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*Department of Anesthesiology, Osaka University Faculty of Medicine; and Japan and Research Institute, National Cardiovascular Center, Suita, Osaka, Japan
Address correspondence and reprint requests to Yukio Hayashi, MD, Department of Anesthesiology, Osaka University Faculty of Medicine (D-7), 2-2 Yamada-oka, Suita, Osaka 565–0871, Japan. Address e-mail to yhayashi{at}anes.med.osaka-u.ac.jp.
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Abstract |
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Introduction |
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Kitamura et al. (9) have demonstrated that adrenomedullin includes two molecular forms: an intermediate and mature adrenomedullin. The mature adrenomedullin is biologically active. This finding indicates that the various reported actions of adrenomedullin are because of the actions of mature adrenomedullin. Thus, mature adrenomedullin may contribute to cardiovascular changes during pregnancy.
Because a simple and reliable assay for mature adrenomedullin has been developed (10), we designed the present study to examine whether the mature adrenomedullin is associated with changes in blood volume during pregnancy. We measured blood volume and mature adrenomedullin concentration in both the maternal plasma and CSF to investigate the relationship between CSF or plasma mature adrenomedullin and blood volume in pregnant women.
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Methods |
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We examined three groups of patients in the first study: the nonpregnant group, the early gestational group, and the full-term group. The nonpregnant group included 8 women undergoing orthopedic surgery, the early gestational group included 10 women between 15 and 18 wk of gestation undergoing gynecological surgery, and the full-term group included 9 women undergoing cesarean delivery. Indications for cesarean delivery were repeat cesarean deliveries in seven patients and breech presentation in two patients.
The second study included 20 healthy, full-term women scheduled for elective cesarean delivery. None of the patients had a history of hepatic, cardiac, respiratory, or renal disease. Patients with abruptio placenta, placenta previa, multiple gestation, and preeclampsia or who were receiving ß-tocolytic drugs were excluded. Indications for cesarean delivery in the second study were repeat cesarean deliveries in 18 patients and breech presentation in 2 patients.
Heart rate, systolic blood pressure, and diastolic blood pressure were determined and Ringer’s lactate solution was infused before the induction of anesthesia. All patients received spinal anesthesia with 1 mL of CSF being withdrawn before the induction of anesthesia. Blood samples were taken soon after the spinal bupivacaine was injected.
For measurement of mature adrenomedullin, 3 mL of blood and 1 mL of CSF were collected into chilled glass tubes containing disodium EDTA (1 mg/mL) and aprotinin (500 U/mL) and were then centrifuged at 4°C for 15 min. The plasma and CSF samples were stored at –40°C until assay of mature adrenomedullin. Plasma and cerebrospinal mature adrenomedullin concentrations were determined by the immunoradiometric assay kit specific for human mature adrenomedullin (10). The inter- and intra-assay variation of our assay kit were <3%.
In the second study, we measured blood volume before the induction of anesthesia. Noninvasive measurement of blood volume in our institute was described in our previous report (11). In brief, blood volume was estimated using indocyanine green (ICG) as an indicator. Ten milligrams of ICG was administered in an IV bolus dose within 1 s through a cannula placed in the peripheral vein, and the blood ICG concentration was monitored by pulse spectrophotometry using a probe fixed on the patient’s left finger. The measurement of blood ICG concentrations by pulse spectrophotometry operates by the same principle as the monitoring of oxygen saturation measured by pulse oximetry (Spo2). It is designed using the principles of light absorbency and pulse detection, in which endogenous hemoglobin is used as the reference material. The integrated pulse spectrophotometry monitoring system is composed of a finger probe, a monitoring device, and a computer for recording and printing the results (DDG 1001; Nihon Kohden Inc., Tokyo, Japan). Before the injection of ICG, approximately 0.5 mL of blood was drawn to measure the hemoglobin concentration, which is required for calculating ICG blood concentration. Blood ICG concentration was measured immediately after the administration of ICG. The blood volume was estimated based on the ICG blood concentration time courses as follows: blood volume = dose/CMTT, where CMTT is the blood concentration of ICG at the mean transit time (MTT) calculated from the first dilution curve. The present method was reported to be as accurate as the conventional radioisotope (131I-human serum albumin) method (12).
The data are expressed as the mean ± sd. The results of the multiple groups were analyzed by one-way analysis of variance, and comparisons among groups were assessed by Student-Newman-Keuls test. Correlation analysis was performed, and correlation coefficient was calculated to examine the relationship between mature adrenomedullin concentrations and blood volume. P < 0.05 was considered statistically significant.
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Discussion |
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Adrenomedullin exerts a number of biological effects in various tissues, and many of them may be related to the control of fluid and electrolyte status and hemodynamics (13,14). There have been various studies about adrenomedullin and pregnancy, and a well summarized review has been published (6). It has been demonstrated that plasma adrenomedullin concentration increases progressively during pregnancy and decreases in the postpartum period in humans (4–6). Because a significant correlation was found between mature and total adrenomedullin (9), it is likely that plasma-mature adrenomedullin also increases progressively during pregnancy, and our data concur (Fig. 1).
Adrenomedullin was also reported to be present in placenta and fetoplacental tissues (15–17) and might contribute to regulation of utero-placental-fetal circulation. Furthermore, adrenomedullin was shown to be involved in some pathological conditions during pregnancy. For example, adrenomedullin concentrations in the umbilical plasma and amniotic fluid were significantly increased in preeclampsia compared with in normal pregnancy (18), although maternal plasma concentration of adrenomedullin showed conflicting results (6). These observations suggest that adrenomedullin may be involved in physiological processes and pathological conditions during pregnancy. However, much remains to be elucidated about the physiological significance of the increasing adrenomedullin concentration during pregnancy.
Significant hemodynamic adaptations occur in the mother during pregnancy. Cardiac output, heart rate, and blood volume are increased, whereas vascular resistance is decreased (1). The principal finding in our study is that maternal plasma-mature adrenomedullin concentration at full term has a significant positive correlation with blood volume per unit body weight (Fig. 2). Because mature adrenomedullin is a potent vasodilating peptide, increases in plasma-mature adrenomedullin concentration may facilitate a decrease in vascular resistance and thus compensate for the increase in blood volume during pregnancy. In other words, mature adrenomedullin may be involved in the defense mechanisms against further volume expansion and against further increase of system or local vascular resistance during pregnancy.
Previous animal studies suggested that CSF adrenomedullin might play a role in the regulation of arterial blood pressure and salt intake (14,19). Thus, we also measured the change of mature adrenomedullin concentration in CSF to examine whether it contributed to the regulation of blood volume during pregnancy. However, our study showed that mature adrenomedullin in CSF did not change during pregnancy, and no significant correlation was noted between CSF-mature adrenomedullin and blood volume (Figs. 1 and 2). These results have confirmed and extended the previous report by Nagata et al. (3), which indicated that adrenomedullin in CSF was regulated independently from that in the plasma during pregnancy.
There are several potential limitations in this study that should be discussed. First, although we found a statistically significant correlation between the plasma concentration of mature adrenomedullin and blood volume in women at full term, this does not necessarily imply a cause and effect relationship. Furthermore, our findings do not allow us to definitely state that mature adrenomedullin is a cause of the increase in blood volume, and the increase in mature adrenomedullin could be a consequence of the increasing blood volume. Clearly, additional studies are required to elucidate the involvement of mature adrenomedullin in the increase in blood volume during pregnancy. Second, the correlation between mature adrenomedullin and blood volume in the second study was modest (r2 = 0.47), whereas our sample size was sufficient to detect the statistically significant relationship. More sampling might improve statistical significance (P value) but not the correlation coefficient (r) value. Thus, the role of mature adrenomedullin in the increasing blood volume may not be highly significant, suggesting that various other factors may also be involved in determining blood volume. Third, the variation of the assay of mature adrenomedullin and the measurement of blood volume may affect the correlation coefficient value. However, the inter- and intra-assay variation of our adrenomedullin assay kit were <3%, and the measurement of blood volume is as accurate as the conventional radioisotope (131I-human serum albumin) method (12). Thus, variation of these values is unlikely to have affected our conclusion. Fourth, our study was not blinded. However, the presence of blinding should not have affected the measurement of blood volume and the assay of mature adrenomedullin. Thus, we believe that the lack of study blinding manifests no obvious source of bias for or against our finding of a significant correlation.
Finally, we believe that there may be a future clinical application of adrenomedullin or adrenomedullin antagonists and that eventually these drugs might contribute to anesthetic management of parturients. Currently, however, these drugs are limited to laboratory investigation.
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