J Appl Physiol 97: 1601-1602, 2004;
doi:10.1152/classicessays.00023.2004 
8750-7587/04 $5.00
EDITORIAL FOCUS
ESSAYS ON APS CLASSIC PAPERS
The paper that completely altered our thinking about cerebral blood flow measurement
Richard J. Traystman
Anesthesiology and Peri-Operative Medicine, Oregon Health and Science University, Portland, Oregon 97239-3098
ABSTRACT
Kety SS and Schmidt CF. The determination of cerebral blood flow in man by the use of nitrous oxide in low concentrations. Am J Physiol 143: 53—66, 1945 (http://ajplegacy.physiology.org/cgi/reprint/143/1/53).
IN 1905, Carl Wiggers wrote "Perhaps no other organ of the body is less adapted to an experimental study of its circulation than the brain" (15). Despite this, however, and long before Wiggers time, studies concerning the cerebral vasculature were indeed performed. These, however, were mostly anatomic studies of the cerebral circulation. The significance of the blood supply to the brain appears to have been known to the Greeks in early times, because they demonstrated that pressure on the vessels of the neck resulted in anesthesia sufficient to carry out certain surgical procedures (for references, see Hill, Ref. 9). The first relatively accurate anatomic illustrations of the cerebral vasculature at the base of the brain were made by Casserius in 1645 (1) and Veslingius in 1651 (14), and then came the magnificent masterpiece of Willis in 1664 (16). In the 19th century, a number of investigators used one of the oldest methods to study the cerebral circulation, the pial window technique (3, 11, 12). Thus, by the middle to the end of the 19th century, techniques were available for the examination of the pial vessels, and subsequently into the early 20th century, investigators began to concentrate more on the physiology aspects of the cerebral vessels (5–8). Since that time, there has been an explosion of techniques to study the cerebral circulation, all really based on evolving technology. The advances in the measurement of cerebral blood flow (CBF) are simply too numerous to cite here; however, it is instructive to at least list these techniques beside the pial window technique: measurement of blood flow in arteries of the neck, measurement of cerebral venous outflow, artificial perfusion of the brain, heat clearance techniques in blood vessels and in brain tissue, hydrogen clearance, angiography, ultrasonography, diffusible and nondiffusible tracer-based measurements of cerebral flow, laser Doppler, transcranial Doppler, near infrared spectroscopy, positron emission tomography (PET), magnetic resonance imaging (MRI), and functional MRI (fMRI; and blood-oxygen-level-dependent fMRI, or BOLD), and it is certain that newer techniques will be developed in the future.
The year was 1944 at a meeting of the Federation of American Societies for Experimental Biology (FASEB), where there was a symposium on the cerebral circulation that dealt with the methods of CBF measurement. Sokoloff (13) writes in a National Academy of Science memoir of Seymour Kety that the dominant theme of the symposium was the need for a method for measuring CBF quantitatively and preferably one applicable to unanesthetized patients. At that time, there were some nonquantitative methods to study CBF in humans: thermoelectric probe placed into the jugular vein to detect changes in flow within the vein; measurement of cerebral arteriovenous O2 difference, which should vary inversely with changes in CBF if cerebral O2 consumption (CMRO2) remained constant, but this technique could not distinguish between CBF and CMRO2. Kety (Fig. 1), then working in Carl Schmidt's (Fig. 2) department, took up the challenge set forth at that 1944 FASEB meeting to develop a technique to measure CBF quantitatively in unanesthetized humans.
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Fig. 1. Seymour Kety. Courtesy of the Office of NIH History, National Institutes of Health, Dept. of Health and Human Services.
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The development of the Kety and Schmidt (10) technique for measurement of CBF in unanesthetized humans represents a major accomplishment in the field, for until this time, quantitative measurements of the total blood flow to the brain had not previously been reported. Kety and Schmidt were keenly aware of Cournand's (2) application of the direct Fick (4) principle for the determination of cardiac output in man by measurement of the rate of O2 uptake into the lungs and the difference in O2 concentrations between blood going to and returning from the lungs. The Fick principle is also used to calculate blood flow to other organs where blood flow is equal to the quantity of a substance removed or added in time, divided by the difference between arterial and venous concentrations of the substance. Obviously, substances that are metabolized can only be utilized if there is some independent way of determining the rate at which they are extracted from the blood. Thus the ideal substance to use is inert and freely diffusible. Kety and Schmidt cleverly adapted the Fick principle to measure CBF in humans. Their central idea, based on Fick's idea, was that the amount of an inhaled, highly diffusible, inert gas (nitrous oxide) taken up by the brain per unit time is equal to the amount of that gas brought to the brain by the arterial blood minus the amount carried away in the cerebral venous blood. Thus, at a time when the nitrous oxide contents of the brain and its cerebral venous blood reached equilibrium (
10–15 min of gas breathing), when brain tissue neither gained nor lost indicator, the brain content of nitrous oxide and CBF could be estimated from the histories of the differential rates of change in the arterial and cerebral venous concentrations of nitrous oxide prior to the steady-state conditions. Basically, this was a very simple technique, which made enormous contributions to our understanding the control of cerebral circulation over the past 60 years. Key and Schmidt (10) measured a mean global CBF of 54 ± 12 ml·100 g–1·min–1 in 14 young, healthy males. This value has been reproduced many times subsequently with newer, better, and far more sophisticated CBF techniques.
The Kety and Schmidt technique has a number of important advantages: it is simple, repeatable, and can be used in conscious humans and animals to provide estimates of whole brain blood flow. Despite the fact that the Kety and Schmidt technique revolutionized our thinking concerning the cerebral circulation and was widely used in the 1950s and 1960s to establish values for normal CBF in humans and blood flow in a wide variety of physiological and pathological conditions, it did have some shortcomings. Alas, even the great techniques, when first described, have some disadvantages. First, there is the important question of how accurately jugular venous blood samples reflect pure cerebral venous drainage. The assumption that jugular venous blood represents cerebral venous blood in humans is reasonable; however, whether this remains true in different physiological and pathological situations is less clear. Secondly, when the technique was first described, the method of estimating nitrous oxide in blood was tedious, and to achieve an accuracy of ±5%, a large number of samples were required. Third, the brain may not always achieve saturation of the nitrous oxide in 10–15 min, because of nonhomogenous perfusion of the brain and/or low blood flow rates in certain areas. Finally, failure to reach equilibrium, within 10 min, or irregularities in the arterial or venous curves during saturation could be a result of fluctuations in alveolar concentrations of nitrous oxide. Thus, over the next 40 years, many major modifications to the original Kety and Schmidt technique have been made, with newer modifications continuing to be made even now. One important modification of the technique is the measurement of CBF by monitoring the washout of 133Xe or 85Kr with external scintillation detectors after injection of the gas into the internal carotid artery, and thus developed the whole area of regional CBF measurements.
Thus the Kety and Schmidt technique was a catalyst for the development of CBF methodologies since 1945. Its impact was to revolutionize research on the human brain, and their paper remains a landmark in the field.
FOOTNOTES
Address for correspondence: R. J. Traystman, Anesthesiology and Peri-Operative Medicine, Oregon Health and Science Univ., 3181 SW Sam Jackson Park Road, L335, Portland, OR 97239-3098 (E-mail: traystma{at}ohsu.edu).
REFERENCES
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- Cournand A. Measurement of the cardiac output in man using the right heart catheterization. Fed Proc 4: 207–212, 1945.[ISI]
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- Forbes HS and Wolff HG. Cerebral circulation. III. The vasomotor control of cerebral vessels. Arch Neurol Psychiatr Chicago 19: 1057–1086, 1928.
- Hill L. The Physiology and Pathology of the Cerebral Circulation. An Experimental Research. London: Churchill, 1896, p. 208.
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- Leiden E. Bietrage und untersuchungen zur physiologie und pathologie des gehirns. Virchows Arch Pathol Anat Physiol 37: 519–559, 1866.
- Ravina AF. Specimen de motu cerebri. Memorie Acad Sci Torino 20: 61–93, 1811.
- Sokoloff L. Seymour S Kety (1915–2000): A Biographical Memoir. In: Biographical Memoirs, vol. 83. Washington, DC: National Academy of Sciences, National Academic Press, 2003.
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- Willis T. Cerebri Anatome. London: Martin and Allestry, 1664.
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