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Ann Thorac Surg 1998;65:1226-1230
© 1998 The Society of Thoracic Surgeons

Cardiopulmonary Bypass Time Does Not Affect Cerebral Blood Flow

^a Division of Cardiac Anesthesia, Department of Anesthesiology, Duke Heart Center, Duke University Hospital, Durham, North Carolina, USA
^b Department of Surgery, Duke Heart Center, Duke University Hospital, Durham, North Carolina, USA

Accepted for publication November 27, 1997.

Address reprint requests to Dr Newman, Department of Anesthesiology, Box 3094, Duke University Medical Center, Durham, NC 27710

	Abstract

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Background. A time-dependent decline in cerebral blood flow (CBF) has been reported in cardiac surgical patients despite stable pump flows and arterial carbon dioxide tension. Other studies have failed to support these hypothermic cardiopulmonary bypass (CPB) results, showing preservation of CBF during CPB. The purpose of the study was to define the influence of mildly hypothermic CPB duration on CBF.

Methods. Cerebral blood flow was measured using xenon-133 washout and alpha-stat blood gas management during nonpulsatile CPB. Cerebral blood flow measurements were made after the initiation of CPB and near the end of bypass during pump flows of 2.4 L · min^-1 · m^-2.

Results. Fifty-two coronary artery bypass patients were studied. The average time between CBF measurements was 54 ± 20 minutes (mean ± standard deviation), with a range of 10 to 100 minutes. Temperature and arterial carbon dioxide tension were controlled: after the initiation of CPB, temperature was 35.5° ± 0.4°C and carbon dioxide tension was 37 ± 2.8 mm Hg; whereas near the end of bypass temperature was 35.6° ± 0.5°C and carbon dioxide tension was 36 ± 2.3 mm Hg. We found no correlation between CBF and time on CPB (p = 0.47; r = 0.101), in contrast to other studies suggesting that CPB duration may intrinsically affect CBF.

Conclusions. Our experimental results include the following: (1) during mildly hypothermic bypass, CBF does not decrease in relation to time and (2) cerebral flow-metabolism coupling is intact at 35°C.

	Introduction

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The effect of cardiopulmonary bypass (CPB) duration on cerebral blood flow (CBF) remains unclear. It has been suggested that CPB is associated with a decrease in CBF because of microemboli, brain edema, inflammatory responses, progressive cerebral vasoconstriction, or extreme temperature gradients during rewarming. A time-dependent decline in CBF has been reported in cardiac surgical patients despite stable pump flows and arterial carbon dioxide tension (PaCO₂) [1, 2]. Rogers and associates [1] found spontaneous CBF reductions ranging from 0 to 14 mL · 100 g^-1 · min^-1 (mean ± standard deviation, 4 ± 4 mL · 100 g^-1 · min^-1) over a period of 16 to 70 minutes (mean ± standard deviation, 26 ± 15 minutes). Prough and colleagues [2] estimated rates of decline ranging from 0.1 ± 0.1 to 4 ± 0.5 mL · 100 g^-1 · min^-1 per minute. The observed decline in CBF was not accompanied with a decline in cerebral metabolic oxygen consumption (CMRO₂) suggesting a loss of cerebral autoregulation [2]. Other studies have failed to support these hypothermic cardiopulmonary bypass results showing preservation of CBF during CPB [3, 4].

The purpose of this study was to better define the influence of mildly hypothermic CPB time on CBF, avoiding the significant changes in temperature that may have complicated previous investigations.

	Material and methods

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Patient management
After institutional review board approval and written informed consent were obtained, 52 patients undergoing elective coronary artery bypass grafting were studied. Ninety minutes after oral premedication (diazepam, 0.1 mg/kg, and methadone hydrochloride, 0.1 mg/kg), catheters were placed in the radial artery and right jugular bulb to allow simultaneous sampling of arterial and jugular venous blood. Anesthesia was induced with midazolam hydrochloride (50 to 75 µg/kg) and fentanyl citrate (5 to 10 µg/kg) intravenously and was maintained with continuous infusion of midazolam (0.5 µg · kg^-1 · min^-1) and fentanyl (0.05 µg · kg^-1 · min^-1) throughout the operation. Pancuronium bromide was given as needed to maintain complete neuromuscular blockade.

The perfusion apparatus consisted of a Cobe CML membrane oxygenator (Cobe Laboratories, Lakewood, CO) and a Sarns 7000 max pump (3M Inc, Ann Arbor, MI). The protocol specified nonpulsatile perfusion of 2.4 L · min^-1 · m^-2 at a nasopharyngeal temperature of 35° to 36°C maintained throughout the study periods. Arterial carbon dioxide tension was maintained throughout CPB at 30 to 40 mm Hg (uncorrected for body temperature) with an arterial oxygen tension of 150 to 250 mm Hg. A mean arterial pressure of 50 to 90 mm Hg was maintained throughout CPB. A crystalloid CPB prime designed to achieve a hematocrit of 0.18 or higher during extracorporeal circulation was used. Packed red blood cells were added when necessary to achieve the desired hematocrit. In all patients an ascending aortic cannula and a Pall SP 3840 arterial line filter (Pall Biomedical Products Co, Glencover, NY) were used.

Extracranial 16-mm cadmium telluride detectors with wide-angle collimators were placed over the right and left temporal lobes, and the average of the values from both sites was used to determine CBF. After correction for background activity, xenon-133 decay curves were analyzed with zero modification of the initial slope method validated during CPB [5]. The following formula was used: where slope is the slope of the natural logarithm of the count rate during the first minute of ¹³³Xe washout obtained by linear regression, and is the blood-brain partition coefficient corrected for temperature and hematocrit. Three millicuries of ¹³³Xe was dissolved in 3 mL of sterile saline solution and injected into the arterial perfusate circuit of the pump oxygenator. Cerebral blood flow and CMRO₂ determinations were made after institution of mildly hypothermic CPB (T1). Cerebral blood flow was again determined toward the end of CPB (T2) at the same nasopharyngeal inflow temperature (<1°C change), mean arterial pressure (±15% initial measurement), and PaCO₂ (< 5 mm Hg change) as the initial measurement. Blood pressure was controlled with sodium nitroprusside or phenylephrine as needed to match within 15% of the first. Simultaneous blood draws from the radial artery and jugular bulb catheters for determination of pH, oxygen tension, and oxygen saturation were performed 1 minute after ¹³³Xe injection. Blood gas values were determined with a BGE blood gas electrolyte analyzer (Instrumentation Laboratories, Lexington, MA). Oxygen saturation and hemoglobin measurements were made on an IL482 cooximeter (Instrumentation Laboratories).

Statistical methods
The primary hypothesis of this study was that there was no association between change in CBF during bypass and length of time on bypass. The change in CBF and the accompanying time change were calculated for each individual as the T2 value minus the T1 value. After we checked for normality of distributions, the univariate association of these changes was tested with simple linear regression. Multivariable linear regression was then used to further assess the association, accounting for simultaneous effects of change in temperature, mean arterial pressure (MAP), PaCO₂, diabetes, and their interactions with change in time. Significance was set at = 0.05. Significant change from T1 to T2 in other physiologic measurements was tested with a two-tailed paired t test, or with the Wilcoxon signed rank test if the distribution was nonnormal. The association between amount of change and time interval was calculated with Pearson’s correlation coefficient and its test of significance. These descriptive measures were tested at = 0.05 unadjusted for multiple comparisons.

	Results

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Seventy-two patients were enrolled in this study, with 8 excluded from analysis because of temperature variations of more than 1°C between CBF measurements. Three were excluded because of inability to perform a second CBF measurement, 3 had MAP changes greater than 15% during the study period, and 6 had greater than 5 mm Hg PaCO₂ change from one measurement to the next. Analysis was performed on the remaining 52 patients described in Table 1. No significant association was seen between amount of change in CBF and time interval, either in the univariate regression (p = 0.47; r² = 0.0103) or in the multivariable regression that accounted for diabetes and changes in temperature, PaCO₂, and MAP (time p = 0.41; partial r² = 0.0119). Figure 1 demonstrates the observed relationship of CBF to time between measures. This study had 80% power to detect an association between change in CBF and time interval as small as r² = 0.14 (Pearson’s r = 0.372). Given the observed variances of the changes, this is equivalent to a CBF-change/time slope as small as 0.115 mL · 100 g^-1 · min^-1 per minute. Although a small average decrease in CBF during bypass was seen (change in CBF = -1.9 ± 6.15 mL · 100 g^-1 · min^-1; p = 0.0306), the amount of decrease was not related to length of time between measurements. The average time between CBF measurements was 54 ± 20 minutes (mean ± standard deviation), with a range of 10 to 100 minutes.

View larger version (20K): [in this window] [in a new window]   Fig 1. Time between cerebral blood flow measurements (T1 = after the initiation of cardiopulmonary bypass at stable mild hypothermia and T2 = at the end of bypass) in minutes is on the horizontal axis, change in cerebral blood flow (mL · 100 g-1 · min-1) is on the vertical axis.

	Comment

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Because the intervals between our CBF measurements varied, we were able accurately to assess the question of the time-dependency of CBF during bypass and account for other important influences. It is important to distinguish this question from asking whether or not any decrease occurs, which may be attributable to other factors. In Figure 1, one point appears as a distinct potential outlier. Although we found no reason to exclude the subject, a secondary analysis was run without him for verification, and the conclusions remained as strong.

A decline in CBF with hypothermic CPB time in adults was first suggested in 1988 by Rogers and associates [1]. They observed CBF reductions ranging from 0 to 14 mL · 100 g^-1 · min^-1 (mean ± standard deviation, 4 ± 4 mL · 100 g^-1 · min^-1) over 16 to 70 minutes corresponding to a 0.2 ± 0.2 mL · 100 g^-1 · min^-1 per minute decline [1]. In subsequent studies, that group has time corrected the CBF measurements based on this assumption [6, 7]. Prough and associates [2] provided support for this in a study of stable hypothermic CPB, estimating decline in CBF to be between 0.1 ± 0.1 and 0.4 ± 0.5 mL · 100 g^-1 · min^-1 per minute over a period of 20 to 30 minutes. In that study, temperature and CMRO₂ showed no decline yet CBF decreased, suggesting an inability of CBF to meet metabolic demands. Prough and associates suggested a mechanism of cerebral vasoconstriction or microvascular obstruction causing the CBF reduction. Various animal models have shown no time-dependent decline in CBF during CPB. Hindman and coworkers [3], in a rabbit model, found an inverse correlation between CBF and bypass duration. When the first time points were omitted (CBF at 23 minutes after initiation of CPB), the correlation between CBF and time disappeared. This suggested to Hindman and coworkers that the early correlation was caused by incomplete cooling of the brain (possibly because of imprecise temperature monitoring of the esophagus). He hypothesized that if the decrease in CBF seen in the other studies were due to progressive cerebral vasoconstriction or embolic obstruction that it would be apparent at stable temperature as well. In this rabbit model brain temperature equilibration occurred in about 40 minutes. Similarly, Johnston and colleagues [8] measured CBF (using microspheres) in dogs after 30, 90, and 150 minutes of hypothermic CPB and found no time-related change. In a study of baboons using low-flow cardiopulmonary bypass at 18°C there also was no time-dependent change in CBF, with CBF being disproportionately preserved [4]. In our experiment, with controlled nasopharyngeal temperature, there was no significant change in CBF or C(a-v)O₂ over time.

We have demonstrated that during CPB, temperature differences exist between nasopharyngeal and jugular bulb temperature monitoring sites [9]. These difference were most pronounced during cooling and rewarming, with jugular venous temperature exceeding nasopharyngeal by as much as 4°C during rewarming. During CPB, temperature in the jugular bulb and nasopharynx correlated well (that is, had a high degree of precision). We believe, as Hindman and associates suggested, that the most likely explanation for the decrease in CBF in the studies by Rogers’ and Prough’s groups is the initial measurement of CBF taken before a stable cerebral temperature.

We found a change in CBF from T1 to T2 (which was not related to time). We speculate cerebral emboli may have been a cause of CBF decline. Prior animal studies that have found no change in CBF over time during CPB may not have the same likelihood of atheromatous or gaseous cerebral embolization as do human patients. Thus cerebral microemboli and macroemboli may account for the change in oxygen extraction seen in the human studies but lacking in the animal studies. Emboli occur during aortic instrumentation and at various times throughout the procedure as documented by transcranial middle cerebral arterial Doppler echography [10, 11]. These emboli are thought to be large macroemboli due to plaque debris or small microemboli due to air or fat [12]. The effects of air embolism on cerebral vasculature are more than simple obstruction of capillary flow. Cerebral circulation bubbles in rabbits produce pial arteriole dilatation that persists for 90 minutes after the bubbles disappear. Changes in vessel diameter are associated with a delayed but significant and progressive decline in cerebral blood flow and neural function measured by somatosensory evoked response [13]. This is evidence of the effect of microembolization on cerebral vasculature and decreased neural function without entrapment.

Leukocytes appear to play an important role in injury produced by cerebral air embolism. Dutka and associates [14] and Helps and colleagues [15] observed that leukodepletion attenuated reductions in CBF after air embolism. Cerebrovascular endothelium is functionally impaired after air embolism [16, 17]. It has been suggested that this endothelial injury is different from models of cerebral ischemia/reperfusion and may initiate early leukocyte involvement [18]. Haller and associates [16] observed cat cerebral arteries that had a reduced vasodilatory response to carbachol (acetylcholine receptor agonist) after transient air embolism. This suggests air-damaged endothelium may have reduced nitric oxide production. We present this as another theory of increased cerebrovascular resistance due to loss of nitric oxide-mediated dilation.

A possible reason for the discrepancy in human studies is that there is more global evidence of emboli in some studies as compared with others. The use of transcranial Doppler echography, intraoperative transesophageal echocardiography, arterial line filters, and membrane oxygenators all have served to decrease the amount of emboli delivered to the cerebral circulation [19].

On the basis of our report as well as the laboratory experiments cited above, we are confident that the flow-metabolism coupling response to nonpulsatile perfusion is intact at a fixed temperature because C(a-v)O₂ does not increase with time. We have previously found a correlation between widening C(a-v)O₂ and impaired postoperative cognitive performance [20]. Flow-metabolism coupling problems documented by increasing C(a-v)O₂ are possibly caused by problems with sluggish CBF compensation during rewarming.

In summary, our experimental results include the following: (1) at mildly hypothermic bypass, CBF does not decrease in relation to time and (2) cerebral flow-metabolism coupling is intact at 35°C.

	Acknowledgments

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We appreciate the enthusiastic support and cooperation of our surgical colleagues: Francis G. Duhaylongsod, Donald D. Glower, Jr, Kevin P. Landolfo, and Peter K. Smith. We also acknowledge the support of our perfusionist colleagues: C. Bob Clark, Edward M. Darling, Carmen R. Giacomuzzi, Joyce A. Hancock, David D. Kaemmer, Curtis L. King, D. Scott Lawson, Tim L. Moretz, Katharine W. Nanry, Calvin C, Rogers, Ian R. Shearer, and Gregory R. Smigla.

This research was supported in part by National Institutes of Health grant R01-AG09663.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Rogers A.T., Stump D.A., Gravlee G.P., et al. Response of cerebral blood flow to phenylephrine infusion during hypothermic cardiopulmonary bypass. Anesthesiology 1988;69:547-551.[Medline]
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16. Haller C., Sercombe R., Verrecchia C., Fritsch H., Seylaz J., Kuschinsky W. Effect of the muscarinic agonist carbachol on pial arteries in vivo after endothelial damage by air embolism. J Cereb Blood Flow Metab 1987;7:605-611.[Medline]
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