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Ann Thorac Surg 1997;63:736-740
© 1997 The Society of Thoracic Surgeons

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Original Article: Cardiovascular

Nitrous Oxide Method of Measuring Cerebral Blood Flow During Hypothermic Cardiopulmonary Bypass

Department of Anesthesiology and Division of Thoracic and Cardiovascular Surgery, Department of Surgery, Mayo Clinic, Rochester, Minnesota

Accepted for publication October 16, 1996.

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Background. Determination of cerebral blood flow and oxygenation is a means of evaluating our cardiopulmonary bypass (CPB) practice. Because much of CPB is hypothermic, our measurement technique must be valid over a range of temperatures. In this study we evaluate the validity of N₂O washin for measurement of cerebral blood flow and oxygenation at three temperatures.

Methods. Cerebral blood flow and oxygenation were measured in 7 dogs undergoing CPB at 37°, 32°, and 27°C using simultaneous direct (sagittal sinus outflow) and indirect (nitrous oxide washin) techniques. Animals underwent CPB with a whole blood prime and -stat pH management.

Results. In the absence of hemodilution, cerebral blood flow and oxygenation were reduced by approximately 38% and 55% at 32°C and 27°C, respectively, by both techniques. Direct and indirect methods showed an excellent correlation (R = 0.87) during CPB between 27.5°C and 37.8°C (21 paired measurements).

Conclusions. This investigation demonstrates that the correlation between a direct measure of global cerebral blood flow and that obtained by the N₂O saturation method is excellent during CPB over the range of common CPB temperatures.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
The purpose of this study was to compare cerebral blood flow (CBF) measurements obtained with two techniques at three cardiopulmonary bypass (CPB) temperatures. The Kety-Schmidt (KS) technique of nitrous oxide (N₂O) washin is based on the Fick principle and has been the gold standard for indirect measurement of CBF in humans under normothermic conditions [1]. However, its use under hypothermic conditions has been challenged. It has been argued that the solubility coefficient for N₂O has not been documented under hypothermic conditions and that the technique may significantly overestimate CBF under conditions of low flow [2]. We therefore compared CBF measurements obtained with the Kety-Schmidt technique at 37°, 32°, and 27°C with those obtained directly during canine CPB.

The sagittal sinus outflow (SSO) method is a well-established, direct means of determining global CBF in an animal model [3, 4]. With this method, cerebral venous drainage is isolated to the sagittal sinus and measured directly. If intracranial pressure is stable, cerebral venous outflow is equal to cerebral arterial inflow. Because the sagittal sinus outflow technique is direct and provides a global measurement of CBF, it is a more appropriate comparison for the Kety-Schmidt technique than regional methods such as xenon-133 washout or radioactive microspheres. Because CPB hemodilution alters the relationship between temperature change and CBF [5], experiments were conducted using a whole blood CPB prime. The absence of hemodilution also allows the comparison of these study results to classic, established studies on the relationship of temperature and CBF.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
After review and approval by the Institutional Animal Care and Use Committee, 7 unmedicated fasting adult mongrel dogs weighing 15 to 20 kg were studied. The dogs were placed in a Plexiglas box and anesthesia was induced with halothane 3% to 4% inspired concentration in oxygen. Peripheral intravenous access was then established, muscle relaxation obtained with pancuronium 0.8 mg/kg, and the trachea intubated. Ventilation was controlled with a Harvard pump set to maintain arterial carbon dioxide tension at 35 to 40 mm Hg and an arterial oxygen tension more than 150 mm Hg. A loading dose of fentanyl (250 µg/kg) and midazolam (350 µg/kg) was given and the halothane was discontinued. Anesthesia was maintained with a fentanyl (3 µg·kg^-1·min^-1) and midazolam (10 µg·kg^-1·min^-1) infusion [6].

Cannulas were surgically inserted into a femoral artery for mean arterial blood pressure measurements and blood sampling. The sagittal sinus was then exposed, isolated, and cannulated as described previously [3, 6] for direct measurements of CBF from the anterior, superior, and lateral portions of both hemispheres. Cerebral venous efflux was recorded continuously with a flowthrough electromagnetic flow probe (EP300 API; Carolina Medical Electronics, Inc, Kin, NC). Body temperature was measured with a nasopharyngeal thermistor and brain temperature with a parietal epidural thermistor. Intracranial pressure was transduced using a fiberoptic epidural sensor. The cranium was then closed with surgicel and adhesive [3, 6].

To establish CPB, a left-sided thoracotomy was performed. After anticoagulation with intravenous heparin (400 units/kg), a 36F cannula was placed in the right atrium through the right atrial appendage. During CPB, the blood was circulated through an oxygenator-heat exchanger unit (Bentley Univox) and was returned through a cannula (inner diameter, 8 mm) in the root of the aorta. The bypass machine was primed with whole blood (1,000 mL) from a donor dog. During bypass, mean arterial blood pressure was maintained between 60 and 70 mm Hg throughout the period of bypass by alteration in pump flow rate and without the use of vasoconstrictors or vasodilators. Arterial hemoglobin concentration and blood gas data were monitored continuously by an in-line detector (CDI 400; CDI 100 Cardiovascular Devices, Inc, Tustin, CA), but all physiologic determinations were based on direct measurements of blood samples. Management of pH was -stat.

After completion of the surgical preparation and before the establishment of CPB, control cerebral and systemic measurements were obtained (Table 1). Cerebral blood flow was determined using the sagittal sinus outflow method, and cerebral metabolic rate for oxygen (CMRO₂) and cerebral oxygen delivery were determined from the product of the CBF and arteriovenous oxygen content difference (AVDO₂) and arterial oxygen content (CaO₂), respectively.

(1)

integrated to infinity [7, 8]; 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 for of 1.06 was used at normothermia [9] and values of 1.0 and 0.94 were used at 32.5° and 27.5°C, respectively. Values for at hypothermia were estimated based on the change in solubility coefficient for N₂O in oil and water at 27°C [8, 10, 11].

Cerebral Metabolism Measurement
The CMRO₂ was determined from the product of the AVDO₂ and the CBF, using the equations:

(2)

Arteriovenous oxygen content difference:

(3)

Arterial or venous oxygen content:

(4)

where Hb = hemoglobin concentration; SxO₂ = oxygen saturation; and PxO₂ = partial pressure of oxygen.

Arterial and sagittal sinus blood gas tensions, saturations, and hemoglobin concentrations were determined (IL-BGE Analyzer; IL 4-286 Co-Oximeter, Instrumentation Laboratories, Inc, Boston, MA) from blood samples drawn midway through each CBF measurement period using coefficients appropriate for dog hemoglobin. Arterial and cerebral venous oxygen contents, cerebral metabolic rate, cerebral oxygen delivery, and cerebral oxygen extraction ratio (CMRO₂/cerebral oxygen delivery) were then calculated.

Mean and standard deviations for CBF and CMRO₂ were determined for each technique at each temperature. A Spearman rank order correlation was determined for the 21 paired values (three pairs per animal). The Mann-Whitney rank sum test was used to compare CBF measurements by both techniques at each temperature. A p value less than 0.05 was considered significant. A Bland-Altman analysis was used to examine for technique bias [12].

	Results

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Physiologic data for the prebypass period are provided in Table 1. Before bypass, cerebral physiologic values were determined using the sagittal sinus outflow method only. Normothermic CPB with a whole blood prime was then initiated with a pump flow of 2.0 to 2.8 L·min^-1·m^-2 to maintain normotension.

During CPB period I (temperature 37.8°C, hematocrit 40%) systemic and cerebral physiologic variables were determined after a 15- to 30-minute stabilization period. Because animals became slightly hypothermic in the pre-CPB period, dural temperature was raised to 37.5°C during this stabilization period. When dural temperature and other systemic variables were stable, CBF measurements were initiated. In the absence of hemodilution, CBF, cerebral oxygen delivery, and CMRO₂ were unchanged in CPB period I relative to the pre-CPB period (Fig 1; see Table 1). Arterial oxygen tension was lower during CPB period I than prebypass, whereas dural temperature and pH were higher. The mean CBF measured by the sagittal sinus outflow method was 31 mL·100g^-1·min^-1 and that measured by the Kety-Schmidt technique was 33 mL·100g^-1·min^-1 (Figs 1, 2). Cerebral blood flow values did not differ between techniques.

View larger version (16K): [in this window] [in a new window]   Fig 1. . Mean cerebral blood flow ( CBF) (mL·100 g-1·min-1) (± standard deviation) during the prebypass period and at three cardiopulmonary bypass (CPB) temperatures in the absence of hemodilution; cardiopulmonary bypass period I (37.8°C), period II (32.5°C), and period III (27.5°C). (*p < 0.05 versus cardiopulmonary bypass period I by repeated measures analysis of variance followed by Bonferroni correction. There were no between-group differences during any cardiopulmonary bypass period by Mann-Whitney rank sum test.) (ks = Kety-Schmidt; sso = sagittal sinus outflow.)

View larger version (15K): [in this window] [in a new window]   Fig 2. . Comparison of values for sagittal sinus outflow cerebral blood flow ( CBF) (x axis) and nitrous oxide saturation CBF (y axis) in mL·100 g-1·min-1. The value of r is by Spearman rank order correlation for 21 paired values.

During CPB period III, dural temperature was reduced to 27.5°C and physiologic measurements were repeated. This reduction in temperature was associated with a further reduction in CMRO₂ (see Table 1) and CBF. The CMRO₂ decreased 59% at 27.5°C relative to that measured during CPB at 37.8°C. In the continued absence of hemodilution, CBF measured by both direct and Kety-Schmidt methods showed a decrease proportional to the change in metabolic rate (52% and 58%, respectively) (see Table 1; Figs 1, 2) and CBF values did not differ between techniques. Cerebral oxygen delivery was reduced relative to CPB period I at 27.5°C. Systemic vascular resistance at 27.5°C was approximately twice that at 37.8°C; this necessitated a reduction in pump flow to a mean of 1.2 L·min^-1·m^-2 to maintain a stable mean arterial blood pressure. Other than temperature and systemic vascular resistance, systemic physiologic variables during period III did not differ from those in CPB periods I and II.

The CBF measurements by the sagittal sinus outflow and Kety-Schmidt techniques correlated very closely between 27.5°C and 37.8°C. Mean CBF values between each of the three temperature periods differed by less than 6%. The correlation coefficient for the 21 paired measurements was 0.87 (p < 0.001) (see Fig 2). The Bland-Altman analysis used to detect bias in a technique showed a mean overestimate of 1 mL·100 g^-1·min^-1 (Fig 3) by the Kety-Schmidt technique.

View larger version (16K): [in this window] [in a new window]   Fig 3. . Bland-Altman plot of cerebral blood flow ( CBF) data. Mean CBF for the two techniques (horizontal axis) is plotted against difference (Diff) from the mean by the nitrous oxide washin technique. The mean bias (x axis, mL·100 g-1·min-1) is shown, as is the mean difference ± 2 standard deviations (SD). (ks = Kety-Schmidt; sso = sagittal sinus outflow.)

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

Under normothermic non-CPB conditions, the sagittal sinus outflow and Kety-Schmidt techniques have shown excellent correlation [15]. However, it has been suggested that the Kety-Schmidt technique may be less valid during CPB or during hypothermia [2]. The suitability of the Kety-Schmidt method during hypothermia has also been questioned because the brain–blood solubility coefficient for N₂O has not been reported. Given the experimental data, both of these criticisms appear inconsequential. A small bias in overestimating CBF by the N₂O saturation technique is known [16], small, and easily corrected. Previously we addressed this by estimating the change in at 32°C and 27°C [5, 8]. On the basis of changing N₂O solubility in oil and water during hypothermic conditions [10, 11], we calculated a decrease in the solubility coefficient for N₂O of 5.5% and 11% at 32°C and 27°C, respectively [5, 8]. These corrections for the effect of temperature on eliminate the predicted [2] overestimation of CBF by N₂O washin at 32°C and 27°C.

In addition to showing the validity of the N₂O saturation method during hypothermic bypass, the data are of interest because the cerebral effects of a whole blood CPB circuit prime is documented at three different bypass temperatures. In the absence of hemodilution and temperature change (CPB period I), CBF, CMRO₂, cerebral oxygen delivery, and intracranial pressure are unchanged between bypass and the nonbypass state. Bypass of the heart and lungs per se with a mechanical pump and oxygenator has surprisingly little effect on global cerebral perfusion or oxygenation.

Similarly, the effects of hypothermia in the absence of hemodilution are clearly documented. At both 32.5°C and 27.5°C, the decrease in CBF is proportional to the decrease in metabolic rate. As such, increases in the CBF–CMRO₂ ratio are not seen. Previously, we suggested that this ratio may be misleading in the context of hemodilution because hemodilution increases CBF independent of a change in oxygen demand [5]. Change in CBF at stable oxygen demand is seen during clinical normothermic CPB with hemodilution [5] and is well described under nonbypass conditions [17–19]. We have made similar (unpublished) observations with moderate hypothermia. However, with progressive temperature reduction, an uncoupling of flow and metabolism does seem to occur [3, 20], even after the effects of hemodilution are accounted for.

This report might be criticized for lack of randomization in the order of temperature exposure; measurements were always made at 37°C followed by 32°C and 27°C. The order of temperature exposure was not randomized so as to reflect temperature management during clinical CPB. Furthermore, the duration of our experiments were approximately 2.5 hours and our preparation has been shown to be stable for 5 hours. Thus, randomization of temperature was not required to eliminate the possible effect of time on the stability of the preparation.

We have documented previously that the 30% reduction in hematocrit typically seen with clinical CPB increases CBF by approximately 40% at a stable CMRO₂ [5]. Similarly, during normothermic CPB in dogs, reducing the hematocrit from 37% to 23% doubles CBF [21]. As such, result differences between this report and a previous one [5] using the same technique in humans are attributed primarily to the absence of hemodilution in this investigation. We would anticipate that the results of the two Kety-Schmidt studies would be extremely similar if hematocrits were equivalent.

This study validates the use of the N₂O saturation method for determination of CBF during CPB at 27°C and 32°C but might be criticized either because it was conducted in a dog model or because cerebral venous blood was sampled from the sagittal sinus rather than the jugular bulb. To respond, first, there is no practical means of doing a comparable study in humans during CPB; a canine model for CBF and CMRO₂ studies is well established and there is no reason to believe that the determinants of N₂O saturation are qualitatively different in a dog than in a human brain. Second, sampling of cerebral venous blood at the sagittal sinus for CBF determination may differ from sampling at the jugular bulb (as is done in human studies), but this difference is insignificant. With proper sampling technique, more than 95% of the blood traversing the jugular bulb is cerebral in origin [22] and, like the sagittal sinus technique, most of this blood originates in the cerebral hemispheres [7, 15, 22]. Finally, any extracerebral contamination of blood at the jugular bulb would tend to lower the CBF_K-S measurements, not raise them. For these reasons, we believe that the data presented provide a solid foundation for use of the N₂O saturation method for determination of CBF and CMRO₂ during clinical CPB between 27°C and 37°C.

	Acknowledgments

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported by the Mayo Foundation.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Address reprint requests to Dr Cook, Department of Anesthesiology, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

	References

Top Footnotes Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Thomas A. Orszulak Richard C. Daly Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by MacVeigh, I. Articles by Munnikhuysen, D. E. Search for Related Content PubMed PubMed Citation Articles by MacVeigh, I. Articles by Munnikhuysen, D. E.