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A Dose-Response Study of Prophylactic Intravenous Ephedrine for the Prevention of Hypotension During Spinal Anesthesia for Cesarean Delivery

Kee, Warwick D. Ngan MBChB, MD, FANZCA*; Khaw, Kim S. MBBS, FRCA*; Lee, Bee B. MBBS, FANZCA*; Lau, Tze K. MBBS, MRCOG; Gin, Tony MBChB, MD, FANZCA, FRCA*

doi: 10.1097/00000539-200006000-00024
Obstetric Anesthesia

We performed a randomized, double-blinded dose-finding study of IV ephedrine for prophylaxis for hypotension in 80 women who received an IV crystalloid preload and spinal anesthesia for elective cesarean delivery. One minute after the intrathecal injection, patients were given saline control or ephedrine 10, 20, or 30 mg IV for 30 s. Systolic arterial pressure (SAP) in the first 12 min after the spinal injection was greater in the 30-mg group compared with other groups (P < 0.05). Hypotension occurred in 7 patients (35%) in the 30-mg group compared with 19 (95%), 17 (85%), and 16 (80%) patients in the control and 10- and 20-mg groups, respectively (P < 0.0001). Maximum decrease in SAP was smaller in the 30-mg group (mean lowest SAP 87% of baseline, range 58%–105%) compared with other groups (P < 0.01). Reactive hypertension occurred in 9 patients (45%) in the 30-mg group (mean highest SAP 120% of baseline, range 104%–143%) compared with 2 (10%), 1 (5%), and 5 (25%) patients in the other groups (P = 0.009). Heart rate changes, total ephedrine requirement, incidence of nausea and vomiting, and neonatal outcome were similar among groups. The proportion of patients with umbilical arterial pH < 7.2 was 10.5%, 25%, 42%, and 22% in the control, 10-, 20-, and 30-mg groups, respectively (P = 0.12). We conclude that the smallest effective dose of ephedrine to reduce the incidence of hypotension was 30 mg. However, this dose did not completely eliminate hypotension, nausea and vomiting, and fetal acidosis, and it caused reactive hypertension in some patients.

Implications We investigated different doses of IV ephedrine as prophylaxis for hypotension during spinal anesthesia for cesarean delivery and found that the smallest effective dose was 30 mg. However, this dose did not completely eliminate hypotension, caused reactive hypertension in some patients, and did not improve neonatal outcome.

Departments of *Anaesthesia and Intensive Care and †Obstetrics and Gynaecology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China

February 7, 2000.

Address correspondence to Dr. Ngan Kee, Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.

Presented in part at the Australian and New Zealand College of Anaesthetists Annual Scientific Meeting, Adelaide, Australia, May 1999.

Hypotension is the most common serious adverse effect of spinal anesthesia for cesarean delivery. Because it may have detrimental maternal and neonatal effects, a number of strategies for preventing hypotension have been investigated. The use of lateral uterine displacement is routine. Other strategies have included the use of IV fluid preload, gravity (Trendelenburg or leg raising), compression devices on the legs, and prophylactic vasopressors. However, no method has proved entirely satisfactory. Of the available vasopressors, ephedrine is most commonly used. IM ephedrine has been described, but its efficacy has been inconsistent (1,2), and its use may be associated with unacceptable hypertension, particularly if spinal anesthesia is unsuccessful (3). As an alternative, IV ephedrine given immediately after the induction of spinal anesthesia has been described (4,5). However, doses of 10–20 mg and 0.25 mg/kg were not effective in reducing the incidence of hypotension (4,5), and the efficacy of larger doses has not been investigated. Therefore, we designed a randomized, double-blinded study to determine the efficacy and optimum dose of IV ephedrine for prevention of hypotension during spinal anesthesia for cesarean delivery.

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Methods

After obtaining approval from the local Clinical Research Ethics Committee, we recruited 80 ASA physical status I and II Asian women with term singleton pregnancies having elective cesarean delivery under spinal anesthesia. Prospective power analysis showed that a sample size of 20 patients per group would have 80% power at the 5% significance level to detect a difference of 50% in the incidence of hypotension in groups compared with control, assuming a baseline incidence of 85%, as reported in a published study of a similar patient group (4). All patients gave written, informed consent. Patients with preexisting or pregnancy-induced hypertension, known cardiovascular or cerebrovascular disease, or contraindications to spinal anesthesia were excluded.

Patients were premedicated with ranitidine 150 mg orally the night before and on the morning of surgery and 0.3 M sodium citrate 30 mL on arrival to the operating theater. Standard monitoring included noninvasive arterial pressure, electrocardiogram, and pulse oximetry. Fetal heart rate was monitored by using cardiotocography (CTG) before, during, and immediately after the administration of spinal anesthesia. Baseline arterial pressure and heart rate were calculated as the mean of three successive measurements, 1 min apart. A large-bore IV catheter was then inserted into a forearm vein and IV preload of 20 mL/kg lactated Ringer’s solution was given for 10–15 min, after which the IV infusion was slowed to the minimum rate required to maintain vein patency. Spinal anesthesia was administered with the patient in the right lateral position. After skin infiltration with lidocaine, a 25-gauge Whitacre needle was inserted at the L2-3 or L3-4 vertebral interspace and hyperbaric 0.5% bupivacaine 2.0 mL and fentanyl 15 μg was injected intrathecally. The patient was then immediately turned supine with left lateral tilt. Oxygen 4 L/min was given by clear face mask until delivery.

One minute after the spinal injection, the onset of spinal anesthesia was confirmed by asking the patient to subjectively verify numbness of the legs; then, saline control or ephedrine 10, 20, or 30 mg was injected IV. Each dose was diluted to 10 mL with saline and injected for 30 s. Randomization was performed by the drawing of coded, opaque, shuffled envelopes, and the study dose was prepared by an anesthesiologist not involved with patient assessments. Arterial pressure and heart rate were recorded at 1-min intervals until delivery. Hypotension, defined as a decrease in systolic arterial pressure (SAP) more than 20% below baseline and to below 100 mm Hg (6), was treated by using IV boluses of ephedrine 10 mg every minute as required. Reactive hypertension was defined as an increase in SAP of more than 20% above baseline. The supplementary and total doses of ephedrine required before delivery and any instances of nausea or vomiting were recorded. Ten minutes after the spinal injection, the upper sensory level of anesthesia was measured by assessing loss of pinprick discrimination. Preparation and surgery were then allowed to start. Times from skin incision to delivery and from uterine incision to delivery were recorded by using a stopwatch. After delivery, Apgar scores were assessed at 1 and 5 min by the attending pediatrician, and arterial and venous blood samples were taken from a double-clamped segment of umbilical cord for blood-gas analysis. The CTG recording was collected for subsequent assessment by an obstetrician (TKL) who was blinded to the patients’ groups.

Intergroup comparisons were made by using analysis of variance for parametric data and the Kruskal-Wallis test for nonparametric data. Proportional data were compared by using the χ2 test. For hemodynamic analysis, we used data up to the time when the first patient underwent skin incision. Sequential measurements of SAP and heart rate were tested for the effects of time, dose, and dose × time by using analysis of variance for repeated measures. The Bonferroni-Dunn procedure was used for post hoc pairwise comparisons, with appropriate adjustments in P values. The effect of different doses on the incidence and timing of hypotension was analyzed by using actuarial survival analysis. A life table was constructed showing the cumulative proportion of patients remaining not hypotensive over time until delivery. Hypotension, requiring treatment with further ephedrine according to the predefined criteria, was defined as the observed event. Observations were considered censored if patients progressed to delivery without an episode of hypotension. The survival pattern among groups was compared by using the Breslow-Gehan-Wilcoxon test. Values of P < 0.05 were considered statistically significant.

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Results

All patients completed the study. Patient characteristics and surgical times were similar among groups (Table 1). The mean time from spinal injection to skin incision was 20 min with a range of 12–33 min. Delivery was difficult in one patient in the 30-mg group, with a uterine incision to delivery time of greater than 5 min. There were no other operative complications. Umbilical cord blood samples were incomplete (arterial, venous, or both not obtainable) in two patients in the control group, two patients in the 20-mg group, and two patients in the 30-mg group. Maternal heart rate data from one patient in the 10-mg group were lost because of technical reasons.

Table 1

Table 1

Changes in SAP in the first 12 min after the spinal injection are shown in Figure 1. Analysis showed that changes in SAP were significantly influenced by time (P < 0.0001), dose of ephedrine (P = 0.002), and the combined effect of dose and time (dose × time;P < 0.0001). Post hoc tests showed that the effect of dose was significant for the 30-mg group compared with the 20-mg group (P = 0.04), the 10-mg group (P = 0.005), and the control group (P = 0.01), but there were no differences among other groups. Changes in heart rate in the first 12 min after the spinal injection are shown in Figure 2. Analysis showed that changes in heart rate were significantly influenced by time (P < 0.0001) but not by dose of ephedrine (P = 0.5) or the combined effect of dose and time (dose × time;P = 0.9).

Figure 1

Figure 1

Figure 2

Figure 2

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).

Figure 3

Figure 3

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.

Table 2

Table 2

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.

Table 3

Table 3

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).

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Discussion

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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