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J Thorac Cardiovasc Surg 1994;107:1006-1019
© 1994 Mosby, Inc.
CARDIOPULMONARY BYPASS, |
New York, N.Y.
Supported by grant HL-45636-02 from the National Heart, Lung, and Blood Institute and in part by the Cardiothoracic Research Fund, Mount Sinai Medical Center, New York, N.Y.
Address for reprints: Craig Mezrow, MS, Department of Cardiothoracic Surgery, Mount Sinai Medical Center, P.O. Box 1028, New York, NY 10029.
Abstract
Although widely used for repair of complex cardiovascular pathologic conditions, long intervals of hypothermic circulatory arrest and low flow cardiopulmonary bypass may both result in cerebral injury. This study examines cerebral hemodynamics, metabolism, and electrical activity to evaluate the risks of cerebral injury after 60 minutes of hypothermic circulatory arrest at 8° C, 13° C, and 18° C, compared with 60 minutes of low flow cardiopulmonary bypass at 18° C. Thirty-two puppies were randomly assigned to one of four experimental groups and centrally cooled to the appropriate temperature. Serial evaluations of quantitative electroencephalography, radioactive microsphere determinations of cerebral blood flow, calculations of cerebral oxygen consumption, cerebral glucose consumption, cerebral vascular resistance, cerebral oxygen extraction, systemic oxygen metabolism, and systemic vascular resistance were done. Measurements were obtained at baseline (37° C), at the end of cooling, at 30° C during rewarming, and at 2, 4, and 8 hours after hypothermic circulatory arrest or low flow cardiopulmonary bypass. At the end of cooling, cerebral vascular resistance remained at baseline levels in all groups, but systemic vascular resistance was increased in all groups. Cerebral oxygen consumption became progressively lower as temperature was reduced: it was only 5% of baseline at 8° C; 20% at 13° C; and 34% and 39% at 18° C. Quantitative electroencephalography was silent in the 8° C and 13° C groups, but significant slow wave activity was present at 18° C. Systemic vascular resistance and cerebral oxygen consumption returned to baseline values in all groups by 2 hours after hypothermic circulatory arrest or low flow cardiopulmonary bypass, but cerebral vascular resistance remained elevated at 2 and 4 hours, not returning to baseline until 8 hours after hypothermic circulatory arrest or low flow cardiopulmonary bypass. All but two of the long-term survivors (27 of 32) appeared neurologically normal; after hypothermic circulatory arrest at 8° and 18° C two animals had an unsteady gait. Comparison of quantitative electroencephalography before operation and 6 days after operation showed a significant increase in slow wave activity (delta activity) after hypothermic circulatory arrest and low flow cardiopulmonary bypass at 18° C, a change that suggests possible cerebral injury. Although undetected after operation by simple behavioral and neurologic assessment, significant differences in cerebral metabolism, vasomotor responses, and quantitative electroencephalography do exist during and after hypothermic circulatory arrest and low flow cardiopulmonary bypass at various temperatures and may be implicated in the occurrence of cerebral injury. The data from this study suggest that for an interval of 60 minutes, hypothermic circulatory arrest at 8° C or 13° C may provide cerebral protection superior to hypothermic circulatory arrest or low flow cardiopulmonary bypass at 18° C. (J THORACCARDIOVASCSURG1994;107:1006-19)
Use of hypothermic circulatory arrest has become common practice for the surgical repair of certain congenital and acquired cardiovascular lesions. The rationale for the use of hypothermia is that it reduces metabolic demands and thereby protects organs from ischemia. The brain is the organ most sensitive to ischemic damage, so cerebral tolerance is the limiting factor with regard to duration of hypothermic circulatory arrest. On the basis of a variety of clinical and animal studies, there has emerged a general consensus that when hypothermic circulatory arrest exceeds 60 minutes there is considerable risk of at least subtle cerebral injury. In the studies that suggest that cerebral injury may occur after prolonged hypothermia, however, hypothermic circulatory arrest was done with a spectrum of hypothermic temperatures, leaving considerable uncertainty as to the best temperature for maximizing cerebral protection during hypothermic circulatory arrest.
This study was undertaken to ascertain which of several levels of hypothermia provides optimal cerebral protection during hypothermic circulatory arrest. To include regimens of clinical interest, we compared the effects of 60 minutes of hypothermic circulatory arrest at 8° C, 13° C, and 18° C with one another and with low-flow cardiopulmonary bypass (CPB) at 18° C, inasmuch as low-flow CPB is a frequent clinical alternative and adjunct to hypothermic circulatory arrest.
The experiments were done in weanling beagle puppies, in which intraoperative and postoperative assessments of cerebral blood flow (CBF), metabolism, vascular resistance, and quantitative electroencephalography (EEG) could be correlated with systematic preoperative and postoperative assessments of neurologic and behavioral status. The usefulness of increases in slow wave frequencies (delta activity) on quantitative EEG analysis as a measure of cerebral injury has been established by other investigators in a variety of circumstances, and previous studies in our laboratory have established the feasibility of obtaining quantitative EEG records on awake puppies by means of telemetry. 
1-3
This experimental model allows us to assess both clinically evident neurologic injury by means of postoperative examination and more subtle neurologic damage by quantitative EEG analysis in the same animals in whom we can also measure cerebral metabolism and CBF before, during, and after hypothermia. Our experimental model puts us in a unique position not only to evaluate the cerebral consequences of hypothermia, but also to investigate their possible mechanisms.
MATERIALS AND METHODS
Thirty-two weanling beagles (Marshall Farms, North Rose, N.Y.), 3 months of age, weighing 3.5 to 5 kg, were randomly assigned to undergo 60 minutes of one of the following: hypothermic circulatory arrest at 8° C, 13° or 18° C or low flow cardiopulmonary bypass at 18° C. Each animal underwent epidural electrode placement, intraoperative measurements/monitoring, preoperative and postoperative telemetric EEG monitoring, and neurologic/behavioral assessment.
Perioperative management
All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH Publication No. 88-23, revised 1985). The protocol for these experiments was approved by the Mount Sinai Institutional Animal Care and Use Committee.
Day 1: Epidural electrode implantation
After anesthesia was induced with ketamine (20 mg/kg) and diazepam (Valium; 1 mg/kg), animals were intubated and maintained on positive pressure ventilation with halothane anesthesia. A midline scalp incision was made and the underlying periosteum removed to facilitate identification of the coronal and sagittal sutures. Four recording electrodes (left and right frontal and parietal) were positioned epidurally and cemented (Durelon cement, ESPE-Premier, Norristown, Pa.) in 2 mm burr-drilled holes. Electrodes were implanted 1.5 cm to the left and to the right of the sagittal suture directly behind the coronal suture, and 1.5 cm caudal to the first electrode on each side. The leads from the electrodes were passed subcutaneously, externalized, and sutured to the dorsum of the neck.
Day 5: Preoperative EEG recording
After the animals had been permitted to recover from procedures done on day 1, two 10-minute sessions of "awake" EEG were acquired in a darkened room. This was done via telemetry (Telefactor Corp., West Conshohocken, Pa.) and transmitted to a Spectrum 32 EEG machine (Cadwell Laboratories, Kennewick, Wash.) where it was further amplified, filtered, digitized, and stored for subsequent analysis.
Day 6: Preoperative neurologic and behavioral evaluation
Puppies were examined preoperatively for evaluation of behavioral and neurologic deficits before hypothermic circulatory arrest or low flow cardiopulmonary bypass. They were evaluated by a veterinarian unaware of the experimental design to determine whether behavioral abnormalities were present, using a list of specific categories including mental status, appetite, and affect. Each animal also underwent neurologic examination including evaluation of gait, reflexes, and cranial nerve responses.
Day 7: Hypothermic circulatory arrest and low flow cardiopulmonary bypass protocol with intraoperative measurements
Anesthesia.
Animals were pretreated with glycopyrrolate (0.025 mg/kg), anesthetized with fentanyl (25 to 50 µg/kg per hour), and isoflurane (less than 1%), and intubated. They were maintained on positive-pressure ventilation (inspired oxygen fraction greater than 40%; arterial carbon dioxide tension 35 to 40 mm Hg) and paralyzed with pancuronium (0.1 mg/kg). Temperature probes were placed in the esophagus and rectum. Femoral artery and vein cannulations were done for monitoring purposes and a thermodilution catheter (93-132-5F, Baxter Healthcare Corp., Irvine, Calif.) was passed into the pulmonary artery.
Sagittal sinus cannulation.
Sagittal sinus cannulation was done before cannulation for CPB as previously described. 4
CPB, cooling, and rewarming.
After heparinization (300 IU/kg), nonpulsatile CPB was instituted with the use of a single cannula in the right atrium with return of the arterial perfusate to the ascending aorta. Surface cooling was achieved with the use of both a cooling blanket and ice packs around the head. Membrane oxygenators (VPCML plus, Cobe Laboratories, Inc., Lakewood, Colo.) were primed with a hemodilute solution containing homologous blood (universal donor), 5% albumin solution, furosemide (1 mg/kg), heparin (2000 IU), 1% dextrose in 0.9% saline solution, and potassium chloride (1 mEq/kg).
CPB was established at 100 ml/kg per minute, and hematocrit value was maintained between 22% and 28%. With use of the principles of 
-stat management, pH during cooling was maintained at 7.4 ± 0.05 and arterial carbon dioxide tension at 35 to 40 mm Hg, uncorrected for temperature. CPB flow was reduced to 50 ml/kg per minute at an esophageal temperature of 20° C and cooling was done to an esophageal temperature of 18°, 13°, or 8° C.
Circulatory arrest was then established in animals assigned to hypothermic circulatory arrest. In animals assigned to low flow cardiopulmonary bypass at 18° C, low-flow CPB was conducted at a rate of 25 ml/kg per minute. After hypothermic circulatory arrest or low flow cardiopulmonary bypass, perfusion/surface rewarming was done (CPB at 75 to 100 ml/kg per minute for 35 to 45 minutes) to an esophageal temperature of higher than 36° C and the animals were then weaned from CPB.
Cerebral and systemic blood flow and metabolism.
CBF was measured with radionuclide-labeled microspheres as originally described by Rudolph and Heymann 5 and as described by us in this model previously. 4
After postoperative neurologic and behavioral evaluation, the animals were anesthetized and killed with sodium pentobarbital (30 mg/kg) and potassium chloride (6 mEq/kg). In all animals (including those that died after the operation), each brain was removed and weighed, and radionuclide determination was made with a gamma counter (Auto-Gamma, Packard Instrument Co., Downers Grove, Ill.). Analyses were done by computer solution of multiple simultaneous linear equations (Compusphere, Packard Instrument Co., Inc., La Grange, Ill.).
Cerebral vascular resistance (CVR) was calculated by the equation CVR (mm Hg/ml/100 gm/min) = (MAP - MSSP)/CBF, where MAP is mean arterial pressure and MSSP is mean sagittal sinus pressure.
Sagittal sinus and arterial samples were obtained simultaneously for calculation of both cerebral oxygen extraction (arteriovenous oxygen content difference) and glucose extraction (arteriovenous glucose difference) and metabolic rates calculated combining these values with CBF. 4
Systemic metabolism and vascular resistance were derived from pulmonary artery samples and cardiac outputs determined by thermodilution.
Intraoperative EEG monitoring.
At the end of CPB cooling, immediately before hypothermic circulatory arrest or low flow cardiopulmonary bypass, a 3-minute session of EEG was acquired (without the use of telemetry) in all animals and stored for subsequent analysis.
Study protocol.
Measurements of CBF, cerebral vascular resistance, systemic vascular resistance, cerebral oxygen consumption, cerebral glucose consumption, and systemic oxygen metabolism were made at six time points during the experiments: (1) at baseline, at 37° C before CPB; (2) after cooling, immediately before hypothermic circulatory arrest or low flow cardiopulmonary bypass; (3) during rewarming at 30° C (approximately 15 minutes after the end of hypothermic circulatory arrest or low flow cardiopulmonary bypass); (4) 2 hours after the end of hypothermic circulatory arrest or low flow cardiopulmonary bypass (after termination of CPB, at 37° C, with closed thorax); (5) 4 hours after the end of hypothermic circulatory arrest or low flow cardiopulmonary bypass; and (6) 8 hours after the end of hypothermic circulatory arrest or low flow cardiopulmonary bypass.
Day 13: Postoperative EEG monitoring
The methods used were the same as those described under preoperative EEG monitoring.
Days 8 to 14: Postoperative behavioral and neurologic assessment
The methods used were the same as those for preoperative assessment.
EEG analysis
Spectral analysis was done on 50 seconds of artifact-free EEG for each of the recording electrodes. The EEG power was calculated as four distinct bands: delta (1.5 to 3.0 Hz), theta (3.0 to 8.0 Hz), (8.0 to 13 Hz), and ß (13 to 20 Hz). Analysis was done on the basis of changes in the spectral bands preoperatively versus postoperatively and intraoperatively.
Statistical analysis
All results are expressed as the mean ± standard error. A p value less than 0.05 was accepted as statistically significant as determined by analysis of variance for metabolic data and by Wilcoxon signed rank test for EEG data.
RESULTS
Morbidity and mortality
All animals were hemodynamically stable during the time all intraoperative measurements were made without the use of vasoactive or inotropic agents, so all animals were included in the analysis.
After operation, 27 of the 32 animal survived and were evaluated for neurologic and behavioral deficits for 7 days. No apparent neurologic or behavioral deficits were present in any of the survivors with the exception of two animals with an unsteady gait: one underwent hypothermic circulatory arrest at 8° C and the other at 18° C.
In this series of 32 animals there were five postoperative deaths. Two deaths occurred in animals that had undergone hypothermic circulatory arrest at 8° C and 18° C. The deaths occurred approximately 12 hours after extubation and were attributed to noncardiogenic pulmonary congestion. Three animals, one that had undergone hypothermic circulatory arrest at 8° C and two that had undergone hypothermic circulatory arrest at 13° C, were killed because of respiratory dysfunction attributed to phrenic nerve paralysis. None of the postoperative deaths was a consequence of cerebral injury.
Independent variables
Comparison of animal weights and CPB times are displayed in Table I. There were no differences among the four animal groups investigated.
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Table II displays the physiologic variables monitored during the six time points at which CBF, metabolism, and vascular resistance data were obtained. Similar values for temperature, mean arterial pressure, arterial PH, arterial oxygen and carbon dioxide tension, and hematocrit value were obtained for each group at the time of each data collection.
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Table III. Similar values for all experimental groups were observed for each time point.
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Table IV displays CBF and vascular resistance data for the four experimental groups. CBF decreased with CPB cooling to 8° and 13° C, whereas it was maintained at baseline levels at 18° C. Somewhat lower mean arterial pressures at the end of the cooling interval were observed in animals cooled to 8° and 13° C compared with those in animals cooled to 18° C.
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During CPB rewarming after 60 minutes of hypothermic circulatory arrest (at 30° C), all animal groups had cerebral hyperperfusion: CBF significantly higher than baseline levels in the presence of cerebral vascular resistance significantly below baseline. This was followed by an interval of low CBF and high cerebral vascular resistance that did not return to baseline levels until 8 hours after hypothermic circulatory arrest. After low flow cardiopulmonary bypass, changes in CBF were similar but less pronounced than after hypothermic circulatory arrest: CBF was maintained at baseline values until 4 hours after low flow cardiopulmonary bypass, at which time it fell significantly, returning to normal values by 8 hours. It should be noted (
Table III) that cardiac output in all groups returned promptly to baseline levels after hypothermia and remained at these levels throughout postoperative surveillance.
Oxygen metabolism
Table V depicts oxygen metabolism data. As expected, cerebral oxygen consumption decreased with temperature: at 8° and 13° C there were approximately 92% and 81% reductions in cerebral metabolic rate of oxygen compared with 63% and 62% reductions after CPB cooling to 18° C before hypothermic circulatory arrest and low flow cardiopulmonary bypass. Oxygen consumption returned to levels not significantly different from baseline by 2 hours after CPB in all groups.
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Cerebral venous and mixed venous oxygen saturation data are displayed in Table VI. Two and 4 hours after hypothermic circulatory arrest, sagittal sinus oxygen saturations decreased to levels as low as 31% in all groups, compared with relatively small changes in mixed venous saturations.
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Less pronounced changes in cerebral oxygen extraction were observed after low flow cardiopulmonary bypass than after hypothermic circulatory arrest. At 18° C, systemic oxygen extraction showed a more prolonged increase after operation in the hypothermic circulatory arrest group, which suggests that use of low flow cardiopulmonary bypass leads to an earlier normalization of the metabolic situation after operation than use of hypothermic circulatory arrest.
Cerebral glucose metabolism
Cerebral glucose metabolism data followed the same trends as those for oxygen metabolism; metabolism was depressed to a greater degree with cooling to 8° C and 13° C than at 18° C. At 2 and 4 hours after hypothermic circulatory arrest, during the previously noted interval of cerebral hypoperfusion and increased cerebral vascular resistance, glucose extraction, like oxygen extraction, was increased to maintain glucose consumption at baseline levels.
Ratio of CBF to cerebral oxygen consumption
The ratio of CBF to cerebral oxygen consumption, as shown in Fig. 1, yields information with regard to the appropriateness of cerebral perfusion. If one assumes that the ratio of CBF to cerebral oxygen consumption at baseline, when autoregulation is intact, represents an ideal value, then an increase in the ratio, such as occurred during hypothermia in all groups, suggests a period of so-called "luxury perfusion": CBF in excess of what is required by metabolic demands. A decrease in the ratio, such as that which occurred at 2 and 4 hours after hypothermic circulatory arrest, suggests suboptimal CBF. Very low values raise the possibility that flow may become rate-limiting with regard to cerebral metabolism.
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The outcome of our experiments with different temperatures and hypothermic techniques, in which there was low mortality and morbidity and a very low incidence of obvious cerebral injury, suggests that all of the techniques investigated are reasonably safe, a conclusion bolstered by clinical results using the same strategies. In this series of experiments, three puppies could not be extubated because of phrenic nerve injury after hypothermic circulatory arrest: although the neurologic outcome in these puppies could not be evaluated, neither these deaths nor the two that occurred as a result of noncardiogenic pulmonary congestion were associated with any obvious cerebral injury. The two animals who had an unsteady gait after hypothermic circulatory arrest at 8° and 18° C might have recovered fully given more time. Thus the neurologic/behavioral results of this study suggest no cause for concern about cerebral injury after hypothermic circulatory arrest at 8°, 13°, or 18° C for 60 minutes or low flow cardiopulmonary bypass for 60 minutes at 18° C.
Nevertheless, several clinical studies that evaluated the long-term cerebral functioning of infants who underwent repair of congenital heart lesions in infancy have suggested that subtle neurologic impairment may be occurring in some of these children despite apparently normal neurologic functioning immediately after operation. These longer-term, more subtle cerebral consequences of operation in infancy with hypothermia have been hard to study because it is difficult to document unequivocally the presence of any impairment in cognitive function in children who underwent cardiac operation in infancy and even harder to prove that such deficits, when they exist, are attributable to the use of deep hypothermia. Many confounding variables are present in these children: differences in genetic intellectual endowment; differences in socioeconomic influences on learning; and differences in the age of the patients, timing of operation, perioperative course, and the type and severity of the congenital heart defects for which operation was undertaken.
The impossibility, in a clinical study, of eliminating or even controlling for many of the confounding variables that impinge on cerebral outcome led us to develop the animal model used for the current investigation in which quantitative EEG is used as a way of assessing possible cerebral injury not severe enough to cause clinically apparent immediate neurologic dysfunction. We embarked on quantitative EEG monitoring as a way of detecting more subtle cerebral injury because such monitoring has been correlated with cerebral injury in a variety of other situations, and it is generally accepted that an increase in slower waveforms on quantitative EEG augurs less complete cerebral recovery from a neurologic insult. 1-3
With quantitative EEG analysis, we observed that there was a significant increase in slower waveform prevalence in postoperative as compared with preoperative studies in the puppies cooled to 18° C, regardless of whether they were subjected to 60 minutes of complete circulatory arrest or to low-flow CPB. This increase in slow wave activity was significantly less pronounced after hypothermic circulatory arrest in both groups of puppies cooled to lower temperatures before being subjected to circulatory arrest (Fig. 3).
From the metabolic and physiologic data that were collected during the period of hypothermia and for several hours thereafter, the most striking differences between the 18° C groups and those subjected to greater degrees of cooling was that there was a significantly greater reduction of oxygen and glucose metabolism in the animals cooled to lower temperatures. In fact, the finding that cerebral metabolism was almost 40% of baseline levels at 18° C is rather alarming, inasmuch as most estimates of the theoretic safety of relatively long ischemic times under hypothermia assume a much greater reduction of metabolic rate than we were able to document. It is particularly noteworthy that calculations both of oxygen and of glucose metabolism give the same relatively high estimate of residual cerebral metabolism at 18° C (Fig. 4).
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6 who showed ongoing cerebral oxygen consumption at 42% of baseline in pigs cooled to 18° C. Studies in children, on the other hand, have shown significantly lower cerebral oxygen consumption during equivalent levels of hypothermia. 7 The lower calculated cerebral oxygen consumptions in children during hypothermia may be the result of sampling from the internal jugular vein rather than from the sagittal sinus, which results in the inclusion, in the children, of a larger proportion of extracerebral tissue, which has a more markedly depressed metabolism than does the brain during hypothermia. Measuring the relatively well-maintained cerebral oxygen consumption in such a way as to include a significant amount of more markedly depressed extracerebral tissue will result in a lower estimate of residual cerebral metabolism and generate a false sense of security regarding the degree of cerebral protection afforded by hypothermia. Our data with regard to differences in the degree of residual metabolism at different temperatures are reinforced by our observations, during intraoperative EEG monitoring, that there is a clear difference in the degree to which electrical activity of the brain is suppressed at different levels of hypothermia. There is much less complete suppression of electrical activity at 18° C than at either 13° C or 8° C (Fig. 2). Taken together, the metabolic and EEG data from our experiments suggest that cooling to 18° C does not provide as great a reduction of cerebral activity, and therefore does not provide cerebral protection as well as deep hypothermia to either 8° or 13° C, the two colder temperatures evaluated in this study (Figs. 2 and 4).
The temperatures used in this study were esophageal temperatures, chosen on the basis of previous experience in our laboratory that documented that esophageal temperatures correlate extremely well with directly measured intracerebral temperatures in dogs. In infants, in whom both esophageal and rectal temperatures are monitored, rectal temperatures are usually several degrees higher than esophageal temperatures at the end of cooling, and this should be borne in mind when the results of our studies are extrapolated to clinical situations.
Our clinical experience suggests that 15 to 20 minutes of cooling is usually adequate for infants: because we are relying on a single core temperature in the puppies, we cool somewhat longer, as documented in Table I, to be absolutely certain that equilibration has taken place before the end of cooling. Other investigators have also stressed the importance of adequately prolonged cooling to achieve and maintain a low intracerebral temperature during long periods of hypothermia; short cooling intervals have been associated clinically with poorer outcomes. 8 To further protect the brain during prolonged hypothermia, we also always pack the head in ice. We believe that these aspects of cooling methods may play an important role in the adequacy of cerebral protection during hypothermia.
The quantitative EEG results show no difference in cerebral outcome between low flow cardiopulmonary bypass at 18° C and hypothermic circulatory arrest at the same temperature (Fig. 3). Although the two groups at 18° C should have been identical throughout the entire cooling interval, we noted some differences in EEG activity between the groups of puppies subsequently subjected to hypothermic circulatory arrest and low flow cardiopulmonary bypass: we are at a loss to explain these differences except as an artifact of small numbers of animals. Both because the outcome was the same, and because the groups may in some subtle way not have been completely comparable, we are loathe to make too much of the apparently milder postoperative rise in cerebral vascular resistance in the low flow cardiopulmonary bypass group, which shortens the interval during which CBF falls to levels so low that very high oxygen and glucose extraction occur to allow cerebral metabolism to continue at or near baseline levels during the postoperative period. We have previously speculated that it is during this vulnerable interval after operation that any further impairment of oxygen delivery—as the result of hypotension, hypoxia, or anemia—may lead to ischemia and cerebral injury. 4
Regardless of which temperature is examined (all are within the range that most surgeons would agree to consider "deep hypothermia") there is recovery to a normal or near-normal level of cerebral metabolism very quickly after hypothermic circulatory arrest, accompanied initially during rewarming by adequate, or even generous, CBF (Fig. 5). By 2 hours after the end of hypothermic circulatory arrest, however, the vulnerable interval begins: there is a rise in cerebral vascular resistance and a fall in CBF, with metabolism maintained by increased extraction of both oxygen and glucose (Figs. 5 through 8). With saturations as low as 31% in the sagittal sinus 4 hours after operation, this is clearly a somewhat precarious situation (Fig. 9).
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We believe that the data from our studies clearly raise the question whether 18° C is cold enough for either hypothermic circulatory arrest or low flow cardiopulmonary bypass in situations in which the duration of hypothermia is likely to be prolonged. This question is concurrently also being raised by an ongoing clinical study at the Boston Children's Hospital, in which electrical seizure activity and hypotonia were found in a considerable percentage of the infants after cardiac operation with hypothermic circulatory arrest and also, to a lesser extent, with low flow cardiopulmonary bypass. 9 The evidence from our study suggests that whatever theoretic advantage the presence of low flow during hypothermia might confer, it does not adequately offset the disadvantage of less effective suppression of cerebral activity that occurs at 18° C compared with that at lower temperatures. It should be noted, however, that we have only examined a single rate of flow, 25 ml/kg per minute, which is lower than the rate recommended by some clinicians: it is conceivable that a higher rate of flow might improve cerebral outcome under these circumstances. On the basis of our evidence to date, we believe strongly that hypothermic circulatory arrest or low flow cardiopulmonary bypass for durations approaching 60 minutes should be done after cooling to 13° C or below.
Ultimately, monitoring cerebral outcome is the only way to be sure that cerebral protection is adequate. Thus far, quantitative EEG is the most sensitive assay we have found to monitor recovery after hypothermic circulatory arrest in an animal model in which we can concurrently monitor the physiologic and metabolic events which may enable us eventually to understand the mechanism of cerebral injury after hypothermia. Further analysis of the results of these experiments, together with ongoing investigations, should enable us to make progress in understanding what happens to the brain during and after hypothermic circulatory arrest and help us design strategies for improving cerebral protection during operations with this now-indispensable technique.
Appendix: DISCUSSION
Dr. Edward L. Bove (Ann Arbor, Mich.).
Could you give us some information on the pH values that you used during the cooling and whether or not you have any data as to the effect of the duration or the rate of cooling on outcome?
Dr. Serafin Y. DeLeon (Maywood, Ill.).
What temperature do you measure? I do not know whether it is esophageal, rectal, or brain temperature.
How would you explain the greater number of deaths in the low temperature group? Also, a couple of dogs had an unsteady gait. We have seen this in patients who had deep hypothermia without circulatory arrest but who were subjected to high perfusion flow. We thought that the problem was due to the hypothermia and when we reviewed the literature we found evidence that hypothermia itself is injurious to the brain.
We believe that because the brain has a high lipid content, which is almost 90%, a certain depth of hypothermia will cause injury that is increased with colder and longer perfusion.
We also believe that there is an absolute low temperature at which brain injury will occur and there is a relative temperature at which multiple factors will take effect. I am interested in this because I am trying to find a model in which I can produce choreoathetosis with deep hypothermia without circulatory arrest to evaluate other contributing factors.
Choreoathetosis, incidentally, seems to be underreported because since we wrote our article, we have seen cases of choreoathetosis not associated with circulatory arrest involved in malpractice suits.
Dr. David R. Clarke (Denver, Colo.).
I would like to delve more deeply into the pH question. You mentioned that you use -stat pH management. Do you have information as to what the carbon dioxide tensions were during cooling, during rewarming, and at the time of the postoperative measurements?
Dr. Richard A. Jonas (Boston, Mass.).
In Boston we have been conducting a clinical study looking at neurologic and developmental outcome variables in neonates and infants undergoing hypothermic bypass with or without circulatory arrest. Preliminary analysis, and I would emphasize preliminary, supports the idea that tympanic temperatures colder than 18° C result in improved protection as determined by perioperative variables such as the prevalence of EEG-determined seizures. We will shortly know whether or not that also correlates with improved developmental outcome.
I believe that there were clinical reports in the 1960s of brain injury occurring with very low temperatures, for example, less than 10° C. It is my understanding that at that time hemodilution was not aggressively practiced. Do you have any comment as to the interaction of hematocrit value and extremely low temperatures?
Dr. Constantine Mavroudis (Chicago, Ill.).
During the rewarming phase after deep hypothermia and circulatory arrest, reperfusion pressure may vary widely as a result of changes in total peripheral vascular resistance. Perhaps you can explain further the pressure response when flows were maintained at 25 ml/kg per minute.
Dr. Mezrow.
We used -stat pH blood gas management in the conduct of this study. With respect to the method and duration of cooling, bypass was begun with a cold perfusate at approximately 10° C, which we refer to as "crash cooling." All animals were cooled for at least 30 minutes at a rate of 100 ml/kg per minute, which was reduced to 50 ml/kg per minute at an esophageal temperature of 20° C. Our method of cooling was associated with low rates of mortality and morbidity.
In response to Dr. DeLeon's questions regarding method of temperature monitoring and the possible injurious effects of deep levels of hypothermia, all measurements were done according to esophageal temperature. We also monitored rectal temperature but find that value to be variable with respect to core temperature. Unpublished studies in our laboratory have shown esophageal temperature to correlate well with brain temperature.
We do not have any data to suggest that deep levels of hypothermia such as 8° or 13° C are associated with higher morbidity or mortality when compared with higher temperatures of hypothermia. Our quantitative EEG and metabolism data suggest the contrary, that hypothermic circulatory arrest and low-flow CPB bypass done at 8° and 13° C are more protective than either method at 18° C.
In response to Dr. Clarke's question regarding carbon dioxide tension values during bypass and after operation, arterial carbon dioxide tension was maintained between 35 and 40 mm Hg during all measurement time points.
In response to Dr. Jonas' question pertaining to the interaction of hematocrit value at low levels of hypothermia, we conducted CPB with a hematocrit value in the range of 22% to 28% with a perfusate consisting of homologous blood and human albumin. We did not observe any adverse effect of high blood viscosity in association with low levels of hypothermia, even at 8° C.
In response to Dr. Mavroudis' questions regarding perfusion pressure and the use of vasoactive agents, all measurements were done without the use of vasoactive or inotropic agents. During CPB we controlled for flow, not pressure. During cooling, bypass was conducted at 100 ml/kg per minute until an esophageal temperature of 20° C was reached, at which time flow was reduced to 50 ml/kg per minute. During low-flow CPB, at a rate of 25 ml/kg per minute, perfusion pressure was approximately 50 mm Hg without the use of vasoactive agents. Rewarming was conducted at a bypass flow rate of 100 ml/kg per minute. During rewarming, mean arterial pressure would sometimes rise to levels as high as 90 mm Hg. We did not observe any adverse effects of allowing the pressure to rise to such high levels.
Acknowledgments
We thank William Brett III, David A. D'Alessandro, and Richard Smith for their technical assistance in the conduct of these experiments.
Footnotes
Read at the Seventy-third Annual Meeting of The American Association for Thoracic Surgery, Chicago, Ill., April 25-28, 1993. 
J THORAC CARDIOVASC SURG 1994;107:1006-19
References
This article has been cited by other articles:
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  M. Arrica and B. Bissonnette Therapeutic hypothermia. Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2007; 11(1): 6 - 15. [Abstract] [PDF]
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M. L. Schlunt and S. D. Brauer Anesthetic management for the pediatric patient undergoing deep hypothermic circulatory arrest. Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2007; 11(1): 16 - 22. [Abstract] [PDF]
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 H. Kamiya, C. Hagl, I. Kropivnitskaya, D. Bothig, K. Kallenbach, N. Khaladj, A. Martens, A. Haverich, and M. Karck The safety of moderate hypothermic lower body circulatory arrest with selective cerebral perfusion: A propensity score analysis J. Thorac. Cardiovasc. Surg., February 1, 2007; 133(2): 501 - 509. [Abstract] [Full Text] [PDF]
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 D. K. Harrington, F. Fragomeni, and R. S. Bonser Cerebral Perfusion Ann. Thorac. Surg., February 1, 2007; 83(2): S799 - S804. [Abstract] [Full Text] [PDF]
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