| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Ann Thorac Surg 1997;64:1639-1647
© 1997 The Society of Thoracic Surgeons
Division of Cardiac Surgery, Johns Hopkins Medical Institutions, and Kennedy-Krieger Research Institute, Baltimore, Maryland
 |
Abstract |
|---|
 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Methods. Fourteen male hound dogs (weight, 20 to 27 kg) were placed on closed-chest cardiopulmonary bypass, subjected to 2 hours of HCA at 18°C, rewarmed to normothermia, and sacrificed 8 hours after HCA. Group 1 (n = 7) dogs were treated with the neuronal nitric oxide inhibitor 7-nitroindazole, 25 mg/kg intraperitoneally, before arrest and every 2 hours until sacrifice. Group 2 (n = 7) dogs received vehicle only. The brains were analyzed histopathologically. Apoptosis, identified by hematoxylin-eosin staining, was confirmed by DNA terminal deoxynucleotidyltransferase–mediated dUTP-biotin nick end-labeling assay and electron microscopy. Apoptosis was scored by a blinded neuropathologist from 0 (normal) to 100 (severe injury).
Results. Apoptosis occurred early after HCA in select neuronal populations, including the hippocampus, stria terminalis, neocortex, and entorhinal cortex. Apoptotic neurons showed a characteristic shrunken cytoplasm and nuclear chromatin condensation. 7-Nitroindazole significantly inhibited apoptosis (group 1 versus 2: 19.17 ± 14.39 versus 61.11 ± 5.41; p < .001).
Conclusions. Our results provide evidence that apoptosis is associated with the neurologic injury that occurs after HCA and that nitric oxide mediates the apoptosis that occurs after HCA. Strategies for cerebral protection during HCA may include the inhibition of neuronal nitric oxide synthase.
|
Introduction |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Initially introduced to facilitate the repair of complex congenital heart lesions, hypothermic circulatory arrest (HCA) has since been adopted for a wide array of cardiac and noncardiac procedures [1]. This technique provides a bloodless operative field, unobstructed by vascular clamps and cannulas. However, the central nervous system is most sensitive to the anoxia associated with HCA, and this therefore prohibits prolonged periods of arrest. Morbidity and mortality increase substantially if HCA lasts for more than 45 to 60 minutes [2]. Characteristic delayed neurologic sequelae seen after HCA include impaired intellectual development, choreoathetosis, and learning and memory deficits [2].
Neuronal cell death causes the HCA-induced neurologic sequelae. There are two types of neuronal cell death, necrosis and apoptosis, or programmed cell death [3]. The neuropathologic hallmark of HCA has traditionally been selective neuronal necrosis of the hippocampus, neocortex, basal ganglia, and cerebellum [4–6]. However, the role of apoptotic cell death in HCA and its mechanism remain unknown.
In previous studies in our laboratory, we have investigated the mechanism of the neuronal cell death that occurs in HCA [4–6]. We have shown that glutamate excitotoxicity plays a role in HCA-induced neurologic damage and that HCA causes induction of neuronal nitric oxide synthase (nNOS) [4–7]. In this study we hypothesized that (1) apoptosis is an additional cause of the neurologic injury seen after HCA, (2) HCA results in increased nitric oxide (NO) production, and (3) NO mediates apoptosis. The purpose of this study was to characterize the nature of neuronal cell death after HCA and to determine whether nNOS inhibition reduces neuronal apoptosis in a canine model of HCA.
|
Material and Methods |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Tympanic membrane, nasopharyngeal, and rectal temperature probes were placed bilaterally. The tympanic membrane temperature closely correlates with brain temperature. Electrocardiographic monitoring was employed. A Swan-Ganz catheter was placed through the left external jugular vein, and a left femoral arterial line was placed for blood pressure and arterial blood gas determinations.
Cardiopulmonary Bypass and Hypothermic Circulatory Arrest
The 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 in-line 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 systemic heparinization (300 U/kg intravenously), dogs were cannulated for closed-chest CPB. The arterial cannula (12F to 14F) was advanced to the descending aorta from the right femoral artery, and venous cannulas (18F to 20F) were advanced to the right atrium through the right external jugular and femoral veins.
Cardiopulmonary bypass was instituted, and animals were cooled by surface (ice bags around head and cooling blanket) and core (CPB) cooling to a tympanic membrane temperature of 18°C, at which time the arterial pump was turned off and venous blood drained by gravity into the reservoir. During CPB the mean arterial pressure was maintained at 50 to 60 mm Hg with pump flows of 80 to 100 mL/kg and reduced to 60 mL/kg when the temperature was less than 32°C. Arterial blood gas values were controlled using the alpha-stat strategy.
Circulatory arrest was maintained for 2 hours at 18°C, followed by the reinstitution of CPB and rewarming. Sodium bicarbonate (50 mEq) and furosemide (20 mg) were given. At normothermia (37°C), animals were weaned from CPB and decannulated. The right femoral artery and vein were ligated. Protamine was administered.
Postoperatively, dogs were followed up for 8 hours after HCA. They remained on a ventilator, and anesthesia was maintained with intravenous fentanyl (10 to 20 µg/kg) and midazolam (1 mg), as needed. Intensive care unit monitoring included electrocardiography, arterial blood pressure measurements, Swan-Ganz parameters, and measurement of the urine output, as well as measurement of the arterial blood gas values, the hemoglobin concentration, and glucose levels. Animals were sacrificed while fully anesthetized and perfused with either ice cold saline solution or 4% paraformaldehyde. Five normal dogs that did not undergo HCA were also sacrificed and their brains harvested to serve as normal controls.
7-Nitroindazole Protocol
Experimental dogs (group 1; n = 7) received a selective nNOS inhibitor 7-nitroindazole sonicated in peanut oil at a dose of 25 mg/kg intraperitoneally before arrest, after arrest, and every 2 hours until the end of the experiment. The HCA control animals (group 2; n = 7) received vehicle only.
Intracerebral Microdialysis
Animals were positioned in a Kopf stereotactic device. The right side of the skull was exposed and burrholes placed 3 mm caudal to the coronal suture and 8 mm from the midsagittal axis. The dura mater was opened, and microdialysis probes (CMA 10/4; Acton, MA) were placed stereotactically to a depth of 20 mm into the corpus striatum. Confirmation of proper placement was determined at sacrifice by cutting the brain and visualizing the probe tract. Tissue was allowed to equilibrate 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 filtered and continuously bubbled with 95% oxygen and 5% carbon dioxide until the oxygen and carbon dioxide tensions were similar to those of normal brain cerebrospinal fluid. Artificial cerebrospinal fluid was infused through the inflow cannula at a rate of 1 µL/min and collected serially every 30 minutes. The effluent was assayed by high-performance liquid chromatography with electrochemical detection for extracellular amino acid concentrations [8]. The citrulline concentration was measured and used as a marker of NO production.
Histopathology
Histopathologic analysis was performed in all animals. The right hemisphere of each brain was postfixed in 10% formalin and embedded in paraffin, and 8-µm sections were stained with hematoxylin-eosin. The left hemisphere was sectioned coronally, frozen on dry ice, and stored at -85°C for DNA nick end-labeling.
Electron Microscopy
Coronal sections of perfused-fixed tissue were postfixed in 0.1% gluteraldehyde and 4% paraformaldehyde, osmicated, dehydrated, and embedded in epoxy resin. Ultrathin sections were cut with an ultramicrotome and examined by electron microscopy.
DNA Nick End-Labeling
Apoptosis activates Ca2+- and Mg2+-dependent endonucleases to cut chromatin into DNA fragments. We used a terminal deoxynucleotidyltransferase (TdT)–mediated dUTP-biotin nick end-labeling (TUNEL) method (Apop Tag kit; Oncor, Inc, Gaithersburg, MD) for sensitive and specific staining of DNA fragmentation and apoptotic bodies associated with apoptosis.
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" (NIH Publications 85-23, revised 1985).
|
Results |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
). In contrast, necrosis occurred at all three time points but most prominently at 72 hours after HCA (unpublished observations). All further experiments investigating the effects of inhibitors on apoptosis have used the 8-hour time point when apoptosis is maximal.
|
). Hematoxylin-eosin–stained sections at the light microscopic level also showed apoptosis, with chromatin condensation, cellular shrinkage, apoptotic bodies, and the absence of inflammation (Fig 3).
|
|
).
|
).
|
). There were no significant differences in the esophageal and rectal temperatures between the two groups throughout the experiment.
|
IN VIVO MICRODIALYSIS.
In the brain, NOS converts oxygen and arginine to NO and citrulline. Citrulline is produced 1:1 stoichiometrically with NO, and the citrulline concentration is a putative marker of NO production. The only other synthetic enzyme for citrulline, ornithine transcarbamylase in the urea cycle, is present in liver but not in brain. We measured the in vivo formation of extracellular citrulline in the basal ganglia as a function of time using a microdialysis technique. In dogs that underwent HCA alone, the citrulline concentration rose significantly above baseline (p < 0.05) during arrest (0.5 hours), during reperfusion (4 and 5 hours), and during recovery (8 hours). Treatment with 7-nitroindazole resulted in a significantly decreased citrulline concentration and therefore NO production throughout arrest, reperfusion, and at 5 and 7.5 hours during recovery (p < 0.05) (Fig 7). 7-Nitroindazole reduced the extracellular citrulline concentration by an average of 58.4% ± 28.3%.
|
). This reduction in apoptosis was confirmed by TUNEL staining (see Fig 4). Quantitatively, apoptosis was scored in a blinded fashion by a neuropathologist from 0 (normal) to 100 (severe injury), based on the percentage of cells that were apoptotic. 7-Nitroindazole significantly reduced apoptosis in dogs that underwent 2 hours of HCA (group 1 versus 2: 19.17 ± 14.39 versus 61.11 ± 5.41; p < 0.001) (Fig 8).
|
|
Comment |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Neuronal cell death causes HCA-induced neurologic injury. Studies investigating pharmacologic agents that can protect the central nervous system have focused on neuronal necrosis as the form of cell death induced by HCA [4–6]. However, the role of apoptotic cell death in HCA is not well understood. In this study, we characterized the nature of the cell death that occurs after HCA. We demonstrated that, in addition to necrosis, apoptosis plays a role in HCA-induced neurologic damage. Apoptosis occurred in a time-dependent fashion: it peaked 8 hours after HCA, diminished by 20 hours, and virtually disappeared by 72 hours. At 20 and 72 hours after HCA, substantial cell loss was noted where apoptosis had occurred, presumably stemming from the clearance of dead cells. Necrosis, in contrast, was present at 8 and 20 hours after HCA but most prominent at 72 hours. Hypothermic circulatory arrest clearly resulted in overlapping but temporally distinct phases of both apoptosis and necrosis, two distinct cell death processes.
Apoptosis, or programmed cell death, is an active, tightly regulated process induced by inciting stimuli that requires energy, macromolecular synthesis, and gene transcription [3]. It results in nonrandom oligonucleosomal-length DNA fragmentation. In contrast, necrosis is a generalized failure of cellular homeostatic processes that does not require energy, macromolecular synthesis, or gene transcription [3]. It results in random DNA digestion and a loss of ion homeostatic regulation. Morphologically, apoptosis and necrosis are distinct. Apoptosis is defined by cellular shrinkage, chromatin condensation and aggregation, apoptotic bodies, membrane integrity, and the absence of inflammation, whereas necrosis is characterized by cellular swelling and lysis, loss of membrane integrity, and significant inflammation [3]. With two cell death processes occurring after HCA, the question arises whether the two processes occur within the same population of neurons or are anatomically distinct.
In previous studies we have investigated anatomically the selective vulnerability of neuronal necrosis [4–6]. Necrosis was found to occur in layers 3 and 5 of the neocortex and entorhinal cortex, the pyramidal cells of the CA-1 region of the hippocampus, the dentate gyrus of the hippocampus, the Purkinje cells of the cerebellum, and the basal ganglia (particularly the globus pallidus) [4–6]. In contrast, apoptosis occurred in layer 2 of the neocortex; layers 2, 3, and 5 of the entorhinal cortex; the dentate gyrus of the hippocampus; the bed nucleus of the stria terminalis; and occasionally in the thalamus and putamen (Table 1). Notably, apoptosis did not occur in the CA-1 region of the hippocampus or in the cerebellum. Necrosis occurred in different layers of the neocortex and was much more prominent than apoptosis in the basal ganglia, whereas apoptosis predominated in the dentate gyrus. Clearly there appeared to be some anatomic specificity; however, both necrosis and apoptosis were present in the entorhinal cortex and dentate gyrus. What triggers a neuron to undergo one form of cell death versus another in response to the same inciting stimulus, that is, hypoxia and ischemia, is still unknown. To further complicate the issue, apoptosis can result in secondary necrosis if it is not cleared away by neighboring cells. Whether the necrosis in the dentate gyrus and entorhinal cortex seen at 72 hours represents primary or secondary necrosis is not known.
|
-amino-3-hydroxy-5-methyl-4-isoxazolepropionate, and kainate glutamate receptors, to result in an increase in the intracellular calcium concentration, which then activates phospholipases, proteases, protein kinases, phosphatases, and NOS. These processes ultimately lead to protein breakdown, lipid peroxidation, and cell death [15]. Previous work in our laboratory has shown the utility of glutamate receptor antagonists in ameliorating the necrosis associated with HCA [5, 6]. Recently NO has been implicated as mediating glutamate excitotoxicity [16]. The activation of NOS by calcium entering through N-methyl-D-aspartate–type glutamate channels results in the production of NO, whose effects depend on its redox state, with NO being neurodestructive and nitrosonium ions being neuroprotective [17]. The damaging effects of NO may result from its reacting with superoxide anions to form peroxynitrite, leading to lipid peroxidation and the oxidation of sulfhydryls [17]. There is some evidence that DNA damage may be the key to NO neurotoxicity [18]. Nitric oxide triggers DNA damage, activating poly(adenosine 5'-diphosphoribose) synthetase, which ultimately depletes the energy sources in the cell [18].
In this study we demonstrated that NO mediates apoptosis. Using a selective nNOS inhibitor, 7-nitroindazole, we have shown that by inhibiting nNOS, neuronal apoptosis is significantly reduced after HCA. Selective inhibition of the neuronal isoform of NOS was crucial, because we have found that the nonselective inhibition of NOS (endothelial, inducible, and neuronal) is not effective in reducing apoptosis, presumably because of a reduction in cerebral blood flow produced by endothelial NOS inhibition (unpublished observations). The reduction in the extracellular citrulline content observed in the 7-nitroindazole–treated group supports the hypothesis that the drug acts by inhibiting nNOS activity. Because citrulline is generated by all three isoforms of NOS, it is possible that the 58% decrease in the citrulline concentration reflected a larger decline in the fraction contributed by nNOS alone. Although this study demonstrated the efficacy of nNOS inhibition with respect to apoptosis, further evaluation of the effect of nNOS inhibition on necrosis after HCA is warranted.
Apoptosis and necrosis were both associated with neurologic injury after HCA. However, the contribution of each form of cell death to the clinical picture of neurologic damage is unknown. Necrosis predominated in the basal ganglia and cerebellum, which could result in uninhibited extrapyramidal activity, leading to choreoathetoid movements. Both necrosis and apoptosis occurred in the hippocampus, entorhinal cortex, and neocortex (see Table 1). Presumably either or both processes could produce the learning and memory deficits and impaired intellectual development seen after HCA, especially in children. The formation of declarative memory involves projections from the neocortex to the perirhinal and parahippocampal cortices and then to the entorhinal cortex, the major source of excitatory glutamatergic projections to the hippocampus. The entorhinal cortex subsequently projects to the dentate gyrus, CA-3, and CA-1. The implications of the selective destruction of the dentate gyrus by apoptosis or of the CA-1 region by necrosis is not known and requires further investigation. However, the intensity of apoptotic changes in the dentate gyrus is consistent with other evidence for an excitotoxic mechanism.
Apoptotic cell death is important not only because of its role in physiologic neural development, but also because of its role in hypoxia, ischemia, Huntington's disease, Alzheimer's disease, and now the neurologic injury that occurs after HCA. Strategies for cerebral protection after HCA must ameliorate both forms of neuronal cell death, necrosis and apoptosis. The clinical safety of inhibiting nNOS, as well as its efficacy in reducing necrosis, requires further evaluation; however, it may be beneficial in reducing the severity of neurologic complications after HCA, given its ability to ameliorate apoptosis.
|
Acknowledgments |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
|
Footnotes |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Address reprint requests to Dr Baumgartner, Division of Cardiac Surgery, Johns Hopkins Hospital, Blalock 618, 600 N Wolfe St, Baltimore, MD 21287 (e-mail: wbaumgar{at}welchlink.welch.jhu.edu).
|
References |
|---|
|
TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
|---|
Related Article
This article has been cited by other articles:
|
|
 |
|
  O. G. Ananiadou, K. Bibou, G. E. Drossos, A. Charchanti, M. Bai, S. Haj-Yahia, C. E. Anagnostopoulos, and E. O. Johnson Effect of profound hypothermia during circulatory arrest on neurologic injury and apoptotic repressor protein Bcl-2 expression in an acute porcine model J. Thorac. Cardiovasc. Surg., April 1, 2007; 133(4): 919 - 926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Schultz, D. Antoni, G. Shears, S. Markowitz, P. Pastuszko, W. Greeley, D. F. Wilson, and A. Pastuszko Brain oxygen and metabolism during circulatory arrest with intermittent brief periods of low-flow cardiopulmonary bypass in newborn piglets J. Thorac. Cardiovasc. Surg., October 1, 2006; 132(4): 839 - 844. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Toth, I. Gyorimolnar, H. Abraham, and A. Hevesi Cannulation and cardiopulmonary bypass produce selective brain lesions in pigs. Asian Cardiovasc Thorac Ann, August 1, 2006; 14(4): 273 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Kerendi, P. M. Kirshbom, M. E. Halkos, N.-P. Wang, H. Kin, R. Jiang, Z.-Q. Zhao, K. R. Kanter, R. A. Guyton, and J. Vinten-Johansen Cobalt Chloride Pretreatment Attenuates Myocardial Apoptosis After Hypothermic Circulatory Arrest Ann. Thorac. Surg., June 1, 2006; 81(6): 2055 - 2062. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Williams, C. J. Barreiro, L. U. Nwakanma, M. S. Lange, L. E. Kratz, M. E. Blue, J. Berrong, N. D. Patel, V. L. Gott, J. C. Troncoso, et al. Valproic Acid Prevents Brain Injury in a Canine Model of Hypothermic Circulatory Arrest: A Promising New Approach to Neuroprotection During Cardiac Surgery Ann. Thorac. Surg., June 1, 2006; 81(6): 2235 - 2242. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. J. Barreiro, J. A. Williams, T. P. Fitton, M. S. Lange, M. E. Blue, L. Kratz, P. B. Barker, M. Degaonkar, V. L. Gott, J. C. Troncoso, et al. Noninvasive Assessment of Brain Injury in a Canine Model of Hypothermic Circulatory Arrest Using Magnetic Resonance Spectroscopy. Ann. Thorac. Surg., May 1, 2006; 81(5): 1593 - 1598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Schears, T. Zaitseva, S. Schultz, W. Greeley, D. Antoni, D. F. Wilson, and A. Pastuszko Brain oxygenation and metabolism during selective cerebral perfusion in neonates Eur. J. Cardiothorac. Surg., February 1, 2006; 29(2): 168 - 174. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. McKhann, M. A. Grega, L. M. Borowicz Jr, W. A. Baumgartner, and O. A. Selnes Stroke and Encephalopathy After Cardiac Surgery: An Update Stroke, February 1, 2006; 37(2): 562 - 571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. G. Ananiadou, G. E. Drossos, K. N. Bibou, G. M. Palatianos, and E. O. Johnson Acute regional neuronal injury following hypothermic circulatory arrest in a porcine model Interactive CardioVascular and Thoracic Surgery, December 1, 2005; 4(6): 597 - 601. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Amir, C. Ramamoorthy, R. K. Riemer, V. M. Reddy, and F. L. Hanley Neonatal Brain Protection and Deep Hypothermic Circulatory Arrest: Pathophysiology of Ischemic Neuronal Injury and Protective Strategies Ann. Thorac. Surg., November 1, 2005; 80(5): 1955 - 1964. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Zaitseva, G. Schears, S. Schultz, J. Creed, D. Antoni, D. F. Wilson, and A. Pastuszko Circulatory Arrest and Low-Flow Cardiopulmonary Bypass Alter CREB Phosphorylation in Piglet Brain Ann. Thorac. Surg., July 1, 2005; 80(1): 245 - 250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. Baumgartner Neuroprotection in Cardiac Surgery Ann. Thorac. Surg., June 1, 2005; 79(6): S2254 - S2256. [Full Text] [PDF]
|
|
|
|
|
|
C.-H. Yeh, Y.-C. Wang, Y.-C. Wu, Y.-M. Lin, and P. J. Lin Ischemic preconditioning or heat shock pretreatment ameliorates neuronal apoptosis following hypothermic circulatory arrest J. Thorac. Cardiovasc. Surg., August 1, 2004; 128(2): 203 - 210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Bonser, C. H. Wong, D. Harrington, D. Pagano, M. Wilkes, T. Clutton-Brock, and M. Faroqui Failure of retrograde cerebral perfusion to attenuate metabolic changes associated with hypothermic circulatory arrest J. Thorac. Cardiovasc. Surg., May 1, 2002; 123(5): 943 - 950. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. G. Shake, E. A. Peck, E. Marban, V. L. Gott, M. V. Johnston, J. C. Troncoso, J. M. Redmond, and W. A. Baumgartner Pharmacologically induced preconditioning with diazoxide: a novel approach to brain protection Ann. Thorac. Surg., December 1, 2001; 72(6): 1849 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Hill The Inflammatory Response to Cardiopulmonary Bypass-- Should It Be Treated? Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 229 - 235. [Abstract] [PDF]
|
|
|
|
|
|
N. Motoyoshi, M. Sakurai, T. Hayashi, M. Aoki, K. Abe, Y. Itoyama, and K. Tabayashi Establishment of a local cooling model against spinal cord ischemia representing prolonged induction of heat shock protein J. Thorac. Cardiovasc. Surg., August 1, 2001; 122(2): 351 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. LeMaire, J. K. Bhama, Z. C. Schmittling, P. J. Oberwalder, C. Koksoy, S. A. Raskin, P. E. Curling, and J. S. Coselli S100{beta} correlates with neurologic complications after aortic operation using circulatory arrest Ann. Thorac. Surg., June 1, 2001; 71(6): 1913 - 1919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Ehrlich, J. McCullough, D. Wolfe, N. Zhang, H. Shiang, D. Weisz, C. Bodian, and R. B. Griepp Cerebral effects of cold reperfusion after hypothermic circulatory arrest J. Thorac. Cardiovasc. Surg., May 1, 2001; 121(5): 923 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. L. Rairigh, L. Storme, T. A. Parker, T. D. le Cras, N. Markham, M. Jakkula, and S. H. Abman Role of neuronal nitric oxide synthase in regulation of vascular and ductus arteriosus tone in the ovine fetus Am J Physiol Lung Cell Mol Physiol, January 1, 2000; 278(1): L105 - L110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C H Wong and R S Bonser Retrograde cerebral perfusion: clinical and experimental aspects Perfusion, July 1, 1999; 14(4): 247 - 256. [PDF]
|
|
|
|
|
|
W. A. Baumgartner, P. L. Walinsky, J. D. Salazar, E. E. Tseng, M. V. Brock, J. R. Doty, J. M. Redmond, M. E. Blue, M. A. Goldsborough, J. C. Troncoso, et al. Assessing the impact of cerebral injury after cardiac surgery: will determining the mechanism reduce this injury? Ann. Thorac. Surg., June 1, 1999; 67(6): 1871 - 1873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. H. Wong, S. J. Rooney, and R. S. Bonser S-100{beta} release in hypothermic circulatory arrest and coronary artery surgery Ann. Thorac. Surg., June 1, 1999; 67(6): 1911 - 1914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
|
