Peripheral vasospasm, systemic hypertension, and increased sensitivity to vasoactive substances characterize preeclampsia. Cerebral edema, hemorrhage, and ischemia, as well as eclamptic seizures, are all complications seen in preeclampsia or eclampsia. The exact etiology of these complications is not known, but they are believed to result from vascular perturbations. Under normal conditions, autoregulation maintains constant cerebral blood flow over a wide range of systemic blood pressures (BP).1 Although this is assumed to occur in normal pregnancy, there are few data addressing normal cerebral hemodynamics and cerebral autoregulation during pregnancy. In preeclampsia, vascular autoregulation appears to be dysfunctional, as found in the kidney2 and in the middle cerebral arterial distribution of the brain.3 Abnormal cerebrovascular responses to elevated cerebral perfusion pressure may be involved in the pathophysiology of the brain dysfunction seen in preeclampsia/eclampsia.
Transcranial Doppler ultrasound is a simple noninvasive technique that is used widely to evaluate cerebrovascular hemodynamics and autoregulation. Using this technology, arterial partial pressure of carbon dioxide (pCO2) has been shown to be a potent physiologic modulator of cerebral blood flow. Hypercapnia is known to induce cerebral vasodilation and increase cerebral blood flow. Controlled inhalation of 5% CO2, in the form of a CO2 stimulation test, has been used widely to evaluate cerebral vasomotor reserve1 especially in patients with unilateral internal carotid artery stenosis. In these patients, ipsilateral reduced vasomotor reactivity after CO2 stimulation is used as a screening test to identify patients who might benefit from carotid endarterectomy.4
Other tests can be used to evaluate cerebrovascular hemodynamics,5,6 including the isometric hand‐grip test, which, unlike the CO2 stimulation test, does not require any special equipment or the administration of any gases and is performed easily at the bedside.
Given the lack of current information and the unavailability of safe, noninvasive tests suitable for use in pregnancy, our objective was to evaluate and compare the cerebrovascular hemodynamics and reactivity in normotensive and preeclamptic pregnant women using both the CO2 stimulation test and the isometric hand‐grip test.
MATERIALS AND METHODS
The institutional review board approved the protocol for human investigation at Baylor College of Medicine in Houston, Texas. All patients gave written informed consent after a full explanation of the procedures and tests.
Women with preeclampsia were recruited from the antenatal clinic or labor and delivery suite. Preeclampsia was defined as BP greater than or equal to 140/90 mmHg and proteinuria greater than or equal to 1+ on a dipstick (or over 300 mg on a 24‐hour collection).7 Patients with twin gestation, vascular disease, or other chronic conditions that might affect cerebral blood flow were excluded. No patient was in active labor or had received volume expansion or drug therapy, specifically magnesium sulfate or antihypertensive treatment, before entering this study.
The normotensive pregnant women were part of a prospective, longitudinal, transcranial Doppler ultrasound study. Pregnant women were recruited from the antenatal clinics at Ben Taub General Hospital between September 1997 and December 1999. Gestational age was confirmed by last menstrual period, ultrasound dating, or both. Patients with twin gestation, vascular disease, or other chronic conditions that might affect cerebral blood flow were excluded. All women who had a transcranial Doppler study in the third trimester and had an uneventful pregnancy and delivery were included in this study. No matching criteria were used for the normotensive pregnant women. Almost all the women who were approached to participate in the study agreed. Unfortunately, we do not have the exact success rate.
A transcranial Doppler ultrasound (Medasonics Cerebrovascular Diagnostic System, Fremont, CA) with a pulsed, range‐gated, 2‐MHz transducer was used to measure middle cerebral artery velocity. The M1 portion of the middle cerebral artery (initial 2‐cm segment) was insonated by the transtemporal approach, and the depth of interrogation was adjusted to obtain an optimal velocity signal. The middle cerebral artery velocity waveform was recorded on both sides of the head, if possible, and the average value was used in the analysis. A minimum of six waveforms was averaged for each variable (systolic, end diastolic, and mean velocities). The cerebral velocity data were recorded directly from the Medasonics system.
Heart rate and the systolic, diastolic, and mean arterial systemic BP were measured automatically (Dinamap, Criticon Inc., Tampa, FL). Peripheral oxygen saturation, and the expired end‐tidal partial pressure of CO2 were also recorded (Nellcor N300; Nellcor Inc, Pleasanton, CA).
For the isometric hand‐grip test we used a bulb dynamometer (Fabrication Enterprises Inc., Irvington, NY). The women were instructed to hold the ball in their dominant hand and to exert maximal compressive force on three separate occasions. Each squeezing period was followed by a rest period of 1 minute. The average value of the three was calculated as the maximal voluntary contraction.
According to the study protocol, all pregnant women were first placed in the left lateral recumbent position and rested for 10 minutes in a quiet room before testing. At that time baseline measurements of systemic BP, heart rate, oxygen (O2) saturation, end‐tidal CO2, and bilateral middle cerebral artery velocities were recorded. The patients were then asked to breathe air with a 5% CO2 concentration (premixed gas supplied in a cylinder; TRI‐GAS Industrial Gases Inc., Irving, TX) through a nonrebreathing face mask. Maternal oxygen saturation and end‐tidal CO2 concentration were measured continuously during this phase of the study. The same set of measurements was repeated once a new steady state of end‐tidal CO2 was achieved (usually within 1–2 minutes). Carbon dioxide inhalation was then stopped, and the patient was allowed to rest. She was monitored until her end‐tidal CO2 returned to baseline. Some women (eight normotensive and six preeclamptic women) did not tolerate the face mask long enough to allow adequate measurement. Some patients were thought to be too unstable to be transported to the research laboratory for the testing (15 preeclamptic women).
After 5 minutes of recovery, the patients were asked to maintain hand‐grip contraction at 30% of the predetermined maximal voluntary contraction force. Hand grip was maintained for up to a maximum of 2 minutes, and the measurement set was repeated. Twelve women with preeclampsia could not complete the isometric hand‐grip test.
Clinical information from the patients' prenatal and delivery records, along with the BP, heart rate, cerebral blood flow velocity and other test data, were entered into a computerized database (Access Database, Microsoft, Redmond, WA).
The derived middle cerebral artery parameters were calculated as follows: Pulsatility index (PI) = (Velocitysystolic − Velocitydiastolic)/Velocitymean; Resistance index (RI) = (Velocitysystolic − Velocitydiastolic)/Velocitysystolic; Cerebral perfusion pressure = (Velocitymean/[Velocitymean − Velocitydiastolic]) × (BPmean − BPdiastolic).
Aaslid et al8 validated a noninvasive method for cerebral perfusion pressure measurement using transcranial Doppler ultrasound of the middle cerebral artery. We used the above modification of this formula, which has been previously reported and validated in pregnant women.9 Cerebrovascular reactivity, in the middle cerebral artery distribution, was assessed as the effect of each maneuver on each parameter, in terms of the percentage change from the baseline values.
All data were tested for normal distribution (Kolmogorov‐Smirnov test; SigmaStat version 2.03, Chicago, IL). Appropriate parametric (Student t test) and nonparametric (Mann‐Whitney rank sum test) tests for unpaired data were then used in the analysis. The two groups were compared at baseline and in response to the two maneuvers using two‐way repeated measures analysis of variance with multiple comparison procedures by Tukey test (SigmaStat version 2.03, Chicago, IL). Analysis of covariance (Minitab version 12.23, State College, PA) was used to compare middle cerebral artery reactivity data between the two groups while controlling for potential confounders, including gestational age at examination, maternal age, heart rate, and end‐tidal CO2. A post hoc power analysis was performed to evaluate the primary measures of the study (middle cerebral artery PI and RI). Using an alpha error of 5%, the statistical power to identify a difference in PI and RI in normotensive women compared with women with preeclampsia was 90% and 67%, respectively. The statistical power to identify a difference in PI and RI in response to the two maneuvers was 69% and 53%, respectively. Data are reported as mean ± standard error (SE) or median and range, and statistical significance was set at P < .05.
There were no significant differences in maternal age, weight, or gravidity between the two groups, although gestational age at examination was approximately 1.5 weeks earlier in the normotensive group. As expected, preeclamptic women delivered significantly earlier, and their neonates had lower birth weight than those of the control women (Table 1).
At rest, mean BP was higher and heart rate lower in the preeclamptic women compared with the normotensive women. Oxygen saturation and end‐tidal CO2 were not significantly different (Table 2). Middle cerebral artery variables showed significant differences between the two groups, with a lower PI and RI and a higher cerebral perfusion pressure in the preeclamptic group compared with normotensive pregnant women (Table 2).
Carbon dioxide inhalation caused a significant increase in end‐tidal CO2 in both groups, although it was slightly higher in the normotensive women compared with the preeclamptic women (Table 2). There were no concomitant significant changes in mean BP, heart rate, or O2 saturation in either group. Normotensive pregnant women showed cerebral vasodilatation as demonstrated by a significant reduction in both PI and RI in response to 5% CO2 inhalation. There was also a small but nonsignificant increase in cerebral perfusion pressure. In contrast, 5% CO2 inhalation caused no significant change in PI, RI, or cerebral perfusion pressure among preeclamptic women (Table 2).
Isometric hand‐grip force as measured by the bulb dynamometer was not significantly different between the groups (P = .29). There were no significant changes in mean BP, heart rate, or O2 saturation in either group during the test. Among the normotensive pregnant women, isometric hand‐grip test caused a significant reduction in PI and RI. There was also a small but nonsignificant increase in cerebral perfusion pressure. In contrast, among preeclamptic women there was no change in any of the middle cerebral artery variable in response to the isometric hand‐grip test (Table 2).
Next we compared the cerebrovascular reactivity between the two groups as measured by the percentage change for each parameter in response to 5% CO2 inhalation and the isometric hand grip. Analysis of covariance was used to control for potential confounders, including gestational age at examination, maternal age, heart rate, and end‐tidal CO2. Table 3 and Figures 1 and 2 summarize the middle cerebral artery reactivity data. Compared with normotensive pregnant women, pre‐eclamptic women had markedly decreased cerebrovascular reactivity to both maneuvers as measured by the percentage changes in PI and RI.
There was no correlation between maternal mean BP and the cerebrovascular reactivity measured as the percentage change in the above middle cerebral artery parameters (Pearson product moment correlation, Minitab version 12.23, State College, PA).
One of the major findings of this study was that women with preeclampsia did not respond to the vasodilatory stimuli of CO2 inhalation or isometric hand grip as effectively as normal pregnant women. This finding can be interpreted on a number of levels. One explanation is that cerebral arterial reactivity might be impaired such that vasodilatation does not occur in response to an increase in tissue HCO3+ (a function of blood CO2 tension) or sympathetic stimulation. This impairment might be construed as supporting the theory that pre‐eclampsia is a condition of uncontrolled vasoconstriction mediated by circulating vasoactive substances. Maeda et al10 reported that cerebrovascular CO2 reactivity was decreased in nonpregnant hypertensive patients, and they suggested that functional changes in vascular responsiveness occur well before cerebral injury supervenes. Our study suggests that this disordered autoregulation might also occur in preeclamptic women.
An alternative and more attractive hypothesis is that cerebral autoregulation is well maintained and functioning exactly as it should in patients with preeclampsia. In this scenario there is protective vasoconstriction that limits the effects of elevated cerebral perfusion pressure on the cerebral tissue distal to the middle cerebral artery and prevents significant increases in cerebral blood flow. This physiologic vasoconstriction remains in effect despite the presence of a vasodilatory stimulus and in this way prevents overperfusion of the brain.
Belfort et al3 suggested that in preeclamptic women, cerebral autoregulation in the middle cerebral artery distribution is ineffective and does not protect the brain from overperfusion. They showed this to be the case in women with headache (who would be classified as having severe preeclampsia), whereas those without headache (most of whom had mild preeclampsia) still had normal autoregulation. The present prospective study complements the previous experiment by finding that baseline thresholds for cerebral perfusion pressure, RI, and PI appear to have been reset in the preeclamptic women, who had significantly lower RI and PI and higher cerebral perfusion pressure. Despite this altered baseline, when the vascular system was further stressed, autoregulation appeared to be effective in preeclamptic women because they did not show any significant changes in PI, RI, or cerebral perfusion pressure in response to the stimuli. In this study we did not differentiate between mildly and severely preeclamptic pregnant women. There might be some selection bias among the preeclamptic group because many were too unstable to be transported to the examination room. If so, mainly mildly preeclamptic women were evaluated using the two maneuvers. Based on the present data, it is not possible to comment on cerebrovascular autoregulation in severe preeclampsia.
We found that, at rest, women with preeclampsia had significantly higher cerebral perfusion pressure and significantly lower PI and RI than normotensive pregnant women. These differences remained highly significant even after controlling for potentially confounding variables. Demarin et al11 and Ohno et al12 both reported findings similar to ours, but neither of those studies controlled for potential confounders, such as gestational age at examination, heart rate, or end‐tidal CO2. We previously reported13 that preeclampsia can cause both overperfusion and underperfusion of the brain, but is more likely to cause overperfusion in women with severe preeclampsia. Our data contrast with those of Williams and Wilson14 who found that pregnant women with preeclampsia and chronic hypertension had significantly higher cerebral perfusion pressure than nonpregnant women but not normotensive pregnant women.
The PI and RI were used to assess arterial resistance because absolute velocity measurements can be inaccurate due to their dependence on the angle of incidence of the Doppler ultrasound beam. In studies where multiple measurements are required, it is not possible to ensure an identical angle of incidence at all measurement times.
We evaluated cerebral vasomotor reactivity with 5% CO2 inhalation and isometric hand grip in normal and preeclamptic pregnant women. We found that during pregnancy normotensive women retain normal cerebral vasomotor reactivity, whereas preeclamptic women had markedly decreased reactivity to CO2 inhalation and isometric hand‐grip tests. Whether these findings indicate abnormal cerebral autoregulation or simply show a resetting of the autoregulatory thresholds because of sustained hypertension is still not known, and further studies will be required to clarify this issue. These changes in the cerebral vasculature probably occur long before the onset of overt preeclampsia. If so, transcranial Doppler ultrasound might be useful to predict subsequent preeclampsia. Furthermore, in patients with pre‐eclampsia, bedside transcranial Doppler ultrasound might help in tailoring medical treatment (either antihypertensive or selective cerebral vasodilator) in order to optimize cerebrovascular hemodynamics.
1. Ringelstein EB, Otis SM. Physiological testing of vasomotor reserve. In: Newell DW, Aaslid R, eds. Transcranial Doppler. New York: Raven Press, 1992:83–99.
2. Kublickas M, Lunell NO, Nisell H, Westgren M. Maternal renal artery blood flow velocimetry in normal and hypertensive pregnancies. Acta Obstet Gynaecol Scand 1996;75:715–9.
3. Belfort MA, Saade GR, Grunewald C, Dildy GA, Varner MA, Nisell H. Effects of blood pressure on orbital and middle cerebral artery resistances in healthy pregnant women and women with preeclampsia. Am J Obstet Gynecol 1999;180:601–7.
4. Hartl WH, Furst H. Application of transcranial Doppler sonography to evaluate cerebral hemodynamics in carotid artery disease. Comparative analysis of different hemodynamic variables. Stroke 1995;26:2293–7.
5. Linkis P, Jorgensen LG, Olesen HL, Madsen PL, Lassen NA, Secher NH. Dynamic exercise enhances regional cerebral artery mean flow velocity. J Appl Physiol 1995;78:12–6.
6. Imms FJ, Russo F, Iyawe VI, Segal MB. Cerebral blood flow velocity during and after sustained isometric skeletal muscle contractions in man. Clin Sci (Colch) 1998;94:353–8.
7. American College of Obstetricians and Gynecologists. Hypertension in pregnancy. Technical bulletin no. 219. (replaces no. 91, February 1986). Int J Gynaecol Obstet 1996;53:175–83.
8. Aaslid R, Lundar T, Lindegaard KF, Nornes H. Estimation of cerebral perfusion pressure from arterial blood pressure and transcranial Doppler recording. In: Miller JD, Teasdale GM, Rowan JO, Galbraith SL, Mendelow AD, eds. Intracranial pressure. Vol VI. Berlin Heidelberg: Springer-Verlag, 1986:226–9.
9. Belfort MA, Tooke-Miller C, Varner M, Saade G, Grunewald C, Nissel H, et al. Evaluation of a noninvasive transcranial Doppler and blood pressure-based method for the assessment of cerebral perfusion pressure in pregnant women. Hypertens Pregnancy 2000;19:331–40.
10. Maeda H, Matsumoto M, Handa N, Hougaku H, Ogawa S, Itoh T, et al. Reactivity of cerebral blood flow to carbon dioxide in hypertensive patients: evaluation by the trans-cranial Doppler method [see comments]. J Hypertens 1994;12:191–7.
11. Demarin V, Rundek T, Hodek B. Maternal cerebral circulation in normal and abnormal pregnancies. Acta Obstet Gynecol Scand 1997;76:619–24.
12. Ohno Y, Kawai M, Wakahara Y, Kitagawa T, Kakihara M, Arii Y. Transcranial assessment of maternal cerebral blood flow velocity in patients with pre-eclampsia. Acta Obstet Gynaecol Scand 1997;76:928–32.
13. Belfort MA, Grunewald C, Saade GR, Varner M, Nisell H. Preeclampsia may cause both overperfusion and under-perfusion of the brain: A cerebral perfusion based model. Acta Obstet Gynaecol Scand 1999;78:586–91.
14. Williams KP, Wilson S. Variation in cerebral perfusion pressure with different hypertensive states in pregnancy. Am J Obstet Gynecol 1998;179:1200–3.