Brain tissue pH, oxygen tension, and carbon dioxide tension in profoundly hypothermic cardiopulmonary bypass

J

THoRAc CARDIOVASC SURG

1989;97:396-401

Brain tissue pH, oxygen tension, and carbon dioxide tension in profoundly hypothermic cardiopulmonary bypass Comparative study of circulatory arrest, nonpulsatile low-flow perfusion, and pulsatile low-flow perfusion The pH, oxygen tension, and carbon dioxide tension of canine brain tissue were experimentally examined during profoundly hypothermic cardiopulmonary bypass. After core cooling, a 6O-minute period of circulatory arrest was performed in group 1 (n = 8), a l2o-minute nonpulsatile low-flow perfusion (25 m1jkgjmin) in group 2 (n = 8), and a l2o-minute pulsatile low-flow perfusion (25 m1jkgjmin) in group 3 (n = 8). When the animal was rewarmed, the core temperature was raised to 32 0 C. Brain tissue pH kept decreasing in group 1, but it showed a delayed recovery in group 2 and a rapid recovery in group 3 during core rewarming. Brain tissue oxygen tension decreased significantly in group 1. Brain tissue carbon dioxide t~ion increased irreversibly in group 1, increased to about 100 mm Hg and recovered to 89.9 ± 15.3 mm Hg in group 2, and reached a plateau of about 85 mm Hg and recovered to 55.4 ± 6.7 mm Hg in group 3. We concluded that a l2o-minute period of nonpulsatile low-flow perfusion provides more protection from brain damage than a 6O-minute period of circulatory arrest Furthermore, pulsatile flow will increase the safety margin of cardiopulmonary bypass even if the flow rate is reduced to 25 m1jkgjmin.

Takao Watanabe, MD, Hiroyuki Orita, MD, Minoru Kobayashi, MD, and Masahiko Washio, MD, Yamagata, Japan

In corrective operations for cyanotic heart disease in infants, reduced cardiopulmonary bypass (CPB) flow or circulatory arrest is often required for adequate surgical exposure. Profound hypothermia is generally used to protect the vital organs. Sixty minutes or less of circulatory arrest has been accepted as a safe limit.!" However, the risk of brain damage still remains;" and an efficient method to avoid brain damage is essential to prolong the period during which the operative field can From the Second Department of Surgery, Yamagata University School of Medicine, Zao-iida, Yamagata, Japan Supported by a grant-in-aid for special project research, 1985, of the Ministry of Education, Science and Culture, Japan. Received for publication Nov. 18, 1987. Accepted for publication May 10, 1988. Address for reprints: Takao Watanabe, MD, Second Department of Surgery, Yamagata University School of Medicine, Zao-iida, Yamagata 990-23, Japan.

396

safely be kept dry. Kirklin" and Miyamoto and associates 7 recommended reduced CPB flow during profound hypothermia. However, can a low-flow perfusion prolong the safe period, and is pulsatile flow efficacious during reduced CPB flow? The second question is the subject of this experiment. Our purpose was to determine the possibility of brain damage when profound hypothermia is induced by CPB. For this purpose, we measured pH, oxygen tension (Po.), and carbon dioxide tension (Pco.) in the brain tissue. Sixty minutes of circulatory arrest, 120 minutes of nonpulsatile low-flow perfusion, and 120 minutes of pulsatile low-flow perfusion were experimentally evaluated. Materials and methods Animal preparation and experimental procedure. Twentyfour mongrel dogs (aged birth to 3 years, weight 7 to 12 kg) were divided into three groups. In group I (n = 8), 60 minutes of circulatory arrest was performed; in group 2 (n = 8), 120

Volume 97 Number 3 March 1989

Brain tissue pH, Po2, and Pco, 3 9 7

pH

Brain Tissue pH

7.5

e-e I

6.5

~ '. ~~IU ~.

I Cooling I Circulatory Arrest Low Flow n.m I Cooling I Pre

I

0

Pulsatile

L F P

I! I

I

6.0

Arrest

o-oR L F P

l>--,m

7.0

Circulatory

Warming

I

Perfusion

I 60min

Warming

I End (I)

I 120min

I End
Fig. 1. Brain tissue pH kept decreasing in group 1. A delayed recovery was found in group 2, and a fast recovery was found in group 3. LFP, Low flow perfusion. minutes of nonpulsatile low-flow perfusion; and in group 3 (n = 8), 120 minutes of pulsatile low-flow perfusion. The animals used in this study 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" prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH Publication No. 80-23, revised 1978). Dogs were anesthetized with pentobarbital sodium (25 mg/kg) and the lungs ventilated mechanically with room air after intubation. The right side of the cranium was opened and electrodes to measure pH, Po 2, and Pco, were introduced into the parietal area of the cerebrum. The chest was opened with a median sternotomy. After heparinization (3 mg/kg), the superior and inferior venae cavae were cannulated via the right atrium. An arterial cannula (l4F, Sherwood Medical, St. Louis, Mo.) was placed in the ascending aorta. Then rapid core cooling was started with high-flow CPB (80 to 100 ml/kg/rnin), and the aortic root was clamped. CPB flow was reduced to 60 ml/kgjrnin when the rectal temperature decreased to 25° C. When the brain and rectal temperature decreased below 20° C, core cooling was stopped and circulatory arrest was continued for 60 minutes in group I. Nonpulsatile low-flow perfusion (25 ml/kg/min) was continued for 120 minutes in group 2, and pulsatile low-flow perfusion (25 nil/kg/min, 0.83 rnl/kg . 30 beats/min) was continued for 120 minutes in group 3. After circulatory arrest (group I), nonpulsatile low-flow perfusion (group 2), or pulsatile lowflow perfusion (group 3), perfusion rewarming was started with a flow rate of 60 ml/kg/rnin, rising to 100 nil/kg/min when the brain temperature reached 25° C. Finally, when

both the brain and rectal temperatures reached 32° C, the final measurement and blood sampling were done and the animals were put to death at CPB completion. Devices and items of measurement. A conventional roller pump was used in groups I and 2 and a pulsatile pump (PP-ll, Nikkiso Co. Ltd., Tokyo, Japan) in group 3. In the pulsatile pump, the one-stroke volume was set at 10 ml during the core cooling and rewarming periods and at 0.83 ml/kg with 30 beats/min during the pulsatile low-flow perfusion period. An oxygenator (Bio-2, Bentley Laboratories, Inc., Baxter Healthcare Corporation, Irvine, Calif.) with an oxygen flow rate of 3 L/min was used; 5% carbon dioxide was added during the core cooling and low-flow perfusion periods. Fresh dog blood (500 ml) with acid-citrate-dextrose, lactated Ringer's solution (500 ml), 20% mannitol solution (5 ml/kg), and 8.4% sodium bicarbonate (60 ml) were used as priming solutions. An MI-41O pH electrode (Micro-Electrodes Inc., Londonderry, N.H.) with a CG-817 digital pH meter (Schott America, Yonkers, N.Y.) was used to measure the brain tissue pH. A KR-500 pH/Pco2 monitor with a CO-1035 Peo2 / temperature sensor (Kurare Co., Inc., Kurashiki City, Okayarna, Japan) was used to measure the brain tissue Pco, and temperature. A P0 2 sensor and a monitor (module 636: Kontron Instruments, Everett, Mass.) was used to measure the brain tissue Po 2• These values, monitored continuously, were recorded every 5 minutes during the cooling period, every 10 minutes during circulatory arrest or low-flow perfusion periods, and were recorded every 5 minutes during the perfusion rewarming period. Blood samples for gas analysis were obtained from arterial and venous CPB lines at 10 minutes of core cooling in all three groups, at 5, 60, and 120 minutes of low-flow perfusion in

398

The Journal of Thoracic and Cardiovascular Surgery

Watanabe et al.

.-. I

Brain

Tissue

P02

P02

Circulatory Arrest

0-0

II L F P

to-to

m

Pulsatile

L F P

(mmHg)

50

20 10 5

I ICooling !I.m ICooling I Pre

I 20min

Circulatory

Arrest

Low

Flow

I 0

Warming

Perfusion

I 60min

Warming

I End( I)

I 120min

I End(ll,

m)

Fig. 2. Brain tissue P0 2 decreased significantly during circulatory arrest (20 to 60 minutes) in group I. Slow but insignificant decreases were found in groups 2 and 3 during low flow perfusion (LFP). groups 2 and 3, at 10 minutes, and at the end of core rewarming in all three groups. The samples were analyzed for pH, POlo Pco-, and base excess with an ABL-2 gas analyzer (Radiometer A/S, Copenhagen, Denmark). On the basis of the Fick principle, whole body oxygen consumption was calculated from arterial and venous blood gas analyses. Perfusion pressure was measured continuously. All results are expressed as the mean ± standard deviation. Statistical analysis was done by Student's t test (paired and unpaired).

Results Brain tissue pH (Fig. 1). Before CPB, the brain tissue pH was 6.96 ± 0.21 in group 1, 6.93 ± 0.11 in group 2, and 6.86 ± 0.11 in group 3. In all three groups, the brain tissue pH decreased during the circulatory arrest or during the low-flow perfusion period. During core rewarming, there was a fast recovery in group 3 and a delayed recovery in group 2, but no recovery in group 1. In all three groups the decrease in pH was statistically significant when compared with the mean values before CPB. The pH value remained low from 20 minutes of circulatory arrest or low-flow perfusion until the end of all procedures in groups 1 and 2 but was low only from 30 minutes of low-flow perfusion until 10 minutes of core rewarming in group 3 (p < 0.05). Brain tissue POz (Fig. 2). In group 1, the brain tissue POl decreased significantly from 20 to 60 minutes of circulatory arrest (p < 0.01). It was significantly lower than that of groups 2 and 3 during the low-flow perfusion period (p < 0.025). Brain tissue Pco, (Fig. 3). During the circulatory arrest and low-flow perfusion periods, the increase in Pco, was evident. In group 1, the rate of Peo l rise

accelerated, the final value reaching 89.9 ± 15.8 mm Hg. In group 2, Pco, rose continously and exceeded 100 mm Hg. In group 3, Pco, reached a plateau of about 85 mm Hg. During the core rewarming period, Pco, increased remarkably and remained high in group 1. In group 2, it decreased gradually after a slight increase. In group 3, it recovered rapidly to the physiologicrange. At the end of all procedures, Pco; was 118.3 ± 37.9 mm Hg in group 1, 89.9 ± 15.3 mm Hg in group 2, and 55.4 ± 6.7 mm Hg in group 3. Brain tissue Pco, in group 3 was significantly lower than that in group 1 after 10 minutes of core rewarming, and it was lower than that of group 2 after 80 minutes of low-flow perfusion (p < 0.05). Arterial blood gas analysis (Table I). Arterial blood pH decreased in all groups. No significant difference was found among groups. Arterial Pco, was maintained at about 40 mm Hg during CPB in all groups. Arterial POl was above 100 mm Hg in all. The base excess kept decreasing in groups 1 and 2 but recovered slightly in group 3. The decrease of base excess was significant in group 1 (p < 0.005), in group 2 (p < 0.01), and in group 3 (p < 0.05). At 10 minutes of core rewarming, the whole body oxygen consumption of group 1 was significantly higher than that of groups 2 and 3 (p < 0.005). Perfusion pressure (Fig. 4). During nonpulsatile low-flow perfusion in group 2, the perfusion pressures were 31.4 ± 3.9/24.5 ± 3.6/29.1 ± 3.8 mm Hg (highest/lowest/mean). During pulsatile low-flow perfusion in group 3, they were 36.9 ± 7.9/19.8 ± 7.2/25.2 ± 6.8 mm Hg (highest/lowest/mean). Pulse pressure was 6.9 ± 1.7 mm Hg in nonpulsatile low-flow perfusion

Volume 97 Number 3 March 1989

Brain tissue pH, Po], and

PC02 (mmHg)

Brain Tissue

399

. - . I Circulatory Arrest

PC02

0-0

150

n

L F P

l>-"M Pulsatile L F P

100

I J-rJ ! ! lJ /J!'r LlkMf1!-1t r'rrt I fltl T

50

n»,

IwjWI~r1 1 'timI r;:::;;;::,1r--

IT

~"h'),""ml

, II

C-i r-c-uI-aI-o-rY-A-r-re-s-I-I

Wa r min g

I(I)

'----------------I

~I

Low

Flow

Perfusion

o

Pre

End(IIl

Warming

End(I) 120min

60min

End
Fig. 3. Brain tissue Pco, kept increasing and remained high in group I, A continuous elevation was followed by a delayed recovery in group 2, A plateau of about 85 mm Hg was followed by a rapid recovery in group 3, LFP. Low flow perfusion.

and 17.1 ± 2.4 nun Hg in pulsatile low-flow perfusion. In group 3, despite a reduced CPB flow, a physiologic waveform was maintained.

.

-aOmmHg - - - - - - - - - - - - -

..

lsecond

Discussion Brain tissue pH, Po 2, and Pco, have rarely been examined during profound hypothermia induced by CPB or surface cooling. Kawakami" showed that, during 30 minutes of circulatory arrest at 20 0 C, brain tissue P0 2 decreases whereas brain tissue Pco, increases. Katogi? showed that, during 45 minutes of low-flow perfusion (25 ml/kg/rnin) at 20 C, the brain tissue Pco, increases without a decrease of brain tissue Po 2• The tissue values for pH, Po 2, and Pco, are thought to indicate their mean values in extracellular fluid in a limited tissue area. Ischemia decreases the brain tissue pH. 10. II The brain tissue Pco, is lower than the venous Pco, during physiologic conditions, 12.13 but high intracranial pressure increases the brain tissue Pco, as a result of tissue malperfusion and hypoxia." Therefore, reflecting the quality of brain microcirculation, these values are thought to indicate the possibility of brain damage. Brain tissue pH before CPB was lower than its physiologic range in all three groups. 10. II This decrease of pH was thought to be the result of the operation including a craniotomy, a mediastinotomy, and a cannu-

o -

aOmmHg

..

..

lsecond

0

....

-.-..

-0 Fig. 4. Perfusion pressure waveform during low flow perfusion with pulsatile pump (top) and with roller pump (bottom).

lation. Throughout the procedure, pH kept decreasing during circulatory arrest. In contrast, pulsatile flow limited the decrease of pH and allowed a fast recovery. Brain tissue P0 2 before CPB was within the physiologic range,":" An evident decrease in P0 2 was found during circulatory arrest but not during low-flow perfusion. Circulatory arrest caused a remarkable elevation in

The Journal of Thoracic and Cardiovascular Surgery

4 0 0 Watanabe et al.

Table I. Arterial blood gas analysis Group

Cooling (10 min)

pH 7.28 ± 0.13 I 7.42 ± 0.08 2 7.35 ± 0.14 3 Base excess I -6.6 ± 2.1* 2 -4.0 ± z.it 3 -5.7 ± 3.4:1: Whole body oxygen consumption (nil/kg/min) I 1.35 ± 0.49 2 1.19 ± 0.24 3 1.19 ± 0.42

LFP (120 min)

Warming (10 min)

End

7.24 ± 0.10 7.22 ± 0.06

7.30 ± 0.24 7.30 ± 0.06 7.32 ± 0.11

7.17 ± 0.11 7.22 ± 0.07 7.27 ± 0.06

-9.3 ± 4.0 -10.7 ± 1.8

0.58 ± 0.11 0.53 ± 0.12

-10.5 ± 3.2 -10.7 ± 3.7 -9.8 ± 2.4 2.66 ± 0.47 1.54 ± 0.65 1.11 ± 0.27

-13.9 ± 2.9* -12.0 ± 4.6t -9.5 ± 2.6:1: 4.18 ± i.ou 3.40 ± 1.38 3.18 ± 0.58:1:

LFP, Low-flow perfusion (25 mljkgjmin). 'p < 0.005. tp < 0.01. :j:p <0.05.

Pco, without a recovery. In contrast, pulsatile low-flow perfusion limited the elevation, resulting in the plateau of Pco, and a fast recovery, whereas nonpulsatile low-flow perfusion caused a continuous elevation with a delayed recovery. We believe that this plateau indicates a homeostatic condition and demonstrates the advantage of pulsatile flow, especially in a prolonged low-flow perfusion. In arterial blood gas analysis, blood base excess decreased the least during pulsatile flow. A significantly high rate of whole blood oxygen consumption, 10 minutes after circulatory arrest, is considered the result of oxygen debt during the circulatory arrest period. In contrast, oxygen consumption was slight after pulsatile low-flow perfusion. These results are also consistent with our hypothesis that pulsatile blood flow can maintain an efficient tissue perfusion, resulting in excellent organic preservation, even if CPB flow is reduced. We think that a 6Q-minute period of circulatory arrest is critical and that low-flow perfusion (25 ml/ kg/min) can prolong the safe period. Furthermore, pulsatile blood flow reduces the risk of brain damage even during low-flow perfusion. Geha," Mori," and their associates, using circulatory arrest, showed the advantage of pulsatile blood flow in brain metabolism. Matsumoto, Wolferth, and Perlman" showed that, at 37° C, pulsatile flow improves microcirculation and eliminates blood sludging. While using high-flow pulsatile perfusion for core cooling and circulatory arrest, Williams and associates" showed excellent clinical results with cardiac operations in infants. Pulsatile blood flow generally has been examined at a high flow rate, as mentioned earlier. However, we believe

that pulsatile blood flow should be particularly applied to low-flow perfusion for the following reasons: First, blood sludging will be more evident during profoundly hypothermic CPB than during normothermic CPB, because of the increased viscosity. Second, the decrease in flow rate will increase the impairment of microcirculation all the more. We think that, in this condition, pulsatile flow alone can improve tissue perfusion, preventing blood sludging. Previously, Orita" showed that myocardial tissue Pco, remained high during the fibrillation period and fell rapidly immediately after defibrillation in man. This rapid fall in myocardial Pco, shows the mechanical effect of pulsation in the myocardium itself, and we considered this an improvement in microcirculation. On the other hand, the brain is quiet, without any mechanical motion, but has a high metabolic rate and is susceptible to hypoxia. In brain tissue, microcirculatory improvement by mechanical methods can be obtained only by pulsatile blood flow during profoundly hypothermic CPB. The results of this study show that, during profoundly hypothermic CPB, pulsatile blood flow is beneficial for brain protection and can increase the safety margin of low-flow perfusion. REFERENCES 1. Niitu K, Okamura H, Yonezawa T. Results in 282 cases

of open heart surgery performed under simple deep hypothermia. Bull Soc Int Chir 1966;25:362-75. 2. Mohri H, Barnes RW, Winterscheid LC, Dillard DH, Merendino KA. Challenge of prolonged suspended animation: a method of surface-induced deep hypothermia. Ann Surg 1968;168:779-87.

Volume 97 Number 3 March 1989

3. Brierley JB. Brain damage complicating open-heart surgery: a neuropathological study of 46 patients. Proc R Soc Med 1967;60:34-5. 4. Muraoka R, Yokota M, Aoshima M, et al. Subclinical changes in brain morphology following cardiac operations as reflected by computed tomographic scans of the brain. J THORAC CARDIOVASC SURG 1981;81:364-9. 5. Treasure TMS, Naftel DC, Conger KA, Garcia JH, Kirklin JW, Blackstone EH. The effect of hypothermic circulatory arrest time on cerebral function, morphology, and biochemistry. J THORAC CARDIOVASC SURG 1983; 86:761-70. 6. Kirklin JW. Advances in cardiovascular surgery. New York: Grone & Stratton, 1973:89-90. 7. Miyamoto K, Kawashima Y, Matsuda H, Okuda A, Maeda S, Hirose H. Optimal perfusion flow rate for the brain during deep hypothermic cardiopulmonary bypass at 20° C. J THORAC CARDIOVASC SURG 1986;92:106570. 8. Kawakami S. Cerebral circulation and metabolism in core cooling. J Jpn Assoc Thorac Surg 1976;24:1501-12. 9. Katogi T. Analysis of brain tissue gas tension during hypothermic low flow perfusion. J Jpn Assoc Thorac Surg 1983;31 :1505-12. 10. Sako K, Kobatake K, Yamamoto YL, Diksic M. Correlation of local cerebral blood flow, glucose utilization, and tissue pH following a middle cerebral artery occlusion in the rat. Stroke 1985;16:828-34. II. Meyer FB, Anderson RE, Sundt TM Jr, Yaksh TL. Intracellular brain pH, indicator tissue perfusion, electroencephalography, and histology in severe and moderate

Brain tissue pH,

POz,

and Pco,

40 1

focal cortical ischemia in the rabbit. J Cereb Blood Flow Metab 1986;6:71-8. 12. Seylaz J, Pinard E, Meric P, Correze JL. Local cerebral POz, PCOz, and blood flow measurements by mass spectrometry. Am J Physiol 1983;245:H513-8. 13. Hogg RJ, Pucacco LR, Carter NW, Laptook AR, Kokko JP. In situ Pco, in the renal cortex, liver, muscle, and brain of the New Zealand White rabbit. Am J Physiol 1984;247:F491-8. 14. Roberts M, Owens G. Direct mass spectrographic measurement of regional intracerebral oxygen, carbon dioxide, and argon. J Neurosurg 1972;37:706-10. 15. Geha AS, Salaymeh MT, Abe T, Baue AE. Effect of pulsatile cardiopulmonary bypass on cerebral metabolism. J Surg Res 1972;12:381-7. 16. Mori A, Sono J, Nakashima M, Minami K, Okada Y. Application of pulsatile cardiopulmonary bypass for profound hypothermia in cardiac surgery. Jpn Circ J 1981;45:315-22. 17. Matsumoto T, Wolferth CC Jr, Perlman MH. Effects of pulsatile and non-pulsatile perfusion upon cerebral and conjunctival microcirculation in dogs. Am Surg 1971; 37:61-4. 18. Williams GD, Seifen AB, Lawson NW, et al. Pulsatile perfusion versus conventional high-flow non-pulsatile perfusion for rapid core cooling and rewarming of infants for circulatory arrest in cardiac operation. J THORAC CARDIOVASC SURG 1979;78:667-77. 19. Orita H. Intramyocardial pH and Pco, monitoring as an index of myocardial preservation during anoxic arrest and reperfusion. J Jpn Assoc Thorac Surg 1985;33:1028-42.