Spinal anaesthesia remains popular for elective Caesarean section as it provides rapid, reliable profound sensory and motor block. Maternal hypotension is a recognized common complication, with a varied reported incidence of 8-70% [1,2]. This variation is partly due to a lack of consensus on the definition of hypotension used, and differing anaesthesia techniques. The dose of intrathecal local anaesthetic, and to a lesser extent the co-administration of intrathecal opioid , appear to play a key role on the incidence of hypotension. This, in addition to techniques of prophylaxis, can have a substantial effect on incidence, severity and duration of hypotension. Maternal hypotension has been shown to produce adverse effects on the neonatal acid-base status through placental hypoperfusion, and can lead to unpleasant maternal symptoms .
Ephedrine has been successfully used in a prophylactic manner as an intravenous (i.v.) infusion , intramuscularly (i.m.) , and as an i.v. bolus  to reduce the incidence of maternal hypotension. In a prospective randomized double blind study, we examined the effects of two different doses of ephedrine given as a prophylactic i.v. bolus compared with a control group on the incidence of hypotension following spinal anaesthesia for Caesarean delivery.
Following hospital Ethics Committee approval and informed patient consent, we studied 68 term and peri-term patients presenting for elective Caesarean section. Exclusion criteria included patients with moderate to severe pre-eclampsia, a history of essential hypertension, or those with a contraindication to spinal anaesthesia.
Patients were premedicated with oral ranitidine 150 mg and 30 mL sodium citrate. Baseline measurements of systolic arterial pressure, using a cuff on the right arm, and heart rate (HR) were recorded in the operating room. Patients did not wear thromboembolic stockings during the study. After an i.v. preload of compound sodium lactate 500 mL over 10 min, the patients received an intrathecal injection of hyperbaric bupivacaine, 2.5 mL 0.5%, combined with fentanyl 25 μg via a 25 G pencil point needle at the L 3/4 in the sitting position. Patients received the study drug simultaneously with the intrathecal injection. The patients were then placed supine with a 15° left-lateral tilt and given 40% oxygen to breathe through a facemask.
Patients were randomized to receive a bolus of 0.9% saline i.v. (Group C), ephedrine 6 mg (Group E-6) or ephedrine 12 mg (Group E-12) in 2 mL of solution pre-prepared by the hospital pharmacy in coded syringes. Randomization was performed by computer-generated random number allocation. All observers were blinded to the study solution. The height of block was recorded as the highest dermatome with loss of fine pinprick sensation prior to incision, and time to incision and delivery were noted. Systolic arterial pressure was recorded every 2 min. Patients were asked to report any symptoms of nausea or vomiting.
Maternal hypotension was defined as a reduction in systolic arterial pressure greater than 30% from baseline, or a reading below 90 mmHg. Further rescue boluses of ephedrine 6 mg were given if hypotension occurred, or if symptoms suggestive of hypotension were reported, without waiting for a recorded fall of arterial pressure. Additional doses of ephedrine were given based on clinical response. All patients received oxytocin 10 units following delivery. Umbilical venous and arterial blood was sampled, and Apgar scores noted at 1-5 min.
An estimate of the sample size required was made using Altman's nomogram method . Maternal hypotension was the main parameter of interest. A 75% incidence of hypotension in the control group was anticipated based on observed practice at our hospital. The individual group size of at least n = 20 was designed to have an 80% probability of detecting a reduction in the incidence of hypotension in either study group of greater than 50%. P < 0.05 was considered significant. One-way analysis of variance was used to compare parametric data. Comparison of proportions using continuity correction was used for frequency data. Confidence intervals provided estimates of quantities of interest.
All groups were comparable in terms of age, weight, height, sensory block height achieved, and induction to delivery time (Table 1). One twin pregnancy was included in Group C. There were four pre-term pregnancies, two in Group E-12 and one each in Groups E-6 and C. One patient in Group E-6 and one in E-12 were post-term. The administration of spinal anaesthesia was uneventful in all patients. One patient in Group C was excluded because an infusion of ephedrine was administered following the spinal injection, and another because of administration of i.v. fentanyl to supplement analgesia.
There was a significantly higher incidence of hypotension in Group C compared with Group E-12 (60% vs. 27.3%, P < 0.05, 95% C.I. 6-60%), but not Group E-6 (Table 2). Less rescue doses of ephedrine were required in Group E-12 compared with the control group (1.8 ± 1.2 vs. 3.3 ± 2.1, P < 0.05) although total mean doses in all three groups were similar when the prophylactic dose was included. The duration of maternal hypotensive episodes was brief in all groups (<4 min). There were no significant differences between groups in the mean lowest and mean highest systolic arterial pressure. No differences were found between groups with regard to mean highest HR. However, the mean lowest maternal HR recorded was significantly lower in Group E-6 compared with Group C (77 ± 10.4 vs. 87 ± 16.2), with no difference in baseline readings. Rebound hypertension was not observed in the groups receiving prophylactic ephedrine with no significant difference in mean systolic arterial pressure at each time point (Fig. 1). Only one patient in Group E-12 was observed to have a rise in systolic arterial pressure above baseline (peak systolic arterial pressure 16% above baseline). One patient in Group E-12 complained of a transient headache that was not associated with a rise in systolic arterial pressure from baseline.
There were no significant differences in the incidence of maternal symptoms of nausea or vomiting. In nine patients ephedrine was administered because of nausea without any evidence of hypotension (four in Group E-12, three in Group E-6 and two in Group C). Six of the 12 patients in the control group who became hypotensive had no nausea, whereas this occurred in one of the six in Group E-12. No differences were observed in the occurrence of neonatal acidaemia between groups (Table 3). One neonate in Group E-12 had an Apgar score of < 7 at 5 min with a birth weight of 1.8 kg. One full term neonate in Group E-12 had a cord arterial pH of 6.8 with normal Apgar scores.
This study demonstrates that a prophylactic bolus dose of ephedrine 12 mg i.v. reduces the incidence of hypotension during elective Caesarean delivery during spinal anaesthesia. Although non-invasive systemic vascular resistance index has been shown to predict risk for maternal hypotension following regional anaesthesia , a reliable and easily reproducible method is not available. Earlier studies that addressed the problem of hypotension following subarachnoid block in the obstetric population concentrated largely on the type and volume of fluid preload or 'volume prophylaxis'. It is apparent that the effects of rapid vasodilatation due to sympathetic blockade cannot be alleviated using volume alone in a large proportion of patients. Conflicting results and non-reproducible data have now led many obstetric anaesthesiologists to abandon routine volume prophylactic measures [9,10]. We administered low volumes of crystalloid in this study. However, even higher volumes of crystalloid solution (1500 mL lactated Ringer's solution) can have a limited effect on intravascular volume, cardiac output, and incidence of hypotension . In a recent review, Morgan and colleagues  reported that studies using crystalloid prophylaxis had a variable effect on maternal hypotension, with colloid prophylaxis proving to be more consistently efficacious but at additional risks and cost.
The ideal prophylactic sympathomimetic drug has not been identified, but ephedrine appears to be the most commonly used. Phenylephrine has been found to have equivalent or lower  clinical efficacy to ephedrine, although a high incidence of bradycardia led to use of rescue anticholinergics in one study . Alahuhta and colleagues found that phenylephrine increased the uteroplacental vascular resistance and modified the fetal circulation whereas ephedrine did not . Angiotensin II has been successfully used to prevent maternal hypotension , and in one study with less fetal acidosis than patients given ephedrine, possibly due to a lesser effect on uterine vasoconstriction .
Previous studies have found that ephedrine given in prophylactic fashion as an i.v. infusion, an i.m. injection or an i.v. bolus reduced the incidence and severity of hypotension [5,6]. Intramuscular ephedrine is less satisfactory due to unpredictable absorption, and the occurrence of hypertension, particularly when a delay in instituting subarachnoid block occurs . The bolus method was chosen over i.v. infusion in this study to provide a fast and reliable early prophylactic dose of vasopressor as the rapid sympathetic blockade was occurring. The bolus doses were chosen on the basis of our clinical impression that more than 12 mg might cause unacceptable hypertension. It is reassuring to find in our study that when a relatively large bolus of ephedrine (12 mg i.v.) was given immediately following spinal anaesthesia, rebound hypertension and tachycardia did not occur. In fact, the mean lowest HR was lower in patients receiving ephedrine 6 mg compared to control. Webb and Shipton  found that i.m. ephedrine 37.5 mg was not associated with a statistically significant reactive hypertension. Future intravenous bolus dosing studies may use more than 12 mg, but the effects on uteroplacental circulation and maternal symptoms will need careful attention.
Vercauteren and colleagues  recently reported the efficacy of prophylactic ephedrine 5 mg i.v. during small dose spinal anaesthesia, although a lower dose of intrathecal bupivacaine (6.6 mg) was used compared with our study (12.5 mg), in addition to generous volume prophylaxis (1000 mL lactated Ringer's solution plus 50 mL hydroxyethyl starch solution 6%). However, King and Rosen failed to find any clinical efficacy of ephedrine 10 mg i.v., compared to controls, in prehydrated patients receiving bupivacaine 12 mg with fentany 10 μg . The reduction in the incidence of hypotension with the 6 mg ephedrine bolus in our investigation was not statistically significant for the number of patients studied. Comparison of dose efficacy between studies is difficult when techniques of spinal anaesthesia, volume prophylaxis and definition of hypotension differ. The dose efficacy of prophylaxis with ephedrine may vary depending on the dose of intrathecal agents and volume prophylaxis given. The addition of an intrathecal injection of fentanyl or sufentanil permits a lower dose of bupivacaine (5-8 mg) to be given [2,21,22], and results in less hypotension when compared with bupivacaine alone . However, the addition of fentanyl, without reducing the bupivacaine dose, results in a higher incidence of hypotension .
Nausea and vomiting during spinal anaesthesia for Caesarean section can be due in part to systemic hypotension. Ephedrine pre-treatment has recently been demonstrated to lower the incidence of maternal nausea . We did not detect a lower incidence of maternal nausea in the ephedrine prophylaxis groups. Factors such as intrathecal lipophilic opioid dose may have affected our findings. Also, although the incidence differed, the severity and duration of maternal hypotensive episodes were not different between groups.
We did not detect a difference in parameters of neonatal well-being in this study. Our assessment tools (Apgar and umbilical pH) were unlikely to have detected an effect on neonatal outcome given the study size and protocol, which included prompt treatment of episodes of maternal hypotension. Reduced placental perfusion pressure through maternal hypotension has previously been shown to have an adverse effect on neonatal acid-base status . Placental transfer of ephedrine can lead to elevated neonatal catecholamine concentrations, but does not seem to affect neonatal outcome [23,24]. Other investigators have been concerned with potential adverse effects of prophylactic ephedrine on uteroplacental perfusion and neonatal acid-base status. In the study by Rolbin and colleagues , lower neonatal cord pH was associated with prophylactic ephedrine 50 mg i.m. which also caused persistent hypertension. Shearer and colleagues  confirmed lower cord pH following prophylactic ephedrine 10 mg i.v. However, the regional anaesthesia technique was not standardized with epidural, spinal and combined techniques in both groups, and the control group patients received significantly more fluid per body weight. Our study was not restricted to term pregnancies although the vast majority of neonates were at term. The neonates with low Apgar scores all had a low birth weight. Future studies on the neonatal effects of prophylactic ephedrine may focus on pre-term neonates or complicated pregnancies.
In conclusion we have found that following spinal anaesthesia for elective Caesarean section, a prophylactic bolus of ephedrine 12 mg i.v. is safe and efficacious in reducing the incidence of maternal hypotension compared to i.v. rescue boluses alone. Consensus regarding the definition of maternal hypotension would be useful for future studies concerning the dose efficacy and benefits of ephedrine prophylaxis.
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