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Ann Thorac Surg 1995;59:614-620
© 1995 The Society of Thoracic Surgeons
Department of Anesthesiology and the Section of Cardiothoracic Surgery, Department of Surgery, and Department of Neurosurgical Research, Mayo Clinic, Rochester, Minnesota
Accepted for publication November 4, 1994.
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Abstract |
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 TopFootnotes Abstract IntroductionMethodsResultsCommentAcknowledgmentsReferences |
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-stat pH management was used. Xenon-133 clearance significantly underestimated CBF and CMRO2 relative to the Kety-Schmidt technique before CPB and at both bypass temperatures. Values obtained by 133Xe clearance were approximately 50% of that measured by the Kety-Schmidt method. The modified 133Xe technique as typically used during cardiac operations does not appear to measure CBF accurately; this leads to corresponding errors in CMRO2 calculations. Determination of CMRO2 and cerebral autoregulatory function during cardiac operations appears to be more appropriate if based on the more direct Kety-Schmidt technique. Accordingly, our management of CPB with respect to cerebral perfusion as it has been determined by the modified 133Xe clearance method may require reassessment. |
Introduction |
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TopFootnotesAbstractIntroductionMethodsResultsCommentAcknowledgmentsReferences |
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For editorial comment, see page 558.
The intraarterial 133Xe technique was modified for use during cardiac operations because it is simple and relatively noninvasive. This was in contrast to the Kety-Schmidt technique, which requires access to cerebral venous drainage and the cumbersome analysis of multiple arterial and venous blood samples for determination of saturation curves.
Because of the inaccessibility of the internal carotid artery, investigators using 133Xe clearance during cardiac operations have used common carotid or brachiocephalic artery 133Xe injection or injection into the arterial inflow line of the extracorporeal circuit, or both. This modification of the original technique may lead to erroneous results.
Delivery of 133Xe at sites proximal to the internal carotid artery are likely to exaggerate the underestimation of CBF using the 133Xe technique. Injection of 133Xe proximal to the internal carotid artery results in the delivery of a greater proportion of the 133Xe bolus to lower the flow to extracranial tissues. Furthermore, proximal injection sites may result in a slurred peak of cerebral radioactivity that would cause further underestimation of calculated CBF. The Kety-Schmidt technique is not subject to these errors.
The Kety-Schmidt technique for measuring CBF is an application of the Fick principle, which is subject to minimal artifact [2]. This methodology depends on the direct measurement of arterial and cerebral venous blood concentrations of an inert, freely diffusible indicator. Rate of uptake of the indicator from cerebral tissue into the cerebral venous blood allows calculation of CBF. If venous sampling is from the jugular bulb, contamination from extracerebral tissues is negligible [3]. Therefore, flows determined by the Kety-Schmidt technique represent global brain–blood flow. Because of its solid theoretical foundation, limited assumptions, and the directness of the technique, the Kety-Schmidt method has been the standard to which other methods are compared [4]. However, because of its complexity, it has been uncommonly used since the introduction of 133Xe clearance.
A comparison of CBF methodologies during cardiac operations recently was called for in an editorial by Prough and Rogers [5]: ``. . . a conclusive validation study must compare the Kety-Schmidt technique to clearance of 133Xe injected into the arterial side of the oxygenator circuit in hypothermic patients undergoing CPB.'' This study compares those methods under prebypass, normothermic (37°C), and hypothermic (27°C) bypass conditions.
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Methods |
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Anesthesia consisted of a high-dose fentanyl–midazolam technique (loading doses, fentanyl 30 µg • kg-1 and midazolam 100 µg • kg-1, followed by an infusion of 0.3 µg • kg-1 • min-1 fentanyl and midazolam 0.4 µg • kg-1 • min-1). Inspired oxygen fraction was maintained between 40% and 70%. Arterial, pulmonary artery, and right atrial blood pressures, heart rate, end-tidal carbon dioxide concentrations, and nasopharyngeal temperature were continuously measured. A catheter was placed percutaneously in the right jugular bulb after anesthetic induction to allow sampling of cerebral venous blood. Catheter position was confirmed by fluoroscopy in all patients.
During CPB, a nonpulsatile pump flow of 2.2 to 2.4 L • min-1 • m-2 was maintained. The arterial carbon dioxide tension (PaCO2) was adjusted to normocapnic levels (35 to 40 mm Hg) without temperature correction (-stat regulation). The bypass pump was primed to maintain a hematocrit of 23% or greater during the bypass period. All aortic cannulations occurred at the ascending aortic arch. Sodium nitroprusside or phenylephrine infusions were used during CPB to maintain a mean arterial blood pressure of 50 to 70 mm Hg. Nasopharyngeal temperature was measured continuously as an indirect indicator of brain temperature.
The CBF both by Kety-Schmidt and 133Xe clearance techniques was measured simultaneously during two periods: (1) prebypass before aortic cannulation and (2) during CPB. In patients undergoing hypothermic CPB, CBF measurements were made when the nasopharyngeal temperature was stable at 27°C; in patients undergoing normothermic CPB, measurements were made after 30 minutes on CPB at 37°C. Mean arterial blood pressure, pump flow rate during CPB, and nasopharyngeal temperature were stable before measurements were made.
Global CBF was measured according to the nitrous oxide (N2O) method of Kety and Schmidt [2]. Prebypass, 10% N2O was introduced into the inspiratory gas flow of an air–oxygen mixture. During CPB, 10% N2O was introduced into the pump oxygenator. Ten timed collections of radial arterial and cerebral venous blood were drawn during 15 minutes of N2O exposure. Each sample of 1.5 mL was drawn over 30 seconds and placed on ice. The N2O concentration was measured in the blood samples on an infrared N2O analyzer (trace N2O monitor, Dynatech Electro-optics, Saline, MI). The CBF was calculated from curves fit to the measured N2O concentrations and integrated to infinity (see Appendix 1).
The CBF during each period was calculated as follows [2]:
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where 
= the brain–blood solubility coefficient for N2O; V(t) = the venous N2O reading at saturation; and 
(a - v)dt = the area circumscribed by the difference in arterial and venous N2O concentration curves.
The brain–blood solubility coefficient () for N2O was corrected for temperature during hypothermic CPB based on N2O solubility changes in oil and water at 27°C [6]. Regional CBF was determined from clearance curves obtained from the extracranial detection of intraarterially injected 133Xe. The measurement technique has been described in detail previously [7], with the exception that in this study the indicator was injected into either the right common carotid (n = 2) or the brachiocephalic artery (n = 18) before CPB. Prebypass, the injectate contained 2 to 4 mCi of 133Xe diluted to 1.5 to 2.0 mL total volume with physiologic saline. The 133Xe was monitored by a single thallium-activated sodium iodide detector placed adjacent to and at right angles to the right parietal bone (see Appendix 1) [7].
During CPB, 4 to 6 mCi of 133Xe diluted in 3.0 to 4.0 mL of saline was injected into a port on the arterial inflow circuit [8–10]. A minimum of 30 minutes elapsed between the before CPB and CPB measurements in all patients. The partition coefficient for 133Xe was corrected as necessary for both alterations in hematocrit and temperature during CPB [11].
If the PaCO2 between the two measurement periods differed, the prebypass CBF (by both methods) was corrected by 3% for each mm Hg difference in PaCO2 [12, 13].
The CMRO2 was calculated to be the product of the CBF (by either method) and the arteriovenous oxygen content difference. Arterial and venous oxygen content at 27°C were calculated after the oxygen tension was determined at 27°C using the method of Severinghaus [14] (see Appendix 1).
For each measurement technique and each patient group (normothermic, hypothermic), the Wilcoxon signed rank test was used to compare changes in CBF and CMRO2 from the before CPB to the CPB periods. In addition, for each study condition, the Wilcoxon rank sum test was used to compare the CBF and CMRO2 determinations made by the two CBF methodologies. When multiple comparisons were made on the same individuals, a p value of less than or equal to 0.01 was considered significant. All data are given as mean ± standard deviation.
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Results |
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TopFootnotesAbstractIntroductionMethodsResultsCommentAcknowledgmentsReferences |
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. Mean arterial blood pressure and hemoglobin differed from the prebypass to the bypass period in both groups. The prebypass PaCO2 tended to be lower than the bypass PaCO2 in both groups. During CPB, the normothermic and hypothermic groups differed only with respect to mean temperature. Mean arterial blood pressure, hemoglobin, arterial oxygen tension, and PaCO2 did not differ between the normothermic and hypothermic groups (Table 1).
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).
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0.01 Wilcoxon signed rank test) (Fig 1
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During normothermic CPB (n = 10), mean CBFK-S was 51 ± 10 mL • 100 g-1 • min-1, whereas CBFxe was 29 ± 8 mL • 100 g-1 • min-1 (n = 10); the 133Xe technique underestimated CBFK-S by 43%. During normothermic CPB, CBFK-S increased significantly as compared with the prebypass value (51 versus 36 mL • 100 g-1 • min-1). Similar increases in CBF during normothermic CPB were demonstrated by the 133Xe technique (29 versus 18 mL • 100 g-1 • min-1). This increase in CBF was highly significant by both techniques (p < 0.01 Wilcoxon signed rank test) (Fig 1). The CBFK-S and CBFxe differed at the level p < 0.01 during all three study conditions (Wilcoxon rank sum test).
The prebypass CMRO2 as determined by the Kety-Schmidt technique was 2.55 ± 1.22 mL • 100 g-1 • min-1 and by CBFxe was 1.23 ± 0.51 mL • 100 g-1 • min-1 (n = 20) (Fig 2).
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). This decrease in CMRO2 with temperature was significant for both techniques at the level of p 0.01 (Wilcoxon rank sum test). The calculated temperature coefficients (Q10) by the Kety-Schmidt and 133Xe clearance techniques were 3.0 and 2.6, respectively.
During normothermic CPB at 37°C, CMRO2 was 2.35 ± 0.33 and 1.32 ± 0.30 mL • 100 g-1 • min-1 by the Kety-Schmidt and xenon techniques, respectively. The CMRO2 did not differ from the prebypass value as measured by either method (Fig 2).
The metabolic rates determined by the Kety-Schmidt and xenon techniques during each study condition differed at the level of p 0.01 by Wilcoxon rank sum test (Fig 2).
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Comment |
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TopFootnotesAbstractIntroductionMethodsResultsCommentAcknowledgmentsReferences |
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The method of regional CBFxe determination used was the initial slope calculation, an analysis technique that emphasizes the cortical, fast flow component of CBF [1]. Conversely, the N2O saturation curves for the Kety-Schmidt technique were integrated to infinity, an analysis technique that will minimize the global flows calculable by the Kety-Schmidt method [4]. In spite of this, the CBF measurements obtained by the two techniques were very different (Fig 3) and opposite to what might have been predicted from the above considerations (ie, the CBFxe would be greater than the CBFK-S).
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Accurate measurement of CBF and CMRO2 using the 133Xe technique is predicated on minimizing artifact attributable to contamination of radioactivity in extracerebral tissues and near instantaneous arrival of the bolus into the counting field [18]. If this is not achieved, CBF is underestimated. In our experience, injection of 133Xe proximal to the internal carotid leads to lower peak counts than is achieved by an internal carotid injection, the rate of rise is slower and the peak somewhat slurred. This, together with distribution of large amounts of 133Xe to the extracerebral tissues, may explain the low CBF values obtained with 133Xe during cardiac operations. Direct injection of 133Xe into the internal carotid artery or common carotid artery injection with external carotid clamping, as during carotid operations, minimizes these problems. However, these techniques are not feasible during cardiac operations as they require either carotid dissection or arteriography.
The Kety-Schmidt technique, on the other hand, is subject to minimal extracerebral contamination [3], therefore, flow determinations closely approximate actual global CBF. Our results and those of Stephan and colleagues [19], who used similar methodology, are in agreement and are significantly greater than those reported with 133Xe. In addition, the Kety-Schmidt values we report closely approach the predicted theoretical [5] and measured values in humans under fentanyl–midazolam anesthesia [19] and those measured by more direct techniques in animals [16, 17].
The Kety-Schmidt technique with shorter N2O uptake periods has the potential to overestimate CBF [20], particularly at low CBFs. However, according to Lassen and Klee [21], this potential error ``. . . may be counteracted by prolonging the saturation period to 15 or 20 minutes and by extrapolation of the curves to infinity.'' Both of these steps were undertaken in our study design and data analysis, therefore, risk for overestimation of CBF by incomplete equilibration of tissue and venous N2O is minimal.
Both the Kety-Schmidt technique and the 133Xe clearance technique appear to measure the relative change in CBF and CMRO2 that occurs with decreasing temperature, but the absolute values determined by the 133Xe technique in our study and in previous reports of CBF and CMRO2 during cardiac operations may be incorrect [8–10, 15]. These values are not consistent with previously measured values in awake or anesthetized humans by either the Kety-Schmidt [2, 4] or internal carotid 133Xe techniques [4, 22].
On the basis of previous hypothermia studies in animals and humans [17, 23], we expected a significant decrease in CBF with cooling but this was not seen. The hemodilution that occurs with initiation of CPB (Table 1) results in a decrease in blood viscosity. This decrease in viscosity probably preserves CBF during decreasing oxygen demand. Decreased CPB hematocrit would also explain the increase in CBF we documented during normothermic bypass where CMRO2 is unchanged. In the absence of this hemodilution, we estimate that CBF at 27°C would have decreased by an additional 43%.
Because the N2O blood–brain partition coefficient has not been reported at 27°C, we estimated this coefficient change. Although this might be criticized, the maximum predicted change in over the 10°C temperature change in our study was 11% [6]. This estimation is consistent with the chemical properties of a gas with a low solubility such as N2O [24] whose partition coefficient is close to unity at 37°C [25]. This solubility change minimally affects our CBFK-S results and does not impact on the qualitative relationship between CBFK-S and CBFxe that we report.
Our use of a single gamma detector for 133Xe measurements might also be criticized. However, single detectors provide reliable values under nonbypass conditions [4], and it appears that our regional measurements are representative of hemispheric flows. The CBF values that we report here using a single probe are not different from investigations that used multiple detectors under similar conditions [8–10, 15].
Lassen [4] proposed that CBF measurements deviating significantly from established values are ``. . . clear indications of gross systematical errors....'' The same is true of CMRO2 measurements. Although the circulatory conditions of CPB are abnormal, reported CBF values of 10 to 20 mL • 100 g-1 • min-1 and CMRO2 values of 0.3 to 0.6 mL • 100 g-1 • min-1 [8, 9, 15] make little physiologic sense even at 27°C. The values we report using the Kety-Schmidt methodology under nonbypass, normothermic, and hypothermic bypass conditions are reasonable and consistent with theoretical predictions in humans and reported values in humans and animals.
The commonly used modification of the 133Xe clearance method for CBF measurements during cardiac operations and CPB appears to be unacceptable. As characteristically used CBF and CMRO2 are systemically underestimated. This has the potential to lead to misunderstandings of cerebral hemodynamics during cardiac operations and accordingly a reevaluation of our management of CPB with regard to the cerebral circulation may be required.
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Appendix |
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).
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where = the brain–blood solubility coefficient for N2O; V(t) = the venous N2O reading at saturation; and (a - v)dt = the area circumscribed by the difference in the arterial and venous N2O concentration curves.
The reported value of 1.06 for was used when body temperature was 37°C [25]. When the patient was hypothermic (27°C), was estimated based on the changing solubility of N2O in oil and water at 27°C [6]. A of 0.94 was used for CBF determinations done at 27°C.
During CPB, 10% N2O was introduced into the fresh gas flow. Paired arterial and jugular bulb venous measurements were taken on the schedule as described. During CPB, arterial blood was drawn from a shunt line taken off the arterial inflow line of the CPB machine rather than the radial artery.
If PaCO2, mean arterial blood pressure, or pump flow rate varied by more than 15% during a study period, the study period was aborted and was resumed a minimum of 15 minutes later to insure residual N2O had been cleared from the circulation. A repeat time zero baseline N2O was then drawn.
Xenon-133 Clearance
Regional CBF was determined from clearance curves obtained from the extracranial detection of intraarterially injected 133Xe. The 133Xe was monitored by a single thallium-activated sodium iodide detector. The crystal, 1.25-inch in diameter by 0.25-inch thick, was recessed 1 inch behind a tapered lead collimator with an opening widening from 0.875 to 1.125 inches at the surface of the crystal. The detector was placed adjacent to and at right angles to the skull over the parietal boss [7].
Prebypass, 133Xe dissolved in saline was injected into the exposed right brachiocephalic artery (18 patients) or the right common carotid artery (2 patients). In the prebypass period, the injectate contained 2 to 4 mCi of 133Xe diluted in 1.5 to 2.0 mL total volume with saline. This measurement was done simultaneously with the Kety-Schmidt method.
An initial slope method was used to determine regional CBF by 133Xe. After injection of 133Xe, a pulse was initiated by the operator to start the timing circuit. The sampling of the logarithmic peak count rate was delayed by 10 seconds to compensate for the lag time of the clearance curve. This peak count was then held for 1 minute by a sample/hold circuit while a differential amplifier subtracted the count rate of the logarithmic curve at the end of 1 minute. This value was then multiplied by a noninverting amplifier, by 20.01 to give the product of the partition coefficient for 133Xe, and the factor 2.3 for converting common to natural logarithms, and to increase the gain 10-fold to drive the digital panel meter [7]. The complete clearance curve for each CBFxe was generated, although the ISI technique used samples of gamma counts at two discrete points.
Regional blood flow computed by this automated analyzer has shown excellent correlation with the manual method of computation. The coefficient of correlation (r) comparing manual computation and this automated method was 0.95 with p < 0.001 based on 181 previous measurements [7].
For the 133Xe measurement during bypass, 4 to 6 mCi of 133Xe diluted in 3.0 to 4.0 mL of saline was injected into a port on the arterial inflow circuit distal to the membrane oxygenator. Detection was as described above. A minimum of 30 minutes elapsed between the before CPB and CPB measurements in all patients. The bypass CBFxe measurement was done simultaneously with the Kety-Schmidt determination. The partition coefficient () for 133Xe was corrected as necessary for both alterations in hematocrit and temperature during CPB according to the method of, and results obtained by Chen and colleagues [11] for brain and blood at 27°C and 37°C:
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where tb = tissue–blood partition coefficient for 133Xe; tp = tissue–plasma partition coefficient for 133Xe; cp = red cell–plasma partition coefficient for 133Xe; and H = hematocrit.
The PaCO2 tended to be different in the prebypass and bypass measurement periods. To allow for CBF comparisons at equivalent PaCO2, the prebypass CBF (by both methods) was corrected by 3% for each mm Hg difference in PaCO2 when the prebypass PaCO2 differed from that during CPB [12, 13].
Cerebral Metabolism Measurement
The CMRO2 was determined from the product of the arteriovenous oxygen content difference and the CBF (by both methods). Arterial and jugular bulb blood gas tensions and saturations were determined (IL-BGE Analyzer, IL 4-286 Co-Oximeter; Instrumentation Laboratories, Inc, Boston, MA) during both CBF measurement periods. Blood gas tensions were measured at 37°C and the arterial and venous oxygen tensions were subsequently back-corrected to a blood temperature of 27°C when the patient was hypothermic. The formula of Severinghaus [14] was used:
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The arterial and venous oxygen content, AVDO2, and CMRO2 at 27°C were calculated based on this temperature correction.
CMRO2 for oxygen:
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Arteriovenous oxygen content difference (determined at 37°C):
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where Hb = hemoglobin concentration; SxO2 = oxygen saturation; and PxO2 = partial pressure of oxygen2, CvO2, and CxO2.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMethodsResultsCommentAcknowledgmentsReferences |
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References |
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TopFootnotesAbstractIntroductionMethodsResultsCommentAcknowledgmentsReferences |
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