Howard Shiang

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.

Cerebral blood flow and metabolism in hypothermic circulatory arrest

Although hypothermic circulatory arrest has been accepted for use in cardiovascular operations, the potential for cerebral injury exists. The mechanism of the cerebral injury remains unclear. To address these questions we studied cerebral blood flow and metabolism. Sixteen puppies were randomly assigned to undergo either 45 or 90 minutes of hypothermic circulatory arrest after perfusion/surface cooling to 13 degrees C. Cerebral blood flow, cerebral oxygen and glucose metabolism, and cerebral vascular resistance measurements were obtained at 37 degrees C, 13 degrees C, 10 minutes after reperfusion, 30 degrees C and 2 and 4 hours after hypothermic circulatory arrest. No neurologic or behavioral changes were observed in any of the long-term survivors (11/16). Metabolic and cerebral blood flow data did not differ between groups. Cerebral blood flow was significantly lower in the late postarrest measurements, whereas oxygen and glucose consumption had returned to baseline values. In the presence of low cerebral blood flow and high cerebral vascular resistance it is notable that control levels of oxygen consumption were attained by abnormally high oxygen extraction. These data strongly suggest a vulnerable interval after hypothermic circulatory arrest in which cerebral metabolism is limited by cerebral blood flow.

Metabolic correlates of neurologic and behavioral injury after prolonged hypothermic circulatory arrest

Thirty-two inbred weanling puppies were divided into four groups to study the effect on cerebral blood flow and metabolism of different hypothermic strategies for cerebral protection similar to those used during cardiac operations in infancy. All animals were cooled to 18 degrees C. The animals in the hypothermic control group were immediately rewarmed. One group underwent 30 minutes of hypothermic circulatory arrest at 18 degrees C; another group had 90 minutes of hypothermic circulatory arrest at 18 degrees C, and the final group had low-flow cardiopulmonary bypass (25 ml/kg per minute) at 18 degrees C for 90 minutes. All animals had preoperative and postoperative neurologic and behavioral evaluation and extensive intraoperative monitoring of cerebral blood flow, cerebral vascular resistance, and oxygen and glucose uptake and metabolism: quantitative electroencephalography was also monitored before, during and after operation, but those results are reported separately. Two animals in the 90-minute arrest group died, and all the survivors showed evidence of clinical, neurologic, and behavioral impairment on postoperative day 1, with residual abnormalities in all but one animal on day 6. In contrast, the survivors in all the other groups showed no significant clinical or behavioral sequelae. Cerebral metabolism was reduced only to 32% to 40% of baseline values at 18 degrees C in all groups, although systemic metabolism was only 16% of normal. Cerebral metabolism returned promptly to baseline in all groups during rewarming and remained at baseline levels throughout the 8 hours of follow-up. Cerebral blood flow showed marked hyperemia in the hypothermic arrest groups during rewarming but then significant reductions below baseline values in all groups except the controls at 2 and 4 hours after the operation, lasting as late as 8 hours after the operation in the 90-minute arrest group. Cerebral vascular resistance showed increases in all groups at 2 and 4 hours after the operation, which persisted in the 90-minute arrest group at 8 hours. Cerebral metabolism was maintained at baseline levels despite postoperative decreases in cerebral blood flow and increases in cerebral vascular resistance by increases in oxygen and glucose extraction. The result was very low sagittal sinus oxygen saturations in all groups, most marked in the 90-minute arrest groups, which had a saturation of only 24% 8 hours after the operation. Our data show a severe, prolonged disturbance in cerebral blood flow and cerebral vascular resistance after 90 minutes of hypothermic circulatory arrest at 18 degrees C, which correlates with clinical evidence of cerebral injury.(ABSTRACT TRUNCATED AT 400 WORDS)

Cerebral effects of low-flow cardiopulmonary bypass and hypothermic circulatory arrest

Although both hypothermic circulatory arrest (HCA) and low-flow cardiopulmonary bypass (CPB) are accepted techniques for the operative management of complex cardiovascular pathology, the potential for neurologic sequelae is still a concern. To assess the relative safety of these techniques, we compared cerebral hemodynamics and clinical outcome in two groups of puppies. Sixteen puppies underwent 45 minutes of either HCA or low-flow CPB (25 mL.kg-1.min-1) after cooling to 13 degrees C. Methodology included radioactive microsphere determination of cerebral blood flow; calculation of cerebral oxygen extraction (arteriovenous oxygen content difference) and consumption; measurement of glucose consumption, and determination of cerebrovascular resistance. Measurements were obtained at baseline (37 degrees C), 13 degrees C, and 30 degrees C and at 2, 4, and 8 hours after HCA or low-flow CPB. No neurologic deficits were observed in any of the survivors (15/16). In both groups, cerebral metabolic rate of oxygen was maintained at baseline or greater levels postoperatively. Cerebrovascular resistance rose slightly in the low-flow CPB group postoperatively in contrast to a marked elevation in the HCA group. During the period of high cerebrovascular resistance after HCA, cerebral metabolic rate of oxygen was maintained by increased oxygen extraction. After low-flow CPB, oxygen extraction was not significantly different from baseline, presumably because of less severe changes in cerebrovascular resistance. Glucose metabolism followed the same trends as oxygen metabolism in both groups. These data suggest that after HCA there is a vulnerable interval, lasting as late as 8 hours postoperatively, in which cerebrovascular resistance remains high and cerebral metabolism is maintained primarily by high oxygen and glucose extraction. Any additional stress during this interval (a decrease in arterial oxygen content or perfusion pressure) could result in cerebral injury.

Quantitative electroencephalography: A method to assess cerebral injury after hypothermic circulatory arrest

Although hypothermic circulatory arrest and low-flow cardiopulmonary bypass are routinely used for surgical correction of congenital cardiac anomalies, use of long durations of arrest, often required for more complex repairs, raises serious concerns about cerebral safety. Searching for an intraoperative assessment that can reliably predict cerebral injury, we have found an excellent correlation between changes in quantitative electroencephalography intraoperatively and immediately postoperatively after prolonged hypothermic arrest, and neurologic and behavioral evidence of cerebral injury. After epidural placement of four recording electroencephalographic electrodes and baseline neurologic/behavioral and electroencephalographic assessment, 32 puppies were randomly assigned to one of four groups: hypothermic controls in which cooling to 18 degrees C was followed immediately by rewarming, 30 minutes of hypothermic circulatory arrest at 18 degrees C, 90 minutes of arrest at 18 degrees C, and 90 minutes of low-flow cardiopulmonary bypass at 25 ml/kg per minute at 18 degrees C. An electroencephalogram was recorded at baseline, after cooling, during rewarming, and at 2, 4, and 8 hours after the start of rewarming, as well as before the operation and 1 week after the operation. Postoperative neurologic and behavioral outcome was assessed 24 hours after cardiopulmonary bypass and daily for 1 week by means of a graded scale in which 0 is normal and 12 and 13 indicate severe neurologic injury (coma and death). Thirty animals survived the experimental protocol: two animals in the 90-minute hypothermic arrest group died before neurologic evaluation could be completed, and the remainder exhibited various degrees of neurologic and behavioral impairment, more severe on day 1 than on day 6. No animal in the remaining groups had a significant neurologic deficit. Quantitative electroencephalographic analysis shows marked differences between the 90-minute arrest group and the controls in the percent electroencephalographic silence during rewarming and at 2 hours, and in the percent recovery of baseline power at 2, 4, and 8 hours. At 2 hours after the start of rewarming, a correlation between electroencephalographic amplitude and neurologic/behavioral score on day 1 was carried out, which predicts with great certainty (p < 0.00001) that if electroencephalographic power at this time is less than 500 microV2, overt neurologic injury will subsequently become apparent. In addition, a significant shift from higher to lower frequency in the day 6 postoperative electroencephalogram compared with baseline occurs only in the 90-minute arrest group.(ABSTRACT TRUNCATED AT 400 WORDS)

Milrinone is superior to epinephrine as treatment of myocardial depression due to ropivacaine in pigs.

Purpose: To determine whether milrinone is more effective than epinephrine in the resuscitation of ropivacaine induced cardiotoxicity in pigs.Methods: Arterial, pulmonary, and LVdP/dt catheters were placed in 12 anesthetized, intubated and mechanically ventilated pigs. They received ropivacaineiv to cardiovascular toxicity: 50% decrease in LVdP/dt, cardiac output and mean arterial pressure (MAP). Group 1 (n=6) was treated with 100 µg·kg−1 milrinoneiv, and Group II (n=6) received 0.5 mg epinephrineiv. Resuscitation was successful if cardiac output returned to baseline, and MAP reached 80% of baseline.Results: After ropivacaine, MAP decreased from 88±7 to 49±8 mmHg (P<0.05), CO decreased from 2.8±0.4 to 1.2±0.2 L·min−1 (P<.05), HR decreased from 103±8 to 74±7 beats·min (P<0.05) and LVdp/dt decreased from 1950±130 to 755±125 mmHg (P<0.05). The LV EDP increased from 5±1 to 8±1 mmHg (P<0.05) and SVR from 2317 to 3000±120 dynes·sec−1·cm−5. Electrocardiogram changes included increases in the QTU interval and QRS duration. In all animals, milrinone restored MAP, CO, SV, HR, and dP/dt to baseline and no animal developed arrhythmias. In contrast, epinephrine produced severe hypertension and tachycardia. There was no improvement in CO or SV, and SVR increased. Epinephrine caused A-V dissociation and ventricular arrhythmias in three animals.Conclusion: Milrinone, was more successful than epinephrine in resuscitating anesthetized pigs from ropivacaine-induced cardiovascular toxicity.RésuméObjectif: Déterminer si la milrinone est plus efficace que l’épinéphrine au moment de réanimer des porcs victimes d’une cardiotoxicité induite par la ropivacaïne.Méthode: Des cathéters artériels, pulmonaires et ventriculaires gauches (dP/dtVG) ont été mis en place chez 12 porcs anesthésiés, intubés et sous ventilation mécanique. Ils ont reçu de la ropivacaïneiv qui a provoqué la cardiotoxicité manifestée par: une baisse de 50 % dP/dtVG, du débit cardiaque (DC) et de la pression artérielle moyenne (PAM). Le groupe I (n=6) a été traité avec 100µg·kg−1 de milrinoneiv et le groupe II (n=6) avec 0,5 mg d’épinéphrineiv. La réanimation était réussie lorsque le DC revenait aux valeurs de base et que la PAM atteignait 80 % des valeurs de base.Résultats: Après l’administration de la ropivacaïne, la PAM a chuté de 88±7 à 49±8 mmHg (P<0,05), le DC de 2,8±0,4 à 1,2±0,2 L·min−1 (P<0,05), la FC de 103±8 to 74±7 battements·min (P<0,05) et dP/dtVG de 1950±130 à 755±125 mmHg (P<0,05). La pression télédiastolique du VG a augmenté, passant de 5±1 à 8±1 mmHg (P<0,05) et la résistance vasculaire périphérique (RVP) de 2317 à 3000±120 dynes·s−1·cm−5. Les changements à l’électrocardiogramme comprenaient des augmentations de l’intervalle QTU et de la durée de QRS. Chez tous les animaux, la milrinone a ramené la PAM, le DC, le débit systolique (DS), la FC et dP/dt aux valeurs de base et aucun animal n’a présenté d’arythmie. Par ailleurs, l’épinéphrine a produit une sévère hypertension et de la tachycardie. Il n’y a pas eu d’amélioration du DC ou du DS et la RVP a augmenté. L’épinéphrine a aussi causé une dissociation AV et des arythmies ventriculaires chez trois animaux.Conclusion: La milrinone a été plus efficace que l’épinéphrine pour la réanimation de porcs anesthésiés qui ont subi une cardiotoxicité provoquée par de la ropivacaïne.

Cardiovascular consequences of the concomitant administration of nifedipine and magnesium sulfate in pigs.

There is concern regarding the interaction of magnesium sulfate and nifedipine used concomitantly in obstetrical patients, because both are calcium channel antagonists and may induce myocardial depression as well as peripheral vasodilatation. The objective of this study was to determine the hemodynamic consequences of concomitant administration of nifedipine and magnesium sulfate in anesthetized pigs. Twelve pigs were anesthetized with sodium pentobarbital, intubated mechanically ventilated. Following placement of invasive monitors, baseline hemodynamic measurements were made. Animals were randomized to one of two groups. Group I received nifedipine first, and then magnesium sulfate. Group II received magnesium sulfate first, and then nifedipine. Hemodynamic measurements were recorded. Hypotension was treated with calcium chloride, ephedrine and phenylephrine. Nifedipine alone (Group I) decreased peripheral vascular resistance and mean arterial pressure (MAP) (P<0.05). Magnesium sulfate alone in group II decreased the first derivative of left ventricular pressure (LVdP/dt) and increased left ventricular end-diastolic pressure (LVEDP) (P<0.05). Magnesium sulfate also decreased peripheral vascular resistance and MAP The concomitant administration of nifedipine and magnesium sulfate in both groups I and 11 led to a further decrease in myocardial contractility, as evidenced by a decrease in LVdP/dt and increase in LVEDP (P<0.05). Treatment with calcium chloride or ephedrine was only partially successful in improving myocardial contractility. Phenylephrine increased peripheral vascular resistance and MAP, but did not improve myocardial function. In conclusion, the depressive effects of nifedipine and magnesium sulfate on the cardiovascular system are potentiated when administered concomitantly.

EVALUATION OF ARTIFICIAL INTERFACES WITH IN VIVO SYSTEMS

There is universal agreement that the adverse reaction which occurs when blood comes in contact with foreign surfaces is the dominant cause of mortality and morbidity associated with prosthetic valve and vascular replacement or protracted mechanical cardiorespiratory support. Thus, during the past two decades major efforts have been made to discover inert, thromboresistant“biocompatib1e”-materials with durable and physiologically acceptable performance characteristics. Evaluation of potential cardiovascular implant materials in the intact animal remains a complex task, since our knowledge of factors associated with in vivo compatibility is so incomplete. The ideal study method would be performed in an environment that would accurately reproduce the clinical conditions demanded of the material, permit controlled perturbation of each of all known variables, and, finally, allow continuous analysis of biophysical and pathophysiologic events associated with or caused by the material. Presently, there is no testing method-in vitro, ex vivo or in vivo-that satisfies the criteria of the ideal study method. Discussion of the former two methods will be found elsewhere in this volume. It is the purpose of this communication to consider progress and problems with in vivo systems employed in evaluating artificial interfaces.

Role of zatebradine and propranolol in attenuation of tachycardia produced by dobutamine in pigs

Background: Zatebradine is a new specific bradycardic agent that selectively slows the depolarization in the pacemaker cells of the sinoatrial node. The purpose of our investigation was to determine whether the tachycardia induced by dobutamine can be attenuated by the administration of zatebradine. The results were compared with those produced by propranolol, which is used in the treatment of sinus tachycardia.

Diltiazem in the prevention and treatment of cocaine-induced cardiotoxicity in dogs

Abstract Cocaine can induce serious cardiovascular sequelae, including myocardial depression and coronary artery constriction. The objective of this study was to determine, in the experimental canine model, whether the calcium channel blocker diltiazem, administered intravenously, can ameliorate cocaine-induced cardiotoxicity. The study was conducted in two parts. In the first part of the study, the protective effect of diltiazem against cocaine-induced cardiotoxicity was evaluated. Dogs given pentobarbital were pretreated with either diltiazem 0.25 mg/kg or saline, and then given a 10-mg/kg intravenous bolus of cocaine. In the second part of the study, the role of diltiazem in the treatment of cocaine-induced left ventricular myocardial dysfunction was evaluated. All dogs received a 10-mg/kg intravenous bolus of cocaine. The dogs then received either diltiazem 0.25 mg/kg intravenously or saline. Administration or diltiazem before cocaine reduced the cardiotoxic effects of cocaine. Compared with the control group, there was less depression of the first derivative of left ventricular pressure (LV dP/dt), cardiac output, and left ventricular end diastolic pressure. ST segment elevation occurred in the majority of the control animals after cocaine injection but in none of the animals pretreated with diltiazem. In the second part of the study, cocaine produced left ventricular dysfunction in all animals and ST segment elevation on the electrocardiogram in a majority of the animals. Treatment with diltiazem after the onset of cocaine-induced myocardial dysfunction did reverse the ST segment elevation. It did not, however, improve the hemodynamics significantly compared with the control group. Partial recovery of left ventricular function occurred at 15 minutes in both groups. It was concluded that, in the canine model, administration of diltiazem before injection of cocaine prevents myocardial depression and ST segment elevation. Diltiazem is also effective as treatment to reverse cocaine-induced ST segment elevation but not cocaine-induced myocardial depression.