Journal of Cerehral Blood Flow and Metaholism 4:368-37 2 1984 Raven Press, New York Dependency of Blood Flow Velocity in the Middle Cerebral Artery on End-Tidal Carbon Dioxide Partial Pressure-A Transcranial Ultrasound Doppler Study Thomas-Marc Markwalder, Peter Grolimund, Rolf W. Seiler, Fritz Roth, and Rune Aaslid Departments of Neurosurgery and Anesthesiology, University of Bern, Bern, Switzerland; and Department of Neurosurgery, Rikshospitalet, Oslo, Norway Summary: The end-tidal carbon dioxide partial pressure (Peoz) response curves for the flow velocity in the middle cerebral artery were studied in 31 normal subjects with transcranial Doppler techniques. An exponential curve with an exponent of.34 mm Hg-1 was found to be a good fit to the recorded data. By means of this relationship, recordings of flow velocity in cerebral arteries can be normalized to a standard value of Peoz' Physiological aspects of cerebrovascular reactivity to Peoz and the clinical implications of the Peoz response curve are discussed. The normal material provides a reference for assessing pathological responses. Key Words: Arterial flow velocity-carbon dioxide partial pressure-cerebral arteries-middle cerebral artery-transcranial Doppler ultrasound- Ultrasonics. Changes of arterial carbon dioxide partial pressure (Peo2) considerably influence CBF in animals (Reivich, 1964; Harper and Glass, 1965; James et ai., 1969; Grubb et ai., 1977) and in humans (Kety and Schmidt, 1946, 1948a,b; Patterson et ai., 1955; Lambertsen et ai., 1961; Wassermann and Patterson, 1961). As demonstrated angiographically by Huber and Handa (1967), the vessel diameter of the large basal cerebral arteries remains constant during changes in Peo2. Depression and elevation of Peo2 cause vasoconstriction and vasodilation of the arteriolar channels, respectively, leading to alterations in peripheral vascular resistance. The decrease and increase of peripheral vascular resistance are responsible for the changes in cerebrovascular circulation time, CBF, and the velocity of flow (V) in cerebral arteries. Transcranial ultrasound Doppler recording represents a noninvasive means of assessing V in the basal cerebral arteries (Aaslid et ai., 1982, 1984). Address correspondence and reprint requests to Dr. Markwalder at Neurochirurgische Klinik, Inselspital, 31 Bern, Switzerland. Abbreviations used: MeA, Middle cerebral artery; SAH, subarachnoid hemorrhage; V, blood flow velocity. Because the diameter of the large basal arteries can be assumed to remain constant during hypo- and hypercapnia, changes in CBF induced by alterations of the Peo2 should also be proportional to changes in V in the basal cerebral arteries. It was our aim to study the CO2 response for V in the middle cerebral artery (MCA) in normal subjects. Since Doppler recording does not provide absolute flow values, we defined vascular reactivity as relative velocity change divided by the Peo2 change, or equal to (dvmcaivmca)ldpeo2' MATERIALS AND METHODS Thirty-one healthy subjects [11 between 5 and 15 years old (Group 1), 1 between 16 and 4 years old (Group 2), and another 1 between 41 and 73 years old (Group 3)] with no history of cerebrovascular disease were investigated. Doppler instrumentation For the present study we used our laboratory rangegated Doppler instrument, the technical characteristics of which have been described in previous reports (Aaslid et ai., 1982, 1984). Its main characteristics are as follows: emitted ultrasonic frequency, 2 MHz; total emitted ultrasound energy, 15 mw; effective range, 3-1 cm; emitting area, 1.5 cm 2 The ultrasonic transducer was equipped with a polystyrene acoustic lens with a focal 368
... CBF VELOCITY AND CO2 PRESSURE 369 length of 5 cm and a beam width of 3-4 mm at this distance. Velocity determination The frequency spectra of the Doppler signals were displayed on a spectrum analyzer with direction discrimination (Angioscan with reverse and forward flow adapter TRA-1; Unigon Industries Inc., Mt. Vernon, NY, U.S.A.). As reported previously, we used the outline or envelope of the spectra to determine the V MeA (Aaslid et ai., 1982). The time mean of this outline was found by adjusting the cursor of the spectral display. Clearly, the reading thus obtained corresponds to the time mean of the maximum component of the velocity profile (Johnston, 1982). We have found that the envelope velocity can be determined with good reproducibility even if the signal-to-noise ratio is low. Care was taken to obtain signals with no interference from other vessels; the proximal portion of the MCA usually gave such conditions. Practical procedure The subjects were installed in a half-sitting position. The blood pressure was determined by the auscultatory procedure, and the ultrasonic probe was positioned in the temporal region ("ultrasonic window") using a circumferential fixation apparatus that was fixed to the subject's head by the use of an elastic bandage to avoid shifting of the probe during the investigation. The MCA Doppler signal was located at a depth of 4.5-5.5 cm using the procedure described previously (Aaslid et ai., 1982, 1984). The depth giving the highest Doppler velocity was chosen for the recording. Thereafter a face mask that was connected with a spirometer sensor (Megamed 18 G) and infrared end-tidal CO2 analyzer (Capnometer 472lOA; Hewlett Packard, Waltham, MA, U.S.A.) was fitted to the subject's face and attached to the head by rubber bandages. Under continuous spirometer control, the subject was instructed to breathe in the individual normocapnic range (end-tidal Peo2 usually between 36 and 4 mm Hg) until a steady state was reached. At this stage V MeA was recorded over a 3- to 5-min period. Thereafter the subject was instructed to hyperventilate stepwise in order to reach a mild hypocapnic (end-tidal Peo2 usually between 28 and 33 mm Hg) and low hypocapnic (end-tidal Peoo usually between 17 and 23 mm Hg) steady state. In a fourth step the respiration mask was connected to air containing 7% CO2 via a system consisting of a 5-L reservoir bag and a one-way valve. In a fifth step the subject was connected to air containing 5% CO2, In each of the five stages, the recording of V MeA was made over a period of 3-5 min after a steady state of Peoo had been reached. In three instances (two subjects from" Group 1, one subject from Group 3), the hypercapnic recordings were not reliable (see Fig. 5, right). The blood pressure was routinely checked at the highest Peo2 level. RESULTS The V MeA value of every subject was plotted as a function of the end-tidal Peo2 (Fig. 1). The best- 12111 + i... Ol "'- E t-... u 1111111 8111 6111 t -1 W > 4111 + + 2111 111 L- I 1111 2111 3111 1 r=i1i.99 3 4111 5111 6111.. 2 "'- E 1 15 I- u D -1 W > 1 5 PC2-2l11mmHg 2 3 1 FIG. 1. Example of an individu 1 regression curve with corresponding Doppler spectral displays at hypocapnic (1), normocapnic (2), and hypercapnic (3) end-tidal Pco2 levels, illustrating the changes of the velocity waveform (peak V to peak V divided by Vmean). V, velocity of blood flow.
37 T.-M. MARKWALDER ET AL. fit curve for these plots was the exponential function: y = a. e bx, where y is V (cm/s); x is the endtidal Peo2 (mm Hg); a is a theoretical quantity and represents V at a Peo2 of mm Hg; and b corresponds to the definition of reactivity (for numerical values see below). Because of the variations in V MCA from one subject to another (Aaslid et ai., 1982), we have chosen the VMCA at a Peo2 of 4 mm Hg (5.2 kpa) as 1% to compare the individual measurements. If the normocapnic end-tidal Peo2 of the investigated subject was not at 4 mm Hg, the V MCA was calculated for this value using the individual regression curve. Then we plotted VMCA as a percentage of the value at a Peo2 of 4 mm Hg as a function of the end-tidal Peo2 (mm Hg) to allow a comparison of the different individual plots. Figures 2-4 show these plots with the corresponding regression curves for each of the three age groups, respectively. The use of an exponential function to fit the data in the range of the present investigation means that the vascular reactivity, defined as relative change in velocity per change in Peo2, is constant within this range. The parameter b in the expression corresponds to this definition of reactivity. We found a value of.35 ±.5 (mean ± SD) mm Hg I for the entire series. Figure 5 shows the distribution of the parameter b in all investigated SUbjects. We found no significant difference between these groups; also, within each group, the vascular reactivity was within a relatively narrow range. When the subjects without 7% CO2 readings were eliminated, the mean value of b was.34 and the SD was.4. In one experiment V MCA was measured during a to-min period after having reached profound hypocapnic (22 mm Hg) and hypercapnic (5 mm Hg) GROUP 2 1 2 3 4 + * *.... [rnrnhg} FIG. 3. Blood flow velocity (V) of the middle cerebral artery as percentage of the V value at an end-tidal Pc2 of 4 mm Hg (Group 2: 1 subjects between 16 and 4 years of age; r =.97). steady-state conditions. The vascular reactivity from this experiment was essentially the same as when the normal procedure was followed. DISCUSSION Provided that end-tidal Peo2 was not influenced by changes in arterial blood pressure and represented a close approximation of the arterial Peo2 (Haldane, 1922; Burki and Albert, 1983), the response curves for VMCA obtained in our study (Figs. 2-4) strongly resemble the CBF response curves obtained from experimental (Reivich, 1964; Harper, 1965; Harper and Glass, 1965; White et ai., 1971; Grubb et ai., 1977) and clinical (Shapiro et ai., 1965, 1966) studies. The assumption that the diameter of the basal cerebral arteries, its flow profile, and the angle between the ultrasonic beam and vessel course all remain relatively constant means that the./.... *.. 1813 GROUP 1 18 GROUP 3 16 16 1413 1413 N 1213 1.1336*x y- -22* e N z 1213 113 y" 28* e.32*x r-- 8 U -" 6 w > 4 2<1 1 2 [rnrnhg} FIG. 2. Blood flow velocity (V) of the middle cerebral artery as percentage of the V value at an end tidal Pc2 of 4 mm Hg (Group 1: 11 subjects between 5 and 15 years of age; r =.96). -+-- -+--"---+I +--'-' --+ 2 313 4 513 6 CrnrnHgl FIG. 4. Blood flow velocity (V) of the middle cerebral artery as percentage of the V value at an end-tidal Pc2 of 4 mm Hg (Group 3: 1 subjects between 41 and 73 years of age; r =.98).
CBF VELOCITY AND CO2 PRESS URE 371 NO 7-7 22.5,.- 6 19.3-5 16. 1 f-- 4 12.9 3 9.67 r- l- 2 6.45 e- I-- e- 3.22 n.1.2.3.4.5.6 VASCULAR REACTIVITY CmmHgl] FIG. 5. Distribution of Pco2 reactivity in all recordings (SO, ± 14.5%; arithmetical mean value,.35). percentage change in CBF is equal to the percentage change in V. Vasodilation and vasoconstriction owing to Peo2 changes have been demonstrated by direct observations of pial vessels through calvarial windows (Florey, 1925) and angiographically (Huber and Handa, 1967). Furthermore, Hauge et al. (198) measured the changes in V in the four main extracranial arterial feeders to the brain during hyperventilation and CO2 breathing using a bidirectional, pulsed, ultrasound Doppler velocitymeter and found the CO2 reactivity between 28.1 and 3.%/kPa with a linear regression analysis. However, to our knowledge, similar Doppler studies of cerebrovascular reactivity to Peo2 have not been performed on human cerebral arteries. The Peo2 response curve is dependent on arterial blood pressure (Harper, 1965; Harper and Glass, 1965; Ackerman et ai., 1973; Tominaga et ai., 1976). In our investigations the cardiovascular conditions were constant, and mean arterial blood pressure was always >9 mm Hg. As already observed by Tominaga et al. (1976), there was a rise of the mean arterial blood pressure of 5-1 mm Hg during profound hypercapnia in our series; however, we have no data to indicate how the Peo2 response curve for YMCA was influenced by this variable. There were no marked distinctions of cerebrovascular reactivity to Peo2 among the three age groups. This contrasts with the findings of Schieve and Wilson (1953) who found a slight decrease of hemodynamic response to 5% CO2 in elderly patients. The Peo2 response curves for CBF (Kety and Schmidt, 1946; Reivich, 1964; Harper, 1965; Shapiro et ai., 1965, 1966; White et ai., 1971) show an S-shaped course demonstrating an upper level where further elevation of Peo2 causes only slight further decrease or increase of CBF. This saturation effect was not observed in our data, probably because we did not record at extreme Peo2 values and because we were not recording CBF but CBF velocity. Moreover, the experiments were not designed to demonstrate the hysteresis effect (Shapiro et ai., 1966). Three sources of error that may have influenced our results are the following: (a) The change in the velocity waveform represents a certain, although small, source of uncertainty in the time mean velocity determination during low Peo2 (Fig. 1). (b) In profound hypocapnia, the respiratory fluctuations became quite marked, leading to similar problems. (c) Figures 2-4 demonstrate a certain dispersion of the YMCA values in profound hypercapnia (upper level of the Peoz response curve for YMCA )' This dispersion was obtained when the subjects were connected to 7% CO2; under these conditions, a steady-state recording was more difficult to achieve owing to restlessness and dyspnea on the part of the subject. Thus, the investigation could not be prolonged to reach high hypercapnic conditions. Transcranial Doppler ultrasound recording of V in the basal cerebral arteries represents a noninvasive means of detecting vasospasm in subarachnoid hemorrhage (SAH) (Aaslid et ai., 1982, 1984). The evaluation of spasm is based on the hemodynamic principle that V is inversely related to the diameter of the vessel lumen (Blaumanis et ai., 1979; Nomes et ai., 1979). The increase of velocity that is due to the arterial narrowing in SAH can be detected by the increased Doppler shift of reflected ultrasound. V is also considerably dependent on Peoz, and the clinical accuracy of the trans cranial Doppler instrument can be enhanced by the correction of V for variations in this parameter. The corrected velocity, V c, at a Peoz of 4 mm Hg is then given by Vc = VI eo. 34 (4-P I C 2 ) (mm Hg) where VI and Pleoz are the measured values. The latter equation is obtained as follows: therefore is and V a' eb'pcoz 4 mm Hg' C4mmHg, VI = a eb,plc2 Vc 4 mm Hg VI eb PcoZ 4 mm Hg eb'plc 2 Vc = VI' eb'(pcoz4mmhg-p I C2) An example of the calculation is the following: At a Peoz of 5 mm Hg (PleoZ), a YMCA of 95 cm/s (VI) was measured. The corrected velocity at a Peoz of 4 mm Hg (Vc) is therefore given by: Vc = 95 eo.34 (4-5) = 67.6 cm/s
372 T.-M. MARK WALDER ET AL. On the other hand, we have to take into account that the vascular reactivity to changes in Pco2 is not the same in normal and ischemic brain. Therefore, a correction is not permissible in high-grade spasm or in any other type of highly significant pathology. The correction also is meaningless when there is a direct pathway from arteries to veins in patients with fistulae or arteriovenous malformations. In these cases determination of vascular reactivity to CO2 may be of diagnostic value. There is good reason to assume that the reactivity of the vascular bed perfused by the anterior and posterior cerebral arteries is similar to that perfused by MCA. The formula for the corrected velocity is probably valid for all basal cerebral arteries that can be investigated with the trans cranial ultrasound Doppler instrument, provided that the intracranial and arterial blood pressures are within the normal range. REFERENCES Aaslid R. 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