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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynaecology, University College London, London, United Kingdom.
Address reprint requests to: Donald Peebles, MD, University College London, Department of Obstetrics and Gynecology, 86-96 Chenies Mews, London, WC1E 6HX, United Kingdom; E-mail: d.peebles{at}ucl.ac.uk.
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ABSTRACT |
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METHODS: Normotensive (n = 13), chronic hypertensive (n = 7), pregnancy-induced hypertensive (n = 9), and preeclamptic (n = 15) women were studied cross-sectionally. The change in cerebral blood volume in response to a change in maternal posture from the left lateral to sitting position was quantified.
RESULTS: In the normotensive, chronic hypertensive, and pregnancy-induced hypertensive groups there was a fall in median (interquartile range) cerebral blood volume of 0.18 (-0.21, -0.15), 0.11 (-0.26, -0.09), and 0.089 (-0.10, -0.049) mL/100 g, respectively. Conversely, in the preeclamptic group there was a rise in median cerebral blood volume of 0.13 (-0.20, 0.15) mL/100 g. Of these, six of the nine women with a median rise in cerebral blood volume of 0.15 mL/100 g (0.13, 0.16) required intravenous antihypertensive therapy, volume expansion, and delivery by cesarean within 48 hours. Conversely, none of the preeclamptic women (n = 6) with a median fall in cerebral blood volume of 0.22 mL/100 g (-0.30, -0.18) required these emergency measures.
CONCLUSION: The cerebral blood volume response, measured noninvasively by near-infrared spectroscopy, provides additional evidence of altered cerebral hemodynamics in women with preeclampsia.
The progression of preeclampsia, a serious pregnancy complication with significant mortality and morbidity,1 to eclampsia is unpredictable. This is partly because the underlying cerebral pathophysiology is complex and remains poorly understood. Eclampsia is associated with cerebral edema and hemorrhage, resulting from blood–brain barrier disruption, which has been demonstrated by computerized tomography and magnetic resonance imaging.2 Damage to the blood–brain barrier is preceded by a failure of normal cerebral autoregulation; however, the nature of the underlying vascular mechanism is controversial.
Eclampsia may represent the end stage of at least two different pathophysiological pathways.3 Angiographic4,5 and Doppler studies6 of the cerebral circulation in women with severe preeclampsia suggest that vasospasm results in cerebral underperfusion to cause local ischemia, arteriolar necrosis, and disruption of the blood–brain barrrier. Conversely, others7 suggest a role for cerebral hyperperfusion due to passive overdistension of cerebral vessels, as a result of loss of autoregulation and raised blood pressure. Furthermore, a third of women with preeclampsia have a normally perfused brain as assessed by Doppler ultrasound.3 Perhaps as a result of these conflicting findings, current methods of assessing the cerebral circulation have not yet found a clinical role in the management of preeclamptic pregnancies.
In this study, we used near-infrared spectroscopy to measure changes in maternal cerebral blood volume. This optical technique allows assessment of changes in tissue oxygenation and cerebral blood volume in realtime. It has been used to provide quantitative data on cerebral blood volume from neonatal,8,9 fetal,10,11 and adult12,13 brains. In anesthetized, ventilated subjects, quantification of absolute cerebral blood volume is possible using near-infrared spectroscopy.8,12 These subjects are oxygen dependent, and by altering the inspired oxygen fraction, changes in cerebral and peripheral oxygenation can be measured by near-infrared spectroscopy and pulse oximetry, respectively. From these measurements, absolute cerebral blood volume can be calculated using a previously defined equation.14 However, the measurement of absolute cerebral blood volume is restricted to oxygen-dependent patients. Near-infrared spectroscopy can also quantify changes in cerebral blood volume in response to a postural change, both in ventilated neonates and in healthy adults.15,16
Our aim was to use near-infrared spectroscopy to compare the cerebral blood volume response to a change in maternal posture in four groups of pregnant women: 1) normotensive, 2) chronic hypertensive, 3) pregnancy-induced hypertensive, and 4) preeclamptic. We hypothesized that women with preeclampsia would have a different cerebral blood volume response to a change in maternal posture compared with those without the disease.
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MATERIALS AND METHODS |
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The women were asked to lie down in the left lateral position, to prevent aortocaval compression. The head was supported such that the coronal plane of the head and spine was horizontal. The women maintained this position for 15 minutes to obtain a steady baseline in the near-infrared spectroscopy recordings. The change in posture was obtained by asking the women to sit by extending their left arm. The sitting position was obtained such that the coronal plane of the head and spine was vertical while the lower limbs hung over the side of the bed, and the women were asked to keep this position for 5 minutes while being monitored. The women were then asked to adopt the original left lateral position from the sitting-up position.
All studies were performed using two fiber-optic bundles placed over the maternal right frontal bone, with an interoptode spacing of 4.5 cm. These were held in a specially constructed neoprene holder. Optical fibers conducted near-infrared light at four discrete wavelengths to and from a commercially available near-infrared spectrometer (Hamamatsu NIRO 500, Hamamatsu Photonics KK, Hamamatsu City, Japan). Changes in light absorption at four wavelengths between 775 and 905 nm were recorded for 15 minutes before, during, and for 5 minutes after a change in maternal position from the left lateral to sitting up. We calculated the mean changes in the concentration of oxyhemoglobin and deoxyhemoglobin in µmol/L per liter of brain tissue, over 1 minute immediately before and after the change in posture, using a previously published algorithm.17 Summing deoxyhemoglobin and oxyhemoglobin provides the total hemoglobin concentration. From the change in hemoglobin concentration in µmol/L, the change in cerebral blood volume (CBV) in mL/100 g can be calculated using the following equation:
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where HbT is total hemoglobin concentration, MWhb is the molecular weight of hemoglobin (64,500 d), Dt is the brain tissue density (1.05 g • mL-1), and tHb is the concentration of hemoglobin in large vessels (g • 100 mL-1), determined from each woman’s most recent full blood count. On the likely assumption that the hematocrit does not change during the 15-minute course of the study, changes in hemoglobin concentration relate directly to changes in cerebral blood volume. An increase in cerebral blood volume indicates an increase in the volume of the cerebrovascular compartment (ie, vasodilatation), and a fall in cerebral blood volume is consistent with vasoconstriction. This could be passive, as a result of a change in arterial perfusion or venous outflow, or active, as a result of changes in vascular tone. Changes in cerebral blood volume were measured during the act of sitting as well as lying down, because we supposed that if the changes were related to a change in posture they should be reversible with a return to the original position. For clarity, data presented are solely those associated with sitting up, as reciprocal changes were observed with lying down.
Women were allocated to one of four groups on the basis of clinical signs at the time of investigation. These groups were normotensive, chronic hypertensive, pregnancy-induced hypertensive, and preeclamptic. Preeclampsia was defined as hypertension (a blood pressure of greater than 140/90 mm Hg on two separate occasions at least 4 hours apart) and significant proteinuria (greater than 300 mg of protein in a 24-hour urine collection, in the absence of a urinary tract infection) in a previously normotensive woman (with no preexisting renal disease) after 20 completed weeks of gestation. Pregnancy-induced hypertension was defined as the development of hypertension after 20 completed weeks of gestation without proteinuria. These findings, combined with the need for delivery within 48 hours, were considered to indicate severe disease. Chronic hypertension was defined as hypertension that developed before the 20th week of gestation.
Comparisons between the four groups were made by one-way analysis of variance (Sigmastat 2.0; SPSS Science, Chicago, IL) using the Tukey test for pair-wise multiple comparisons, unless the data were not normally distributed, in which case Kruskal-Wallis analysis of variance with Dunn test for multiple comparisons was performed. Correlation between cerebral blood volume response and demographic data was tested for, using multi-linear regression analysis.
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RESULTS |
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. There were no significant differences in maternal age or gestation between the four groups. Multiparity was significantly more common in the chronic hypertensive compared with the normotensive group (P < .05). As expected, diastolic blood pressure was significantly higher in the three hypertensive groups compared with the normotensive group.
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. In normotensive control subjects, there was no correlation between size of the cerebral blood volume response and maternal age, gestation, or parity. A similar fall in cerebral blood volume of 0.20 ± 0.10 and 0.08 ± 0.10 mL/100 g was observed in women with chronic and pregnancy-induced hypertension, respectively, which did not differ significantly from the normotensive group (Figure 2). The posture-related decrease in cerebral blood volume was significantly attenuated in the preeclamptic group compared with the normotensive group (P < .05), falling by a mean of only 0.01 ± 0.22 mL/100 g. The large variance of measurements in the preeclamptic group is explained by the fact that in nine of these women, cerebral blood volume actually increased, by a mean value of 0.14 ± 0.04 mL/100 g. Figure 1B shows a typical response in these nine women. The remaining six women in the preeclamptic group had a fall in cerebral blood volume of 0.25 ± 0.11 mL/100 g. In none of the groups was there a significant difference in the magnitude of the response compared with the opposite response calculated when the women were asked to adopt the original left lateral position.
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. The women with preeclampsia who had a rise in cerebral blood volume had a significantly higher mean diastolic blood pressure than those in whom it fell (P = .04), but no difference in the median levels of urates and proteinuria were observed (Table 2). Three of the six women with a fall in cerebral blood volume and five of the nine women with a rise in cerebral blood volume had been commenced on antihypertensive therapy prior to being studied. There was a significant difference in the median time to delivery between those with a rise or fall in cerebral blood volume (P < .05). Of the nine women with a rise in cerebral blood volume, six required delivery by cesarean within 48 hours of recruitment to the study because of the severity of preeclampsia. Worsening maternal disease was the main indication for delivery in all cases, although in one case the cesarean delivery was performed for fetal distress after induction of labor. Delivery was premature (<37 weeks) in three of the six cases. All six of these women required intravenous antihypertensive therapy and volume expansion with colloids within 24 hours of admission. Of the remaining three women with a rise in cerebral blood volume, all were recruited at an early gestation, and two were delivered by emergency cesarean at 26 and 35 weeks’ gestation. Conversely, of the six women with a fall in cerebral blood volume, none required emergency resuscitation or delivery within 48 hours of monitoring. None of the women with preeclampsia developed eclampsia, and there were no admissions to the intensive care unit.
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DISCUSSION |
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The changes in cerebral blood volume reported here are derived from the sum of changes in the cerebral concentrations of oxy- and deoxyhemoglobin from a baseline set at the beginning of the study. Owing to the scattering effect of biological tissue on light in the near-infrared part of the spectrum, these are global changes occurring within all vascular compartments. Because approximately 70% of cerebral blood volume is within the venous compartment, it is likely that changes here will dominate the signal. The significance of a change in cerebral blood volume is that, assuming hematocrit does not change during the course of the study, an increase or decrease in cerebral blood volume will reflect vasodilation or vasoconstriction, respectively.
Most studies of maternal cerebral circulation in preeclampsia have used transcranial Doppler ultrasound. This technique provides extensive information on changes in cerebral blood flow velocities, which, when combined with blood pressure, gives an index of cerebral perfusion and cerebrovascular resistance.3 Transcranial Doppler studies have shown increased cerebral blood flow velocity in the middle cerebral artery6,7,18,19 of preeclamptic women; cerebral blood flow velocity is increased further immediately postpartum20,21 and reduced by antihypertensive22 and magnesium sulfate therapy.23 However, cerebral hemodynamics may not differ between some women with preeclampsia and normotensive control subjects. Although a positive relationship was observed between the resistance index in the middle cerebral artery and blood pressure in preeclamptic women without headache, the relationship was negative in those with headache, which was similar to the findings in normotensive controls.24 Other authors report that although women with mild and severe preeclampsia are more likely to have low and high cerebral perfusion pressures, respectively, approximately one third of both will have cerebral perfusion pressures within the normal range for normotensive pregnant women.3
The data presented here provide further evidence of abnormalities in the maternal cerebral circulation in preeclampsia. We found that approximately one third of the preeclamptic women had a cerebral blood volume response similar to normotensive controls. This is similar to the 39% of women with mild preeclampsia and 34% of women with severe preeclampsia reported to have normal cerebral perfusion measured by transcranial Doppler ultrasound.3 The preeclamptic women who had an abnormal response in our study were more likely to have an emergency cesarean delivery because of the severity of the disease. Similarly, Williams found that women with preeclampsia delivered by cesarean had higher antepartum middle cerebral artery blood flow velocities than those delivered vaginally.20 Using a maternal postural change (similar to our study), a significant increase in cerebral blood flow velocity (30%) in the middle cerebral artery occurred in women with preeclampsia compared with normotensive and chronic hypertensive controls.25
The majority of the women in our study had a cerebral blood volume response to postural change similar to that observed in nonpregnant subjects,15 which suggests that this response reflects normal physiologic control mechanisms for the maintenance of cerebral blood flow during postural change. It has been shown that the increase in venous outflow that should accompany body elevation is minimized by collapse of the jugular vein and a marked decrease in jugular flow.26 However, the small fall in cerebral blood volume observed in our study may result from continuing loss of venous blood via the vertebral veins. Cerebral blood volume will be affected by the balance between arterial inflow and venous out-flow. Therefore, the increase in cerebral blood volume observed in women with severe preeclampsia could reflect either an increase in arterial flow with sitting up or an even greater fall in venous outflow than that seen in normal patients. Support for the concept of increased arterial flow is provided by data from a study using transcranial Doppler ultrasound that showed an increase in cerebral blood flow velocity in the middle cerebral artery of patients with severe preeclampsia.25 Mechanisms for the increase in cerebral blood flow are unclear. Different responses in the renin–angiotensin–aldosterone system may alter control of vascular tone and have been reported in response to a maternal postural change in hypertensive pregnancies compared with controls.27,28 In addition, preeclampsia is characterized by endothelial dysfunction, abnormal nitric oxide metabolism, and increased free radical activity, all of which will affect the response of the cerebral circulation. The effect of antihypertensive therapy on changes in cerebral blood volume is not known, although transcranial Doppler ultrasound data suggest lower cerebral blood flow velocity in patients with preeclampsia treated with antihypertensives.22 Theoretically, the use of antihypertensives could therefore have led to more women having a normal cerebral blood volume response to postural change. However, the fact that approximately 50% of both preeclamptic groups were on antihypertensive treatment suggests that their effect on the observed cerebral blood volume response is unlikely to be large.
The contribution of artefact to these data is likely to be small. The speed of the postural change is unrelated to the response in cerebral blood volume,15 and contraction of the abdominal muscles during the change in posture, which may increase intra-abdominal pressure and contribute to a rise in cerebral blood volume, was minimized by elevating the patient using arm extension. Movement of the probe on the head could potentially affect the data, although again the specially designed neoprene holder minimized this. Extracerebral tissue may potentially affect the attenuation of near-infrared spectroscopy light,29 although changes in scalp blood flow appear to have no effect on near-infrared spectroscopy measurements of cerebral hemodynamics.30 Adequate separation of the light-emitting and -receiving optodes appears to be critical in determining the dominance of the signal by extra-cerebral tissue,31 with increasing distance improving depth of penetration. The optode separation used in this study, 4.5 cm, is toward the upper range of those normally used and is close to the limit imposed by light penetration through tissue. We report changes in cerebral blood volume from a baseline determined at the beginning of the study; if there were no change in extracerebral blood volume during the study, the calculated change in blood volume measured would be entirely cerebral. Although this cannot be assumed, the similarity of our findings to those obtained by Doppler ultrasound, which only measures intracerebral blood flow velocity, suggests it is likely. In addition, all of these potential sources of error should not affect one group more than another and could not therefore lead to the differences seen.
This study reports the use of near-infrared spectroscopy to measure changes in maternal cerebral blood volume in a safe, noninvasive manner at the bedside. A previous study confirms that measurements using this technique are reproducible and show small systematic and random error.32 The equipment is portable and simple to use, and the changes observed in cerebral blood volume during postural changes are identifiable in real time. The technique could therefore be used in a day assessment unit setting, where knowledge of posture-related changes in cerebral blood volume would complement other indicators of the severity of preeclampsia. It is encouraging that in this study cerebral blood volume changes, measured by near-infrared spectroscopy, were always abnormal in those with severe preeclampsia. This contrasts with cerebral blood flow velocity measurements using transcranial Doppler ultrasound, in which a normal response could be observed in some of those with severe disease.3 However, these are preliminary data and need to be followed by longitudinal studies using near-infrared spectroscopy to investigate the natural history of the cerebral blood volume response in preeclampsia. Combined studies with transcranial Doppler ultrasound may provide better evidence of the relationship of cerebral blood flow velocity and cerebral blood volume changes in preeclampsia and define the clinical role of near-infrared spectroscopy and transcranial Doppler ultrasound in the management of severe preeclampsia and in the prediction of eclampsia.
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Footnotes |
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Received November 27, 2001. Received in revised form June 3, 2002. Accepted July 25, 2002.
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REFERENCES |
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