Cerebral Metabolism and Blood Flow after Circulatory Arrest - NCBI

Cerebral Metabolism and Blood Flow after Circulatory Arrest During Deep Hypothermia AVIO M. PERNA, M.D., TIMOTHY J. GARDNER, M.D., KAMRAN TABADDOR, M.D., ROBERT K. BRAWLEY, M.D., VINCENT L. GOTT, M.D.

THE USE OF induced hypothermia as an adjunct to surgery has been of considerable interest to surgeons for many years. Bigelow,4 Lewis,18 and Swan28 reported both experimental and some clinical experience with hypothermic technics in their early cardiac surgical work in the 1950's. The clinical employment of body cooling during operation, however, has generally been confined to levels of only moderate hypothermia. Mohri, et al.,8,'22 and more recently Barratt-Boyes' have reported the use of deep hypothermia with body temperature lowered to 18 to 200 C during the surgical treatment of severe cardiac anomalies in infants. They have induced marked body cooling in these patients in order to safely accomplish complete circulatory arrest for periods of up to 1 hour. The technic of body cooling and circulatory arrest described by Mohri differs significantly from other methods of inducing deep hypothermia in that no extracorporeal circuitry or pump is employed. Mohri's method of hypothermic surgery, used both experimentally and clinically,7 involves the exclusive use of surface cooling and a combination of deep ether anesthesia and relative hyperventilation. As a result of the hyperventilation, very marked respiratory alkalosis develops at deep hypothermic levels and the previously common problem of ventricular irritability, seen as the body temperature falls below 25 C, is rarely encountered. The clinical usefulness of this hypothermic technic seems to be limited not by the effects of the circulatory arrest on the heart, but by the neurologic damage which results from the prolonged circulatory arrest Suibmitted for publication June 7, 1972. Supported by USPHS Grant No. HE-09997.

95

From the Department of Surgery. The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

even at deep hypothermic levels. Mohri feels that the development of a high-stepping gait after circulatory arrest is a reliable indicator of neurologic damage in these animals. The appearance of a gait disturbance or some more serious neurologic deficits after hypothermia and arrest has enabled Mohri to define a safe time period of circulatory arrest in dogs undergoing deep hypothermia.22'23 In the present study, we have attempted to evaluate the effects of hypothermia and circulatory arrest on cerebral blood flow and the cerebral oxygen metabolism using Mohri's technic of hypothermia and confining the length of the circulatory arrest to what Mohri has described as a safe period. Several reports describe the effects of moderate hypothermia on cerebral metabolism21'26 and a study by Edmunds describes the changes in cerebral metabolism after profound hypothermia and circulatory arrest using extracorporeal circuitry.9 This paper describes the first reported attempt to study the changes in cerebral metabolism using this particular technic of induced hypothermia and circulatory arrest which does not involve extracorporeal circulation. Methods Ten mongrel dogs of both sexes weighing 10 to 15 Kg., with negative blood tests for filariasis, were used in this study. Atropine, 0.02 mg./Kg., was administered intramuscularly 30 minutes prior to induction of anesthesia, which was accomplished using sodium thiamylal (Surital) in a dosage of 30 mg./Kg. After insertion of a cuffed endotracheal tube, the animal was placed on a piston-type respirator, and respirations

PERNA, GARDNER, TABADDOR, BRAWLEY AND GOTT

96 were controlled an oxygen flow was

adjusted

at a rate of 20 cycles per minutes with rate of 4-6 1/ min. The tidal volume to maintain intratracheal pressure at

mm. H120. After the normothermic cerebral metabolic measurements were made, ether was used for anesthetic maintainence until the animal's body temperature reached 27 C. Below this temperature level, no anesthetic agent was given. The depth of anesthesia achieved with ether was sufficient to block any shivering by the animal, but was carefully maintained to avoid any cardiovascular depression. During the rewarming phase, small increments of Surital were administered in some animals as required for anesthetic maintainence. Low molecular weight Dextran, 10 cc. /Kg., was slowly administered intravenously during the cooling of the animal. After the induction of anesthesia, arterial and venous catheters were inserted in the left femoral vessels and a silastic-coated stainless steel blood gas probe was inserted through a purse string suture into the right femoral artery. A 3 cm. diameter midline cranial defect was made and a similar blood gas probe was inserted into the sagittal sinus. A third stainless steel probe, this one coated with Teflon, was placed on the parasagittal cortical surface of the brain through a 3 mm. incision in the dura mater about 1 cm. lateral to the sagittal sinus. The silastic coated cannulae were attached to a two-channel mass spectrometer* which, as described earlier,5 continuously analyzes specific blood gases in amounts directly proportional to the partial pressures of the substances in the blood. This apparatus, which has been used both in clinical and experimental studies,,56"10 contains a high pressure vacuum pump which draws blood or tissue gases into the machine through the steel cannulae. The silastic or Teflon membranes provide both a thromboresistant surface and act as diffusion membranes, with the silastic membrane allowing nearly instantaneous diffusion of gases from the blood into the cannula and limiting its use therefore to a flowing liquid or a gaseous medium. The Teflon membrane, on the other hand, achieves a diffusion lag time, thus providing sufficient time for the constant equilibration of tissue gases around the sampling tip of the cannula. After the blood or tissue gases have been drawn into the machine, the specific substances being measured are identified and quantitated according to their molecular weights by the technic of mass spectrography. The first mass spectrometer used in this study was constructed to measure Po.,, Pco2, and PARGON. The

10 to 14

spectrometer was connected to a two-channel recorder which provided a continuous quantitative tracing of the measured oxygen and argon levels in the femoral artery and sagittal sinus. In five of the animals in which the Teflon cannula was placed on the surface of the cerebral cortex, a second mass spectrometer, calibrated for tissue measurement of Po2 and Pco2, was used for continuous monitoring of cortical oxygen and carbon dioxide levels. After these preparations were made, the animal was given argon by inhalation at a flow rate of 1.5 I/min with oxygen administration continuing. Using argon as the inert gas and obtaining saturation-desaturation curves for argon by monitoring its concentration in the femoral artery and sagittal sinus during and after argon administration, cerebral blood flow (CBF) could then be determined using a modification of the Kety-Schmidt formula, as described earlier.24 After determining the oxygen content of the arterial and sagittal sinus blood, the cerebral oxygen consumption (CMR02) could then be calculated. These cerebral metabolic measurements were repeated in all of the animals at body temperatures of 20 to 18 C prior to circulatory arrest and again at 36 to 38 C following arrest and after rewarming. When the metabolic studies were completed at 20 C, a right thoracotomy was performed through the fifth intercostal space and the superior and inferior vena cavae and azygos vein were occluded, the ascending aorta was cross clamped and the respirator was stopped. Young's solution* was injected into the aortic root in amounts sufficient to produce immediate cardiac arrest, usually 2 cc./Kg. After 45 minutes of complete circulatory arrest, the venous channels were opened, the lungs were reinflated, and the aortic cross clamp was released. Gentle cardiac massage was then performed, calcium chloride was administered intravenously (300 to 500 mg.), and within 10 to 20 minutes spontaneous heart action ensued. The animal was then placed in a warm water bath and the thoracotomy closed. After rewarming was completed and the body temperature had returned to 36 C, argon administration was again begun and the CBF, 02(A-V) and CMR02 were measured in the same manner as above. The entire experiment required 6 to 8 hours from the induction of anesthesia to completion of the final argon study. Results The changes observed in the CMR02, 02 (A-V), and CBF in the ten animals are summarized in Table *

Medspect Model MMS-8, Scientific Research Corporation, Baltimore, Maryland. *

Ann. Surg. . July 1973

Young's solution: 0.81 Gm. potassium citrate, 2.46 Gm. mag-

nesium sulfate 0.001 Gm. neostigmine methyl sulfate, water q.s. to 100 cc., pH adjusted to 7.4 with sodium bicarbonate.

Vol. 178 . No. I

CIRCULATORY ARREST DURING DEEP HYPOTHERMIA

TABILE 1. Cerebral Metabolic Measurements 370 (Before Cooling)

Animal Number 1 2 3 4 5 6 7

A-V 02* Difference 3.65 3.38 4.70 3.48 3.82 4.80 3.08 4.35 5.20 5.30 4.18

CMRO2** 1.03 0.85 1.36 1.12 1.22

1.52 1.54 2.81

200 (Before Circulatory Arrest) CBF*** 28 25 29 32 32 31 50 50 37 36 32

A-V 02* Difference 2.94 1.57 2.10 2.20 2.42

2.62

1.41 2.10 8 9 1.92 2.96 10 1.91 2.20 1.44 2.20 Median % Change 147% * Oxygen extraction expressed as cc. 02/100 cc. blood ** Oxygen consumption expressed as cc. 02/100 Gm. brain/minute *** Cerebral blood flow expressed as cc./100 Gm. brain/minute

I. The median value for the cerebral oxygen consumption at 20 C decreased by 69% of the measured normothermic value, while the median oxygen extraction decreased by 47% of the observed normothermic 02 (A-V) and the CBF decreased an average of 469% of the normothermic flow rate. These changes are illustrated in Figure 1. Measurements of oxygen consumption made after circulatory arrest and at the end of the rewarming period when the body temperature had returned to normothermic levels showed a median increase of 15% over the initial normothermic level. There was a median increase of 45% in oxygen extraction and a median decrease of 18% in the cerebral blood flow. Table 2 summarizes the observed values for the mean systemic arterial blood pressures (MBP) and the cerebral vascular resistances (CVR) noted at the three periods of metabolic measurements. Although there were considerable variations noted in these parameters among the ten animals, a comparison of median values of MBP and CVR shows a decrease from 125 mm. Hg at 38 C to 70 mm. Hg at 20 C without any change in the CVR. Arterial Pco2 values, at this time, ranged from 12 to 20 mm. Hg in the ten animals. In the post-rewarming period at a body temperature of 36 to 38 C, the median MBP was 110 mm. Hg while the median CVR had increased to 3.8. At this time, the arterial Pco. level ranged from 45 to 60 mm. Hg. The cerebral Po2 and Pco. levels monitored directly on the cortical surface during circulatory arrest in five animals are summarized in Table 3 and 4. Figure 2 represents a typical tracing of the cerebral cortical Po2 and Pco, levels obtained during circulatory arrest and demonstrates the characteristic decrease in the Po2 level during the first 10 to 15 minutes of arrest as well as the

370 (After Rewarming)

CMRO2** 0.46 0.22 0.46 0.35 0.49 0.46 0.44 0.77 0.54 0.33 0.46

CBF*** 16 14 22 16 20 17 31 37 18 15 18

A-V 02* Difference 6.38 5.22 5.75 3.42 4.20 6.57 6.68 4.01 6.82 7.22 6.06

169%

146%

T45%

CMRO2** 1.41 1.25 1.78 1.19 1.09 1.65 2.21 1.64 1.97 1.87 1.65

CBF*** 22 24 31 32 26 25 33 41 29 26 28

T15%

118%

steady increase in the cortical Pco2 level which began as the Po, level equilibrated. The mean per cent decline in the cerebral Po2 level during circulatory arrest was 39% of the pre-arrest value with nearly all of this decrease being observed in the first 15 minutes of arrest. The mean per cent increase in the cerebral cortical Pco2 level, on the other hand, was 163% with most of the observed increase occurring during the final 30 minutes of the circulatory arrest. Discussion The most significant fact to be derived from the data obtained in this study, is that cerebral oxygen consumption data obtained after circulatory arrest and rewarming demonstrate an average increase of 15% over the pre-cooling oxygen consumption values. As shown in Table 1, seven animals had an increase in oxygen consumption after hypothermia and circulatory CBF (A-V)02 6.0

CMR02 3.0

50 - 5.0

-

40 - 4.0

-

--____- ( A-V) 02 CBF CMRO2

"s

- 2.5

,I8 -,9 C

30 - 3.0

.s >. .

I

. -

2.0

-

1.5

-

1.0

.,

20 - 2.0 10 cc./

-

,-

1.0

-TORY-

-

ARREST

PERIODRS

./

"I

.-

-

1009

1OOg./ IOOcc. min.

0.5

CC.02/

cC.02/ BLOOD

min.

I

2

3 4 TIME IN HOURS

7

FiG. 1. Changes in cerebral metabolism during deep hypothermia.

TABLE 2.

(Before Cooling)

200 (Before Circuilatory Arrest)

370 (After Rewarming)

MBP* CV'R** 4.7 115 130 5.2 125 4.3 2.7 85 3.9 125 3.9 125 140 2.8 130 2.6 115 3.1 110 3.1

MBP* CVR** 4.2 65 70 5.0 75 3.4 60 3.7 70 3.5 60 3.4 100 3.2 80 2.2 65 3.5 6.6 100

MBP* CVR** 5.0 110 5.0 120 4.1 125 2.0 65 110 4.2 4.6 115 120 3.6 100 2.4 90 3.1 75 2.9

370

Animal Ntumber 1 2 3 4 5 6 7 8 9 10

110 3.8 70 3.5 3.5 125 Median * Mean blood pressture in mm. Hg ** Cerebral vasIcular resistance expressed as mm. Hg/cc. blood/100 Gm.

Ann. Surg.


98

brain/minutite

arrest, two animals showed essentially no change, while only one dog had a decline in oxygen consumption. This return of the rate of oxygen metabolism following deep hypothermia and complete circulatory arrest for 45 minutes to the pre-hypothermic CMRO, levels indicates a resumption of adequate, if not normal, cerebral metabolic activity. Despite this return to pre-arrest levels of cerebral oxygen consumption, cerebral blood flow declined an average of 18% after hypothermia and arrest. Oxygen consumption was maintained at generally higher than pre-cooling levels by an increase in oxygen extraction from the arterial blood in the brain, as is illustrated in Figure 1. The decline in CBF as well as a slight increase in the cerebral vascular resistance in the posthypothermic condition indicates some degree of cerebral damage as a result of deep hypothermia and the circulatory arrest. Although Dextran was administered, as Mohri had recommended, intravascular coagulation in small vessels would appear to be the most likely explanation for the decline in cerebral blood flow and the increase in cerebral vascular resistance. It is noteworthy, however, that no increase in the CVR was measured in the studies performed at 20 C. and prior to the arrest, when vascular sludging from an increased blood viscosity should have been at its greatest level.

.

July 1973

An additional explanation for the decline of the cerebral blood flow after circulatory arrest and rewarming might be the presence of some form of cerebral parenchymal damage. Factors inducing cerebral edema as well as space-occupying intracranial lesions may reduce CBF'146 and, although there was no evi-

dence of the latter, some cerebral swelling may have been present in the post-arrested state. Regardless of what specific factors resulted in a fall in CBF, the most noteworthy finding in this study was the return of cerebral oxygen consumption to the normothermic control level. The capability of the brain to compensate for a decline in blood flow with an increase in oxygen extraction after the double insults of deep hypothermia and complete circulatory arrest explains the restoration of adequate cerebral metabolic activity. In the post-hypothermic period, a decrease in the mean blood pressure as compared to the pre-cooling period was noted (Table 2). It has been demonstrated that the cerebral blood flow is unaffected by the level of systemic blood pressure provided the mean systemic blood

pressure

remains above 60 to 65

mm.

Hg.'1217

This fact is important when interpreting the decline of the CBF since, despite a fall of systemic blood pressure after rewarming, the decrease in cerebral blood flow at this time must be due to intrinsic cerebral factors and not the result of altered systemic hemodynamics.

A comparison of the oxygen consumption values obtained in the initial pre-cooling state with the oxygen consumption values measured at the end of the rewarming phase must take into account several variables introduced by necessity into the study. The initial cerebral metabolic measurements were made with the animals anesthetized with sodium thiamylal, a barbiturate derivative. Barbiturates are well known to affect cerebral metabolic activity, with the degree of metabolic depression related to the depth of anesthesia.13'19'27 At the time of the post-rewarming cerebral metabolic studies, these animals were beginning to recover from the obtunded state in which they had been during rewarming. In some of the animals, small doses of sodium thiamylal were administered during rewarming, but only when the animals began to move or struggle against the respirator before com-

'1 ABLE 3. Cerebral Po, Measurements

Beginning of circuilatory arrest After 15 minutes of circtulatory arrest After 30 minuLtes of circtulatory arrest After 45 minultes of circulatory arrest % decrease dturing circulatory arrest

No. 1 57 49 46 46

119.3%

(mm. Hg) No. 2 100 68 66 66

33%

No. 5

62

No. 4 106 75 60 59

39.2%

44.4%

39%

No. 3 102 67 66

95 62 59 58

Median 100 67 60 59

Vol. 178 . No. 1


TABLE 4. Cerebral Pco0 Measurements

Beginning of circulatory arrest After 15 mintutes of circulatory arrest After 30 minutes of circulatory arrest After 45 miniutes of circulatory arrest % increase during circulatory arrest

(mm. Hg)

No. 1

No. 2

No. 3

29 29 46 62

11 12 22 29

23 36 48 63

No. 4 20 24 41 52

T114%

163%

174%

160%

pletion of the rewarming. It is not possible to assess accurately how these different types of neurologic depression counterbalance when considering the effects on cerebral oxygen consumption. It is likely, however, that during the initial measurements the degree of metabolic depression was greater. The other major variables which are present in this study involve the changes in the blood gas and pH levels before and after hypothermia. When the initial measurements were made, the arterial Po2 and pH were higher and the Pco2 levels were lower (Po2 450 to 600 mm. Hg., Pco2 40 to 45 mm. Hg, and pH 7.40 to 7.50). After rewarming, the Po2 ranged from 150 to 250 mm. Hg despite continued 100% oxygen inhalation. The pH levels were between 7.22 and 7.34 and the Pco2 ranged from 45 to 60 mm. Hg. Despite the reduction in the blood Po2 levels after rewarming, the arterial oxygen saturation remained nearly 100% and the decrease in the arterial Po2 levels should, therefore, have no effect on the CMRO.). A reduction in the pH levels might have affected the post-hypothermia metabolic studies since cerebral blood flow has been shown to be greater in an acidotic state regardless of the level of the Pc02.14 In addition, the hypercapnia seen in all of these animals following rewarming would have produced a definite cerebral vasodilatation with a resultant increase in the CBF, as has been demonstrated both experimentally and clinically."1 15 There was, however, a decrease in CBF at this time confirming the fact that some degree of cerebral damage must exist in the animals' in the posthypothermic state. The changes observed in the blood pressure and the cerebral vascular resistance during the three periods of measurements are noteworthy for several reasons. The characteristic decline in the systemic arterial pressures during cooling is well established, as is the gradual decline in the pulse rate.25 Of special interest is the lack of any increase in the cerebral vascular resistance during deep hypothermia in spite of very low arterial Pco, levels at that time. This finding is at variance with the observations of Edmunds, who used a pump to supply blood to the brain at a constant pulse pressure regardless of the level of body temperature.9 At 18 to 20 C and prior to circulatory arrest in this present study, the arterial Pco2 levels in the dogs ranged be-

No. 5 44 58 106 118 170%

Median 23 24 46 62

tween 12 and 20 mm. Hg as a result of hyperventilation. Kety described a direct relationship between ar-

terial carbon dioxide levels and cerebral blood flow and, because of this relationship, Belsey and others have recommended the use of hypercapnia as a means of achieving cerebral vascular dilatation during hypothermia.220 Using Mohri's method of surface induced hypothermia with hyperventilation and a resultant respiratory alkalosis, arterial Pco2 levels fell to very low levels, but despite this marked decline there was no significant change in the cerebral vascular resistance, as noted in Table 2. The direct monitoring of cerebral cortical Po2 and Pco2 using the mass spectrometer during circulatory arrest provides a means of observing the basic metabolic activity of the brain during a period of prolonged anoxia. The typical pattern of change of the cortical Po2 level

90 80 70

60 mm. Hg

50 40

30

-

20 P02 PCO2

10-

5

10

15 20 25 30 35 40 TIME IN MINUTES

45

FIG. 2. Changes in cerebral cortical Po2 and Pco2 levels during circulatory arrest.

100


observed in this study, namely an early anid significant decline in Po2 followed bv stabilization of the oxvgen at a reduced level suggests that cerebral cortical oxygen is depleted during the initial 10 to 15 minutes of arrest. The subsequent elevation of the cortical Pco2 level after oxygen depletion is closely similar to what occurs in the myocardium during anoxic cardiac arrest,"'J0 and the Pco., elevation is interpreted as being a result of anaerobic metabolism. The fact that the rate of elevation of the Pco2 level is nearly cbnstant during the arrest suggests a steady rate of metabolic activity in the brain despite the complete lack of circulation. Although there is no apparent correlation between the cortical gas tension changes during the circulatory arrest period and the post-arrest metabolic changes in these five animals, the direct cortical measurements do provide a means of monitoring the basic metabolic changes in the brain during the period of circulatory arrest. Summary

1. Cerebral metabolic activity was measuired in ten

dogs undergoing deep hypothermia and circulatory arrest for 45 minutes using a method of surface induced cooling, ether anesthesia, and hyperventilation. Cerebral blood flow and cerebral oxygen consumption were measured utilizing a mass spectrometer by the inert gas technic. 2. Cerebral oxygen consumption at the completion of circulatory arrest and rewarming increased 15% over the mean pre-cooling rate of oxygen consumption, indicating a restoration of adequate cerebral metabolic activity. A mean decrease in the cerebral blood flow of 18% and an increase of cerebral vascular resistance of 8% in the post-arrest state was found, suggesting mild cerebral vascular damage. 3. Direct and continuous measurements of the cerebral cortical Pco, and Pco2 levels during the 45 minuites of circulatory arrest in five animals indicate continuing cerebral metabolic activity during the arrest period, with braini oxygen utilization ceasing after the first 15 minutes of the arrest period. 4. Despite the marked lowering of the blood Pco2 levels in the aniimals at deep hypothermic levels as a restult of the hyperventilation, there was no evidence of an increase in cerebral vascular resistance. 5. Using the technic of surface induced hypothermia with ether anesthesia anid hyperventilation, circulatory arrest for 45 minutes at 18 C was tolerated by the animals without evidence of impairment of cerebral metabolism, despite a consistent reduction in cerebral blood flow.

Anni. Surg.

.

July 1973

References 1. Barratt-Boyes, B. G., Simpson, M. and Neutze, J. M.: Intracardiac Surgery in Neonates and Infants using Deep Hypothermia with Surface Cooling and Limited Cardiopulmonary Bypass. Circulation, 43, Suppl. 1:25, 1971. 2. Belsey, R. H., Dowlatshaki, K. and Skinner, D. B.: Profound Hypothermia in Cardiac Surgery. J. Thorac. Cardiovasc. Surg., 56:497-506, 1968. 3. Bigelow, W. G., Lindsav, WV. K. and Greenwood, W. F.: Hypothermia: Its Possible Role in Cardiac Surgery. Ann. Surg., 132:849, 1950. 4. Bigelow, W. G. and McBirnie, J. E.: Further Experience with Hypothermia for Intracardiac Surgery in Monkeys and Groundhogs. Ann. Surg., 137:361, 1953. 5. Brantigan, J. W., Gott, V. L., Vestal, M. L., Fergusson, G. J. and Johnston, WV. H.: A Nonthrombogenic Diffusion Membrane for Continuous in vivo Measurement of Blood Gases by Mass Spectrometry. J. Appl. Physiol., 28:375, 1970. 6. Brantigan, J. W., Perna, A. M., Gardner, T. J. and Gott, V. L.: Intramyocardial Gas Tensions in the Canine Heart During Anoxic Cardiac Arrest. Surg. Gynecol. Obstet., 134:67, 1972. 7. Dillard, D. H., Mohri, H. and Merendino, K. A.: Correction of Heart Disease in Infancy Utilizing Deep Hypothermia and Total Circulatory Arrest. J. Thorac. Cardiovasc. Surg., 61:64, 1971. 8. Dillard, D. H., Mohri, H., Merendino, K. A., Morgan, B. C., Baum, D. and Crawford, E. W.: Total Surgical Correction of Transposition of the Great Arteries in Children Less Than Six Months of Age. 129:1258, 1969. 9. Edmunds, L. H. and Folkman, J.: Cerebral Metabolism During Hypothermia and Circulatory Arrest. J. Surg. Res., 1:201, 1961. 10. Gardner, T. J., Brantigan, J. W., Perna, A. M., Bender, H. W., Brawley, R. K. and Gott, V. L.: Intramyocardial Gas Tensions in the Human Heart During Saphenous Vein-coronary Artery Bypass. J. Thorac. Cardiovasc. Surg., 62:844, 1971. 11. Gibbs, F. A., Maxwell, H. and Gibbs, E. L.: Volume Flow of Blood Through the Huiman Brain. AMA Arch. Neurol. Psych., 57:132, 1947. 12. Hafkenschiel, J. H., Crumpton, C. W., Shenkin, H. A., Mayer, J. H., Zintel, H. A., Wendel, H. and Jeffers, W. A.: The Effects of 200 Head-up Tilt upon the Cerebral Circulation of Patients with Arterial Hypotension Before and After Sympathectomy. J. Clin. Invest., 30:793, 1951. 13. Homburger, E., Himwich, W. A., Etsten, B., York, G., Mlaresca, R. and Himwich, H. E.: Effect of Pentothal Anesthesia on the Canine Cerebral Cortex. Am. J. Physiol., 147:343, 1946. 14. Ketv, S. S.: Circulation and Metabolism of the Human Brain in Health and Disease. Am. J. Med., 8:205, 1950. 15. Kety, S. S. and Schmidt, C. F.: The Effects of Altered Arterial Tensions of Carbon Dioxide and Oxygen on Cerebral Blood Flow and Cerebral Oxygen Consumption of Normal Young MIen. J. Clin. Invest., 27:484, 1948. 16. Kety, S. S., Shenkin, H. A. and Schmidt, C. F.: The Effects of Increased Intracranial Pressure on Cerebral Circulatory Functions in Man. J. Clin. Invest., 27:493, 1946. 17. Lassen, N. A.: Cerebral Blood Flow and Oxygen Consumption in Man. Physiol. Rev., 39:183, 1959. 18. Lewis, F. J. and Tauffic, M.: Closure of Atrial Septal Defects wzith the Aid of Hypothermia: Experimental Accomplishments and the Report of One Successful Case. Surgery, 33: 52, 1953.

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19. McCall, M. L., Tavlor, H. W. an(d Finch, T. V.: The Effects of Intravenouslv Administered Sodium Amytal on Cerebral Circulation and Metabolism in Toxemia of Pregnancy. J. Phila. Gen. Hosp., 3:110, 1952. 20. Malette, W. G., Fitzgerald, J. B. and Eiseman, B.: Hypercapnia: A Means of Inereasing Oxygen Availability During Hypothermic Perfusion. Surg. Forum, 12:184, 1961. 21. Miclhenfelder, J. D. and Theye, R. A.: Hvpothermia: Effects on Canine Brain and WVhole Body Metabolism. Anesthesiology, 29:1107, 1968. 22. Mohri, H., Barnes, R. XV., Winterscheid, L. C., Dillard, D. H. and Merendino, K. A.: Challenge of Prolonged Suspended Animation: A Mlethod of Surface-induced Deep Hypothermia. Ann. Surg., 168:779, 1968. 23. Mfohri, H., Hessel, E. A., Nelson, R. J., NIatano, I., Anderson, H. N., Dillard, D. H. and Mlerendino, K. A.: Use of Rheomacrodex and Hyperventilation in Prolonged Circulatory

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