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J Thorac Cardiovasc Surg 1994;108:984-985
© 1994 Mosby, Inc.

LETTERS TO THE EDITOR

Invited letter concerning: Cerebral blood flow, carbon dioxide, and pH

Cardiac Surgery
Children's Hospital
300 Longwood Ave.

Boston, MA 02115

To the Editor:

In this issue of the JOURNAL, Tominaga and colleagues ¹ from the Cleveland Clinic have described a study in which total cerebral blood flow was measured at various levels of inspired carbon dioxide in three calves with permanently implanted biventricular bypass devices. The authors demonstrated that carotid blood flow was independent of arterial pressure (preservation of flow/pressure autoregulation) but was closely related to arterial carbon dioxide tensions, as well as to the flow rate of the device. The limitations of the study have been clearly defined by the authors and include the fact that carotid rather than cerebral blood flow was measured. In addition, blood flow alone was studied with no assessment of cerebral metabolic rate. In future studies the authors plan to study flow/metabolism coupling. Nevertheless, the finding that pressure/flow autoregulation can be maintained with chronic biventricular bypass is an important observation.

Pressure flow autoregulation
Autoregulation is the mechanism that protects the brain against the dangers of hypoxia at low perfusion pressures and the risks of brain edema at high arterial pressures. ² Suggested mechanisms of autoregulation include the myogenic hypothesis ³ and the metabolic hypothesis. ⁴ The role of the endothelium and more specifically nitric oxide in autoregulation is currently under study. ²

Carbon dioxide and autoregulation
Carbon dioxide has an important modulating effect on the normal autoregulatory curve. Carbon dioxide is highly diffusible and can readily cross the blood-brain barrier. It is thought that carbon dioxide exerts its cerebrovascular effects by modulating extracellular pH in the immediate vicinity of the vascular smooth muscle cells. The situation becomes considerably more complicated in the setting of hypothermia. Hypothermia affects the solubility of carbon dioxide and in addition resets the pH of neutrality of both water and blood in an alkaline direction. If pH is to be maintained at 7.40 corrected to the patient temperature during hypothermic cardiopulmonary bypass, it is necessary to add carbon dioxide to the oxygenator gas mixture. This constitutes the pH-stat strategy. With the alternative alpha-stat strategy, no compensation is made for the alkaline shift with hypothermia. ⁵ Global and regional cerebral blood flow according to pH-stat strategy.

Global and regional cerebral blood flow according to pH-stat strategy
Many studies have demonstrated that global cerebral blood flow is significantly increased by the pH-stat strategy relative to the alpha-stat strategy. ^6,7 However, a recent laboratory study at Boston Children's Hospital ⁸ also found that regional blood flow distribution was affected by pH-stat strategy. During cooling to deep hypothermic temperatures in miniature piglets, intracerebral distribution of blood flow in animals undergoing the alpha-stat strategy showed a significant decrease in the fraction perfusing the basal ganglia. In contrast, in animals undergoing pH-stat strategy the percent distribution to the basal ganglia, cerebellum, and pons and medulla oblongata increased. Perhaps the decreased blood flow to deep subcortical structures with the alpha-stat strategy leads to less uniform cooling and is relevant to the complication of choreoathetosis, which is a widely described complication of hypothermic circulatory arrest. ⁹

Loss of autoregulation
Various pathologic states can lead to disordered autoregulation. Neonatal asphyxia, cerebral ischemia, head injury, and diabetes mellitus have all been described in association with disordered autoregulation. ² Autoregulation is abolished by deep hypothermic circulatory arrest, ¹⁰ as well as by deep hypothermic cardiopulmonary bypass without circulatory arrest. ¹¹ Studies of autoregulation after cardiopulmonary bypass with mild or moderate hypothermia have produced variable results. ^12,13 Probably the most important determinant as to whether autoregulation is preserved with moderately hypothermic bypass is the pH strategy used. In general, if the alpha-stat strategy is used autoregulation is preserved, whereas if the pH-stat strategy is used autoregulation is lost and excessive cerebral blood flow results. ^6,7 This excessive blood flow will increase the microembolic load to the brain.

Flow/metabolism coupling
Distinct from the concept of pressure/flow cerebral autoregulation is the concept, first described by Roy and Sherrington ¹⁴ more than 100 years ago, that the brain is able to regulate flow at a local level so as to adjust regional cerebral blood flow to match levels of local functional activity. Over the past year considerable evidence has accumulated that nitric oxide is the link molecule in flow/metabolism coupling. ¹⁵ The central nervous system has at least three sources of nitric oxide, namely, endothelial cells, neurons, and glia. Several recent morphologic studies have demonstrated a close association between nitric oxide–containing neurons and cerebral vessels. ¹⁶ Furthermore, activation of excitatory (N-methyl-D-aspartate) neuroreceptors has been demonstrated to be associated with nitric oxide release and subsequent vasodilation. ¹⁷ One of the most exciting areas of this work is the application of functional magnetic resonance imaging. Because oxyhemoglobin and deoxyhemoglobin have different magnetic properties, it is now possible with ultrahigh speed and high resolution magnetic resonance imaging to observe local increases in cerebral blood flow in response to neuronal activity. Application of this and other emerging techniques holds great promise in increasing the understanding of the normal physiology of cerebral blood flow and metabolism. Ultimately this information will allow techniques of cardiopulmonary bypass to be improved, including long-term support with ventricular assist devices, which in the past have been plagued by central nervous system complications.

References

1. Tominaga R, Smith WA, Massiello A, Harasaki H, Golding LAR. Chronic nonpulsatile blood flow. I. Cerebral autoregulation in chronic nonpulsatile biventricular bypass: Carotid blood flow response to hypercapnia. J THORAC CARDIOVASC SURG 1994;108:907-12.[Abstract/Free Full Text]
   
2. Edvinsson L, MacKenzie ET, McCulloch J. Cerebral blood flow and metabolism. New York: Raven Press, 1993.
   
3. Folkow B. Description of the myogenic hypothesis. Circ Res 1964;15(Suppl. 1):279-87.
   
4. Kuchinsky W, Wahl M. Local chemical and neurogenic regulation of cerebral vascular resistance. Physiol Rev 1978;58:656-89.[Free Full Text]
   
5. Swan H. The hydroxyl-hydrogen ion concentration ratio during hypothermia. Surg Gynecol Obstet 1982;155:897-912.[Medline]
   
6. Murkin JM, Farrar JK, Tweed WA, McKenzie FN, Guiraudon G. Cerebral autoregulation and flow/metabolism coupling during cardiopulmonary bypass: the influence of PaCO₂. Anesth Analg 1987;66:825-32.[Abstract/Free Full Text]
   
7. Henriksen L. Brain luxury perfusion during cardiopulmonary bypass in humans: a study of the cerebral blood flow response to changes in CO₂, O₂ and blood pressure. J Cereb Blood Flow Metab 1986;6:366-78.[Medline]
   
8. Aoki M, Nomura F, Stromski ME, et al. Effects of pH on brain energetics after hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1093-103.[Abstract]
   
9. Wong PC, Barlow CF, Hickey PR, et al. Factors associated with choreoathetosis following cardiopulmonary bypass in children with congenital heart disease. Circulation 1992;86(Suppl):II118-26.
   
10. Greeley WJ, Ungerleider RM, Smith LR, Reves JG. The effect of deep hypothermic cardiopulmonary bypass and total circulatory arrest on cerebral blood flow in infants. J THORAC CARDIOVASC SURG 1989;97:737-45.[Abstract]
    
11. Fox LS, Blackstone EH, Kirklin JW, Bishop SP, Bergdahl LAL, Bradley EL. Relationship of brain flow and oxygen consumption to perfusion flow rate during profoundly hypothermic cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1984;87:658-64.[Abstract]
    
12. Govier AV, Reves JG, Mckay RD, et al. Factors and their influence on regional cerebral blood flow during nonpulsatile cardiopulmonary bypass. Ann Thorac Surg 1984;38:592-600.[Abstract]
    
13. Rogers AT, Newman SP, Stump DA, Prough DS. Neurologic effects of cardiopulmonary bypass. In: Gravlee GP, Davis RF, Utley JR, eds. Cardiopulmonary bypass: principles and practice. Baltimore: Williams & Wilkins, 1993:556.
    
14. Roy CS, Sherrington CS. On the regulation of the blood supply of the brain. J Physiol 1890;11:85-108.
    
15. Macrae IM, Dawson DA, Norrie JD, McCullooch J. Inhibition of nitric oxide synthesis: effects on cerebral blood flow and glucose utilisation in the rat. J Cereb Blood Flow Metab 1993;13:985-92.[Medline]
    
16. Harper AM. Comment on [Toda N, Ayaijiki K, Yoshida K, Kimura H, Okamura T. Impairment by damage of the pterygopalatine ganglion of nitroxidergic vasodilator nerve function in canine cerebral and retinal arteries. Circ Res 1993;72:206-13]. Cerebrovasc Brain Metab Rev 1993;5:229.
    
17. Faraci FM, Breese KR. Nitric oxide mediates vasodilation in response to activation of N-methyl-D-aspartate receptors in brain. Circ Res 1993;72:476-80.[Abstract/Free Full Text]
    

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This Article 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): Richard A. Jonas Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jonas, R. A. Search for Related Content PubMed PubMed Citation Articles by Jonas, R. A.