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Relationship of brain blood flow and oxygen consumption to perfusion flow rate during profoundly hypothermic cardiopulmonary bypass
J
THoRAc CARDIOVASC SURG
87:658-664, 1984
Relationship of brain blood flow and oxygen consumption to perfusion flow rate during profoundly hypothermic cardiopulmonary bypass An experimental study A study was made of the relation of brain blood flow and oxygen co~ption to changes in pe~ion flow rate during cardiopulmonary bypass at 20° C in nine cynomolgus monkeys. Four ~ion flow rates varyingfrom 0.25 to 1.75 L . min-I. m- 1 were randomlyinstituted, each for a 10 minute period.At the end of each period, brain arteriovenolfi oxygen content differencewas measured and 15 J.I. radioactive microsphereswere injected into the arterial perflfiionline. The brain was then removed and sectionedinto anatomic regions and radioactivity was counted. Regional and total brain bloodflows were calculated, as was whole brain oxygen consumption. Brain pert'miion continued in all areas at all perflfiionflow rates. Whole brain blood flow decreased (P < 0.0001) as pe~ion flow rate was reduced (45 ± 6.5,41 ± 7.9, and 23 ± 2.8 mI . min-I . 100 gm-I at 1.5, 1.0, and 0.5 L . min-I. m- 1, respectivefy), The proportion of the total pe~ion delivered to the brain increased (P = 0.003) with decreasing pert'miion flow rates (5.4% ± 0.78%,7.1 % ± 1.24%, and 8.2% ± 1.11% atl.5, 1.0, and 0.5 L . min-I. m- 1, respectively). Brain blood flow resistance remained unchanged (p = 0.4) while that of the remaining body increased (p < 0.0001~ There was a greater reduction of bloodflow in the cortical white matter (p = 0.01) than in other regions of the brain. Brain oxygen consumption was the same (p = 0.5) at all pe~ion flow rates, related to an increasing percent oxygen extraction with decreasing pe~ion flow rate (p < 0.0001~ The data indicate that all areas of the brain remain pert'm;ed, even at low perflfiion flow rates, during profoundly hypothermic cardiopulmonary bypass, and that brain oxygen co~ption is maintained in part by increased oxygen extraction and in part by redistribution of the perfusate from the remaining body to the brain.
Lawrence S. Fox, M.D., Eugene H. Blackstone, M.D., John W. Kirklin, M.D., Sanford P. Bishop, D.V.M., Ph.D., Leif A. L. Bergdahl, M.D.,· and Edwin L. Bradley, Ph.D., Birmingham. Ala.
"W:ole body oxygen consumption falls progressively as the perfusion flow rate is reduced during profoundly From the Departments of Surgery and of Biostatistics and Biomathematics, University of Alabama in Birmingham, Birmingham, Ala. Supported in part by the Birmingham Veterans Administration Hospital and by Program Project Grant HLl131O, National Heart, Lung and Blood Institute, NIH, Bethesda, Md. Received for publication March 4, 1983. Accepted for publication June 6, 1983. Address for reprints: Eugene H. Blackstone. M.D., Department of Surgery, University Station, Birmingham, Ala. 35294. *Current address: The Thoracic Surgical Clinic, Karolinska Hospital, Stockholm, Sweden.
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hypothermic total cardiopulmonary bypass (CPB) in man. I However, the pattern of changes in internal jugular venous oxygen levels during these reductions indicate that brain oxygen consumption may behave differently.' Therefore, an experimental study was undertaken to investigate possible differences between the responses of the brain and those of the body as a whole to changing perfusion flow rates during profoundly hypothermic CPB.
Materials and methods Experimental design. Nine cynomolgus (Macaca irus) monkeys were cooled to 20° C by hypothermic CPB. Then during each of four consecutive 10 minute
Volume 87 Number 5 May, 1984
experimental periods, a different perfusion flow rate was used. At the end of each period, arterial, internal jugular venous, and mixed venous blood samples were drawn for determination of oxygen content and calculation of arteriovenous oxygen content difference, and 15 J.L radioactive microspheres were injected. A 3 minute period was then allowed for distribution, during which time 3 to 4 mI of arterial and internal jugular venous blood samples were withdrawn at a constant rate for determination of microsphere nonentrapment (found to be 3% to 4% of that injected in two instances, 2% to 3% in one, 1% to 2% in four, and less than 1% in the other 29 samples). A new perfusion flow rate was then established and the second experimental period was begun. The sequence was repeated until all four experimental periods had been completed. The animal then was rendered asystolic by an intravenous dose of potassium chloride, after which the brain was removed for completion of the studies of flow by the microsphere method. The flow rate used during the experimental periods varied from 0.25 to 1.75 L . min-I. m'. Flows of 0.5, 1.0, and 1.5 L . min:" . m- 2 were used in each animal, as was one additional flow, either 0.25, 0.75, 1.25, or 1.75 L . min-I. rn", Both the order in which the flows were instituted and the fourth flow for each animal were selected by randomization. An experimental period of 10 minutes was selected because the oxygen tension (Po 2) of mixed venous blood (measured by a continuously recording P0 2 electrode in the venous line to the oxygenator) stabilized within 9 minutes of changing the flow in a previous study in patients. I Preparation of animals and CPR methods. The monkeys weighed 4.5 to 5.7 kg. The body surface area, calculated by formula,' was between 0.32 and 0.38 m'. Anesthesia was induced with ketamine hydrochloride, 10 mg . kg:", given intramuscularly. After orotracheal intubation, the animal was ventilated mechanically with room air. The ventilator rate and tidal volume (generally 10 to 12 ml . kg-I) were adjusted to maintain the arterial carbon dioxide tension (Pco.) between 35 and 40 mm Hg. Anesthesia was maintained with intravenous doses of sodium pentobarbitol, 7.5 to 15 mg . kg-I. One catheter was placed in a femoral artery for the withdrawal of blood samples, and another was inserted for continuous measurement of systemic arterial blood pressure. A catheter was placed in the internal jugular vein, with the tip directed toward the brain. A recording thermistor was placed in the esophagus, and another was inserted 3 mm into the outer cerebral cortex of the
Perfusion flow rate during CPR
659
mid-central parietal lobe through a burr hole in the skull. A median sternotomy was used. CPB was established at a flow rate of 2.0 L· min' . m ? utilizing the ascending aorta for arterial cannulation and a single venous catheter in the right atrium for venous return. The pump oxygenator system was a Shiley* infant oxygenator Model 070, modified by removing the original defoamer-reservoir section. A reusable defoamer-reservoir section, fabricated with polyurethane foam covered with knitted nylon cloth, replaced the original and was constructed so as to minimize the priming volume to approximately 300 mi. The pump oxygenator system was primed with electrolyte solution (Normosol R-pH 7.4). This resulted in a combined animaloxygenator hematocrit value of 4% to 14%. A Pall] filter was placed into the arterial line as a bubble trap. The animal was cooled with the perfusate to a cerebral temperature of 20° C, and then the perfusate temperature was maintained at 20° C. At this temperature, the main pulmonary artery was cross-clamped to effect total CPB but allow continuing coronary artery perfusion. During CPB a constant oxygenator ventilation/ perfusion ratio was maintained with 100% oxygen, and no carbon dioxide was added, so that an appropriate acid-base state was maintained according to the principles of Davis,' Rahn," Rahn, Reeves and Howell,' and Reeves.v? No interventions were made to treat various levels of blood pressure during CPB. The pump flows were set on a mechanical tachometer to which the pump had been calibrated prior to each experiment. Analyses. The blood samples were drawn into heparinized syringes, immediately placed on ice, and subsequently analyzed at 37° C for pH, Po2, Pco., hematocrit, and oxygen content. P0 2 was analyzed with the Clark electrode, Pco, with the Severinghaus electrode, and pH with the Glass electrode. Hematocrit was measured by centrifugation and oxygen content with the Lex-Or-Con fuel cell.:!: Carbonized (polystyrene) uniform-density gammaemitting microspheres of 15 ± 1 J.L diameter were utilized.§ Batches were labeled with 51Cr, 85Sr, 95Nb, or 1251 and were injected in that order, no matter what randomized order of perfusion flow rates was used. The *Shiley Inc.• Irvine. Calif. tPall Biomedical Products Corporation. Glen Cove. N. Y. :j:Lexington Instruments Corporation. Waltham. Mass. §3M brand tracer microspheres, Minnesota Mining and Manufacturing Company. St. Paul. Minn.
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Fox et al.
iodine was given last because of leaching of radioactive material from the microspheres. Each batch of microspheres was suspended in 0.5% polysorbate (Tween-80) in 10% dextran and ultrasonically agitated. Microscopic examination showed absence of clumping. Then 500,000 microspheres in suspension were placed in injector vials of 1 to 2 ml, and their radioactivity was counted in a Picker Autowell II gamma scintillation counter with a 3 inch sodium iodide crystal. After injection (see below) the injector vials were again counted. The amount of radioactive material injected was determined by subtraction of the postinjection count from that present initially. Just prior to injection, the suspension of labeled microspheres was mechanically agitated for 3 minutes. The injection was made slowly over a 30 second interval 75 cm upstream to the tip of the arterial perfusion cannula to allow complete mixing with the arterial blood.8 In studies in puppies in this laboratory (unpublished data), the evenness of distribution of the microspheres was documented by finding the same radioactivity per volume of blood samples withdrawn simultaneously from subclavian and femoral arteries. After the last experimental period and the rendering of the anesthetized animal asystolic by intravenously administered potassium chloride, the brain was removed and placed in 10% phosphate buffered formalin for 48 hours prior to sectioning. The brain was initially sectioned into right and left halves. The cerebrum and midbrain were then cut into five frontal sections approximately 1 cm thick. The dorsal and ventral halves of each slice were divided into predominantly white or gray matter, and in two slices the thalamus was identified and isolated. In all, 44 separate tissue samples were obtained from each brain. Each sample, weighing 0.5 to 2.0 gm, was covered with formalin and separately counted in the gamma spectrometer. The counter was connected to a 400 channel pulse height analyzer. Corrections for use of multiple isotopes were performed by a matrix inversion technique for solving simultaneous equations. In addition to the whole brain, 0.5 to 3 gm samples of the heart, lungs, liver, kidney cortex, and kidney medulla were removed at the termination of the experiment and fixed in formalin. These tissues were counted by means of methods identical to those used for the brain to estimate blood flow to these organs. Calculations. Tissue sample blood flow was calculated by multiplying cardiac output (the perfusion flow rate) times tissue counts per minute and divided by injected counts per minute," " I fl perfusion flow rate . tissue counts T Issue samp e ow = (I ) injected counts
The Journal of Thoracic and Cardiovascular Surgery
These tissue blood flows are expressed as milliliters per minute per 100 gm of tissue. Total brain blood flow was calculated by summing the blood flows of all of the brain tissue samples. Regional brain blood flow was calculated by pooling all brain tissue samples into eight regional flows. These were right and left cortical white matter, cortical gray matter, thalamus, and combined brain stem and cerebellum. Blood flow to the remaining body was calculated as perfusion flow rate minus total brain blood flow. Flow resistance was calculated as mean systemic arterial blood pressure divided by flow (expressed as milliliters) per 100 gm of tissue. The assumption is made that venous pressure was zero, which is probable since a large venous cannula was used to assure unrestricted venous return. Cerebral oxygen consumption was calculated from the difference between arterial and internal jugular venous oxygen contents and the total brain blood flow, by means of the Fick equation. Cerebral oxygen extraction was calculated from the arterial-internal jugular venous oxygen content difference divided by arterial oxygen content. Total body oxygen consumption was calculated from the arterial-mixed venous oxygen content difference multiplied by the perfusion flow rate. Oxygen consumption of the remaining body was calculated as total body oxygen consumption minus brain oxygen consumption. Data analysis. The experimental design permitted an analysis of variance which took into account variability from monkey to monkey and treated perfusion flow rate as either a categorical or a continuous variable. Separate analyses were made of the three flows all monkeys had in common and of all flows used. The results were similar, and the p values presented are for the latter analysis. Because the relationships between total and regional brain flow rates and perfusion flow rate, as well as remaining body oxygen consumption, were nonlinear, a hyperbolic transformation was used in the analysis: I/y = a + b/perfusion flow rate
(2)
where y is the dependent variable of interest, a is the inverse of the asymptotic value of y at high perfusion flow rates, and b relates to the slope of the relationship of y to perfusion flow rate. For analysis of regional brain flow, appropriate contrasts were generated within the analysis of variance to test for regional differences in flow-perfusion flow rate relationships. All means are expressed plus or minus one standard deviation of the mean (±SE). Experimental conditions. At the various perfusion flow rates, the temperature, arterial oxygen content, hematocrit, and acid-base status were not different
Volume 87 Number 5 May, 1984
Perfusion flow rate during CPR
661
Table I. Variables during profoundly hypothermic. nonpulsatile. hemodiluted cardiopulmonary bypass at various perfusion flow rates Experimental conditions 1.5*
Variable Esophageal temperature (0C) Brain temperature (0C) Arterial (oxygen content (ml oxygen· dr') Hematocrit (%) pHt Pco,t (mm Hg) Mean arterial pressure (mm Hg)
18.8 ± 19.73 ± 4.3 ± 8.3 ± 7.41 ± 35 ± 32.8 ±
0.24 0.113 0.22 0.96 0.029 3.2 1.95
I
I
1.0* 18.6 ± 0.26 19.62 ± 0.092 4.2 ± 0.34 8.2 ± 0.92 7.37 ± 0.40 38 ± 2.0 24.5 ± 1.34
0.5* 18.6 19.86 4.4 8.7 7.37 39 16.3
± 0.30 ± 0.195 ± 0.38 ± 1.07 ± 0.041 ± 2.5 ± 1.142
p Value 0.99 0.6 0.7 0.9 0.4 0.22 <0.0001
Legend: Data are presented as the mean ± I standard deviation of the mean (SE). 'Perfusion flow rate (L . min-I. m- 2) . f Measured at 37° C.
Table II. Organ blood flow rates during profoundly hypothermic (20· C), nonpulsatile, hemodiluted cardiopulmonary bypass Organ blood flow rate (ml . min-I. 100 gm:'] Organ
1.5*
1.0*
0.5*
Whole body Brain
10.29 ± 0.080 45 ± 6.3 (5.4%) 280 ± 84 3.8 ± 0.96 70 ± 36
6.86 ± 0.053 41 ± 7.9 (7.1%) 170 ± 48 2.8 ± 0.75 36 ± 8.4
3.44 ± 0.026 23 ± 2.8 (8.2%) 52 ± 9.3 1.0 ± 0.28 12 ± 2.5
18 ± 5.7 410 ± 63
8.4 ± 1.52 220 ± 22
Heart Lung Liver Kidney Medulla Cortex
55 ± 14.2 580 ± 112
Legend: Figures in parentheses indicate the brain blood flow as percent of total body blood flow. The presentation is as in Table I. 'Perfusion flow rate (L . min-I. m"),
(Table I). Mean arterial blood pressure was reduced at the lower perfusion flow rates. Results Brain blood flow. Whole brain blood flow decreased as perfusion flow rate decreased (Table II). The p value was less than 0.0001 for the differences in the table and also for the trend and differences across the entire range of perfusion flow rates studied. However, the proportion of the perfusion flowing to the brain increased (p = 0.00(3) as the total perfusion flow rate decreased. All regions of the brain were perfused at all perfusion flow rates since radioactive microspheres were entrapped in all brain slices at all perfusion flow rates. In each region, blood flow decreased (p = 0.00(1) as perfusion flow rate decreased (Table III). However, the rate of decrease in blood flow to cortical white matter was greater (p = 0.01) than that of the rest of the brain as a whole or its regions (p = 0.0009, p = 0.03, and
m.
Table Regional brain blood flow rates during profoundly hypothermic (20· C). nonpulsatile. hemodiluted cardiopulmonary bypass Region of brain
Regional blood flow rate (ml . min-I. 100 gm:'] 1.5*
Cortical white matter Right 41 ± 5.9 Left 42 ± 6.5 Cortical gray matter Right 46 ± 6.4 Left 48 ± 6.9 Thalamus Right 43 ± 6.2 Left 44 ± 7.9 Brain stem and cerebellum Right 54 ± 8.2 Left 51 ± 7.9
1.0*
0.5*
34 ± 6.6 37 ± 8.1
19 ± 2.7 18.3 ± 1.90
40 ± 8.3 45 ± 9.6
23 ± 3.1 24 ± 3.2
43 ± 8.0 43 ± 8.7
26 ± 3.7 26::!: 3.5
49 ± 9.5 48 ± 8.9
29 ± 3.0 29 ± 3.1
Legend: The presentation is as in Table I. 'Perfusion flow rate (L . min-I. m").
p = 0.08 for comparison of the rate of decrease in cortical white matter with that in brain stem and cerebellum, cortical gray matter, and thalamus, respectively). Both the magnitude and rate of change in blood flow were similar (p = 0.3) for right and left halves of the brain within all regions. Brain blood flow resistance. Brain blood flow resistance was unchanged over all perfusion flow rates (Table IV). In contrast, blood flow resistance in the remaining body increased (p < 0.00(1) with decreasing perfusion flow rate. Brain oxygen consumption and extraction. Brain oxygen consumption was not demonstrably different (p = 0.5) over the entire range of perfusion flow rates (Table V). This unchanged oxygen consumption was accompanied by an increasing (p < 0.00(1) percent oxygen extraction by the brain with decreasing perfusion flow rate (25.6% ± 1.71%,31% ± 2.7%, and 42.8% ±
The Journal of Thoracic and Cardiovascular Surgery
662 Fox et al.
Table IV. Brain and body minus the brain blood flow resistance at various perfusion flow rates Resistance (units . /00 gm) Organ
1.75*
Brain Whole body minus brain
1.2 ± 0.51 2.8 ± 0.157
I
/.5* 0.80 ± 0.080 3.3 ± 0.22
I
/.25* 0.8 ± 0.22 3.3 ± 1.21
I
/.0* 0.78 ± 0.126 3.9 ± 0.24
I
0.75*
I
1.05 ± 0.165 4.6 ± 0.077
0.5*
I
0.80 ± 0.117 5.1 ± 0.49
0.25*
p Value
1.02 ± 0.173 9.5 ± 0.70
0.4 <0.0001
'Perfusion now rate (L . min" . rn").
Table V. Oxygen consumption during profoundly hypothermic, nonpulsatile, hemodiluted cardiopulmonary
bypass Oxygen consumption (m/ . min-I. /00 gm:']
/.5*
Organ Whole body Brain Whole body minus brain
0.119 (17.3 0.51 0.114
± ± ± ±
0.0077 1.16) 0.095 0.0074
I
/.0* 0.086 (12.5 0.47 0.081
± ± ± ±
0.0045 0.65) 0.076 0.0085
I
0.057 (8.3 0.45 0.0518
0.5*
p Value
± ± ± ±
<0.0001
0.0029 0.44) 0.113 0.00176
0.5 <0.0001
Legend: The numbers in parentheses are the whole body oxygen consumption expressed as ml . min" . m''. The presentation is as in Table I. 'Perfusion now rate (L . min" . m"),
1.76% at 1.5, 1.0, and 0.5 L . min-I . m", respectively). Comparison of oxygen comsumption in brain and remaining body. In contrast to the brain, oxygen consumption in the remaining body decreased with decreasing (p < 0.00(1) perfusion flow rate (Table V). The proportion indicating the relation between brain and whole body oxygen consumption increased (p = 0.0009) as perfusion flow rate decreased (5.3%, 7.2%, and 9.5% at 1.5, 1.0, and 0.5 L . min-I. m', respectively). Discussion Materials and methods. The cynomolgus monkey has cerebral arteriovenous anatomy similar to that of man. 10. II It has carotid and vertebral arteries proportionately the same size as does man and an anterior and posterior cerebral circulation interconnected by a completely formed circle of Willis. This makes reasonable the assumption that man would respond to the conditions of the experiment as did the monkey. Others have used the monkey for studies of the physiology of CPB.8.12 Microspheres of 15 IL were selected to avoid nonentrapment, a risk in the use of smaller microspheres, and to avoid streaming and hemodynamic sequelae from occlusion of larger than capillary vessels, a risk in the use of larger microspheres.'>" Limiting an experiment to a maximum of four isotopes avoided inaccuracy from a greater spectral overlap and difficulty in separation during counting when a greater number is used." An
injected dose of microspheres of 500,000 was determined to be optimal in previous studies in 5 kg puppies (unpublished data from this laboratory). This was the smallest dose sufficient to effect a deposition of at least 400 microspheres in each tissue sample and thus guarantee statistical accuracy and a randomization error of less than 10% with 95% confidence.'? A dose larger than 500,000 would have had a greater probability of iatrogenically altering microcirculatory hemodynamics because of occlusion of a larger number of cardiac capillary beds. The tissue sample size ranged from 0.5 to 2.0 gm. This was the smallest size that could yield at least 400 microspheres per sample with an injection dose of 500,000, and allow accurate sectioning of the brain into regions, and yet be large enough to weigh and count with precision. The hematocrit value during CPB was low since no homologous blood was used. This degree of hemodilution is greater than that used clinically. The finding that blood flow is preserved in all areas of the brain at even the lowest perfusion flow rates may reflect, in part, the superior rheological characteristics of the perfusate, since Rudy, Heymann, and Edmunds" found hemodilution from 37% to 25% to return brain blood flow to control values during normothermic CPB. Results. The brain blood flow at 20 0 C during nonpulsatile CPB at flow rates of about 1.5 L . min-I . m ? in these experiments are comparable to those reported by others. Alm20 showed that blood flow to cortical gray matter in cynomolgus monkeys under sodium pentobarbital anesthesia is 28 to 40 ml . min-I.
Volume 87 Number 5
Perfusion flow rate during CPB
May, 1984
100 gm " and to cortical white matter 18 to 22 ml . min-I. 100 grrr ', as measured by 15 JL microspheres. When similar experimental techniques were used in the dog, blood flow to the cortical gray matter was 44.7 ± 3.6, cortical white matter 30.5 ± 2.2, thalamus 49.6 ± 4.3, and brain stem and medulla 34 to 40 ml . min-I. 100 gm- I.2 1 The total brain blood flow does decrease as perfusion flow rate is reduced, but even at the lowest perfusion flow rates all areas of the brain appear to remain perfused. Cortical white matter, however, received proportionally less flow. In this regard, it must be recalled that the animals were severely hemodiluted. As the perfusion flow rate was reduced, however, the brain received an increasing proportion of the total perfusion flow as a result of an increase in blood flow resistance in the rest of the body. These observations of the redistribution of flow with changing total blood flow rates during CPB at 20 Care consistent with observations in dogs and rats during hemorrhagic shock."?' Aoyagi and colleagues" also found a greater decrease in blood flow to cortical white matter than to other regions of the brain in infant baboons during CPB with hypothermia to 18 C. The brain maintained a constant and higher oxygen consumption than the remaining body during conditions of decreasing perfusion flow rates to as low as 0.25 L . min-I. m- 2• This observation is consistent with those made previously in man, which suggested that the oxygen consumption of the brain may remain constant while that of the remaining body may decreased markedly at lower perfusion flow rates. I A similar observation was made by Halley, Reemtsma, and Creech" in dogs subjected to normothermic CPB at high «50 ml . min-I. kg') and low «50 ml . min-I. kg-I) perfusion flow rates. Cerebral oxygen consumption was 2.4 ml . min-I. 100 gm" during both. Oxygen consumption of the brain in the present study performed at 20 C was one fifth that in Halley's study at normothermia, and this is the effect of hypothermia on metabolic processes. Clinical applications. The optimal flow rate during hypothermic CPB remains controversial, with some surgeons insisting that it be the same as at normothermia and others using reduced flows of 1.4 to 1.6 L· min-I. m- 2 at a body temperature of 20 0 to 25 0 C. Whatever flows are used, at times good surgical exposure requires either total circulatory arrest or very low perfusion flow rates. Some have doubted that in these situations very low perfusion flow rates, such as 0.5 L . min-I. -2, actually provide any more protection than does total circulatory arrest. These animal experi0
ments demonstrate that considerable protection to the brain is provided by very low perfusion flow rates.
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REFERENCES Fox LS, Blackstone EH, Kirklin rw, Stewart RW, Samuelson PN: Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic cardiopulmonary bypass. 1 THORAC CARDIOVASC SURG 83:239-248, 1982 Altman PL, Dittmer DS: Biology Data Book, Federation of American Societies for Experimental Biology, Washington, D. c, 1964, pp 120-121 Davis BD: On the importance of being ionized. Arch Biochem Biophys 78:497-509, 1958 Rahn H: Body temperature and acid-base regulation. Pneumonologie 151:87-94, 1974 Rahn H, Reeves RB, Howell Bl: Hydrogen ion regulation, temperature, and evolution. Am Rev Respir Dis 112:165172, 1975 Reeves RB: An imidazole alphastat hypothesis for vertebrate acid-base regulation. Tissue carbon dioxide content and body temperature in bull frogs. Respir PhysioI14:219236, 1972 Reeves RB: The interaction of body temperature and acid-base balance in ectothermic vertebrates. Ann Rev Physiol 39:559-586, 1977 Rudy LW lr, Heymann MA, Edmunds LH lr: Distribution of systemic blood flow during cardiopulmonary bypass. 1 Appl Physiol 34:194-200, 1973 Rudolph AM, Heymann MA: The circulation of the fetus in utero. Methods for studying distribution of blood flow, cardiac output and organ blood flow. Circ Res 21:163184, 1967 Watts lW: A comparative study of the anterior cerebral artery and the circle of Willis in primates. 1 Anat 68:534-550, 1933 Coceani F, Gloor P: The distribution of the internal carotid circulation in the brain of the macaque monkey (Macaca mulatta). 1 Comp Neur 128:419-430, 1966 Rudy LW, Boucher lK, Edmunds LH lr: The effect of deep hypothermia and circulatory arrest on the distribution of systemic blood flow in rhesus monkeys. 1 THORAC CARDIOVASC SURG 64:706-713, 1972 Archie IP lr, Fixler DE, Ullyot Dl, Hoffman lIE, Utley lR, Carlson EL: Measurement of cardiac output with and organ trapping of radioactive microspheres. 1 Appl Physiol 35: 148-154, 1973 Fan FC, Schuessler GB, Chen RYZ, Chien S: Determinations of blood flow and shunting of 9- and 15-~m spheres in regional beds. Am 1 Physiol 237:425-433, 1979 Marcus ML, Heistad DD, Ehrhardt lC, Abboud FM: Total and regional cerebral blood flow measurement with 7-, 10-, 15-,25-, and 50-~m microspheres. 1 Appl Physiol 40:501-507, 1976 Harell GS, Corbet AB, Dickhoner WH, Bradley BR: The intraluminal distribution of 15~ diameter carbonized
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microspheres within arterial microvesse1s as determined by vital microscopy of the golden hamster check pouch. Microvasc Res 18:384-402, 1979 Phibbs RH, Dong L: Nonuniform distribution of microspheres in blood flowing through a medium size artery. Can J Physiol Pharmocol 48:415-421, 1970 Heymann MA, Payne BD, Hoffman JIE, Rudolph AM: Blood flow measurements with radionuclide labelled particles. Prog Cardiovasc Dis 20:55-79, 1977 Buckberg GD, Luck JC, Payne BD, Hoffman JIE, Archie JP Jr, Fixler DE: Some sources of error in measuring regional blood flow with radioactive microspheres. J Appl Physiol 31:598-604, 1971 AIm A: The effect of stimulation of the cervical sympathetic chain of regional cerebral blood flow in monkeys. A study with radioactively labelled microspheres. Acta Physiol Scand 93:483-489, 1975 Fan FC, Chen RYZ, Schuessler GB, Chien S: Comparison between the 13JXe clearance method and the micro-
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sphere technique in cerebral blood flow determinations in the dog. Circ Res 44:653-659, 1979 Kaihara S, Rutherford RB, Schwentker EP, Wagner HN Jr: Distribution of cardiac output in experimental hemorrhagic shock in dogs. J Appl Physiol 27:218-222, 1969 Slater GI, Vladeck BC, Bassin R, Kark AE, Shoemaker WC: Sequential changes in distribution of cardiac output in hemorrhagic shock. Surgery 73:714-722, 1973 Sapirstein LA, Sapirstein EH, Bredemeyer A: Effect of hemorrhage on the cardiac output and its distribution in the rat. Circ Res 8:135-148, 1960 Aoyagi M, Flasterstein AH, Barnette J, Von Koch L, Ross IN Jr, Kennedy JH: Cerebral effects of profound hypothermia (18° C) and circulatory arrest. Circulation 51, 52:Suppl 1:52-59, 1975 Halley MM, Reemtsma K, Creech 0 Jr: Cerebral blood flow, metabolism, and brain volume in extracorporeal circulation. J THORAe SURG 36:506-518, 1958
Notice of correction
In the March, 1984, issue of the JOURNAL, in the article by Inoue and associates entitled, "Clinical Application of Transvenous Mitral Commissurotomy by a New Balloon Catheter," an error was made. On page 395, column 1, line 11, the figure "0.28 inch" should be "0.028 inch."
THoRAc CARDIOVASC SURG
87:658-664, 1984
Relationship of brain blood flow and oxygen consumption to perfusion flow rate during profoundly hypothermic cardiopulmonary bypass An experimental study A study was made of the relation of brain blood flow and oxygen co~ption to changes in pe~ion flow rate during cardiopulmonary bypass at 20° C in nine cynomolgus monkeys. Four ~ion flow rates varyingfrom 0.25 to 1.75 L . min-I. m- 1 were randomlyinstituted, each for a 10 minute period.At the end of each period, brain arteriovenolfi oxygen content differencewas measured and 15 J.I. radioactive microsphereswere injected into the arterial perflfiionline. The brain was then removed and sectionedinto anatomic regions and radioactivity was counted. Regional and total brain bloodflows were calculated, as was whole brain oxygen consumption. Brain pert'miion continued in all areas at all perflfiionflow rates. Whole brain blood flow decreased (P < 0.0001) as pe~ion flow rate was reduced (45 ± 6.5,41 ± 7.9, and 23 ± 2.8 mI . min-I . 100 gm-I at 1.5, 1.0, and 0.5 L . min-I. m- 1, respectivefy), The proportion of the total pe~ion delivered to the brain increased (P = 0.003) with decreasing pert'miion flow rates (5.4% ± 0.78%,7.1 % ± 1.24%, and 8.2% ± 1.11% atl.5, 1.0, and 0.5 L . min-I. m- 1, respectively). Brain blood flow resistance remained unchanged (p = 0.4) while that of the remaining body increased (p < 0.0001~ There was a greater reduction of bloodflow in the cortical white matter (p = 0.01) than in other regions of the brain. Brain oxygen consumption was the same (p = 0.5) at all pe~ion flow rates, related to an increasing percent oxygen extraction with decreasing pe~ion flow rate (p < 0.0001~ The data indicate that all areas of the brain remain pert'm;ed, even at low perflfiion flow rates, during profoundly hypothermic cardiopulmonary bypass, and that brain oxygen co~ption is maintained in part by increased oxygen extraction and in part by redistribution of the perfusate from the remaining body to the brain.
Lawrence S. Fox, M.D., Eugene H. Blackstone, M.D., John W. Kirklin, M.D., Sanford P. Bishop, D.V.M., Ph.D., Leif A. L. Bergdahl, M.D.,· and Edwin L. Bradley, Ph.D., Birmingham. Ala.
"W:ole body oxygen consumption falls progressively as the perfusion flow rate is reduced during profoundly From the Departments of Surgery and of Biostatistics and Biomathematics, University of Alabama in Birmingham, Birmingham, Ala. Supported in part by the Birmingham Veterans Administration Hospital and by Program Project Grant HLl131O, National Heart, Lung and Blood Institute, NIH, Bethesda, Md. Received for publication March 4, 1983. Accepted for publication June 6, 1983. Address for reprints: Eugene H. Blackstone. M.D., Department of Surgery, University Station, Birmingham, Ala. 35294. *Current address: The Thoracic Surgical Clinic, Karolinska Hospital, Stockholm, Sweden.
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hypothermic total cardiopulmonary bypass (CPB) in man. I However, the pattern of changes in internal jugular venous oxygen levels during these reductions indicate that brain oxygen consumption may behave differently.' Therefore, an experimental study was undertaken to investigate possible differences between the responses of the brain and those of the body as a whole to changing perfusion flow rates during profoundly hypothermic CPB.
Materials and methods Experimental design. Nine cynomolgus (Macaca irus) monkeys were cooled to 20° C by hypothermic CPB. Then during each of four consecutive 10 minute
Volume 87 Number 5 May, 1984
experimental periods, a different perfusion flow rate was used. At the end of each period, arterial, internal jugular venous, and mixed venous blood samples were drawn for determination of oxygen content and calculation of arteriovenous oxygen content difference, and 15 J.L radioactive microspheres were injected. A 3 minute period was then allowed for distribution, during which time 3 to 4 mI of arterial and internal jugular venous blood samples were withdrawn at a constant rate for determination of microsphere nonentrapment (found to be 3% to 4% of that injected in two instances, 2% to 3% in one, 1% to 2% in four, and less than 1% in the other 29 samples). A new perfusion flow rate was then established and the second experimental period was begun. The sequence was repeated until all four experimental periods had been completed. The animal then was rendered asystolic by an intravenous dose of potassium chloride, after which the brain was removed for completion of the studies of flow by the microsphere method. The flow rate used during the experimental periods varied from 0.25 to 1.75 L . min-I. m'. Flows of 0.5, 1.0, and 1.5 L . min:" . m- 2 were used in each animal, as was one additional flow, either 0.25, 0.75, 1.25, or 1.75 L . min-I. rn", Both the order in which the flows were instituted and the fourth flow for each animal were selected by randomization. An experimental period of 10 minutes was selected because the oxygen tension (Po 2) of mixed venous blood (measured by a continuously recording P0 2 electrode in the venous line to the oxygenator) stabilized within 9 minutes of changing the flow in a previous study in patients. I Preparation of animals and CPR methods. The monkeys weighed 4.5 to 5.7 kg. The body surface area, calculated by formula,' was between 0.32 and 0.38 m'. Anesthesia was induced with ketamine hydrochloride, 10 mg . kg:", given intramuscularly. After orotracheal intubation, the animal was ventilated mechanically with room air. The ventilator rate and tidal volume (generally 10 to 12 ml . kg-I) were adjusted to maintain the arterial carbon dioxide tension (Pco.) between 35 and 40 mm Hg. Anesthesia was maintained with intravenous doses of sodium pentobarbitol, 7.5 to 15 mg . kg-I. One catheter was placed in a femoral artery for the withdrawal of blood samples, and another was inserted for continuous measurement of systemic arterial blood pressure. A catheter was placed in the internal jugular vein, with the tip directed toward the brain. A recording thermistor was placed in the esophagus, and another was inserted 3 mm into the outer cerebral cortex of the
Perfusion flow rate during CPR
659
mid-central parietal lobe through a burr hole in the skull. A median sternotomy was used. CPB was established at a flow rate of 2.0 L· min' . m ? utilizing the ascending aorta for arterial cannulation and a single venous catheter in the right atrium for venous return. The pump oxygenator system was a Shiley* infant oxygenator Model 070, modified by removing the original defoamer-reservoir section. A reusable defoamer-reservoir section, fabricated with polyurethane foam covered with knitted nylon cloth, replaced the original and was constructed so as to minimize the priming volume to approximately 300 mi. The pump oxygenator system was primed with electrolyte solution (Normosol R-pH 7.4). This resulted in a combined animaloxygenator hematocrit value of 4% to 14%. A Pall] filter was placed into the arterial line as a bubble trap. The animal was cooled with the perfusate to a cerebral temperature of 20° C, and then the perfusate temperature was maintained at 20° C. At this temperature, the main pulmonary artery was cross-clamped to effect total CPB but allow continuing coronary artery perfusion. During CPB a constant oxygenator ventilation/ perfusion ratio was maintained with 100% oxygen, and no carbon dioxide was added, so that an appropriate acid-base state was maintained according to the principles of Davis,' Rahn," Rahn, Reeves and Howell,' and Reeves.v? No interventions were made to treat various levels of blood pressure during CPB. The pump flows were set on a mechanical tachometer to which the pump had been calibrated prior to each experiment. Analyses. The blood samples were drawn into heparinized syringes, immediately placed on ice, and subsequently analyzed at 37° C for pH, Po2, Pco., hematocrit, and oxygen content. P0 2 was analyzed with the Clark electrode, Pco, with the Severinghaus electrode, and pH with the Glass electrode. Hematocrit was measured by centrifugation and oxygen content with the Lex-Or-Con fuel cell.:!: Carbonized (polystyrene) uniform-density gammaemitting microspheres of 15 ± 1 J.L diameter were utilized.§ Batches were labeled with 51Cr, 85Sr, 95Nb, or 1251 and were injected in that order, no matter what randomized order of perfusion flow rates was used. The *Shiley Inc.• Irvine. Calif. tPall Biomedical Products Corporation. Glen Cove. N. Y. :j:Lexington Instruments Corporation. Waltham. Mass. §3M brand tracer microspheres, Minnesota Mining and Manufacturing Company. St. Paul. Minn.
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Fox et al.
iodine was given last because of leaching of radioactive material from the microspheres. Each batch of microspheres was suspended in 0.5% polysorbate (Tween-80) in 10% dextran and ultrasonically agitated. Microscopic examination showed absence of clumping. Then 500,000 microspheres in suspension were placed in injector vials of 1 to 2 ml, and their radioactivity was counted in a Picker Autowell II gamma scintillation counter with a 3 inch sodium iodide crystal. After injection (see below) the injector vials were again counted. The amount of radioactive material injected was determined by subtraction of the postinjection count from that present initially. Just prior to injection, the suspension of labeled microspheres was mechanically agitated for 3 minutes. The injection was made slowly over a 30 second interval 75 cm upstream to the tip of the arterial perfusion cannula to allow complete mixing with the arterial blood.8 In studies in puppies in this laboratory (unpublished data), the evenness of distribution of the microspheres was documented by finding the same radioactivity per volume of blood samples withdrawn simultaneously from subclavian and femoral arteries. After the last experimental period and the rendering of the anesthetized animal asystolic by intravenously administered potassium chloride, the brain was removed and placed in 10% phosphate buffered formalin for 48 hours prior to sectioning. The brain was initially sectioned into right and left halves. The cerebrum and midbrain were then cut into five frontal sections approximately 1 cm thick. The dorsal and ventral halves of each slice were divided into predominantly white or gray matter, and in two slices the thalamus was identified and isolated. In all, 44 separate tissue samples were obtained from each brain. Each sample, weighing 0.5 to 2.0 gm, was covered with formalin and separately counted in the gamma spectrometer. The counter was connected to a 400 channel pulse height analyzer. Corrections for use of multiple isotopes were performed by a matrix inversion technique for solving simultaneous equations. In addition to the whole brain, 0.5 to 3 gm samples of the heart, lungs, liver, kidney cortex, and kidney medulla were removed at the termination of the experiment and fixed in formalin. These tissues were counted by means of methods identical to those used for the brain to estimate blood flow to these organs. Calculations. Tissue sample blood flow was calculated by multiplying cardiac output (the perfusion flow rate) times tissue counts per minute and divided by injected counts per minute," " I fl perfusion flow rate . tissue counts T Issue samp e ow = (I ) injected counts
The Journal of Thoracic and Cardiovascular Surgery
These tissue blood flows are expressed as milliliters per minute per 100 gm of tissue. Total brain blood flow was calculated by summing the blood flows of all of the brain tissue samples. Regional brain blood flow was calculated by pooling all brain tissue samples into eight regional flows. These were right and left cortical white matter, cortical gray matter, thalamus, and combined brain stem and cerebellum. Blood flow to the remaining body was calculated as perfusion flow rate minus total brain blood flow. Flow resistance was calculated as mean systemic arterial blood pressure divided by flow (expressed as milliliters) per 100 gm of tissue. The assumption is made that venous pressure was zero, which is probable since a large venous cannula was used to assure unrestricted venous return. Cerebral oxygen consumption was calculated from the difference between arterial and internal jugular venous oxygen contents and the total brain blood flow, by means of the Fick equation. Cerebral oxygen extraction was calculated from the arterial-internal jugular venous oxygen content difference divided by arterial oxygen content. Total body oxygen consumption was calculated from the arterial-mixed venous oxygen content difference multiplied by the perfusion flow rate. Oxygen consumption of the remaining body was calculated as total body oxygen consumption minus brain oxygen consumption. Data analysis. The experimental design permitted an analysis of variance which took into account variability from monkey to monkey and treated perfusion flow rate as either a categorical or a continuous variable. Separate analyses were made of the three flows all monkeys had in common and of all flows used. The results were similar, and the p values presented are for the latter analysis. Because the relationships between total and regional brain flow rates and perfusion flow rate, as well as remaining body oxygen consumption, were nonlinear, a hyperbolic transformation was used in the analysis: I/y = a + b/perfusion flow rate
(2)
where y is the dependent variable of interest, a is the inverse of the asymptotic value of y at high perfusion flow rates, and b relates to the slope of the relationship of y to perfusion flow rate. For analysis of regional brain flow, appropriate contrasts were generated within the analysis of variance to test for regional differences in flow-perfusion flow rate relationships. All means are expressed plus or minus one standard deviation of the mean (±SE). Experimental conditions. At the various perfusion flow rates, the temperature, arterial oxygen content, hematocrit, and acid-base status were not different
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Perfusion flow rate during CPR
661
Table I. Variables during profoundly hypothermic. nonpulsatile. hemodiluted cardiopulmonary bypass at various perfusion flow rates Experimental conditions 1.5*
Variable Esophageal temperature (0C) Brain temperature (0C) Arterial (oxygen content (ml oxygen· dr') Hematocrit (%) pHt Pco,t (mm Hg) Mean arterial pressure (mm Hg)
18.8 ± 19.73 ± 4.3 ± 8.3 ± 7.41 ± 35 ± 32.8 ±
0.24 0.113 0.22 0.96 0.029 3.2 1.95
I
I
1.0* 18.6 ± 0.26 19.62 ± 0.092 4.2 ± 0.34 8.2 ± 0.92 7.37 ± 0.40 38 ± 2.0 24.5 ± 1.34
0.5* 18.6 19.86 4.4 8.7 7.37 39 16.3
± 0.30 ± 0.195 ± 0.38 ± 1.07 ± 0.041 ± 2.5 ± 1.142
p Value 0.99 0.6 0.7 0.9 0.4 0.22 <0.0001
Legend: Data are presented as the mean ± I standard deviation of the mean (SE). 'Perfusion flow rate (L . min-I. m- 2) . f Measured at 37° C.
Table II. Organ blood flow rates during profoundly hypothermic (20· C), nonpulsatile, hemodiluted cardiopulmonary bypass Organ blood flow rate (ml . min-I. 100 gm:'] Organ
1.5*
1.0*
0.5*
Whole body Brain
10.29 ± 0.080 45 ± 6.3 (5.4%) 280 ± 84 3.8 ± 0.96 70 ± 36
6.86 ± 0.053 41 ± 7.9 (7.1%) 170 ± 48 2.8 ± 0.75 36 ± 8.4
3.44 ± 0.026 23 ± 2.8 (8.2%) 52 ± 9.3 1.0 ± 0.28 12 ± 2.5
18 ± 5.7 410 ± 63
8.4 ± 1.52 220 ± 22
Heart Lung Liver Kidney Medulla Cortex
55 ± 14.2 580 ± 112
Legend: Figures in parentheses indicate the brain blood flow as percent of total body blood flow. The presentation is as in Table I. 'Perfusion flow rate (L . min-I. m"),
(Table I). Mean arterial blood pressure was reduced at the lower perfusion flow rates. Results Brain blood flow. Whole brain blood flow decreased as perfusion flow rate decreased (Table II). The p value was less than 0.0001 for the differences in the table and also for the trend and differences across the entire range of perfusion flow rates studied. However, the proportion of the perfusion flowing to the brain increased (p = 0.00(3) as the total perfusion flow rate decreased. All regions of the brain were perfused at all perfusion flow rates since radioactive microspheres were entrapped in all brain slices at all perfusion flow rates. In each region, blood flow decreased (p = 0.00(1) as perfusion flow rate decreased (Table III). However, the rate of decrease in blood flow to cortical white matter was greater (p = 0.01) than that of the rest of the brain as a whole or its regions (p = 0.0009, p = 0.03, and
m.
Table Regional brain blood flow rates during profoundly hypothermic (20· C). nonpulsatile. hemodiluted cardiopulmonary bypass Region of brain
Regional blood flow rate (ml . min-I. 100 gm:'] 1.5*
Cortical white matter Right 41 ± 5.9 Left 42 ± 6.5 Cortical gray matter Right 46 ± 6.4 Left 48 ± 6.9 Thalamus Right 43 ± 6.2 Left 44 ± 7.9 Brain stem and cerebellum Right 54 ± 8.2 Left 51 ± 7.9
1.0*
0.5*
34 ± 6.6 37 ± 8.1
19 ± 2.7 18.3 ± 1.90
40 ± 8.3 45 ± 9.6
23 ± 3.1 24 ± 3.2
43 ± 8.0 43 ± 8.7
26 ± 3.7 26::!: 3.5
49 ± 9.5 48 ± 8.9
29 ± 3.0 29 ± 3.1
Legend: The presentation is as in Table I. 'Perfusion flow rate (L . min-I. m").
p = 0.08 for comparison of the rate of decrease in cortical white matter with that in brain stem and cerebellum, cortical gray matter, and thalamus, respectively). Both the magnitude and rate of change in blood flow were similar (p = 0.3) for right and left halves of the brain within all regions. Brain blood flow resistance. Brain blood flow resistance was unchanged over all perfusion flow rates (Table IV). In contrast, blood flow resistance in the remaining body increased (p < 0.00(1) with decreasing perfusion flow rate. Brain oxygen consumption and extraction. Brain oxygen consumption was not demonstrably different (p = 0.5) over the entire range of perfusion flow rates (Table V). This unchanged oxygen consumption was accompanied by an increasing (p < 0.00(1) percent oxygen extraction by the brain with decreasing perfusion flow rate (25.6% ± 1.71%,31% ± 2.7%, and 42.8% ±
The Journal of Thoracic and Cardiovascular Surgery
662 Fox et al.
Table IV. Brain and body minus the brain blood flow resistance at various perfusion flow rates Resistance (units . /00 gm) Organ
1.75*
Brain Whole body minus brain
1.2 ± 0.51 2.8 ± 0.157
I
/.5* 0.80 ± 0.080 3.3 ± 0.22
I
/.25* 0.8 ± 0.22 3.3 ± 1.21
I
/.0* 0.78 ± 0.126 3.9 ± 0.24
I
0.75*
I
1.05 ± 0.165 4.6 ± 0.077
0.5*
I
0.80 ± 0.117 5.1 ± 0.49
0.25*
p Value
1.02 ± 0.173 9.5 ± 0.70
0.4 <0.0001
'Perfusion now rate (L . min" . rn").
Table V. Oxygen consumption during profoundly hypothermic, nonpulsatile, hemodiluted cardiopulmonary
bypass Oxygen consumption (m/ . min-I. /00 gm:']
/.5*
Organ Whole body Brain Whole body minus brain
0.119 (17.3 0.51 0.114
± ± ± ±
0.0077 1.16) 0.095 0.0074
I
/.0* 0.086 (12.5 0.47 0.081
± ± ± ±
0.0045 0.65) 0.076 0.0085
I
0.057 (8.3 0.45 0.0518
0.5*
p Value
± ± ± ±
<0.0001
0.0029 0.44) 0.113 0.00176
0.5 <0.0001
Legend: The numbers in parentheses are the whole body oxygen consumption expressed as ml . min" . m''. The presentation is as in Table I. 'Perfusion now rate (L . min" . m"),
1.76% at 1.5, 1.0, and 0.5 L . min-I . m", respectively). Comparison of oxygen comsumption in brain and remaining body. In contrast to the brain, oxygen consumption in the remaining body decreased with decreasing (p < 0.00(1) perfusion flow rate (Table V). The proportion indicating the relation between brain and whole body oxygen consumption increased (p = 0.0009) as perfusion flow rate decreased (5.3%, 7.2%, and 9.5% at 1.5, 1.0, and 0.5 L . min-I. m', respectively). Discussion Materials and methods. The cynomolgus monkey has cerebral arteriovenous anatomy similar to that of man. 10. II It has carotid and vertebral arteries proportionately the same size as does man and an anterior and posterior cerebral circulation interconnected by a completely formed circle of Willis. This makes reasonable the assumption that man would respond to the conditions of the experiment as did the monkey. Others have used the monkey for studies of the physiology of CPB.8.12 Microspheres of 15 IL were selected to avoid nonentrapment, a risk in the use of smaller microspheres, and to avoid streaming and hemodynamic sequelae from occlusion of larger than capillary vessels, a risk in the use of larger microspheres.'>" Limiting an experiment to a maximum of four isotopes avoided inaccuracy from a greater spectral overlap and difficulty in separation during counting when a greater number is used." An
injected dose of microspheres of 500,000 was determined to be optimal in previous studies in 5 kg puppies (unpublished data from this laboratory). This was the smallest dose sufficient to effect a deposition of at least 400 microspheres in each tissue sample and thus guarantee statistical accuracy and a randomization error of less than 10% with 95% confidence.'? A dose larger than 500,000 would have had a greater probability of iatrogenically altering microcirculatory hemodynamics because of occlusion of a larger number of cardiac capillary beds. The tissue sample size ranged from 0.5 to 2.0 gm. This was the smallest size that could yield at least 400 microspheres per sample with an injection dose of 500,000, and allow accurate sectioning of the brain into regions, and yet be large enough to weigh and count with precision. The hematocrit value during CPB was low since no homologous blood was used. This degree of hemodilution is greater than that used clinically. The finding that blood flow is preserved in all areas of the brain at even the lowest perfusion flow rates may reflect, in part, the superior rheological characteristics of the perfusate, since Rudy, Heymann, and Edmunds" found hemodilution from 37% to 25% to return brain blood flow to control values during normothermic CPB. Results. The brain blood flow at 20 0 C during nonpulsatile CPB at flow rates of about 1.5 L . min-I . m ? in these experiments are comparable to those reported by others. Alm20 showed that blood flow to cortical gray matter in cynomolgus monkeys under sodium pentobarbital anesthesia is 28 to 40 ml . min-I.
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Perfusion flow rate during CPB
May, 1984
100 gm " and to cortical white matter 18 to 22 ml . min-I. 100 grrr ', as measured by 15 JL microspheres. When similar experimental techniques were used in the dog, blood flow to the cortical gray matter was 44.7 ± 3.6, cortical white matter 30.5 ± 2.2, thalamus 49.6 ± 4.3, and brain stem and medulla 34 to 40 ml . min-I. 100 gm- I.2 1 The total brain blood flow does decrease as perfusion flow rate is reduced, but even at the lowest perfusion flow rates all areas of the brain appear to remain perfused. Cortical white matter, however, received proportionally less flow. In this regard, it must be recalled that the animals were severely hemodiluted. As the perfusion flow rate was reduced, however, the brain received an increasing proportion of the total perfusion flow as a result of an increase in blood flow resistance in the rest of the body. These observations of the redistribution of flow with changing total blood flow rates during CPB at 20 Care consistent with observations in dogs and rats during hemorrhagic shock."?' Aoyagi and colleagues" also found a greater decrease in blood flow to cortical white matter than to other regions of the brain in infant baboons during CPB with hypothermia to 18 C. The brain maintained a constant and higher oxygen consumption than the remaining body during conditions of decreasing perfusion flow rates to as low as 0.25 L . min-I. m- 2• This observation is consistent with those made previously in man, which suggested that the oxygen consumption of the brain may remain constant while that of the remaining body may decreased markedly at lower perfusion flow rates. I A similar observation was made by Halley, Reemtsma, and Creech" in dogs subjected to normothermic CPB at high «50 ml . min-I. kg') and low «50 ml . min-I. kg-I) perfusion flow rates. Cerebral oxygen consumption was 2.4 ml . min-I. 100 gm" during both. Oxygen consumption of the brain in the present study performed at 20 C was one fifth that in Halley's study at normothermia, and this is the effect of hypothermia on metabolic processes. Clinical applications. The optimal flow rate during hypothermic CPB remains controversial, with some surgeons insisting that it be the same as at normothermia and others using reduced flows of 1.4 to 1.6 L· min-I. m- 2 at a body temperature of 20 0 to 25 0 C. Whatever flows are used, at times good surgical exposure requires either total circulatory arrest or very low perfusion flow rates. Some have doubted that in these situations very low perfusion flow rates, such as 0.5 L . min-I. -2, actually provide any more protection than does total circulatory arrest. These animal experi0
ments demonstrate that considerable protection to the brain is provided by very low perfusion flow rates.
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REFERENCES Fox LS, Blackstone EH, Kirklin rw, Stewart RW, Samuelson PN: Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic cardiopulmonary bypass. 1 THORAC CARDIOVASC SURG 83:239-248, 1982 Altman PL, Dittmer DS: Biology Data Book, Federation of American Societies for Experimental Biology, Washington, D. c, 1964, pp 120-121 Davis BD: On the importance of being ionized. Arch Biochem Biophys 78:497-509, 1958 Rahn H: Body temperature and acid-base regulation. Pneumonologie 151:87-94, 1974 Rahn H, Reeves RB, Howell Bl: Hydrogen ion regulation, temperature, and evolution. Am Rev Respir Dis 112:165172, 1975 Reeves RB: An imidazole alphastat hypothesis for vertebrate acid-base regulation. Tissue carbon dioxide content and body temperature in bull frogs. Respir PhysioI14:219236, 1972 Reeves RB: The interaction of body temperature and acid-base balance in ectothermic vertebrates. Ann Rev Physiol 39:559-586, 1977 Rudy LW lr, Heymann MA, Edmunds LH lr: Distribution of systemic blood flow during cardiopulmonary bypass. 1 Appl Physiol 34:194-200, 1973 Rudolph AM, Heymann MA: The circulation of the fetus in utero. Methods for studying distribution of blood flow, cardiac output and organ blood flow. Circ Res 21:163184, 1967 Watts lW: A comparative study of the anterior cerebral artery and the circle of Willis in primates. 1 Anat 68:534-550, 1933 Coceani F, Gloor P: The distribution of the internal carotid circulation in the brain of the macaque monkey (Macaca mulatta). 1 Comp Neur 128:419-430, 1966 Rudy LW, Boucher lK, Edmunds LH lr: The effect of deep hypothermia and circulatory arrest on the distribution of systemic blood flow in rhesus monkeys. 1 THORAC CARDIOVASC SURG 64:706-713, 1972 Archie IP lr, Fixler DE, Ullyot Dl, Hoffman lIE, Utley lR, Carlson EL: Measurement of cardiac output with and organ trapping of radioactive microspheres. 1 Appl Physiol 35: 148-154, 1973 Fan FC, Schuessler GB, Chen RYZ, Chien S: Determinations of blood flow and shunting of 9- and 15-~m spheres in regional beds. Am 1 Physiol 237:425-433, 1979 Marcus ML, Heistad DD, Ehrhardt lC, Abboud FM: Total and regional cerebral blood flow measurement with 7-, 10-, 15-,25-, and 50-~m microspheres. 1 Appl Physiol 40:501-507, 1976 Harell GS, Corbet AB, Dickhoner WH, Bradley BR: The intraluminal distribution of 15~ diameter carbonized
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microspheres within arterial microvesse1s as determined by vital microscopy of the golden hamster check pouch. Microvasc Res 18:384-402, 1979 Phibbs RH, Dong L: Nonuniform distribution of microspheres in blood flowing through a medium size artery. Can J Physiol Pharmocol 48:415-421, 1970 Heymann MA, Payne BD, Hoffman JIE, Rudolph AM: Blood flow measurements with radionuclide labelled particles. Prog Cardiovasc Dis 20:55-79, 1977 Buckberg GD, Luck JC, Payne BD, Hoffman JIE, Archie JP Jr, Fixler DE: Some sources of error in measuring regional blood flow with radioactive microspheres. J Appl Physiol 31:598-604, 1971 AIm A: The effect of stimulation of the cervical sympathetic chain of regional cerebral blood flow in monkeys. A study with radioactively labelled microspheres. Acta Physiol Scand 93:483-489, 1975 Fan FC, Chen RYZ, Schuessler GB, Chien S: Comparison between the 13JXe clearance method and the micro-
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sphere technique in cerebral blood flow determinations in the dog. Circ Res 44:653-659, 1979 Kaihara S, Rutherford RB, Schwentker EP, Wagner HN Jr: Distribution of cardiac output in experimental hemorrhagic shock in dogs. J Appl Physiol 27:218-222, 1969 Slater GI, Vladeck BC, Bassin R, Kark AE, Shoemaker WC: Sequential changes in distribution of cardiac output in hemorrhagic shock. Surgery 73:714-722, 1973 Sapirstein LA, Sapirstein EH, Bredemeyer A: Effect of hemorrhage on the cardiac output and its distribution in the rat. Circ Res 8:135-148, 1960 Aoyagi M, Flasterstein AH, Barnette J, Von Koch L, Ross IN Jr, Kennedy JH: Cerebral effects of profound hypothermia (18° C) and circulatory arrest. Circulation 51, 52:Suppl 1:52-59, 1975 Halley MM, Reemtsma K, Creech 0 Jr: Cerebral blood flow, metabolism, and brain volume in extracorporeal circulation. J THORAe SURG 36:506-518, 1958
Notice of correction
In the March, 1984, issue of the JOURNAL, in the article by Inoue and associates entitled, "Clinical Application of Transvenous Mitral Commissurotomy by a New Balloon Catheter," an error was made. On page 395, column 1, line 11, the figure "0.28 inch" should be "0.028 inch."