20 hours after HCA. Changes in amino acid concentrations were measured in the basal ganglia, an area easily and reproducibly accessible by microdialysis probes, where significant neuronal cell death occurred. To exclude the damaging effects of the microdialysis probe on histopathology, we examined an area separate from the probe tract, the dentate gyrus of the hippocampus, where apoptosis occurred most significantly and was most easily quantifiable. Apoptosis also occurred in the neocortex, hippocampus, entorhinal cortex, and basal ganglia, but these areas were not as amenable to quantification. Normal dogs and dogs that underwent CPB alone (unpublished observations) had no apoptosis. In addition to apoptosis, neuronal necrosis occurred in the neocortex, hippocampus, basal ganglia, and cerebellum after HCA, although it was much less prominent [11, 12] at these time periods.

The decrease in apoptotic score at 20 hours demonstrated less ongoing apoptosis at the later time period as well as the loss of dead neurons that had been cleared. Histopathologically, the density of neurons in the dentate gyrus was significantly less at 20 hours as compared with 8 hours, with spaces where neurons had been present. Most apoptotic neurons appeared to have been cleared away, and in a previous study, we demonstrated that apoptosis essentially stopped by 72 hours [11, 12].

We found direct evidence that HCA causes increased intracerebral excitatory amino acids, extracellular glutamate and aspartate, along with coagonist glycine. We conclude that HCA causes glutamate excitotoxicity with subsequent nitric oxide production resulting in neurologic injury, beginning during arrest but continuing until 20 hours after arrest. Pharmacologic strategies to reduce glutamate excitotoxicity require intervention beyond the initial ischemic insult to provide effective cerebral protection.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This work was supported by The Dana and Albert Broccoli Center for Aortic Diseases and grant 2RO1NS31238-05 from the National Institutes of Health. Elaine Tseng was supported by the Nina Braunwald Research Fellowship Award from the Thoracic Surgery Foundation for Research and Education.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Elaine E. Tseng Malcolm V. Brock Michael V. Johnston William A. Baumgartner Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tseng, E. E. Articles by Baumgartner, W. A. Search for Related Content PubMed PubMed Citation Articles by Tseng, E. E. Articles by Baumgartner, W. A.