Survival analysis curves are shown in Figure 3. Cumulative survival (proportion of patients who did not become hypotensive) over time until delivery was greater in the 30-mg group compared with the control group (P < 0.0001), but there was no difference for the 10-mg group versus the control group (P = 0.3) or the 20-mg group versus the control group (P = 0.09).
The incidences of hypotension, hypertension, and nausea or vomiting, the lowest and highest recorded SAP, and the supplementary and total ephedrine requirements are summarized in Table 2. The incidence of hypotension was different among groups (P < 0.0001) and was smallest in the 30-mg group. The lowest recorded SAP, as a percentage of baseline, was different among groups (P < 0.0001); this value was greater in the 30-mg group compared with the 20-mg group (P = 0.002), the 10-mg group (P = 0.002), and the control group (P < 0.0001). There was no difference between other groups. The incidence of hypertension was different among groups (P = 0.009) and was greatest in the 30-mg group. The highest recorded SAP, as a percentage of baseline, was different among groups (P = 0.04); this value was greater in the 30-mg group compared with the control group (P = 0.03). There was no difference among other groups.
The number of patients who had nausea or vomiting was similar among groups. Supplementary ephedrine requirement was different among groups (P = 0.008) and was smallest in the 30-mg group. There was no difference in the total ephedrine requirement among groups.
Analysis of neonatal data showed no differences among groups (Table 3). No Apgar scores were below 7 at 1 min or 5 min and umbilical arterial and venous blood gases were similar among groups. There was no difference among groups in the proportion of patients with umbilical arterial pH < 7.2. Analysis of umbilical cord blood gases from patients who had one or more episodes of hypotension showed that arterial pH was lower (mean 7.21 [95% confidence interval 7.18–7.24] vs 7.28 [7.25–7.31]) and venous pH was lower (mean 7.27 [95% confidence interval 7.25 - 7.29] vs 7.33 [7.31–7.35]) compared with patients who did not have hypotension. There was no difference in umbilical cord blood gases in patients who had one or more episodes of hypertension compared with patients who did not have hypertension.
CTG tracings could only be interpreted in 53 cases because of technical difficulties. All tracings were normal before the induction of anesthesia. Seven tracings (13%) were judged to be abnormal after the induction of anesthesia and injection of ephedrine because of increased fetal heart rate (2 of 10 in the control group, 2 of 16 in the 10-mg group, 1 of 13 in the 20-mg group, and 2 of 14 in the 30-mg group). The proportion of abnormal CTG tracings was similar among groups. The mean (sd) total ephedrine dose was greater in patients with abnormal CTG tracings (60.0 [25.2] mg) compared with patients with normal tracings (34.6 [20.0] mg;P = 0.004).
Protocols that aim to prevent hypotension during spinal anesthesia for cesarean delivery may result in better outcomes than those designed to treat hypotension after it has occurred. This was demonstrated by Datta et al. (7), who compared patients who were given IV ephedrine 10–30 mg as soon as any decrease in arterial pressure was detected with patients in whom treatment with IV boluses of ephedrine 10 mg was withheld until hypotension occurred. They found that patients who received early administration of ephedrine had less nausea and vomiting and better neonatal acid-base status. Simple methods of preventing hypotension, such as IV preload and left lateral uterine displacement, have generally not been effective alone; thus, prophylactic ephedrine has been considered (1). IM ephedrine has been recommended (1), but this has not been consistently effective (2). Furthermore, absorption of IM ephedrine is unpredictable, it may be difficult to predict the peak effect, and reactive hypertension may be a problem, particularly if spinal anesthesia is unsuccessful (3). In comparison, the advantages of IV administration include the ability to withhold drug administration until after the onset of anesthesia is confirmed and better timing of drug effect to the onset of sympathetic block.
We found that, to reduce the incidence of hypotension during spinal anesthesia for cesarean delivery by using IV ephedrine, a bolus dose of 30 mg was required. This is consistent with the findings of previous studies in which smaller doses were not effective (4,5). Although the incidence of hypotension was reduced to 35% in patients who received ephedrine 30 mg compared with the control rate of 95%, this was at the expense of an increased incidence of hypertension, which occurred in 45% of the patients. Therefore, this technique may not be suitable in some patients, for example those with cardiovascular or cerebrovascular disease. It would be of interest to determine whether different timing of the bolus, injection over a longer period of time, or injection in divided doses would reduce the incidences of hypotension and hypertension.
In our study, patients were given “rescue” ephedrine as soon as hypotension occurred, and the total dose of ephedrine given was similar among groups. Because this caused the SAP in hypotensive patients to return toward baseline, it is a confounding factor in the repeated measures analysis, with the tendency to reduce the likelihood of finding a difference between doses. This explains the convergence of SAP measurements in the latter part of the recording period. Despite this, there was a difference in the effects of dose and dose × time, and the study design is appropriate because it reflects normal practice. We found no difference in heart rate among groups, despite a large difference in the initial dose of ephedrine. This could be explained by both by the effect of “rescue” ephedrine and by baroreceptor-mediated reflex increases in heart rate in patients who became hypotensive.
The dose of bupivacaine we used is at the lower end of the range used by others. Our clinical practice is normally to use small doses because of the smaller stature of Asian women compared with Western women. The median upper level of the blocks and the incidence of hypotension in our study are comparable to that seen in other studies, and therefore, our results are comparable. We added fentanyl 15 μg to the intrathecal local anesthetic, which is our usual practice to improve surgical anesthesia. Previously, it was suggested that this dose of fentanyl increased the speed of onset of sympathetic block (8). This complicates comparison of our results with studies in which intrathecal local anesthetic alone was used.
Although SAP was maintained better in patients who received ephedrine 30 mg compared with the other groups, this was not reflected in a difference in neonatal outcome. In particular, there was no difference in the incidence of fetal acidosis, defined as umbilical arterial pH < 7.2, despite a difference in the incidence of hypotension. Previous studies have shown that the use of ephedrine to prevent or treat hypotension associated with spinal and epidural anesthesia for cesarean delivery may not correct fetal acidosis and may even increase it, especially if hypotension still occurs (2,9–11). Furthermore, comparative studies have suggested that the use of ephedrine may be associated with greater fetal acidosis compared with phenylephrine (12–14) and angiotensin II (15). These data suggest that, contrary to common practice, ephedrine may not be the ideal drug for managing hypotension in the obstetric patient. Of interest, we found that umbilical arterial and venous pH values were lower in patients who had hypotension compared with patients who did not, whereas hypertension was not associated with adverse effects. Although we did not measure uteroplacental flow, our results suggest that, within the range of doses used in our study, the potential vasoconstrictive effects of ephedrine may have a less detrimental effect on uteroplacental blood flow than the effects of hypotension. Fetal tachycardia was recorded in 13% of the cases. This appeared to be dose-related, because the mean total ephedrine dose was greater in patients with abnormal CTG tracings compared with patients with normal tracings. Hughes et al. (10) showed that ephedrine readily crosses the placenta, with an umbilical vein:maternal artery ratio of 0.71. However, despite causing increases in fetal heart rate and variability, these changes have not been considered harmful (10,16).
All of our patients received a crystalloid preload of 20 mL/kg. The efficacy of crystalloid preload has been questioned (17,18), and there are advocates for abandoning its use (18). Because ephedrine is predominantly a β agonist and exerts its effects mainly by increasing cardiac output, which is dependant on adequate venous return, it may not be valid to extrapolate our finding to patients who do not receive IV fluid before the induction of spinal anesthesia.
In conclusion, we have found that, in patients having spinal anesthesia for cesarean delivery after IV crystalloid preload, the minimum effective dose of IV ephedrine given one minute after the spinal injection to reduce the incidence of hypotension was 30 mg. However, this dose did not completely eliminate hypotension, nausea and vomiting, or fetal acidosis, and it caused reactive hypertension in some patients. Further investigation of other methods of reducing the incidence of hypotension during spinal anesthesia for cesarean delivery is indicated.
The authors wish to thank the nurses of the Labor ward, Prince of Wales Hospital, for their cooperation during this study.
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© 2000 International Anesthesia Research Society
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