Ann Thorac Surg 1996;62:115-122
© 1996 The Society of Thoracic Surgeons
Original Articles: Cardiovascular
Influence of Age on Cerebral Recovery After Deep Hypothermic Circulatory Arrest in Piglets
Fumikazu Nomura, MD,
Joseph M. Forbess, MD,
Richard A. Jonas, MD,
Takeshi Hiramatsu, MD,
Adre J. du Plessis, MD,
Gene Walter, Reegt,
Michael E. Stromski, PhD,
David H. Holtzman, MD, PhD
Departments of Cardiac Surgery and Neurology, Children's Hospital, and Departments of Surgery and Neurology, Harvard Medical School, Boston, Massachusetts
Accepted for publication February 26, 1996.
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Abstract
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Background. In the first weeks of life there are important maturational changes in the central nervous system in many species in energy metabolism, synapse number, and concentration of neuronal excitatory receptors.
Methods. Four groups of 10 piglets (aged 1, 2, 4, and 10 weeks) underwent 1 hour of deep hypothermic circulatory arrest at 15°C, with cooling and rewarming on cardiopulmonary bypass. Cerebral blood flow and metabolic rate measurements and electroencephalographic recordings were obtained from 5 animals per group. The remaining animals underwent cerebral magnetic resonance spectroscopy.
Results. Preoperative cerebral blood flow and glucose consumption were higher at 4 and 10 weeks than at 1 and 2 weeks. Cerebral adenosine triphosphate content decreased more rapidly during deep hypothermic circulatory arrest at 4 and 10 weeks. Phosphocreatine recovery was greater at 30 minutes of reperfusion at 10 weeks compared with 1 week. Recovery of cerebral phosphocreatine/adenosine triphosphate ratio and intracellular pH was remarkably uniform at all ages. Latency to recovery of electroencephalographic activity decreased with increasing age (p = 0.04).
Conclusions. Differences in acute recovery of brain energy metabolism and electroencephalogram after cardiopulmonary bypass and 1 hour of deep hypothermic circulatory arrest in piglets between 1 and 10 weeks of age are small. Further studies are required to correlate these acute findings with subsequent neurologic outcome.
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Introduction
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Specific neurologic abnormalities in neonates and young infants after cardiac operations may be affected by maturational changes in the central nervous system. A recent prospective study comparing hypothermic circulatory arrest with continuous bypass in babies less than 3 months of age showed that older age increased the risk of seizures in the first 48 hours after circulatory arrest [1]. A retrospective analysis of children after cardiac operations showed choreoathetosis occurs predominantly in children who were between 9 months and 2 years of age at the time of operation but does not occur in children operated on during the neonatal period [2].
Maturational changes that have been defined in the central nervous system of the human and other altricial mammals in the first weeks and months of life include a rapid increase in the number of synapses, particularly in the first month of life, with a more gradual increase in the amount of insulating myelin during the first year [3]. Parallel to the increasing number of synapses is a rapid increase in specific receptors such as those for N-methyl-D-aspartate, which may play a role in synapse formation [4]. Brain energy metabolism has been demonstrated in some species to change importantly in the first few months of life. In the rat, for example, the rate of adenosine triphosphate (ATP) production increases in association with increased rates of aerobic glycolysis and creatine kinase activity, increased numbers of mitochondria, and increased mitochondrial enzymes [5, 6]. Maturational changes such as these may contribute to the apparent greater resistance of the neonate to a global cerebral ischemic insult relative to the adult.
To better understand the role of maturation in the pathogenesis of brain injury for the neonate or young infant undergoing cardiac operations, we have applied age as a variable in our piglet model of hypothermic circulatory arrest. We have previously demonstrated that cerebral blood flow and metabolic rate measurements are poor predictors of acute cerebral metabolic recovery [7]. Therefore, we have measured changes in cerebral high-energy phosphate concentrations and intracellular pH using phosphorus-31 magnetic resonance spectroscopy. Because seizures and electroencephalographic (EEG) recovery may be important age-related indicators of brain injury after circulatory arrest, the EEG was recorded throughout these experiments.
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Material and Methods
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Animals
Forty Yucatan miniature piglets (Charles River Laboratories, Wilmington, MA) were studied at the following ages: 1 week (n = 10; age = 7 to 9 days old; weight = 1.4 ± 0.2 kg [mean ± standard deviation], 2 weeks (n = 10; age = 14 to 16 days; weight = 2.0 ± 0.4 kg), 4 weeks (n = 10; age = 28 to 30 days; weight = 4.1 ± 0.7 kg), and 10 weeks (n = 10; age = 67 to 71 days; weight = 7.1 ± 1.3 kg). The animals were obtained 1 to 2 days before the study and fasted for 12 hours before operation. The studies were performed in compliance with the "Principles of Laboratory Animal Care" formulated for the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the National Academy of Science (NIH publication 86-23, revised 1985).
Surgical Preparation
Details of the surgical preparation and surgical protocol are given in Appendix 1. Details of blood flow measurement, metabolic measurements, and magnetic resonance spectroscopy have been described previously [7].
Electroencephalogram
Five platinum subdermal EEG electrodes (Grass Instrument Co, Quincy, MA) were applied with two frontal brain, one central brain, and two posterior brain regions. Bipolar linkages were recorded from the left and right hemispheres in the anteroposterior and transverse directions. In addition, referential recordings were made using the vertex electrode as a reference. One additional electrode placed in each of the front limbs recorded the electrocardiogram. Continuous recordings were made on a Grass Model 8 EEG instrument from after anesthesia induction to the end of cooling. Notes of time, temperature, blood pressure, and administration of drugs were made by an observer throughout the procedure.
Electroencephalograms were evaluated according to ongoing background activity at the time of initial recording (after induction recording). In addition, the presence or absence of "paroxysmal" activity was noted. Analysis was made according to the quantification of changes in frequency of EEG during cooling.
The latency to recovery of EEG activity was defined as the duration in minutes from the onset of rewarming to the point at which electrical activity of greater than 10 µV was clearly distinguishable from background noise and artifact and was sustained for longer than 3 seconds.
Experimental Design
In 20 piglets, 5 in each age group (1 week, 2 weeks, 4 weeks, and 10 weeks) cerebral metabolic rate determined by arteriovenous differences in oxygen and glucose, blood flow by radioactive microspheres, and EEG were studied. Measurements were made at the end of normothermic perfusion, at the end of cooling, and at 15 minutes, 45 minutes, and 225 minutes after reperfusion. Another set of 20 animals, also 5 from each age group, underwent the same surgical and bypass procedures and in addition underwent 31P magnetic resonance spectroscopy.
Statistics
All values are reported as mean ± standard deviation and were analyzed by means of a statistical analysis system (SPSS; SPSS Inc, Chicago, IL). Repeated-measures analysis of variance (ANOVA) and the Student-Neuman-Keuls test were used to detect differences between groups.
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Results
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There were no deaths in this acute study, which incorporates cardiopulmonary bypass support. The systemic flow calculated from the total radioactivity in each injection and the reference blood correlated well with the pump flow measured by the electromagnetic flowmeter (y = 0.98x + 22.1; r = 0.9871; p = 0.0001).
Experimental Conditions
There were no significant differences between the four groups in heart rate, arterial oxygen tension and carbon dioxide tension, and nasopharyngeal temperatures at baseline during normothermic cardiopulmonary bypass (Table 1
). Mean arterial pressure was greater at 4 and 10 weeks than in the 1- and 2-week-old animals. At 10 weeks arterial pressure was greater during cooling and after 45 minutes of reperfusion and continued to be high compared with the other groups. Nasopharyngeal temperature was approximately 15°C at the end of cooling and recovered to approximately 36°C after 45 minutes of reperfusion (Table 2). Rectal temperature decreased to approximately 20°C at the end of cooling, recovered to 34°C at 45 minutes of reperfusion, and then returned to 36°C in all groups (see Table 2).
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Table 1. . Baseline Measurements at Normothermia in Piglets of Varying Ages on Cardiopulmonary Bypass Before Deep Hypothermic Circulatory Arrest
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Table 2. . Heart Rate, Mean Arterial Pressure, Temperatures, and Electroencephalographic Parameters Before and After Deep Hypothermic Circulatory Arrest in Piglets of Varying Ages on Cardiopulmonary Bypassa
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Global and Regional Cerebral Blood Flow
Global cerebral blood flow at the normothermic baseline was greater in the older animals at 4 and 10 weeks compared with the two younger ages (ANOVA p = 0.001) (Fig 1). Regional cerebral blood flow analysis revealed a more rapid return of blood flow in all groups in the midbrain, basal ganglia, and brainstem but not in the cerebral hemispheres during early reperfusion. Although blood flow remained depressed after 45 minutes of reperfusion and rewarming in all groups, by 225 minutes cerebral blood flow had returned to baseline in all groups (Fig 2).
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Fig 1. . Global cerebral blood flow. (HT = hypothermic cardiopulmonary bypass; NT = normothermic cardiopulmonary bypass; RP(15) = 15 minutes after initiation of reperfusion and rewarming after 1 hour of total circulatory arrest; RP(45) = after 45 minutes of rewarming, when normothermia [nasopharyngeal temperature >35°C] was achieved; W = week; RP(225) = 225 minutes after reperfusion; *,#,$ = p < 0.05 versus 1 week, 2 weeks, and 4 weeks, respectively.)
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Fig 2. . Regional cerebral blood flow: (A) brainstem, (B) midbrain, (C) basal ganglia, (D) cerebellum, and (E) cerebral hemispheres. (HT = hypothermic cardiopulmonary bypass; NT = normothermic cardiopulmonary bypass; RP(15) = 15 minutes after initiation of reperfusion and rewarming after 1 hour of total circulatory arrest; RP(45) = after 45 minutes of rewarming, when normothermia [nasopharyngeal temperature >35°C] was achieved; W = week; RP(225) = 225 minutes after reperfusion; *,#,$ = p < 0.05 versus global 1-week, 2-week, and 4-week values, respectively.)
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Cerebral Oxygen and Glucose Consumption
The normothermic cerebral metabolic rates determined by oxygen consumption values were the same at all ages (Fig 3A). Cooling was associated with a decrease in oxygen consumption to approximately 20% of baseline. The oxygen consumption rate remained depressed after 45 minutes of reperfusion and reached baseline after 225 minutes of reperfusion. The precooling baseline was regained in all groups.
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Fig 3. . (A) Cerebral oxygen metabolism (CMR-O2). (B) Cerebral glucose metabolism (CMR-G). (HT = hypothermic cardiopulmonary bypass; NT = normothermic cardiopulmonary bypass; RP(15) = 15 minutes after initiation of reperfusion and rewarming after 1 hour of total circulatory arrest; RP(45) = after 45 minutes of rewarming, when normothermia [nasopharyngeal temperature >35°C] was achieved; RP(225) = 225 minutes after reperfusion; * = p < 0.05 for group difference by Newman-Keuls test versus the other groups.)
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Glucose consumption began at a higher baseline and did not decrease as much in the 4-week-old animals relative to all other groups with cooling (Fig 3B
) (ANOVA p = 0.02). The percent recovery of cerebral metabolic rate determined by glucose consumption was less for the 4-week-old group relative to all other groups because there were no differences among the groups at 225 minutes of reperfusion. The percent recovery of glucose consumption for all groups tended to be less than the recovery of oxygen consumption at 225 minutes of reperfusion.
Cerebral High-Energy Phosphates and Intracellular pH
The prebypass phosphocreatine (PCr)/ATP (inferred from ß-nucleoside triphosphate) ratio and intracellular pH and the recoveries of these values after circulatory arrest were remarkably uniform at all ages (Table 1; Fig 4). Initiation of normothermic cardiopulmonary bypass did not affect the concentrations of PCr or ATP or the intracellular pH. The ratio of PCr/ATP at baseline after 20 minutes on cardiopulmonary bypass tended to be greater at 4 and 10 weeks than at younger ages, although this difference did not reach statistical significance. Both ATP and PCr contents increased, and intracellular pH became more alkaline during cooling in all groups. The ATP signal decreased more rapidly after the onset of circulatory arrest at 4 and 10 weeks than at younger age (see Fig 4A). In contrast, there were no significant differences between groups in PCr and pH during circulatory arrest (see Fig 4B, 4C).
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Fig 4. . Cerebral high-energy phosphates and pH by nuclear magnetic resonance spectroscopy. (A) Adenosine triphosphate (ATP). (B) Phosphocreatine (PCr). (C) Intracellular pH (PHi). (CA = total circulatory arrest; HT = hypothermic cardiopulmonary bypass; NT = normothermic cardiopulmonary bypass; REP = reperfusion and rewarming with minutes in parentheses.)
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The mean recovery rate of ATP was the same for the four groups during 45 minutes of rewarming reperfusion and 3 hours of normothermic reperfusion bypass. Recovery of intracellular pH was more rapid during the first 60 minutes of reperfusion at 4 and 10 weeks (6.998 ± 0.094 and 7.032 ± 0.057 U/min) compared with 1 and 2 weeks (6.828 ± 0.191 and 6.970 ± 0.110 U/min) (ANOVA p = 0.08). Recovery of PCr was greater (p < 0.05) during the first 30 minutes of reperfusion at 10 weeks (73.6% ± 19.1%) compared with 1 week (32.2% ± 14.9%). The final recovery of ATP was the same at all ages, about 70% of the value before deep hypothermic circulatory arrest, with no significant differences between groups. The final intracellular pH values demonstrated no significant differences among groups. Final PCr recovery was greatest at 2 weeks (94.4% ± 21.5%) compared with the other groups (1 week, 70.3% ± 15.4%; 4 weeks, 66.2% ± 12.1%; 10 weeks, 59.3% ± 23.9%; ANOVA p = 0.027; p < 0.05 for 2 weeks versus 10 weeks).
Electroencephalogram
BACKGROUND AMPLITUDE.
At the onset of normothermic cardiopulmonary bypass there was a decrease in the mean amplitude (range, 15% to 30%) in all but the 1-week-old piglets. During hypothermia the EEG became isoelectric in all animals. There were no significant differences in amplitude among the groups before circulatory arrest. After reperfusion the percent recovery to baseline voltage showed greater recovery in the 1-week-old piglets than the older age groups (see Table 2).
PAROXYSMAL ACTIVITY.
During the cooling period a striking paroxysmal pattern was noted in all animals (Fig 5). At various points close to the onset of isoelectricity, brief bursts of generalized polyspike activity were noted in every animal studied. The pattern was sustained for 7 to 25 minutes. Neither the time of onset nor duration was different among the age groups. In more than half the animals this paroxysmal pattern persisted until after the onset of circulatory arrest. At no other phase of this acute experiment did such repetitive paroxysmal activity or any suggestion of seizure activity occur.
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Fig 5. . (A) Baseline electroencephalogram before cardiopulmonary bypass. (B) Striking paroxysmal pattern noted on the electroencephalogram during the cooling period in all animals, irrespective of age. (EKG = electrocardiogram.)
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ELECTROENCEPHALOGRAM REAPPEARANCE LATENCY.
In no animal did EEG activity reappear during the circulatory arrest phase. The mean latency to recovery of EEG activity after the onset of reperfusion decreased with increasing age of the animals: 1 week, 92 ± 40 minutes; 2 week, 67 ± 15 minutes; and 10 week, 34 ± 15 minutes (one-way ANOVA p = 0.04). However, in the 4-week-old group, only 2 of the 4 animals recovered any recognizable electrocortical activity, occurring at 115 and 158 minutes. The remaining 2 animals showing persistent isoelectricity in all areas. If the 4-week-old animals are included in the ANOVA, the significance of the difference among the age groups increases to p = 0.006. In none of the groups did the group mean background amplitude at 180 minutes of normothermic reperfusion recover to the onset of normothermia voltage, the ratio of recovery ranging from 71% in the 1-week-old piglets to 11% in the 4-week-old piglets.
Body Weight Gain
Body weight gain was 37.6% ± 8.5% in 1-week-old animals, 42.6% ± 11.9% in 2-week-old animals, 38.6% ± 14.8% in 4-week-old animals, and 49.1% ± 18.3% in 10-week-old animals (p = 0.20).
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Comment
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The age-dependent differences in acute recovery of brain energy metabolism after cardiopulmonary bypass and deep hypothermic circulatory arrest in piglets between 1 and 10 weeks of age are small. This study has confirmed that older piglets have greater mean arterial blood pressure, global cerebral blood flow, and cerebral metabolic rates determined by glucose consumption than younger piglets. Loss of cerebral ATP is more rapid during circulatory arrest in older animals and recovery of cerebral intracellular pH in the first 60 minutes of reperfusion is more rapid. The recovery of phosphocreatine in the first 30 minutes of reperfusion is greater in 10-week-old animals than younger animals, although the final recovery of phosphocreatine is greater in 2-week-old animals. Latency to EEG recovery is shorter with increasing age.
In view of known maturational changes in energy metabolism and synapse density in many species, we anticipated that this study would demonstrate more pronounced differences in acute recovery from 1 hour of deep hypothermic circulatory arrest in young piglets of various ages. Presumably the protective effects of hypothermia are equally effective at different ages. Thus the protection afforded by a profound level of hypothermia during a 1-hour period of circulatory arrest may have been sufficient to mask metabolic differences that are in effect with normothermic metabolism. This finding has important implications regarding the pathogenesis of age-dependent differences in cerebral morbidity, which we have demonstrated in a clinical study that compared circulatory arrest and continuous hypothermic bypass [1]. One of the principal findings of that study was that seizures were more likely to occur in the first 24 to 48 hours postoperatively in neonates who underwent approximately 1 hour of circulatory arrest, particularly in slightly older patients. A lack of age-dependent differences in recovery in the first 3 to 4 hours after circulatory arrest as demonstrated by this animal study supports the concept of an important role for delayed mechanisms of cerebral injury such as excitotoxicity [8]. These questions are important because psychomotor delay 1 year postoperatively in children was predicted by the occurrence of seizures occurring 24 to 48 hours postoperatively rather than being predicted by intraoperative or very early postoperative variables other than the use of circulatory arrest per se [9].
In contrast to the traditional end points of blood flow and oxygen consumption, we have found that magnetic resonance spectroscopy is a sensitive measure of cerebral energetics during and after circulatory arrest [7]. However, in this study magnetic resonance spectroscopic differences among animals of different ages were subtle. A more rapid decline in phosphocreatine level was anticipated in older animals during circulatory arrest because of the age-dependent greater activity of creatine kinase [5]. We observed no differences in the rate of decline of phosphocreatine level, although ATP content declined more rapidly in older animals, consistent with the higher ATPase activities in the more mature brain. As anticipated there was a more rapid recovery of phosphocreatine content in older animals during reperfusion, presumably secondary to greater activity of creatine phosphokinase. These maturational differences might have been greater if piglets less than 3 to 4 days of age were used [10].
The EEG findings of the study are intriguing, although their significance remains unclear. Although it is possible that the anesthetic agent used for induction may have influenced the EEG recordings, nevertheless it was our observation that the effects of this dose given intraperitoneally in the pig were extremely transient, lasting at most 10 minutes. In general there was a period of approximately 2 to 3 hours between the induction of anesthesia and collection of the baseline EEG. Paroxysmal EEG activity was not observed in baseline EEGs but was observed during the later stages of cooling when even less methohexital would have been available to influence the EEG. Levy [11] described a burst-suppression pattern during hypothermic bypass, particularly in the presence of certain anesthetics including fentanyl, as was used in this study. The absence of paroxysmal activity in the reperfusion phase is consistent with our clinical findings, where seizure activity was generally observed 24 to 48 hours after circulatory arrest and was rare in the first 3 to 4 hours of reperfusion [1]. The latency to EEG recovery increased with increasing age. In our clinical study of circulatory arrest, greater duration of circulatory arrest was associated with a longer latency time to EEG recovery [1]. In that study, there was a tendency for neurodevelopmental outcome to be worse at age 1 year when there was longer latency time to EEG recovery perioperatively.
In conclusion, this study has demonstrated that there are age-dependent differences in cerebral blood flow and metabolism in young piglets. However, the differences in acute recovery after 1 hour of hypothermic circulatory arrest at a nasopharyngeal temperature of 15°C are less pronounced than might be anticipated from the differences known to exist at normothermia and demonstrated over a longer period of observation in a parallel clinical study. These differences between acute and longer term outcome could be explained by species differences in maturation early in life or by inadequate study numbers to achieve appropriate statistical power to identify subtle differences. On the other hand, these findings may carry important implications regarding the predominant mechanisms of cerebral injury after deep hypothermic circulatory arrest with subsequent potential therapeutic implications. There is a need for a survival animal model that would allow correlation of acute metabolic and blood flow changes with subsequent neurologic and histologic outcome.
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Appendix 1. Method Details
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Surgical Preparation
The animals were anesthetized with an intraperitoneal injection of methohexital (40 mg/kg), and after intubation were ventilated with 100% O2 at a tidal volume and a respiratory rate that produced an arterial carbon dioxide tension of 35 to 45 mm Hg. Venous and arterial catheters were inserted through the surgically exposed right femoral vein and artery into thoracic inferior vena cava and aorta, respectively. After an intravenous injection of 30 µg/kg of fentanyl and 0.3 mg/kg of pancuronium, anesthesia was maintained with continuous infusion of fentanyl (25 µg•kg-1•h-1) and pancuronium (0.1 (mg•kg-1•h-1). The electrocardiogram and arterial and venous pressures were monitored continuously. Temperature was monitored throughout the study by rectal and nasopharyngeal temperature probes. Temperature greater than 35°C was maintained before cardiopulmonary bypass by means of a heating lamp. A catheter was inserted in the bladder to measure urine output.
The heart was exposed through a median sternotomy. Pericardial traction sutures were avoided in order not to compromise venous drainage. A 16- to 20-gauge sampling catheter was inserted into the right internal jugular vein retrogradely to the level of the jugular bulb. The piglet was fully heparinized (300 IU/kg). Cannulas were inserted through pursestring sutures into the ascending aorta and into the right atrial appendage and were connected to the bypass circuit. The pump-oxygenator system consisted of a roller pump and a Bio-2 (for 1-, 2-, and 4-week-old animals) or Bentley-5 (for 10-week-old animals) infant bubble oxygenator (Bentley Laboratories Inc, Irvine, CA). The venous drainage was accomplished by gravity. No arterial filter was used. After systemic heparinization, shed blood in the operating field was returned to the system through a 20-µm transfusion filter. An electromagnetic flow probe (FF-060T; Nihon Kohden, Irvine, CA) was placed in the arterial perfusion circuit to measure the pump flow. The pump-oxygenator system was primed with 400 mL (for 1-, 2-, or 4-week-old piglets) or 600 mL (for 10-week-old piglets) of homologous blood collected 2 days before the study (Charles River Laboratories, Wilmington, MA) plus 180 to 450 mL of Normosol R pH 7.4 (Abbott Laboratories, North Chicago, IL) to a final hematocrit of 20% to 25%. Methylprednisolone, 30 mg/kg; cephazolin sodium, 25 mg/kg; and NaHCO3 to achieve a pH of 7.4 were added to the prime. Normosol R pH 7.4 heparinized with 2,500 IU/L was used when there was a decrease in reservoir volume during cardiopulmonary bypass. Temperature of the perfusate was controlled by the heat exchanger within the oxygenator and a water bath system warmed by a thermostat-controlled heater-circulator. During the cooling phase, the blood was cooled by circulating ice water.
Perfusion Protocol
Bypass flow was set at 150 mL•kg-1•min-1 calibrated at a perfusate temperature of 37°C. Cooling of the perfusate resulted in 15% to 20% decrease in pump flow, which was not adjusted. During hypothermic perfusion, pH was maintained at 7.40 corrected to hypothermic body temperature (pH stat) by adjusting the flow of 95% oxygen and 5% carbon dioxide to the oxygenator. The piglet was perfused for 20 minutes at normothermia (37°C arterial temperature) to stabilize body temperature. Then, the perfusate was cooled to an arterial temperature of 14°C maintaining a temperature gradient of less than 10°C between blood and nasopharyngeal temperature. Ventilation was stopped at the initiation of cooling and the ventilator was disconnected. Ice packs were placed around the head throughout the cooling period and circulatory arrest periods. After 30 minutes of perfusion cooling, when nasopharyngeal temperature was 14.0° to 15.0°C, perfusion was stopped for 1 hour. The animal was exsanguinated through the venous drainage line for 2 minutes, and then the arterial and venous lines were clamped. No cardioplegic solution was given. A bolus of 0.2 mg/kg of phentolamine was given at the beginning of the cooling period. Reperfusion was begun at 150 mL•kg-1•min-1 with the perfusate at room temperature (20° to 25°C) initially and then rewarmed to 37°C by circulating warm water through the heat exchanger in the oxygenator. When normothermia was achieved and reperfusion had been in progress for 45 minutes, ventilation was restarted. Pump perfusion was continued for 3 more hours with the perfusate temperature at 37°C. During this 3-hour period of perfusion, pulsatile assistance was achieved by raising central venous pressure minimally (<5 mm Hg). At the end of each study the animal was euthanized by a bolus injection of Beuthanasia (Schering, Kenilworth, NJ) and KCl into the circuit.
Another set of 20 animals underwent the same surgical procedure and cardiopulmonary bypass as described above and in addition underwent phosphorus-31 magnetic resonance spectroscopy in an Oxford horizontal-bore superconducting 4.7-Tesla magnet, as described previously in detail [7]. A 3.0-cm-diameter surface coil, which was matched and tuned to the phosphorous frequency, was sutured on the scalp overlying the cerebral hemispheres. Arterial and venous lines were inserted for blood gas measurement and drug infusion, but no instrumentation for metabolic or blood flow measurements was made. All ferromagnetic surgical instruments were removed or replaced with plastic equivalents before the animal was placed in the magnet.
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Acknowledgments
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We thank Mark A. Cioffi for his technical assistance and Laura Young for preparation of the manuscript. All experiments were performed at the Enders Laboratory (Children's Hospital, Boston, MA) and the Francis Bitter Magnet Laboratory, Massachusetts Institute of Technology, Cambridge, MA. This work was funded by an NIH resource grant (RR 00995) and the Research Fund of the Department of Cardiac Surgery (Children's Hospital).
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Footnotes
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Address reprint requests to Dr Jonas, Department of Cardiac Surgery, Children's Hospital, 300 Longwood Ave, Boston, MA 02115.
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References
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- Newburger JW, Jonas RA, Wernovsky G, et al. A comparison of the perioperative neurologic effects of hypothermic circulatory arrest versus low flow cardiopulmonary bypass in infant heart surgery. N Engl J Med 1993;329:1057–64.[Abstract/Free Full Text]
- Wong PC, Jonas RA, Barlow CF, et al. Factors associated with choreoathetosis after cardiopulmonary bypass in children with congenital heart disease. Circulation 1992;86(Suppl 2):118–26.
- McDonald JW, Trescher WH, Johnston MV. Susceptibility of brain to AMPA induced excitotoxicity transiently peaks during early postnatal development. Brain Res 1992;583: 54–70.[Medline]
- Greenamyre JT, Penney JB, Young AB, et al. Evidence for transient perinatal glutamatergic innervation of globus pallidus. J Neurosci 1987;7:1022–30.[Abstract]
- Holtzman D, McFarland EW, Jacobs D, Offutt MC, Neuringer LJ. Maturational increase in mouse brain creatine kinase reaction rates shown by phosphorus magnetic resonance. Dev Brain Res 1991;58:181–8.[Medline]
- Holtzman D, Olson J, Zamvil S, Nguyen H. Maturation of potassium stimulated respiration in rat cerebral cortex slices. J Neurochem 1982;39:274–6.[Medline]
- Kawata H, Fackler JC, Aoki M, et al. Recovery of cerebral blood flow and energy state after hypothermic circulatory arrest versus low flow bypass in piglets. J Thorac Cardiovasc Surg 1993;106:671–85.[Abstract]
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- Bellinger DC, Jonas RA, Rappaport LA, et al. Developmental and neurologic status of children after heart surgery with hypothermic circulatory arrest or low-flow cardiopulmonary bypass. N Engl J Med 1995;332:549–55.[Abstract/Free Full Text]
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Abstract
Introduction
