1 Department of Anaesthesiology and 2 Department of Obstetrics and Gynaecology, University Hospital of Oulu, PO Box 21, FIN-90029 OYS, Finland
* Corresponding author. E-mail: tiina.erkinaro{at}pp.fimnet.fi
Accepted for publication July 14, 2004.
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Abstract |
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Methods. At 117132 days gestation, chronically instrumented, anaesthetized and mechanically ventilated ewes were randomized to receive boluses of ephedrine (n=9) or phenylephrine (n=8) for maternal epidural-induced hypotension after a period of fetal hypoxaemia. Uterine (QUtA) and placental (QUA) volume blood flows were measured with perivascular transit-time ultrasonic flow probes, and uterine (RUtA) and placental (RUA) vascular resistances were computed from volume blood flows and maternal and fetal mean arterial pressures. Uterine (PIUtA) and umbilical artery (PIUA) pulsatility indices were obtained by Doppler ultrasonography.
Results. Ephedrine increased QUtA and decreased RUtA and PIUtA from a hypotensive to baseline level and had no significant effect on umbilical circulation. With phenylephrine, QUtA remained lower (P=0.011) and RUtA higher (P=0.043) than at baseline, although PIUtA decreased to baseline level. PIUA increased from baseline with phenylephrine (P=0.007), whereas QUA decreased (P=0.050). Maternal volume expansion with hydroxyethyl starch decreased RUtA significantly irrespective of the vasopressor used. There were no significant differences in fetal blood gas values or lactate concentrations between the ephedrine and phenylephrine groups.
Conclusions. Despite the more favourable effects on uterine and placental circulations of ephedrine over phenylephrine, no significant differences in fetal acidbase status or lactate concentrations were observed.
Keywords: anaesthesia, obstetric ; anaesthetic techniques, epidural ; sympathetic nervous system, pharmacology, ephedrine ; sympathetic nervous system, pharmacology, phenylephrine
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Introduction |
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In this randomized study in a chronic sheep model we tested the hypothesis that ephedrine and phenylephrine, administered for epidural-induced hypotension in anaesthetized and mechanically ventilated ewes after a period of maternal and fetal hypoxaemia, are equal in respect of fetal outcome despite their divergent effects on maternal haemodynamics. The specific aims were to investigate the two vasopressors as regards (i) uterine and placental volume blood flows, vascular resistances, and uterine and umbilical artery pulsatility indices, (ii) the effects of maternal volume expansion on these parameters, and (iii) fetal acidbase status and lactate concentrations.
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Methods |
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During the recovery period of 5 days, fetal acidbase status and uterine (QUtA) and placental (QUA) volume blood flows were monitored daily. On the day of the experiment (117132 days gestation), general anaesthesia was induced with propofol 47 mg kg1 and maintained throughout the experiment with isoflurane 11.5% in an oxygen/air mixture via a tracheal tube and mechanical ventilation. Muscle relaxation was induced with rocuronium 20 mg and monitored with a neurostimulator, with additional boluses given as needed. A thermodilution catheter (Criticath SP5107H, Becton Dickinson, Sandy, UT, USA) was introduced through a jugular vein introducer placed during the primary operation. Under local anaesthesia, a 16-G polyurethane catheter was inserted into the descending aorta of the ewe via a femoral artery, and a 19-G epidural catheter was inserted percutaneously using the loss of resistance technique into the epidural space one inter-space above or at the lumbosacral junction. The ewe was then placed supine with right lateral tilt and allowed to stabilize for 30 min before baseline measurements. Ringer's solution was infused freely until pulmonary capillary wedge pressure (PCWP) reached a value of 6 mm Hg, and thereafter at a rate of 100 ml h1.
Experimental protocol
After all the haemodynamic parameters were stabilized, baseline measurements were obtained (phase 1).
At time zero, maternal and fetal hypoxaemia, defined as maternal oxyhaemoglobin saturation of 8090%, were induced by replacing oxygen by medical air in the rebreathing circuit (phase 2). At 15 min, the maternal inhaled oxygen concentration was returned to baseline, and the ewe and the fetus were allowed to recover from hypoxaemia (phase 3). At 30 min, the ewe was given 5 ml of bupivacaine 0.5% through the epidural catheter as a test dose, followed in 2 min by a 2-min injection of bupivacaine 0.5% to a total dose of 0.3 ml kg1. The dose was chosen to achieve a high thoracic level of epidural anaesthesia on the basis of the results of previous studies5 6 and our experience. Hypotension to at least a 30% decrease in maternal systolic arterial pressure (SAP) was allowed to develop (phase 4). At 45 min, the ewes were randomized into the ephedrine or phenylephrine group by picking a sealed envelope and administration of 1 ml boluses of either ephedrine (5 mg ml1) or phenylephrine (0.1 mg ml1) was started to achieve a maternal SAP of at least 90% of the baseline (phase 5). At 75 min, administration of the vasopressor was discontinued. At 80 min, the crystalloid infusion (Ringer's solution 100 ml h1) was discontinued and 500 ml of hydroxyethyl starch solution (HES) was infused over a period of 10 min, after which the crystalloid infusion was restarted. At 90 min, the vasopressor boluses were restarted, aiming at a maternal SAP of at least 90% of baseline (phase 8). At 120 min, the administration of vasopressor was discontinued. At 165 min, the ewe and the fetus were killed by an i.v. overdose of pentobarbital.
Monitoring protocol
Maternal arterial pressures, central venous pressure (CVP), and pulmonary arterial pressure were measured via disposable pressure transducers (DT-XX, Ohmeda, Hatfield, UK). The transducers used for fetal arterial and venous blood pressure measurements were reusable (Biopac Systems Inc., Santa Barbara, CA, USA). Maternal and fetal mean arterial pressures (MAPs) were computed arithmetically, and the heart rates (HRs) were computed from the arterial waveforms. QUtA and QUA were measured with the perivascular flow probes attached to a flow meter (T206, Transonic Systems Inc., Ithaca, NY, USA). Uterine (RUtA) and placental (RUA) vascular resistances were computed by dividing maternal and fetal MAPs by QUtA and QUA, respectively. All those variables were recorded continuously at a sampling rate of 100-Hz using a polygraph (UIM100A, Biopac Systems Inc., Santa Barbara, CA, USA) and computerized data acquisition software (Acqknowledge v. 3.5.7 for Windows, Biopac Systems Inc., Santa Barbara, CA, USA). The recordings were later analysed at 1-min periods and the median value of the 6000 measurements per variable was chosen to represent a particular minute.
CO was measured in triplicate at the end of each phase with the thermodilution catheter and Datex A/S3 monitor (Datex Inc., Espoo, Finland). PCWP and systemic vascular resistance (SVR) were obtained with the CO measurements. The surface area of the ewe was calculated14 and cardiac index (CIND) and systemic vascular resistance index (SVRI) were derived from CO and SVR. Maternal and fetal arterial blood samples drawn at the end of each phase were immediately analysed for acidbase values (39°C). Maternal and fetal lactate concentrations were determined in blood samples drawn at the end of phases 1, 4, and 8.
Doppler ultrasonographic recordings (Acuson Sequoia 512, Mountain View, CA, USA) from the maternal main uterine artery and the fetal umbilical artery were obtained at the end of each phase. Mean values for the uterine (PIUtA) and umbilical artery (PIUA) pulsatility indices (PI=(peak systolic velocity end diastolic velocity)/time-averaged maximum velocity over the cardiac cycle) were derived from three consecutive blood velocity waveforms.
Statistical analysis
Data were analysed using SPSS 10.1 for Windows software package (SPSS Inc., Chicago, IL, USA). Comparisons of single parametric variables between the groups were made using Student's t-test. For parameters that were continuously or repeatedly monitored, analyses of variance for repeated measurements (ANOVA) were used to evaluate whether there were significant differences between the groups (between-subjects P), or significant changes in measurements over time (within-subjects P), or significant differences in changes over time between the groups (interaction P). Because of skewed distribution, logarithmic transformation of RUtA was used. The means of the last 5 min for phases 1, 2, 3, and 4 and the second to last 5 min for phases 5 and 8 were considered representative for each phase and used in the analyses. Two-tailed P-values were used. The data are presented as mean (SD) or mean differences with 95% confidence intervals (95% CI).
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Results |
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The mean weights of ewes and fetuses, gestational age on the day of experiment, degree of fetal hypoxaemia (the percentage of fetal during hypoxaemia vs baseline fetal
), duration of hypotension, and degree of hypotension (the percentage of mean maternal SAP during the last 5 min of hypotension vs baseline SAP) were comparable between the groups (Table 1). Mean total volume of vasopressor given was significantly greater (P=0.001) in the phenylephrine group (22.4 (8.1) ml) than in the ephedrine group (9.4 (4.5) ml). During the whole experiment, maternal blood gas values and lactate concentrations (Tables 2 and 4) and end-tidal isoflurane concentrations were comparable between the two groups. In 15 ewes and fetuses, mean QUtA (726 (163) vs 760 (287) ml min1; P=0.6) and QUA (407 (125) vs 401 (136) ml min1; P=0.8) measured before the induction of general anaesthesia were comparable with values during phase 1 (baseline).
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With phenylephrine (phase 5) maternal MAP, HR, and CIND remained significantly lower than at baseline. SVRI increased to baseline levels, and CVP and PCWP increased significantly from baseline values. QUtA increased significantly but remained lower than at baseline. PIUtA decreased to baseline levels. RUtA decreased but returned to baseline only after maternal volume expansion (phase 8). Phenylephrine corrected fetal hypoxaemia, restored fetal MAP to baseline level, and had no effect on fetal HR. PIUA increased (phase 5) and, after prolonged phenylephrine administration (phase 8), QUA decreased significantly, but there were no significant changes in RUA, fetal blood gases, or lactate concentrations (ANOVA of phases 1, 5, and 8 for the phenylephrine group; Figs 1 and 2 and Tables 4 and 5).
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Discussion |
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There are several limitations in our study to consider before extrapolating our results to humans. First, both the macrostructure of the ovine placenta with the arrangement of fetal and maternal blood compartments and the structure of the maternal cell layers differ from those of the human placenta. Accordingly, differences in the placental transfer of vasopressors may exist. In addition, human and ovine responses to vasopressors may vary because there are species differences in - and ß-adrenergic receptor distribution. Secondly, for ethical reasons and to allow a supine position, the experiments were performed under general anaesthesia. Although QUtA and QUA before the induction of general anaesthesia were comparable with values measured during general anaesthesia at baseline, the combination of general and regional anaesthesia may have modified maternal haemodynamics more extensively than epidural anaesthesia alone. Thirdly, because of a relatively complex and long-lasting study protocol the fetuses were exposed to vasopressors for a longer period than is clinically relevant. Fourthly, although the number of animals was comparable with that of previous experimental studies, the sample size was limited, which may reduce the power of this study. However, previous studies on fetal sheep have shown that physiologic changes in the umbilicoplacental circulation can be applied to human pregnancies.15 17
As shown in earlier animal studies,5 6 we observed that QUtA decreased significantly during hypotension and was restored to baseline level by ephedrine. Phenylephrine increased QUtA but this remained lower than at baseline. The concomitant increase in RUtA during hypotension was normalized by ephedrine but not phenylephrine. This indicates that the lower QUtA with phenylephrine did not merely result from the lower maternal MAP during phenylephrine treatment than at baseline, but was caused by increased vascular resistance and vasoconstriction of the uterine arterial bed. To our knowledge, placental circulation has not been monitored directly in any previous studies of vasopressors. In the present study, ephedrine had no significant effect on placental circulation whereas QUA decreased after prolonged administration of phenylephrine. This may reflect the passage of phenylephrine through the placenta and its direct effect on the umbilicoplacental circulation. Previously, phenylephrine has been shown to induce concentration-dependent contractions in human umbilical artery in vitro.17
Placental vascular resistance comprises the vascular resistances across the umbilical arteries, umbilical veins and the cotyledons, corresponding at rest to 30, 15, and 55% of the total resistance.18 PIUA is determined by the ratio of total placental resistance to umbilical artery resistance.19 It has been shown in fetal sheep that PIUA does not reveal changes in vascular resistance mediated by umbilical arterial vasoconstriction caused by angiotensin II infusion but reflects increases in resistance of the cotyledons caused by placental embolization.20 An exponential increase in PIUA is obtained only after more than 60% of the terminal vascular branches are obliterated.19 Likewise, increasing the peripheral resistance of the uterine vascular bed in a computer model caused a marked increase in PIUtA, and although a decrease in uterine artery radius also increased PIUtA, the effect was accentuated when the resistance of the distal vascular bed was high.21 In the present study, PIUtA and PIUA were compared with continuously monitored volume blood flows and vascular resistances. Our results suggest that PIUtA and PIUA may not directly reflect changes in vascular resistance caused by vasopressors or volume expansion, as discussed earlier.20 22
I.V. volume loading is used in human pregnancies to reduce the incidence and severity of maternal hypotension caused by regional anaesthesia.1 Recent clinical studies on humans showed no beneficial effect of a crystalloid bolus on the incidence of hypotension or total requirements of ephedrine23 or metaraminol.24 However, uteroplacental perfusion was not monitored in these studies. In a chronic sheep preparation, 500 ml of HES increased CO and QUtA significantly.25 In the present study, 500 ml of HES was infused after 30 min of vasopressor therapy. We observed a significant decrease in RUtA in each vasopressor group. Thus, volume expansion with 500 ml of HES had a similar favourable effect on uteroplacental perfusion irrespective of the vasopressor used.
We found no significant differences in fetal blood gases or lactate concentrations between the groups. This contradicts the findings of clinical studies on Caesarean delivery under spinal anaesthesia suggesting higher umbilical cord pH values with -agonists than with ephedrine.1012 Furthermore, Cooper and co-workers showed that the incidence of fetal acidosis, defined as umbilical artery pH less than 7.20, was significantly higher with ephedrine than with phenylephrine after elective Caesarean section at term gestation.13 Combination of both drugs allowed a marked reduction in the dose of ephedrine, resulting in lower incidence of acidosis.13 In the present study, the amount of ephedrine given over 75 min was similar to doses administered in clinical studies10 11 13 within 30 min. Thus, the dose of ephedrine per minute was relatively low compared with that used in humans. In addition, the concentrations of vasopressor solutions we chose on the basis of clinical experience8 26 were not equipotent in sheep under combined general and epidural anaesthesia. The mean total volume of ephedrine given was significantly lower than that of phenylephrine. However, the dose of phenylephrine per minute was comparable with that used clinically.13 These divergencies in vasopressor requirement may partly explain why no pH differences were observed even after prolonged exposure to vasopressors. Furthermore, the present study was performed in near term fetuses. Cooper and colleagues proposed that increased fetal metabolic rate secondary to ß-adrenergic stimulation is the mechanism for lower pH values with ephedrine.13 A progressive increase in fetal pressor response to ephedrine has been demonstrated in fetal sheep, suggesting enhanced release of noradrenaline with advancing gestation.27 Term fetuses may thus be more sensitive to ephedrine as regards the development of fetal acidaemia.
In summary, ephedrine had more favourable effects on uterine and placental circulations than phenylephrine. However, no significant differences in fetal acidbase status or lactate concentrations were observed.
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Acknowledgments |
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Footnotes |
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References |
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