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© 2001 International Anesthesia Research Society
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Abstract |
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We randomly allocated women having elective cesarean delivery to receive either no bolus (Control Group, n = 31) or 20 mL/kg lactated Ringer’s solution (Bolus Group, n = 35) IV before spinal anesthesia. An infusion of metaraminol started at 0.25 mg/min was titrated to maintain systolic arterial blood pressure in the target range 90%–100% of baseline. The total dose of metaraminol required up to the time of uterine incision was similar between the Control Group and the Bolus Group (3.62 ± 1.20 vs 3.27 ± 1.39 mg, P = 0.3). However, the Control Group required more metaraminol in the first 5 min (1.29 ± 0.60 vs 0.96 ± 0.58 mg, P = 0.025) and a faster maximum infusion rate (0.45 ± 0.20 vs 0.32 ± 0.13 mg/min, P = 0.002) compared with the Bolus Group. There was no difference between groups in regards to changes in systolic arterial blood pressure or heart rate over time, or maternal or neonatal outcome. We conclude that when metaraminol is used to maintain arterial pressure during spinal anesthesia for cesarean delivery, crystalloid bolus is not essential provided that sufficient vasopressor is given in the immediate postspinal period.
IMPLICATIONS: In patients receiving spinal anesthesia for elective cesarean delivery, when arterial pressure was maintained using an IV infusion of metaraminol, crystalloid bolus reduced the early vasopressor requirement but had no effect on overall vasopressor requirement or maternal or neonatal outcome.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Hypotension remains the most common complication associated with spinal anesthesia for cesarean delivery (1). Common strategies used to prevent or reduce the incidence and severity of hypotension include the use of lateral uterine displacement, IV fluid bolus, and the use of vasopressors. Lateral uterine displacement is considered routine and mandatory. Crystalloid bolus, although advocated for many years, has now come under question by studies that have shown no (2,3) or only a small (4) beneficial effect on the incidence of hypotension and vasopressor requirements. However, many practitioners have continued to advocate the use of bolus (5,6). Of the available vasopressors, ephedrine has been most commonly used but evidence supports the use of
agonists, which have been associated with superior umbilical acid-base status compared with ephedrine (7–9).
Recently, we investigated the use of the potent agonist metaraminol for maintaining arterial blood pressure in women undergoing elective cesarean delivery under spinal anesthesia (10). We found that systolic arterial pressure could be readily maintained in the target range of 90%–100% of baseline using a titrated infusion of metaraminol. The neonatal outcome in patients who received metaraminol was excellent, as evidenced by no cases of fetal acidosis, which we defined as umbilical arterial pH <7.2, and was significantly better compared with patients who received infusion of ephedrine. However, all patients in that study were hydrated with 20 mL/kg lactated Ringer’s solution before induction of anesthesia. Similarly, the previous studies that have demonstrated the safety and efficacy of phenylephrine in obstetrics have also been performed in patients who received crystalloid bolus. Thus, the safety of infusions of agonists in patients who have not received IV bolus has not been established. Specifically, it is possible that when bolus is not given, a larger total dose of vasopressor may be required; this could potentially increase the risk of uteroplacental vasoconstriction and fetal acidosis.
Therefore, we designed this prospective randomized study of patients receiving spinal anesthesia for cesarean delivery during which arterial pressure was maintained using an infusion of metaraminol. The objective was to compare patients who received IV crystalloid bolus with a control group who received no bolus. The primary end point we evaluated was the total dose of metaraminol required up to the time of delivery. Secondary end points that we evaluated included changes in metaraminol requirement over time and at different time intervals, maternal hemodynamic changes, and neonatal outcome assessed clinically and biochemically.
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Methods |
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After obtaining approval from the Clinical Research Ethics Committee of the Chinese University of Hong Kong, we consecutively recruited 70 ASA physical status I–II women with term singleton pregnancies having elective cesarean delivery under spinal anesthesia. Prospective power analysis was based on data from previous studies from our department of patients who had spinal anesthesia for cesarean delivery. This indicated that a sample size of 33 patients per group would have 80% power at the 5% significance level to detect a 20% difference in the total metaraminol requirement between groups. To allow for a potential 5% dropout rate, we decided to recruit 35 patients per group. All patients gave written informed consent. Patients with preexisting or pregnancy-induced hypertension, cardiovascular or cerebrovascular disease, known fetal abnormalities, 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 room. Standard monitoring included noninvasive arterial blood pressure measurement, electrocardiography, and pulse oximetry. Fetal heart rate was monitored by external cardiotocography until the time of surgical preparation. Baseline systolic arterial blood pressure (SAP) and heart rate (HR) were calculated as the mean of three successive measurements 1 min apart after a brief settling period. A wide-bore IV catheter was then inserted under local anesthesia. Patients were then randomly allocated to one of two groups by drawing of sequentially numbered sealed envelopes that each contained a computer-generated randomization code. Patients in the Control Group received no bolus; patients in the Bolus Group were given 20 mL/kg lactated Ringer’s solution over 15 min. Fluid administration was supervised by a research nurse who was not involved with subsequent patient assessments. To maintain blinding, the anesthesiologists and other investigators remained outside the operating room during the bolus period. We did not attempt to blind the patients.
Spinal anesthesia was induced with all patients 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. Patients were then immediately turned supine with left lateral tilt. Oxygen 5 L/min was given by clear face mask until delivery. Arterial pressure was measured at 1-min intervals beginning 1 min after spinal injection. Hemodynamic data were downloaded to a Macintosh computer (Apple, Cupertino, CA) from the anesthetic machine using software developed within our department.
After induction of spinal anesthesia, all patients received an IV infusion of lactated Ringer’s solution at 2 mL/min using a peristaltic infusion pump (IVAC 531; IVAC Corporation, San Diego, CA) to maintain vein patency. No other IV fluid was given before delivery. Arterial pressure was maintained with an IV infusion of metaraminol 0.5 mg/mL using a syringe pump (Terfusion STC-527; Terumo Corporation, Tokyo, Japan) that was connected to the IV line via a three-way stopcock. The metaraminol infusion was titrated based on a protocol we have used in a previous investigation (10). Our target was to maintain arterial pressure within the range 90%–100% of baseline. Metaraminol was started when SAP decreased to <90% of the baseline value; an initial bolus of 0.5 mg (1 mL) was given and the infusion was started at 0.25 mg/min (0.5 mL/min) and adjusted after each 1 min measurement of arterial pressure. If SAP decreased to <80% of the baseline value, the infusion was increased to 0.5 mg/min (1 mL/min); if SAP decreased to <70% of the baseline value, the infusion was increased to 0.75 mg/min (1.5 mL/min); if SAP increased above the baseline value, the infusion was stopped and restarted if the SAP decreased to below 90% of the baseline value again. The rate of metaraminol infusion was recorded each minute and the cumulative consumption of metaraminol was recorded 5 min and 10 min after spinal injection and at the time of uterine incision. Nausea and vomiting not associated with hypotension were treated with IV metoclopramide 10 mg.
After 10 min, the upper sensory level of anesthesia was measured by assessing loss of pinprick discrimination and preparation and surgery were allowed to start. The times of skin incision, uterine incision, and delivery were recorded by stopwatch. After delivery, oxytocin 10 IU was given IV. Further management of the patients, including fluid and vasopressor therapy, was then at the discretion of the attending anesthesiologist. Apgar scores of the infants were assessed at 1 min and 5 min by the attending pediatrician, and arterial and venous blood samples were taken from a double-clamped segment of umbilical cord for immediate blood gas analysis using a Ciba-Corning 278 Blood Gas System blood gas analyzer (Ciba-Corning, Medfield, MA).
Data were presented as mean (SD) unless otherwise stated. Single variable intergroup comparisons were made using Student’s unpaired t-test or the Mann-Whitney U-test as appropriate. Nominal data were compared using the 
2 test or Fisher’s exact test. For hemodynamic analysis, because the time from induction to delivery varied among patients, we only compared data recorded up to the earliest time of uterine incision. Sequential measurements of SAP, HR, and metaraminol consumption were tested for the effects of time, group, and group x time by using analysis of variance for repeated measures. Analyses were performed using StatView for Windows 4.53(Abacus Concepts Inc, Berkeley, CA). Values of P < 0.05 were considered statistically significant.
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Results |
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Sixty-six patients completed the study, all of whom received metaraminol. Four patients in the Bolus Group were excluded; two because severe shivering prevented accurate measurement of arterial pressure, one because of technical difficulty with performance of spinal anesthesia, and one because of a protocol violation. Umbilical cord blood samples were incomplete (arterial, venous, or both not obtainable) in one patient in the Control Group and four patients in the Bolus Group. Patient characteristics, and block height were similar between groups (Table 1). The mean uterine incision-to-delivery (U-D) time was larger in the Bolus Group compared with the Control Group; surgical times were otherwise similar between groups (Table 1).
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Changes in SAP are shown in Figure 1. In both groups, SAP changed significantly over time (P < 0.0001), with a transient initial decrease in SAP, which after starting the metaraminol infusion, was maintained approximately within the target range. There was no difference between groups (effect of group, P = 0.9) or between groups over time (effect of group x time, P = 0.3). Twenty patients (65%) in the Control Group had one or more episodes in which SAP decreased by more than 20% from baseline compared with 15 patients (43%) in the Bolus Group (P = 0.08).
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Changes in HR are shown in Figure 2. In both groups, HR changed significantly over time (P < 0.0001), with a transient initial increase followed by a decrease below baseline. There was no difference between groups (effect of group, P = 0.07) or between groups over time (effect of group x time, P = 0.3).
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The consumption of metaraminol per minute is shown in Figure 3. There was no difference between groups in overall consumption (effect of group, P = 0.6), but infusion rates were significantly different between groups over time (effect of group x time, P = 0.004). Cumulative metaraminol consumption is summarized in Table 2. There was no difference between groups in the time of starting the infusion. Cumulative metaraminol requirement was larger in the Control Group compared with the Bolus Group at 5 min but was similar at 10 min and at the time of uterine incision. The maximum infusion required was larger in the Control Group compared with the Bolus Group.
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Six patients (19%) in the Control Group and 5 patients (14%) in the Bolus Group had nausea or vomiting (P = 0.8). Of these patients, 4 in the Control Group (67%) and 5 in the Bolus Group (100%) had one or more episodes in which SAP decreased by more than 20% from baseline (P = 0.5).
Neonatal outcome is summarized in Table 3. No infant in either group had an Apgar score <8 at 1 min or 5 min. There was no difference in umbilical arterial or venous blood gas results between groups. No infant in the Control Group had umbilical arterial pH < 7.2 compared with one infant in the Bolus Group; this was associated with a difficult delivery, with U-D time of 339 s (all other U-D times were <280 s). Retrospective power analysis showed that our study had >90% power to detect a difference in mean umbilical arterial pH of 0.03 U at the 0.05% significance level.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Our study showed that, regardless of whether crystalloid bolus was given, infusion of metaraminol was effective at maintaining arterial pressure during spinal anesthesia for cesarean delivery. Giving bolus slightly reduced the early vasopressor requirement but did not affect overall requirement. Furthermore, there was no difference between groups in maternal outcome or neonatal outcome, which was excellent with all Apgar scores
8 at 1 minute and 5 minutes and mean umbilical arterial pH equal to 7.32 in both groups. Although our sample size was small, the retrospective power analysis showed that our study had sufficient power to detect a relatively small difference in umbilical arterial pH of 0.03 U. Therefore, our data provide evidence for the safety of infusions of agonists in obstetric patients who are not given crystalloid bolus. However, by chance, the U-D time was larger in the Bolus Group compared with the Control Group. Because differences in this time can potentially affect neonatal outcome, although the difference was small, it potentially favored a better outcome in the Control Group and is thus is a confounding factor in our analysis.
Several previous studies have questioned the efficacy of crystalloid bolus in the management of hypotension associated with spinal anesthesia for cesarean delivery. Rout et al.(4), in a nonblinded study that used a sequential analysis design found that bolus of 20 mL/kg lactated Ringer’s solution reduced the incidence of hypotension from 71% to 55% but did not affect neonatal outcome or ephedrine requirement. After this, randomized blinded studies by Jackson et al. (2) and Husaini et al. (3) showed no beneficial effect of 1000 mL crystalloid bolus on the incidence of hypotension or ephedrine requirement compared with either 200 mL crystalloid or no bolus, respectively. These findings are similar to those in nonobstetric patients in whom the value of crystalloid bolus has also been questioned (11).
In common with these previous studies, our results support the contention that bolus should not be considered essential before spinal anesthesia for cesarean delivery. However, our two groups were not entirely equivalent; we found that the Control Group required approximately one third more metaraminol in the first 5 min to maintain the SAP within our target range compared with the Bolus Group. The clinical implication of this is that when bolus is not given, anesthesiologists should be prepared to give larger doses of vasopressor in the immediate postspinal period than they would otherwise use in patients who have received bolus. In our patients, this involved infusing a mean of 1.29 mg of metaraminol in the first 5 min.
The reason why crystalloid bolus has only limited efficacy can be attributed to its rapid redistribution out of the intravascular space, which results in a relatively small augmentation of circulating volume. Ueyama et al. (12) investigated the effects of crystalloid (lactated Ringer’s solution) and colloid (hydroxyethyl starch) on the incidence of hypotension in parturients during spinal anesthesia and found that the effectiveness of bolus, regardless of the fluid used, was directly related to the extent of intravascular volume expansion and resultant increase in cardiac output achieved. In our study, to facilitate blinding, we administered bolus to patients over a period of 15 min before the start of the induction of spinal anesthesia. Thus, by the time the spinal injection was completed, significant redistribution of the fluid out of the intravascular space had probably already begun. It is possible that administering IV fluid either during the performance of spinal anesthesia or immediately after injection might prove more effective.
As an alternative to metaraminol, phenylephrine has also been used to maintain arterial pressure during spinal anesthesia for cesarean delivery, both by bolus and infusion (7–9,13–15). Randomized comparisons of phenylephrine with ephedrine in parturients during spinal anesthesia have confirmed the safety of phenylephrine, and several studies have also shown superior umbilical acid-base status when phenylephrine was used compared with ephedrine (7–9). There have been no clinical comparisons of phenylephrine with metaraminol in pregnant humans.
Because we found that relatively large doses of metaraminol were required to maintain arterial pressure at near-baseline levels in our patients, there may be some concern about the potential for uterine or umbilical vasoconstriction. Unfortunately, our study protocol did not include assessment of uterine or umbilical vessel vascular resistance or flow. However, in our previous study, we showed no difference in uterine artery pulsatility index between women who received a similar metaraminol infusion protocol compared with women who received ephedrine infusion (10). Furthermore, all infants in both studies were delivered in excellent condition with no evidence of fetal acidosis. This suggests that, in the dose range that we studied, maintenance of optimum perfusion pressure is more important than concerns about adverse effects of potential uterine or umbilical vessel vasoconstriction. However, our patients were all elective cases with no known fetal abnormalities or maternal disease; caution may be warranted in the application of our results to emergency cases or situations when there is potential fetal compromise. Although the incidence of hypotension is reduced in laboring patients compared with nonlaboring patients (16), further work is required to determine the optimum combination of fluids and vasopressors in these patients.
In conclusion, we have found that IV bolus of 20 mL/kg lactated Ringer’s solution did not affect overall vasopressor requirement or maternal or neonatal outcome when an infusion of metaraminol was used to maintain arterial pressure in women having cesarean delivery under spinal anesthesia. Our results support the contention that, if uterine displacement is maintained and IV metaraminol infusion is administered, crystalloid bolus should not be considered mandatory in patients undergoing cesarean delivery under spinal anesthesia.
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Acknowledgments |
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Supported, in part, by a Direct Grant for Research from The Chinese University of Hong Kong.
We wish to thank the nurses of the Labor Ward, Prince of Wales Hospital, for their assistance and cooperation during this study.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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- Rout CC, Rocke DA. Prevention of hypotension following spinal anesthesia for cesarean section. Int Anesthesiol Clin 1994; 32: 117–35.[Web of Science][Medline]
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Jackson R, Reid JA, Thorburn J. Volume preloading is not essential to prevent spinal-induced hypotension at Caesarean section. Br J Anaesth 1995; 75: 262–5.
[Abstract/Free Full Text] - Husaini SW, Russell IF. Volume preload: lack of effect in the prevention of spinal-induced hypotension at caesarean section. Int J Obstet Anesth 1998; 7: 76–81.[Web of Science][Medline]
- Rout CC, Rocke DA, Levin J, et al. A reevaluation of the role of crystalloid preload in the prevention of hypotension associated with spinal anesthesia for elective cesarean section. Anesthesiology 1993; 79: 262–9.[Web of Science][Medline]
- Birnbach DJ, Datta S. Intravenous fluid preload in the prevention of spinal block-induced hypotension in parturients: I. Anesthesiology 1994; 80: 701.[Web of Science][Medline]
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Lawes EG. Volume preloading, spinal anaesthesia and Caesarean section. Br J Anaesth 1996; 76: 334–5.
[Free Full Text] - Moran DH, Perillo M, LaPorta RF, et al. Phenylephrine in the prevention of hypotension following spinal anesthesia for cesarean delivery. J Clin Anesth 1991; 3: 301–5.[Medline]
- LaPorta RF, Arthur GR, Datta S. Phenylephrine in treating maternal hypotension due to spinal anaesthesia for caesarean delivery: effects on neonatal catecholamine concentrations, acid base status and Apgar scores. Acta Anaesthesiol Scand 1995; 39: 901–5.[Web of Science][Medline]
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Thomas DG, Robson SC, Redfern N, et al. Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anaesthesia for Caesarean section. Br J Anaesth 1996; 76: 61–5.
[Abstract/Free Full Text] - Ngan Kee WD, Lau TK, Khaw KS, Lee BB. A comparison of metaraminol and ephedrine infusions for maintaining arterial pressure during spinal anesthesia for elective cesarean section. Anesthesiology 2001, in press.
- Coe AJ, Revanas B. Is crystalloid preloading useful in spinal anaesthesia in the elderly? Anaesthesia 1990; 45: 241–3.[Web of Science][Medline]
- Ueyama H, He YL, Tanigami H, et al. Effects of crystalloid and colloid preload on blood volume in the parturient undergoing spinal anesthesia for elective cesarean section. Anesthesiology 1999; 91: 1571–6.[Web of Science][Medline]
- Alahuhta S, Räsänen J, Jouppila P, et al. Ephedrine and phenylephrine for avoiding maternal hypotension due to spinal anaesthesia for caesarean section: effects on uteroplacental and fetal haemodynamics. Int J Obstet Anesth 1992; 1: 129–34.[Medline]
- Pierce ET, Carr DB, Datta S. Effects of ephedrine and phenylephrine on maternal and fetal atrial natriuretic peptide levels during elective cesarean section. Acta Anaesthesiol Scand 1994; 38: 48–51.[Web of Science][Medline]
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Hall PA, Bennett A, Wilkes MP, Lewis M. Spinal anaesthesia for Caesarean section: comparison of infusions of phenylephrine and ephedrine. Br J Anaesth 1994; 73: 471–4.
[Abstract/Free Full Text] - Clarke RB, Thompson DS, Thompson CH. Prevention of spinal hypotension associated with cesarean section. Anesthesiology 1976; 45: 670–4.[Web of Science][Medline]
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