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J Thorac Cardiovasc Surg 1998;116:503-507
© 1998 Mosby, Inc.

Cardiopulmonary Support and Physiology

Regional cerebral blood flow during rewarming of cardiopulmonary bypass correlates with posthypothermic regional glucose use

From the Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute,^a and the Institute for Biofunctional Research,^b Osaka, Japan.

Received for publication June 4, 1997. Revisions requested August 8, 1997; revisions received Feb. 27, 1998. Accepted for publication Feb. 27, 1998. Address for reprints: Hiroshi Miyano, MD, Department of Cardiovascular Dynamics, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan.

	Abstract

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Background and objectives: Although global measurements of cerebral blood flow and metabolism during and after profoundly hypothermic cardiopulmonary bypass have been performed both in experimental animals and in human beings, little is known about their regional changes. The purpose of this study was to investigate the changes in regional cerebral blood flow during profoundly hypothermic cardiopulmonary bypass and regional cerebral glucose use after cardiopulmonary bypass.
Methods: We measured regional cerebral blood flow with positron emission tomography during both the cooling (n = 5) and rewarming (n = 5) of hypothermic cardiopulmonary bypass in anesthetized dogs by continuously infusing ¹⁵O-labeled water. We altered the core temperature between 20° and 37° C. To assess the integrity of brain metabolism, we measured the regional cerebral glucose use by bolus injections of ¹⁸F-labeled 2-fluoro-2-deoxy-D-glucose.
Results: Regional cerebral blood flow decreased homogeneously during cooling. The regional cerebral blood flow at 20° C was about one fourth of that at 37° C. In contrast, at 24°, 28°, and 32° C during rewarming, there were significant interregional differences in the regional cerebral blood flow for given temperatures (p = 0.0075, 0.034, and 0.048, respectively). These interregional differences disappeared after rewarming. Although the regional cerebral blood flow significantly correlated with the regional cerebral glucose use in the control condition at 37° C without cardiopulmonary bypass (r = 0.75; p = 0.00012), this correlation disappeared after profoundly hypothermic cardiopulmonary bypass (r = 0.204; p = 0.388). Regional cerebral blood flow at 32° C during rewarming positively correlated with the regional cerebral glucose use after cardiopulmonary bypass (r = 0.655; p = 0.0017).
Conclusion: The altered regional cerebral blood flow during rewarming of profoundly hypothermic cardiopulmonary bypass might affect regional brain metabolism.

	Introduction

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Postoperative brain damage remains one of the major complications after profoundly hypothermic cardiopulmonary bypass (CPB). ^1-3 Various investigators have ascribed it to the prolonged cerebral hypoperfusion ³ and/or the embolization of air, fat, or particulate materials derived from aortic atheroma. ^3-7 Global changes in cerebral blood flow (CBF) and cerebral oxygen use (CMRO₂) after profoundly hypothermic CPB have been investigated in human beings ⁸ and in experimental animals. ^9,10 However, how regional cerebral blood flow (rCBF) and metabolism change during and after profoundly hypothermic CPB remain unknown.

Recent development of positron emission tomography (PET) has made it possible to accurately measure regional cerebral metabolism both in experimental and in clinical settings. In particular, the use of PET to measure rCBF with ¹⁵O-labeled water, regional cerebral glucose use (rCMR_glc) with ¹⁸F-labeled 2-fluoro-2-deoxy-D-glucose (¹⁸FDG), and regional CMRO₂ (rCMRO₂) with ¹⁵O-labeled carbon dioxide has been well established. ¹¹ Because it allows repetitive measurements, PET is particularly useful in studying how hypothermic CPB affects brain perfusion and metabolism. To investigate the mechanism by which hypothermic CPB damages the brain, we measured rCBF using PET during the cooling and rewarming of profoundly hypothermic CPB at 20° C, which has often been used for complex aortic arch repair with the combination of circulatory arrest or retrograde cerebral perfusion. ¹² To evaluate the ischemic damage and the integrity of brain metabolism, we measured rCMR_glc.

	Materials and methods

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Animal preparation
All animals involved in this study received humane care in compliance with the "Guiding Principles in the Care and Use of Animals" approved by the Council of American Physiological Society (revised in 1980) and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication No. 85-23, revised in 1985).

Fifteen mongrel dogs, weighing between 14 and 20 kg, were used in this study. We conducted hypothermic CPB in 10 dogs; the other five dogs served as controls without CPB. Anesthesia was induced with ketamine hydrochloride (5 mg · kg^-1 intramuscularly), followed by an intravenous injection of pentobarbital sodium (25 mg · kg^-1). Animals were artificially ventilated with a volume-cycled respirator and maintained on 78.5% nitrous oxide, 20% oxygen, and 1.5% halothane inhalation anesthetics. An arterial catheter for the continuous measurement of blood radioactivity was inserted into the descending aorta via the right femoral artery. Another arterial catheter for measuring arterial blood pressure and for blood sampling was inserted into the abdominal aorta via the left femoral artery. A venous catheter was inserted via the right femoral vein for drug administrations. Core temperature was continuously monitored by a precalibrated thermistor placed in the cervical esophagus.

In 10 dogs with the CPB protocols, the chest was opened by a median sternotomy. After an intravenous administration of heparin sodium (500 IU/kg intravenously), the left subclavian artery was cannulated retrogradely with a 16F straight-type, polyvinyl chloride infusion cannula (PAA-016-SB; Research Medical, Inc., Midvale, Utah) for inflow. A two-staged venous drainage cannula (TF-1824-O; Research Medical) was inserted through the right atrial appendage into the inferior vena cava. The left ventricle was vented via the left atrium after CPB had been established.

The bypass circuit consisted of a variable-volume venous reservoir (maximum volume, 800 ml), a roller pump (HAD 101; Mera, Tokyo, Japan), a membrane oxygenator–heat exchanger (Module 1500; Dideco, Mirandola, Italy), and an in-line arterial filter. Priming fluid consisted of 500 ml of lactated Ringer's solution, 600 ml of homologous blood, 100 ml of 20% mannitol, 200 ml of low-molecular-weight dextran solution, 20 mEq of sodium bicarbonate, and 5000 IU of heparin. About 30 minutes before CPB, we discontinued halothane and nitrous oxide and switched the anesthesia to systemic administrations of fentanyl (10 µg · kg^-1 every 30 minutes), diazepam (0.1 mg · kg^-1 every hour), and pancronium bromide (0.1 mg · kg^-1 every 30 minutes). After the conclusion of CPB, we switched back to anesthesia with nitrous oxide and halothane. Arterial carbon dioxide tension was measured without temperature correction and maintained between 40 to 50 mm Hg throughout the experiment. The temperature of the oxygenated blood from the oxygenator was continuously monitored with an in-line thermistor. The difference between the esophageal temperature and the blood temperature was kept within 5° C during CPB. During rewarming, no additional fluid was administered because this acutely decreased the blood radioactivity.

Experimental protocols
Measurement of rCBF during hypothermic CPB
A blank scan was performed before the animals were placed on the scanner table. After the completion of surgical preparation, animals were positioned in the PET scanner (EXACT HR 47; Siemens AG–Bereich Medizinische Technik, Erlangen, Germany). The head of the animals were fixed so that their orbitomeatal line was parallel with the axis of the PET scanner. We instituted CPB at a flow rate of 60 ml · kg^-1 · min^-1, which was fixed until the end of the rewarming. The transmission images were obtained with a rotating rod source of ⁶⁸Ga/⁶⁸Ge in each animal to measure the photon attenuation and to correct the subsequent emission scans.

Protocol 1
We measured rCBF in five dogs during the cooling phase of hypothermic CPB. We infused ¹⁵O-labeled water (2.0 mCi · 1.8 ml saline^-1 · min^-1) continuously into the artery via the CPB circuit at a point 30 cm upstream from the tip of the arterial cannula after CPB was established. We withdrew arterial blood at a rate of 3 ml · min^-1 for continuous measurements of blood radioactivity to obtain an arterial input function. After the radioactivity reached a steady state in both the arterial blood and the head, which usually took about 15 minutes, we acquired PET images at 37° C before cooling. Then the dogs were cooled to 20° C. We acquired the PET images at 32°, 28°, 24°, and 20° C during cooling. This protocol was terminated after rCBF was measured at 20° C because of the hardware limitation of the cyclotron for producing radio-labeled water.

Protocol 2
To measure the rCBF during rewarming of CPB in another five dogs during the hypothermic CPB experiments, we first conducted hypothermic CPB and maintained the temperature at 20° C for 60 minutes. From 30 minutes before rewarming, we began to infuse ¹⁵O-labeled water (2.0 mCi · 1.8 ml saline^-1 · min^-1) continuously into the artery via the CPB circuit. After the radioactivity reached a steady state in both the arterial blood and the head, we acquired PET images before rewarming. Then the dogs were rewarmed to 37° C. During rewarming, we acquired PET images at 20°, 24°, 28°, and 32° C. When the esophageal temperature reached to 37° C, the dogs were weaned from CPB. Then, ¹⁵O-labeled water (2.0 mCi · 1.8 ml saline^-1 · min^-1) was continuously infused into the venous catheter placed in the inferior vena cava. After stabilization of the radioactivity, we acquired PET images at 37° C.

Protocol 3
In another five dogs without CPB, we estimated control rCBF under halothane anesthesia with nitrous oxide by infusing ¹⁵O-labeled water (2.0 mCi · 1.8 ml saline^-1 · min^-1) continuously into the venous catheter placed in the inferior vena cava.

Measurement of rCMR_glc
To measure rCMR_glc, ¹⁸FDG (0.9 mCi · kg^-1) was injected via a femoral venous catheter. PET scanning was performed for 15 minutes from 45 minutes after the injection of ¹⁸FDG, according to the autoradiography method. ¹³ We used halothane inhalation anesthesia with nitrous oxide during the measurement of rCMR_glc both after the weaning process from hypothermic CPB (protocol 2) and under the control condition (protocol 3). This was because of the necessity of metabolic stability during the measurement of rCMR_glc. With this anesthesia, brain function as judged by electroencephalography has been shown to be stable. ¹⁴

After rCMR_glc was measured in protocol 2, the descending aorta was clamped and 3 L of 10% formalin was infused into the arterial catheter for fixing the brain. The brain was taken out on the next day and was cut into 5 mm slices to examine the occurrence of cerebral hemorrhage and/or cerebral infarction.

Data analyses
Estimation of rCBF
Details of rCBF estimation with ¹⁵O-water have been described elsewhere. ¹¹ In brief, if we assume each sample volume consists of one compartment, mass-specific regional flow (f) would be expressed as a function of brain radioactivity ( mCi · gm^-1) and arterial blood radioactivity (C_a mCi · ml^-1) as

To validate the assumption that dX/dt is zero, we continuously monitored the radioactivity in both the arterial blood and the head. We confirmed, at each measurement, that the input radioactivity remained constant. This confirmation was also done at a time of data analysis.

Estimation of rCMR_glc
Details of rCMR_glc estimation with ¹⁸FDG have been described elsewhere. ¹¹ In brief, ¹⁸FDG entered the brain tissues would be trapped as ¹⁸FDG-6-phosphate by hexokinase phospholylation. This process is considered to quantify glucose use. In this investigation, we used a three-compartment model. ^13,16 We adopted the rate constants k₁, k₂, k₃, and k₄ ¹⁷ and lumped constant ¹⁵ from literature. With the measurements of brain radioactivity X and arterial blood radioactivity C_a as an input function, one can derive rCMR_glc. ¹⁵

The best spatial resolution of the PET scanner (ECAT EXACT HR47) ¹⁸ at full-width half-maximum was 3.6 mm in the center of the scan field of the cross plane, with 784 crystals per ring. This scanner had 24 rings and could obtain 47 slices simultaneously. The plane spacing was 3.125 mm. We reconstructed a functional image consisting of 128 x 128 pixels, with each pixel measuring 0.875 x 0.875 mm. For the sake of convenience, we derived rCBF and rCMR_glc of the frontal cortex, parietal cortex, temporal cortex, and basal ganglia to set a circular region of interest in each region.

Statistics
All data were expressed as mean ± one standard deviation. Changes in rCBF and physiologic variables during cooling and rewarming were tested by two-way analysis of variance with repeated measures (factor: temperature and rCBF or physiologic variables) followed by Dunnet's multiple comparison test. ¹⁹ The inhomogeneity of rCBF and rCMR_glc among the four brain regions at each temperature was tested by two-way analysis of variance with repeated measures (factor: each animal and region). ¹⁹ The difference between the two groups was tested by Mann-Whitney test. ¹⁹

	Results

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There was no obvious hemorrhage or infarction in the brain after the end of the rewarming experiment (n = 5).

Changes of rCBF during the cooling phase of hypothermic CPB
In the cooling experiment, core temperature was cooled to 20° C in 55.0 ± 10.6 minutes. Systemic physiologic variables during cooling are summarized in Table I.Mean arterial pressure significantly decreased at temperatures below 28° C. Blood hemoglobin concentration was significantly lower during cooling than in the control. Neither arterial pH nor carbon dioxide tension significantly changed during cooling.

View larger version (42K): [in this window] [in a new window]   Fig. 1. Changes in rCBF in the frontal cortex, parietal cortex, temporal cortex, and basal ganglia during cooling. The rCBF decreases with decreases in temperature. There were no interregional differences throughout cooling. Values are expressed as mean ± one standard deviation. p < 0.05, compared with rCBF at 37° C before cooling.

View larger version (40K): [in this window] [in a new window]   Fig. 2. A, Changes in rCBF during rewarming. At 24°, 28°, and 32° C, two-way analysis of variance with repeated measures showed significant differences among the regions. Values are expressed as mean ± one standard deviation. p < 0.05 compared with rCBF before rewarming. *Significant interregional difference (p < 0.05). B, The rCBF at 37° C without CPB. There was no interregional difference in rCBF.

View larger version (43K): [in this window] [in a new window]   Fig. 3. rCMRglc with the use of halothane anesthesia with nitrous oxide without CPB (left) and after being weaned from hypothermic CPB (right). There was no interregional difference in rCMRglc without CPB. However, a significant interregional difference was observed after hypothermic CPB by two-way analysis of variance with repeated measures. Values are expressed as mean ± one standard deviation. *p = 0.010.

View larger version (23K): [in this window] [in a new window]   Fig. 4. Correlation between rCBF and rCMRglc in the control condition without CPB (A) and after being weaned from hypothermic CPB (B). Although there was a significant positive correlation between rCBF and rCMRglc in the control condition, this significant correlation disappeared after profoundly hypothermic CPB.

View larger version (23K): [in this window] [in a new window]   Fig. 5. Significant positive correlation between rCBF at 32° C during rewarming and rCMRglc after weaning from profoundly hypothermic CPB.

	Discussion

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Mechanism of the inhomogeneity of rCBF during rewarming
During rewarming, significant interregional differences in rCBF were observed at 24°, 28°, and 32° C (Fig. 2). Because rCBF is closely coupled with regional CMRO₂, ²⁰ which was the case in the control condition without CPB (Fig. 4, A), it is conceivable that the inhomogeneity of rCBF during rewarming reflected that of cerebral metabolism. Although we did not observe the inhomogeneity of rCBF at any time during the cooling (Fig. 1), the regional difference in the brain temperature during rewarming ²¹ might vary the rCBF. The regional difference in the recovery of the brain function might also affect the rCBF during the rewarming without the regional difference in temperature. However, the disappearance of the tight relation between rCBF and rCMR_glc after hypothermic CPB (Fig. 4, B) and the close relation between rCBF at 32° C and rCMR_glc after CPB (Fig. 5) suggest that the inhomogeneity of rCBF might be a manifestation of the loss of temperature-coupled or function-coupled regulation of rCBF.

The long-lasting hypothermia might alter the regional cerebral vascular response. This might explain why the inhomogeneity of rCBF did not occur during cooling. The microemboli of air, fat, or particulate materials derived from aortic atheroma ^3-7,22 might also be responsible for the observed changes in the rCBF during rewarming. Because we chose the left subclavian root for arterial cannulation and did not clamp the aorta, the particulate materials from the aortic root might not be responsible for microembolization. Instead, gaseous emboli might be a candidate for microembolization during hypothermic CPB in our experiment. In fact, Johnston and associates ²² have shown significant gaseous emboli even with the use of the membrane oxygenator and arterial filter in dogs.

Although we cannot clearly determine which factor is primarily responsible for the observed changes in rCBF, the close correlation between rCBF at 32° C and rCMR_glc after CPB suggests that rCBF during rewarming might affect brain metabolism after CPB.

rCBF during rewarming as a possible determinant of rCMR_glc after CPB
The flow-metabolic decoupling during rewarming might be responsible for rCMR_glc after CPB. Markand and associates ²³ showed the temperature-dependent hysteresis in cortical-evoked potentials. They showed the initial exaggerated response of cortical-evoked potential latencies at the onset of rewarming. ²³ On the contrary, the recovery in rCBF in our experiment was slow and became prominent above 28° C (Fig. 2, A). Thus it is conceivable that rCBF for brain metabolism during rewarming may not be sufficient and thereby affects rCMR_glc after CPB.

Several investigations have shown that hypothermic CPB did not affect cerebral energy production ^9,10,22 or global CMRO₂. ^8-10 These results indicated that aerobic glycolysis remained unimpaired. The discrepancy between those results and ours might be explained in part by the uncoupling between CMRO₂ and rCMR_glc, which has been shown to occur in acute cerebral ischemia. ^24-26 Alternatively, there is also a possibility that the global measurement of the brain metabolism in the previous studies might not be sensitive enough to reflect these regional metabolic changes. Therefore our results suggest that profoundly hypothermic CPB may alter both rCBF and metabolism, although the precise mechanism remains to be elucidated.

Neurologic implications of the reduced rCMR_glc detected by PET
In patients who have experienced stroke, Heiss and associates ²⁵ reported that the increase in rCMR_glc paralleled a significant clinical improvement. This observation supports the notion that regional decreases in glucose use indicate the functional depression in the corresponding regions. On the other hand, Powers and associates ²⁷ showed that CMRO₂ under normal central nervous system function has some degree of variability. Because it was impossible to perform the neurologic examination after hypothermic CPB in our experimental setting, it is not clear whether the observed change in rCMR_glc correlates with the change in brain function. However, the fact that a certain percentage of patients experience neuropsychologic dysfunction after hypothermic CPB, even though most of the neuropsychologic dysfunctions are subtle and transient, ^1-3 might support our results that show a pathologic implication of profoundly hypothermic CPB. Further investigations are required to clarify the relation between the altered brain glucose metabolism induced by hypothermic CPB and neuropsychologic function.

Methodologic considerations
The prolonged cerebral hypoperfusion during CPB has been thought to affect rCMR_glc after CPB. ³ In our experiments, mean arterial blood pressure was above 55 mm Hg at 20° C, and it was always above 60 mm Hg during rewarming. Swain and associates ²⁸ have shown that cerebral perfusion at a rate of 10 ml/kg per minute, with mean arterial pressure ranging from 40 to 50 mm Hg at 15° C, preserved brain high-energy phosphate in sheep. Also in human children, Greeley and associates ⁸ reported that mean arterial pressure even below 60 mm Hg during deep hypothermia and rewarming did not affect oxygen metabolism after CPB. Although these earlier studies suggest that mean arterial pressure in this study would be high enough not to significantly affect rCBF or rCMR_glc, there is still a possibility that global measurements of cerebral blood flow and metabolism ^8,28 could not reflect their regional changes. It is worthy of further investigation to examine whether or not arterial pressure during hypothermic CPB affects rCBF and regional metabolism.

We used the combination of fentanyl and diazepam as anesthetics during CPB. Although fentanyl has been shown to not significantly affect CBF in dogs, ²⁹ diazepam might affect rCMR_glc after hypothermic CPB. However, it does not explain the inhomogeneity of rCBF during rewarming, nor does it explain the interregional difference in rCMR_glc. Both nitrous oxide and halothane have been reported to increase the CBF ^14,30 and CBF/CMRO₂ ratio in human beings. ¹⁴ However, the fact that rCBF closely correlated with rCMR_glc in our study (Fig. 4, A) might indicate the combination of nitrous oxide and halothane little affected the cerebral flow-metabolic coupling.

We assumed that the distribution volume of the cerebral cortex did not alter during hypothermic CPB. Although it has been reported that the changes in brain water content, such as brain edema, may change the distribution volume, this change has been thought to be significant in the white matter rather than in the gray matter. ¹¹ Therefore the changes in the distribution volume may not significantly affect our estimation of rCBF. We also assumed that the rate constant and the lumped constant of ¹⁸FDG did not change after hypothermic CPB. Because we used the autoradiography method, the changes in the rate constant might not significantly affect our estimation of rCMR_glc. ¹¹ However, because the lumped constant has been shown to vary in certain pathological states, ¹¹ there is a possibility that the changes in the lumped constant might affect our estimation of rCMR_glc after rewarming.

In summary, we have shown a possibility that rCBF during rewarming might affect the cerebral metabolism after hypothermic CPB. However, because of the small number of the animals used in this study, further investigations are mandatory to establish the regional flow-metabolism relation during and after profoundly hypothermic CBP.

	Acknowledgments

 
This study was prepared in consultation with a statistician, Masaru Sugimachi, MD.

	Footnotes

 
12/1/90016

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