Postischemic hyperthermia exacerbates neurologic injury after deep hypothermic circulatory arrest

BACKGROUND: Aggressive surface warming is a common practice in the pediatric intensive care unit. However, recent rodent data emphasize the protective effect of mild (2 degrees - 3 degrees C) hypothermia after cerebral ischemia. This study evaluates different temperature regulation strategies after deep hypothermic circulatory arrest with a survival piglet model. METHODS: Fifteen piglets were randomly assigned to 3 groups. All groups underwent 100 minutes of deep hypothermic circulatory arrest at 15 degrees C. Brain temperature was maintained at 34 degrees C for 24 hours after cardiopulmonary bypass in group I, 37 degrees C in group II, and 40 degrees C in group III. Neurobehavioral recovery was evaluated daily for 3 days after extubation by neurologic deficit score (0, normal; 500, brain death) and overall performance category (1, normal; 5, brain death). Histologic examination was assessed for hypoxic-ischemic injury (0, normal; 5, necrosis) in a blinded fashion. RESULTS: All results are expressed as mean +/- standard deviation. Recovery of neurologic deficit score (12.0 +/- 17.8, 47.0 +/- 49.95, 191.0 +/- 179.83; P = .05 for group I vs III), overall performance category (1.0 +/- 0.0, 1.4 +/- 0.6, 2.8 +/- 1.3; P < .05 for group I vs III), and histologic scores (0.0 +/- 0.0, 1.0 +/- 1.2, 2.8 +/- 1.8; P < .05 for group I vs III cortex) were significantly worse in hyperthermic group III. These findings were associated with a significantly lower cytochrome aa3 recovery determined by near-infrared spectroscopy in group III animals (P = .0041 for group I vs III). No animal recovered to baseline electroencephalographic value by 48 hours after deep hypothermic circulatory arrest. Recovery was significantly delayed in the hyperthermic group III animals, with a lower amplitude 14 hours after the operation, which gradually increased with time (P < .05 for group III vs groups I and II). CONCLUSIONS: Mild postischemic hyperthermia significantly exacerbates functional and structural neurologic injury after deep hypothermic circulatory arrest and should therefore be avoided.     

Prolongation of total permissible circulatory arrest duration by deep hypothermic intermittent circulatory arrest

Single-headed myosin was prepared by digestion of porcine aorta smooth muscle myosin with Staphylococcus aureus V8 protease in the presence of actin. The single-headed myosin preparation contained intact light chains, a rod fragment of a heavy chain, and a heavy chain of which only a minor fraction contained a nick in the head segment. Below 0.2 M NaCl, the single-headed myosin showed a decrease in Ca2+-ATPase activity and an increase in the elution time on gel filtration HPLC in a phosphorylation-dependent manner, indicating a phosphorylation-dependent conformational transition between the extended and folded forms. These conformations were confirmed by electron microscopic observation of rotary-shadowed samples of single-headed myosin. However, the conformational transition of single-headed myosin occurred in a narrower range with lower salt concentrations than that of double-headed myosin. The filament assembly of single-headed myosin was thus facilitated and phosphorylation-independent. The single-headed myosin also showed high actin-activated ATPase activity independent of phosphorylation. These results indicate that the two-headed structure of smooth muscle myosin is not essential for the conformational transition, but is required for the phosphorylation-dependent regulation of enzymatic activity and filament assembly.     

Deep hypothermic circulatory arrest and retrograde cerebral perfusion

The RNA Modification Database (http://medlib.med.utah.edu/RNAmods/) provides a comprehensive listing of naturally modified nucleosides in RNA. Each file includes: chemical structure; common name and symbol; type(s) of RNA in which found and corresponding phylogenetic distribution; Chemical s registry number and index name; and initial literature citations for structure characterization and chemical synthesis. New features include capability to search database files by name or substructural features, modifications in tmRNA, and links to related data and sites.     

Depression of cardiac function after deep hypothermic circulatory arrest in deeply anesthetized neonatal lambs

Cardiac dysfunction is common after neonatal cardiac operations. Previous in vivo studies in neonatal animal models however, have failed to demonstrate decreased left ventricular function after ischemia and reperfusion. Cardiac dysfunction may have been masked in these studies by increased endogenous catecholamine levels associated with the use of light halothane anesthesia. Currently, neonatal cardiac operations are often performed with deep opiate anesthesia, which suppresses catecholamine surges and may affect functional recovery. We therefore examined the recovery of left ventricular function after ischemia and reperfusion in neonatal lambs anesthetized with high-dose fentanyl citrate (450 micrograms/kg administered intravenously). Seven intact neonatal lambs with open-chest preparation were instrumented with left atrial and left ventricular pressure transducers, left ventricular dimension crystals, and a flow transducer. The lambs were cooled (< 18 degrees C) on cardiopulmonary bypass (22 +/- 6 minutes), exposed to deep hypothermic circulatory arrest (46 +/- 1 minutes), and rewarmed on cardiopulmonary bypass (30 +/- 10 minutes). Catecholamine levels and indexes of left ventricular function were determined before (baseline) and 30, 60, 120, 180, and 240 minutes after termination of cardiopulmonary bypass. Levels of epinephrine, norepinephrine, and dopamine were unchanged from baseline values. Left ventricular contractility (slope of end-systolic pressure-volume relationship) was depressed from baseline value (31.7 +/- 9.3 mm Hg/ml) at 30 minutes (15.7 +/- 6.4 mm Hg/ml) and 240 minutes (22.7 +/- 6.4 mm Hg/ml) but unchanged between 60 and 180 minutes. Left ventricular relaxation (time constant of isovolumic relaxation) was prolonged from baseline value (19.0 +/- 3.0 msec) at 30 minutes (31.4 +/- 10.0 msec) and 240 minutes (22.1 +/- 2.8 msec) but unchanged between 60 and 180 minutes. Afterload (left ventricular end-systolic meridional wall stress) was decreased at 30, 60, and 240 minutes. Indexes of global cardiac function (cardiac output, stroke volume), preload (end-diastolic volume), and left ventricular compliance (elastic constant of end-diastolic pressure-volume relationship) were unchanged from baseline values. In deeply anesthetized neonatal lambs exposed to ischemia and reperfusion, left ventricular contractility, relaxation, and afterload are markedly but transiently depressed early after reperfusion and mildly depressed late after reperfusion.     

Deep hypothermic circulatory arrest with and without retrograde cerebral perfusion

Our study indicated that RCP provided significant protection against both postoperative strokes and early death. However, in the subjects studied, the combined detrimental effects of postoperative stroke, COPD, cardiac complications, and procedures requiring composite valve replacement outweighed the protective benefit afforded by RCP in the prevention of early death. RCP's protective benefit was also diminished in the presence of pre-existing cerebrovascular disease. Although the major factors leading to the incidence of postoperative stroke and early mortality were the etiologies and pathologies brought to the operating theater by the patient, RCP when used in conjunction with DHCA significantly diminished the likelihood of either outcome. Therefore, given its simplicity of application in the surgical repair of aortic arch abnormalities, its indication seems warranted.     

Monosialoganglioside GM1 inhibits neurotoxicity after hypothermic circulatory arrest

BACKGROUND/AIM: A herbal medicine, Sho-saiko-to (TJ-9), has recently been orally administered to patients with chronic liver disease in Japan and has been reported to inhibit the development of hepatocellular carcinoma. The aim of this study was to investigate whether TJ-9 has an inhibitory effect on the development of preneoplastic lesions and liver fibrosis in rats. METHODS: The effects of the TJ-9 were examined using the choline-deficient L-amino acid-defined (CDAA) diet-induced liver fibrosis model in 16-week-old male Wistar rats. RESULTS: TJ-9 (1% w/w) prevented fibrosis, as indicated by reduced hydroxyproline content in the liver and inhibition of the increase in a serum marker of fibrosis (hyaluronic acid), without reducing the increase in serum alanine aminotransferase and aspartate aminotransferase. TJ-9 also reduced the expression of type III procollagen alpha 1 mRNA in the liver, as well as the proliferation of myofibroblast-like cells (activated stellate cells, activated Ito cells). Furthermore, TJ-9 reduced the number of preneoplastic lesions, detected as enzyme-altered (glutathione S-transferase placental form-positive) lesions, in the liver. CONCLUSIONS: These results indicate that the herbal medicine Sho-saiko-to (TJ-9) prevents fibrosis as well as preneoplastic lesions, not by inhibiting hepatocyte cell death but by inhibiting the activation of stellate cells, which are considered to be the main collagen-producing cells, leading to a reduction in the development of preneoplastic lesions.     

Glucose plus insulin infusion improves cerebral outcome after asphyxial cardiac arrest

Hyperglycemia before ischemia worsens cerebral outcome. The aim of this study was to determine the cerebral effects of giving glucose with or without insulin after asphyxial cardiac arrest. Rats underwent 8 min of asphyxial cardiac arrest. After arrest, Group 1 received NaCl; Group 2, insulin; Group 3, glucose; and Group 4, glucose plus insulin, all intravenously. Neurological deficit (ND) scores were 14+/-10%, 22+/-12%, 12+/-10% and 2+/-2% in Groups 1-4, respectively, 72 h after reperfusion. Overall histological damage (HD) scores were 4, 2, 3 and 1, respectively. Group 4 fared significantly better than group 1 on both scores. Glucose after asphyxial cardiac arrest in rats produces no increased brain damage while glucose plus insulin improves cerebral outcome.     

Consequences of electroencephalographic-suppressive doses of propofol in conjunction with deep hypothermic circulatory arrest

BACKGROUND: Some patients who undergo cerebral aneurysm surgery require cardiopulmonary bypass and deep hypothermic circulatory arrest. During bypass, these patients often are given large doses of a supplemental anesthetic agent in the hope that additional cerebral protection will be provided. Pharmacologic brain protection, however, has been associated with undesirable side effects. These side effects were evaluated in patients who received large doses of propofol. METHODS: Thirteen neurosurgical patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest to facilitate clip application to a giant or otherwise high-risk cerebral aneurysm. Electroencephalographic burst suppression was established before bypass with an infusion of propofol, and the infusion was continued until the end of surgery. Hemodynamic and echocardiographic measurements were made before and during the prebypass propofol infusion and again after bypass. Emergence time also was determined. RESULTS: Prebypass propofol at 243 +/- 57 micrograms.kg-1.min-1 decreased vascular resistance from 34 +/- 8 to 27 +/- 8 units without changing heart rate, arterial or filling pressures, cardiac index, stroke volume, or ejection fraction. Propofol blood concentration was 8 +/- 2 micrograms/ml. Myocardial wall motion appeared hyperdynamic at the end of cardiopulmonary bypass, and all patients were weaned therefrom without inotropic support. After bypass, vascular resistance decreased further, and cardiovascular performance was improved compared to baseline values. Nine of the 13 patients emerged from anesthesia and were able to follow commands at 3.1 +/- 1.4 h. Three others had strokes and a fourth had cerebral swelling. CONCLUSIONS: Propofol infused at a rate sufficient to suppress the electroencephalogram does not depress the heart or excessively prolong emergence from anesthesia after cardiopulmonary bypass and deep hypothermic circulatory arrest.     

Anesthesia for deep hypothermic circulatory arrest in adults: experience with the first 50 patients

A method is presented for assigning classification codes to pathology reports by searching similar reports from an archive collection. The key for searching is textual similarity, which estimates the true, semantic similarity. This method does not require explicit modeling, and can be applied to any language or any application domain that uses natural language reporting. A number of simulation experiments was run to assess the accuracy of the method and to indicate the role of size of the archive and the transfer of document collections across laboratories. In at least 63% of the simulation trials, the most similar archive text offered a suitable classification on organ, origin and diagnosis. In 85 to 90% of the trials, the archive's best solution was found within the first five similar reports. The results indicate that the method is suitable for its purpose: suggesting potentially correct classifications to the reporting diagnostician.     

pH strategies and cerebral energetics before and after circulatory arrest

The pH-stat strategy compared with the alpha-stat strategy provides more rapid recovery of brain high-energy phosphate stores and intracellular pH after 1 hour of hypothermic circulatory arrest in pigs. Possible mechanisms for this difference are (1) improved oxygen delivery and homogeneity of brain cooling before deep hypothermic circulatory arrest and (2) greater cerebral blood flow and reduced reperfusion injury owing to extracellular acidosis during the rewarming phase. To identify which of these mechanisms is predominant, we studied 49 4-week-old piglets undergoing 1 hour of deep hypothermic circulatory arrest. Four groups were defined according to cooling/rewarming strategy: alpha/alpha, alpha/pH, pH/alpha, and pH/pH. In 24 animals cerebral high-energy phosphate levels and intracellular pH were measured by magnetic resonance spectroscopy (alpha/alpha group 7, alpha/pH group 5, pH/alpha group 7, pH/pH group 5). In 25 animals cerebral blood flow was measured by labeled microspheres, cerebral metabolic rate by oxygen and glucose extraction, and the redox state of cytochrome aa3 and hemoglobin oxygenation by near infrared spectroscopy (alpha/alpha group 7, alpha/pH group 5, pH/alpha group 7, pH/pH group 6). Cerebral blood flow was greater with pH-stat than alpha-stat during cooling (56.3% +/- 3.7% versus 32.9% +/- 2.1% of normothermic baseline values, p < 0.001). Cytochrome aa3 values became more reduced during cooling with alpha-stat than with pH-stat (p = 0.049). Recovery of adenosine triphosphate levels in the initial 45 minutes of reperfusion was more rapid in group pH/pH compared with that in the other groups (p = 0.029). Recovery of cerebral intracellular pH in the initial 30 minutes was faster in group pH/pH compared with that in group alpha/alpha (p = 0.026). Intracellular pH became more acidic during early reperfusion only in group alpha/alpha, whereas it showed continuous recovery in the other groups. This study suggests that there are mechanisms in effect during both the cooling and rewarming phases before and after deep hypothermic circulatory arrest that could contribute to an improved cerebral outcome with pH-stat relative to more alkaline strategies.     

Retrograde cerebral perfusion enhances cerebral protection during prolonged hypothermic circulatory arrest: a study in a chronic porcine model

BACKGROUND: This study was undertaken to confirm earlier findings that retrograde cerebral perfusion (RCP) can improve cerebral outcome after prolonged hypothermic circulatory arrest (HCA), and to determine whether RCP with inferior vena caval occlusion, which is more effective in removing particulate emboli, is superior to conventional RCP in enhancing cerebral protection. METHODS: Sixty-two pigs (27 to 30 kg) were randomly assigned to undergo one of the following for 90 minutes at 20 degrees C: antegrade cerebral perfusion (ACP); conventional RCP (RCP); RCP with occlusion of the inferior vena cava (RCP-O), or HCA with the head packed in ice. RCP flow was regulated to a sagittal sinus pressure of 20 mm Hg. Hemodynamic, electrophysiologic, and metabolic monitoring were carried out until 4 hours after rewarming, daily behavioral and neurologic assessments until elective sacrifice on day 7, and histologic analysis of the brain after death. RESULTS: Complete behavioral recovery was seen in all surviving animals by day 5 after ACP or RCP, but in only 83% after RCP-O and 50% after HCA (p = 0.001). A histopathologic score of 2 or more, indicating more than mild injury, was not found in any animal after ACP, in 27% after RCP, in 47% after HCA, and in 68% after RCP-O (p = 0.002). The median oxygen consumption was 6.66 mL/min after ACP, 1.37 mL/min with RCP, and 1.02 mL/min with RCP-O (p < 0.0001). The median amount of fluid sequestered was 2,450 mL after RCP-O, 760 mL after RCP, and -200 mL after ACP (p < 0.0001). CONCLUSIONS: Conventional RCP without inferior vena caval occlusion results in a significantly better outcome than RCP-O after prolonged HCA, despite more efficient cerebral perfusion during RCP-O, and also provides cerebral protection superior to prolonged HCA alone, but care must be taken during its implementation to minimize cerebral edema and other possible causes of retroperfusion-related cerebral injury.     

Aortic valve operations under deep hypothermic circulatory arrest for the porcelain aorta: "no-touch" technique

BACKGROUND: Aortic valve replacement or repair becomes a high-risk procedure in patients in whom the ascending aorta cannot be clamped either because of extensive calcification and risk of cerebral embolus or because of extensive adhesions precluding safe dissection and clamping. METHODS: We report the results of aortic valve replacement or repair with deep hypothermic circulatory arrest in 3 patients. Techniques to improve results include routine use of epiaortic and transesophageal echocardiography, avoidance of manipulation of the ascending aorta until the circulation is arrested, avoidance of antegrade cardioplegia, routine use of retrograde cardioplegia and retrograde cerebral perfusion, when feasible, and minimal aortotomy (just enough to excise and replace or repair the valve). RESULTS: Operations were accomplished in approximately 1 hour each with minimal manipulation of the aorta, thus minimizing aortic trauma and subsequent risk of cerebral embolus. Each patient had an unremarkable recovery without neurologic complications. CONCLUSIONS: Aortic valve replacement or repair using the "no-touch" technique and deep hypothermic circulatory arrest is the preferred method when dealing with the porcelain or unclampable aorta.     

Cerebral metabolic effects of sequential periods of hypothermic circulatory arrest

During repair of congenital heart defects, extended periods of hypothermic circulatory arrest (CA) have been shown to cause short-term cerebral metabolic and flow abnormalities as well as long-term neuropsychologic dysfunction. Occasionally, a second period of CA is required during the same operative setting to revise a complicated repair. However, the metabolic effects of two consecutive periods of CA on the brain are unclear. In this study, we compared the recovery of cerebral metabolism after 60 minutes of CA with that after two sequential 30-minute periods of CA separated by a brief period of rewarming (30'SEQ). Fifteen neonatal piglets (2 to 3 kg) were placed on cardiopulmonary bypass at 100 mL.kg-1 x min-1 and cooled to 18 degrees C. Each animal then underwent either 60 minutes of uninterrupted cardiopulmonary bypass at 18 degrees C, 60 minutes of CA, or two 30-minute periods of CA separated by a brief period of rewarming. After these experimental periods, animals were rewarmed to 37 degrees C and weaned from cardiopulmonary bypass. Data were obtained before cardiopulmonary bypass and after cardiopulmonary bypass at 37 degrees C and included measurements of cerebral blood flow by xenon 133 clearance, arterial and sagittal sinus blood gases, and cerebral metabolism (mL O2.100 g-1 x min-1). Our results demonstrated that acute recovery of cerebral metabolism was significantly impaired after 60 minutes of CA and that recovery of cerebral metabolism after two sequential 30-minute periods of CA was significantly better than after 60 minutes of continuous CA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of cardiopulmonary bypass and deep hypothermic circulatory arrest on the thyroid axis during and after repair of congenital heart defects: preservation by deep hypothermia?

YM-60828 was found to potently inhibit human factor Xa following oral administration. YM-60828 showed high affinity for factor Xa (Ki = 1.3 nM), but did not affect thrombin (Ki > 100 microM). YM-60828 doubled factor Xa clotting time, prothrombin time (PT) and activated partial thromboplastin time (APTT) at 0.10, 0.21, 0.24 microM, respectively. Importantly, it did not prolong thrombin time at 100 microM. YM-60828 also inhibited factor Xa in the prothrombinase complex with an IC50 value of 7.7 nM. In addition to its anticoagulant activity, YM-60828 inhibited platelet aggregation induced by various agonists (IC50 = 3 to 23 microM). Squirrel monkeys were used to study the ex vivo anticoagulant activity and pharmacokinetic properties of YM-60828. One hour after oral administration at 3 mg/kg, YM-60828 strongly prolonged PT and APTT by 4.8- and 1.9-fold, respectively, and plasma concentration reached 788 +/- 167 ng/ml. Bioavailability was calculated to be 20.3%. These results strongly suggest that YM-60828 will be a valuable orally active and potent anticoagulant agent showing potential antithrombotic activity.     

Psychomotor and intellectual development after deep hypothermia and circulatory arrest in early infancy

Somatic, psychomotor, and intellectual development were studied in 11 patients who had total correction of congenital cardiac malformation in early infancy by the method of surface-induced deep hypothermia and circulatory arrest up to 43 minutes. Time between operation and re-evaluation ranged from 3 to 11 years (average 7 years). Somatic development was normal in all children. Psychomotor and intellectual behavior, measured by a battery of specially adapted test methods, failed to show a statistically significant difference when compared between the study group, a matched control group, and the normal population. Normal scores in psychomotor tests and normal intelligence quotients (I.Q.) were present in 8 patients; mental retardation was found in 2 patients: and unstable behavior, evident from different tests, was present in one. Except for the last case, in none of the patients was the method was found to be the primary cause of the abnormal behavior. Deep hypothermia and circulatory arrest in early infancy does not appear to have a negative influence on somatic, psychomotor, or intellectual development.     

Aprotinin and deep hypothermic circulatory arrest: there are no benefits even when appropriate amounts of heparin are given

OBJECTIVE: To evaluate retrospectively the effect of 'high-dose' aprotinin on blood losses, donor blood requirements and morbid events on patients undergoing ascending aorta and/or aortic arch procedures with the employ of deep hypothermic circulatory arrest (HCA). METHODS: During the period 1987-1994, 39 patients underwent a thoracic aorta procedure with the employ of circulatory arrest; of these 18 (46.2%) were operated on during the period 1990-1994 and were given aprotinin intraoperatively following the 'high-dose' protocol (group I), while 21 (53.8%) who underwent surgery during the years 1987-1989, did not receive intraoperative aprotinin and served as historical controls (group II). Twenty-seven (69.2%) patients were male, 18 (46.2%) were operated on on an emergency basis, 15 (38.5%) were acute type A dissections, and two (5.1%) were redo-operations. Circulatory arrest times were not significantly different between the two groups (40 +/- 4 (S.E.) group I vs. 43 +/- 4 min group II, P = 0.62) likewise cardiopulmonary bypass (CPB) times (181 +/- 9 vs. 201 +/- 20 mm, P = 0.74) and the amount of heparin administered (32056 +/- 1435 vs. 31 691 +/- 1935 IU, P = 0.56). RESULTS: Postoperative blood loss was comparable between the two groups (1213 +/- 243 (median 850) group I vs. 1528 +/- 377 (median 880) ml group II, P = 0.87), as well as the number of units of donor blood transfused (9.4 +/- 3.0 (median 6) vs. 9.9 +/- 3.6, (median 5) P = 0.87), and revisions for bleeding (2/18, 11.1% vs. 3/21, 14.3%, P = 0.77). In-hospital mortality rate was not statistically different (5/18, 27.7% group I vs. 6/21, 28.6% group II, P = 0.92). There were no significant differences between the two groups in myocardial infarction (2/18, 11.1% vs. 0/21, 0%, P = 0.21), and postoperative renal failure rates (3/18, 16.7% vs. 2/21, 9.5%, P = 0.65). On the other hand, there was a trend towards an increased incidence of permanent neurological deficit (5/18, 27.7% group I vs. 1/21, 4.8% group II, P = 0.07) and towards a more complicated postoperative course (perioperative renal failure and/or myocardial infarction and/or neurological deficit either transient or permanent) (8/18, 44.4% group I vs. 4/21, 19% group II, P = 0.09) in group I patients. Forward stepwise logistic regression analysis, performed on the whole group of patients, identified chronic obstructive pulmonary disease (P = 0.010, Odds ratio (OR) = 5.7), aprotinin use (P = 0.017, OR = 5.1), and the number of units of blood collected intraoperatively by the cellsaver (P = 0.045, OR = 1.3/unit) as independent predictors of complicated postoperative course in the whole group of patients. CPB time (P = 0.040, OR = 1.032/min), circulatory arrest time (P = 0.053, OR = 1.22/min), and overall donor blood units transfused (P = 0.067, OR = 1.37/unit) emerged as independent risk factors for in-hospital mortality at multivariate analysis. CONCLUSIONS: Even when appropriate amounts of heparin are administered, 'high-dose' aprotinin probably is not an effective blood-sparing drug in deep HCA. Aprotinin should be employed cautiously in this clinical setting because of its possible correlation with an increased rate of postoperative morbid events.     

Glutamate excitotoxicity: a mechanism of neurologic injury associated with hypothermic circulatory arrest

Glutamate, the major central nervous system neurotransmitter, may have potent neurotoxic activity under conditions of metabolic stress. By receptor autoradiography, we have demonstrated that brain regions most vulnerable to injury during prolonged hypothermic circulatory arrest have the highest density of glutamate receptors. To test the hypothesis that such injury could be mediated by glutamate excitotoxicity, we used dizocilpine (MK-801), a selective N-methyl-D-aspartate-glutamate receptor antagonist in a canine survival model of hypothermic circulatory arrest. Eighteen male dogs (20 to 25 kg) were supported by closed-chest cardiopulmonary bypass, subjected to 2 hours of hypothermic circulatory arrest at 18 degrees C, and rewarmed on cardiopulmonary bypass. All were mechanically ventilated and monitored for 20 hours before extubation and survived for 3 days. Group A dogs (n = 9) received a prearrest intravenous bolus of dizocilpine (0.75 mg/kg) followed by continuous infusion (75 micrograms/kg per hour), resulting in electroencephalographic silence. Dizocilpine was weaned before extubation. Group B dogs received vehicle only. According to a species-specific behavior scale that yielded a neurologic deficit score ranging from 0 (normal) to 500 (brain dead), all animals were neurologically assessed every 12 hours. After the dogs were killed at 72 hours, brains were examined by receptor autoradiography and histologically for patterns of selective neuronal necrosis; they were scored blindly from 0 (normal) to 100 (severe injury). Group A dogs had better neurologic function than group B (neurologic deficit score 21 +/- 15 versus 192 +/- 40, p < 0.001) and had less neuronal injury (7.3 +/- 3 versus 48.3 +/- 9, p < 0.0001). Densitometric receptor autoradiography revealed preservation of neuronal N-methyl-D-aspartate-glutamate receptor expression in group A only. These results represent the first direct evidence of a role for glutamate excitotoxicity in the development of hypothermic circulatory arrest-induced brain injury and suggest that selective glutamate receptor antagonists may have a neuroprotective capacity in prolonged periods of hypothermic circulatory arrest.     

Comparison of pH-stat and alpha-stat cardiopulmonary bypass on cerebral oxygenation and blood flow in relation to hypothermic circulatory arrest in piglets

Melagatran, a new, competitive and rapid inhibitor of thrombin with a molecular mass of 429 Da is described. Melagatran is well tolerated when administered in very high doses, and the oral bioavailability in the dog is relatively high. The aim of the study was to determine, in the preclinical setting, the degree of selectivity against the fibrinolytic system required for entering the clinical development phase. Melagatran was compared with two structurally similar thrombin inhibitors, inogatran and H 317/86. The potent inhibition of thrombin by melagatran was demonstrated by a low inhibition constant (Ki) for thrombin (0.002 micromol/l) and prolongation of clotting time to twice the control value in coagulation assays at low concentrations (0.010, 0.59 and 2.2 micromol/l for thrombin time, activated partial thromboplastin time and prothrombin time, respectively). Furthermore, thrombin-induced platelet aggregation was inhibited at the same concentration (IC50-value 0.002 micromol/l) as the Ki-value for thrombin. In two assays of global fibrinolysis, inhibition was observed at a concentration of 1.1 micromol/l in a euglobulin plasma fraction model, while no inhibition was observed at a concentration of < or = 10 micromol/l in a plasma model. In an in vivo model of endogenous fibrinolysis in the rat, inhibition of fibrinolysis was observed at > or = 1.0 micromol/l. In all assays, except the Ki-ratio determinations, the compounds could be graded with regard to selectivity against the fibrinolytic system: inogatran > melagatran > H 317/86. For melagatran, inhibition of fibrinolysis was not observed at concentrations below the upper limit of the proposed therapeutic plasma concentration interval (< 0.5 micromol/l). Thus, melagatran seems to have a sufficient selectivity against the fibrinolytic system, while H 317/86 was considered to be insufficient for clinical development.     

Normoxic ventilation after cardiac arrest reduces oxidation of brain lipids and improves neurological outcome

BACKGROUND AND PURPOSE: Increasing evidence that oxidative stress contributes to delayed neuronal death after global cerebral ischemia has led to reconsideration of the prolonged use of 100% ventilatory O2 following resuscitation from cardiac arrest. This study determined the temporal course of oxidation of brain fatty acyl groups in a clinically relevant canine model of cardiac arrest and resuscitation and tested the hypothesis that postischemic ventilation with 21% inspired O2, rather than 100% O2, results in reduced levels of oxidized brain lipids and decreased neurological impairment. METHODS: Neurological deficit scoring and high performance liquid chromatography measurement of fatty acyl lipid oxidation were used in an established canine model using 10 minutes of cardiac arrest followed by resuscitation with different ventilatory oxygenation protocols and restoration of spontaneous circulation for 30 minutes to 24 hours. RESULTS: Significant increases in frontal cortex lipid oxidation occurred after 10 minutes of cardiac arrest alone with no reperfusion and after reperfusion for 30 minutes, 2 hours, and 24 hours (relative total 235-nm absorbing peak areas=7.1+/-0.7 SE, 17.3+/-2.7, 14.2+/-3.2, 16.1+/-1.0, and 14.0+/-0.8, respectively; n=4, P<0.05). The predominant oxidized lipids were identified by gas chromatography/mass spectrometry as 13- and 9-hydroxyoctadecadienoic acids (13- and 9-HODE). Animals ventilated on 21% to 30% O2 versus 100% O2 for the first hour after resuscitation exhibited significantly lower levels of total and specific oxidized lipids in the frontal cortex (1.7+/-0.1 versus 3.12+/-0.78 microg 13-HODE/g wet wt cortex., n=4 to 6, P<0.05) and lower neurological deficit scores (45.1+/-3.6 versus 58.3+/-3.8, n=9, P<0.05). CONCLUSIONS: With a clinically relevant canine model of 10 minutes of cardiac arrest, resuscitation with 21% versus 100% inspired O2 resulted in lower levels of oxidized brain lipids and improved neurological outcome measured after 24 hours of reperfusion. This study casts further doubt on the appropriateness of present guidelines that recommend the indiscriminate use of 100% ventilatory O2 for undefined periods during and after resuscitation from cardiac arrest.