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Ullevaal University Hospital, Department of Obstetrics and Gynecology, University of Oslo, Oslo, Norway
Submitted 26 August 2005 ; accepted in final form 1 December 2005
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ABSTRACT |
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ultrasound Doppler; internal carotid artery; pressor response
A decrease in resting cerebral blood flow has been reported in late pregnancy (3, 23), and, interestingly, pregnant women may complain of headaches, dizziness, and fatigue at this stage (6), which may indicate cerebral malperfusion (4, 13). Headaches as a symptom of preeclampsia may therefore be difficult to recognize. Tests used to evaluate cerebral autoregulation in pregnancy are ventilation with high or low PCO2 (9, 19, 23) and isometric handgrip (14, 19). In the third trimester, previous investigations have shown decreased cerebral flow during hyperventilation (23) and decreased pulsatility index in the middle cerebral artery during isometric handgrip (19).
The pressor response is a well-known simultaneous increase in MAP and HR during static muscle work, probably caused by an increase of the baroreflex set point (10, 12). The increase in MAP is explained by a marked increase in peripheral resistance (10); the magnitude of the response is related to the intensity of contraction (10, 21). This response has been of interest because it may give information about the baroreflex set point during pregnancy. However, previous investigations have shown conflicting results. For example, in the third trimester, one study (19) found no change in HR and MAP after isometric handgrip, whereas others found significant increases (2, 16, 17). Further, Nisell et al. (17) concluded that pregnancy had no impact on pressor response because they found equal increases in HR and MAP in the third trimester and after delivery. Barron et al. (2), however, concluded that there is a blunted pressor response in the third trimester because they found the increment in plasma catecholamine levels and HR to be significantly lower than after delivery.
In the present investigation, the impact of pregnancy on the cerebral autoregulation and the pressor response were studied in a longitudinal study design (gestational weeks 8, 15, 22, 29, and 36 and 12 wk postpartum).
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METHODS |
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Sixteen healthy, spontaneously pregnant women were recruited from the public health service. All subjects were nonsmokers and were not allowed to drink coffee or tea on the experimental day. No exercise or eating was permitted for at least 2 h before the start of each experiment. None of the subjects had any symptoms of cardiovascular disorders, and none used any medication. A urine dip-stick test was always used before the experiments to check for any symptoms of proteinuria or glucosuria. Informed consent was obtained from all subjects, and the experimental protocol was approved by the regional ethics committee. The subjects were scheduled for experiments five times during pregnancy (weeks 8, 15, 22, 29, and 36) and then again 12 wk after delivery. All subjects were given a vaginal ultrasound scan at 8 wk gestation to ensure a singleton pregnancy and confirm gestational length. At 36 wk, a repeat ultrasound scan was made to check that the fetus was growing normally and that blood flow velocity waveforms in the maternal uterine arteries and fetal umbilical artery were normal.
Instrumental Setup and Protocols
The experiments were carried out in a quiet room at an ambient temperature of 25–27°C. The subjects were dressed in standard running trousers and t-shirts and rested in a semisupine position on a bench. In advanced pregnancy, they twisted their knees to the left side to avoid vena caval compression. They were acclimatized for 30 min before the start of the experiment. Simultaneous continuous measurements were made of blood velocities recorded from the right internal carotid artery (ICA), MAP, HR, end-tidal CO2, and handgrip contraction force.
Protocol 1. After 5 min of control measurements, the subject started to hyperventilate until PCO2 was lowered by 1.2 kPa and then maintained at this value for 2 min. Feedback was given if end-tidal CO2 values became too high or too low during the test period.
Protocol 2. After 5 min of control measurements, the subjects performed an isometric muscle contraction with the right hand to a predetermined standardized value for 2 min (40% of maximal voluntary force). Continuous feedback from a display showing the contraction force exerted allowed the subject to maintain the required force.
The pressor and hyperventilation protocols were randomized, and the subjects rested for 20 min between protocols.
Instrumentation
Continuous blood velocity measurements in the ICA were made by using an ultrasound Doppler Duplex system (CFM-750, Vingmed Sound, Norway) with an operating frequency of 7.5 MHz. The carotid artery bifurcation was identified by imaging the field, and the characteristic blood velocity profile of the ICA was identified using the Doppler unit. The transducer was held at an angle of 
45° to the direction of flow in the artery, beneath the angle of the jaw. Instantaneous cross-sectional mean velocities were calculated by the instrument and fed on-line to a computer for beat-by-beat time averaging, gated by the ECG R-waves (23). Based on the assumption that the diameter of such a large artery is unaffected by the changes in PCO2 and MAP during the experiment, the change in mean velocity is proportional to the change in flow (1, 8). Instantaneous arterial blood pressure was obtained from the left fourth finger using a photoplethysmographic device (Ohmeda 2300 Finapres, Madison, WI). The blood pressure data were fed to a computer, and MAP was calculated by numerical integration for each R-R interval. Continuous measurements of end-tidal CO2 (face mask) were obtained by infrared spectroscopy (Artema Multigas Monitor MM201, Stockholm, Sweden; sampling rate 150 ml/min). For handgrip contraction, a specially designed handgrip aperture (Gripit, AB Detector, Gothenburg) was used. The subjects were asked to grip a handle with their right hand while resting their arm on the bench. The maximal voluntary contraction force was measured by asking the subjects to press with maximal force for 10 s; 40% of this value was calculated once and this value was used in all experiments for that subject (10).
Data Analyses and Statistics
The 50th and 90th percentiles of the blood velocity measured were calculated in a ±25-s sliding window. Before averaging between the subjects, all velocity recordings were scaled to convert the 5-min mean of the 90th percentile before tests started to unity. This procedure was also followed for the recordings of end-tidal CO2, MAP, and HR (see Fig. 1, C and D; Fig. 3; and Tables 2–4). The 90th percentile values were used for the analyses of velocity in the ICA and end-tidal CO2 values, while the 50th percentile values were used for the analyses of HR and MAP. We used the Wilcoxon signed rank test, two-sided test, with the significance level set at P = 0.05. The confidence intervals for the medians were calculated using nonparametric statistics (17). The statistical analyses were conducted using SPSS version 12.00 (SPSS; Chicago, IL).
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RESULTS |
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The subjects included were of mean age 31.6 ± 2.0 yr, mean weight 68.7 ± 11 kg, mean height 171 ± 5.6 cm, and with parity 0–2 (13 nullipara, 2 primipara, 1 multipara). All subjects delivered spontaneously at term (mean birth weight 3,569 ± 515 g). One subject was excluded at week 22 because of thrombocytopenia, one subject could not wear a face mask after week 15 because of claustrophobia, and one subject did not take the tests at weeks 22 and 29 of the study because of missed appointments. This subject later developed severe thromboembolic disease after delivery and did not attend the 12-wk postpartum tests either.
Resting Values
The resting values for end-tidal CO2, blood velocity in ICA, MAP, and HR are presented in Table 1. End-tidal CO2 showed a slight decrease during pregnancy that became significant in week 36 (P = 0.04, ANOVA, repeated measurements). After delivery, end-tidal CO2 showed a significant increase (P < 0.01, ANOVA, repeated measurements). Blood velocity in the ICA showed a nonsignificant decrease in week 36 (ANOVA, repeated measurements, P = 0.06) and a significant increase after delivery (P < 0.01, ANOVA, repeated measurements). MAP showed a decrease to a nadir at week 22 followed by a steady increase, whereas HR increased throughout pregnancy.
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Figure 1, A and B, shows simultaneous beat-by beat measurements of blood velocity in the ICA (Fig. 1A) and end-tidal CO2 (Fig. 1B) in one experimental run during hyperventilation at gestational week 15. Figure 1, C and D, shows relative, normalized mean values for blood velocity in the ICA (Fig. 1C) and end-tidal CO2 (Fig. 1D) obtained at weeks 8, 15, 22, 29, and 36 and after delivery. A dotted line is used for week 36, and solid lines for all other weeks. The start of hyperventilation is shown by an arrow on the x-axis. Figure 1B shows the typical fall in PCO2 values to the predetermined PCO2 level during hyperventilation. The mean time interval needed to reach this level was 73 ± 34 s in week 8, 74 ± 65 s in week 36, and 34 ± 19 s after delivery. The subjects managed to perform standardized hyperventilation, so that the fall in PCO2 was significant (Table 2) and equal in each test (Fig. 1D, Wilcoxon matched-pair signed-ranks test, 2-sided test, weeks 8and 36: P = 0.11, week 8 and after delivery: P = 0.88). At the start of the hyperventilation period, the blood velocity in the ICA decreased until a plateau was reached (Fig. 1, A and C). The time course of the fall in velocity depended on the time course of fall in PCO2, and there was always a close relationship between the PCO2 and blood velocity curves. The fall in velocity in the ICA during standardized hyperventilation was significant (Table 2) and equal during pregnancy and after delivery (Fig. 1C, Wilcoxon matched-pair signed-ranks test, 2-sided test, weeks 8 and 36: P = 0.64, week 8 and after delivery: P = 0.64). The MAP values typically showed a small drop during hyperventilation, which became significant only after delivery (Table 2).
Protocol 2: Isometric Handgrip
Figure 2 shows simultaneous recordings of beat-by-beat blood velocity in the ICA (Fig. 2A), end-tidal CO2 (Fig. 2B), MAP (Fig. 2C), and HR (Fig. 2D) in one experimental run during static muscle work at gestational week 8. Figure 3 shows relative normalized mean values for the same four variables in weeks 8, 15, 22, 29, and 36 and after delivery. The time interval for static muscle work is shown by a dashed horizontal line on the x-axis. A dotted line is used for week 36, and solid lines for all other weeks. The subjects managed to maintain 40% of maximal contraction force in all experiments but reported that this was more difficult in weeks 29 and 36 than earlier in pregnancy and after delivery. It is clear that end-tidal CO2 was stable during the experimental run, and this was found in all experiments (Figs. 2B and 3B; Table 3). There was no statistically significant difference between the velocity values in the ICA obtained immediately before work and those obtained at the end of the working period (Table 3; Figs. 2A and 3A). Furthermore, there was no difference between gestational weeks 8 and 36 or between gestational week 8 and postpartum (Wilcoxon matched-pair signed-ranks test, 2-sided test, weeks 8 and 36: P = 0.13, week 8 and postpartum: P = 0.13). In the present experimental protocol, blood velocity was measured ipsilaterally to the isometric muscle work. Thus any change in cerebral blood velocity is mainly related to change in blood pressure or PCO2, not to local metabolic change (7).
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During isometric handgrip, MAP increased steadily. This was followed by a rapid fall at rest (Fig. 2C). The resting value was reached after a few heart beats. The increase in MAP was statistically significant during pregnancy and after delivery (Fig. 3, Table 3). However, Fig. 3C clearly shows that the slope and peak values recorded in week 36 (dotted line) were smaller than at all other times. The rise in MAP was significantly smaller in week 36 than in all other weeks (Table 4, P < 0.05, ANOVA, repeated measurements) except week 29; the latter result is probably explained by the greater confidence interval at this stage. HR showed a similar pattern to MAP in weeks 8, 15, and 22, with a steady increase during the working period followed by a rapid fall at rest (Fig. 2D). In weeks 29 and 36 and postpartum, the pattern was somewhat different, and HR reached a plateau before the end of the exercise period (Fig. 3D, three lowest curves; dotted line shows week 36). However, the increase in HR during handgrip was statistically significant during pregnancy and after delivery (Fig. 3, Table 3). The peak value was lower in week 36 than in the other weeks (Table 4), but the only statistically significant difference was between week 36 and week 22 (ANOVA, repeated measurements, P < 0.05).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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The present study shows a mean increase in MAP of 18.5 mmHg (10.6 mmHg in week 36) during the handgrip test, which is similar to that reported by Nisell at al (17). On the other hand, nonpregnant subjects showed an increase of 30–40 mmHg during a similar protocol using isometric handgrip (10, 14). It is known that the increase in MAP during static muscle work is proportional to force (21). Pregnant subjects might not be able to perform such hard sustained static work and could thus show a smaller MAP response than nonpregnant subjects.
Our study shows that cerebral autoregulation is unchanged during a healthy pregnancy. The ability of the cerebral arterioles to constrict, as tested by standardized hyperventilation, is unchanged. Furthermore, we found no covariance between blood velocities in the ICA and blood pressure during isometric exercise. The method we used for the hyperventilation test was identical to that used by Hauge et al. (9), who found a linear relationship between blood flow in the ICA and end-tidal CO2 during hyperventilation in nonpregnant students. The results also agree with those of Zatik et al. (23), who studied pregnant women in the third trimester and found a significant decrease in blood velocity in the mean cerebral artery; however, they did not measure PCO2.
The MAP values in the present study typically show a small drop during hyperventilation, which became significant only after delivery. This is in accordance with earlier reports in nonpregnant subjects (11).
The finding that resting cerebral blood flow is significantly lower during pregnancy compared with after birth is in accordance with earlier findings (3, 22) and may explain why some pregnant women feel dizzy and complain of headaches. Resting end-tidal CO2 was also significantly lower during pregnancy than after birth, illustrating maternal hyperventilation with an increased tidal volume (11). This further suggests that the lowered resting blood velocity values in the ICA may be caused by a state of continuous hyperventilation. However, it is difficult to compare absolute blood velocity values obtained at different time intervals because there will be slight differences in the measuring sites.
During severe preeclampsia/eclampsia, cerebral edema may develop, resulting in central nervous system damage, hemorrhage, and seizures (24). It is not yet known whether this is caused by disturbance of the cerebral autoregulation or dysfunction of the general cerebral vascular bed (18, 23, 24).
In conclusion, pregnancy has an impact on the pressor response, resulting in a blunted reaction at week 36, probably caused by a reduction in the baroreflex set point. Pregnancy has no impact on cerebral autoregulation.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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  R. V. Immink, N. H. Secher, and J. J. van Lieshout Cerebral Autoregulation and CO2 Responsiveness of the Brain Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H2018 - H2018. [Full Text] [PDF]
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T. K. Bergersen, T.W. Hartgill, and J. Pirhonen REPLY Am J Physiol Heart Circ Physiol, October 1, 2006; 291(4): H2019 - H2019. [Full Text] [PDF]
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