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ORIGINAL ARTICLE
Year : 2016  |  Volume : 6  |  Issue : 2  |  Page : 86-91

Exploring novel infusion regimens of phenylephrine during spinal anesthesia for caesarean delivery: The effects on hemodynamic control and fetal acid-base status


1 Department of Critical Care Medicine, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Luckow, Uttar Pradesh, India
2 Department of Anaesthesia and Intensive Care, Post Graduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Paediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication7-Oct-2016

Correspondence Address:
Sukhen Samanta
17 Dr A N Paul Lane, Bally, Howrah, West Bengal - 711 201
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2249-4472.191602

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  Abstract 

Background: A renewed interest has emerged in the use of bolus or intravenous (IV) infusion of phenylephrine for management of hypotension during spinal anesthesia (SA) for caesarean section to achieve optimal maternal and neonatal outcome. The aim of our study was to investigate the efficacy of using three different phenylephrine infusion regimens to maintain maternal baseline blood pressure during SA for caesarean delivery.
Materials and Methods: Ninety parturients undergoing SA for elective caesarean delivery received an IV infusion of phenylephrine in one of three different concentration ratios. The groups contained a potency equivalent of 100 μg/min, 80μg/min, and 60 μg/min infusion doses. The infusions were adjusted to maintain systolic blood pressure (SBP) near the baseline until uterine incision. Hemodynamic changes in mother and umbilical cord blood gases were compared.
Results: As concentration of phenylephrine increased, following significant trends were noticed: in group A, 10/29 (34.5%) patients had hypotension as compared to 2/28 (7.4%) patients in group B and 4/28 (14.3%) patients in group C. On the other hand, we found that the incidence of hypertension and bradycardia was higher in groups B (22/28; 4/28) and C (26/28; 10/28) as compared to those in group A (3/29; 2/29), respectively. Neonatal acid-base status in all three groups was favorable.
Conclusions: As the concentration of phenylephrine increased, the tendency for SBP to be above the baseline increased, along with an incidence of bradycardia. Therefore, we conclude that low dose infusion regimens of phenylephrine, i.e. between 60 μg/min and 80 μg/min, will be more effective in prevention of hypotension during SA for caesarean delivery.

Keywords: Acid-base status, caesarean delivery, hemodynamics, phenylephrine, spinal anesthesia


How to cite this article:
Muzaffar SN, Jain K, Samanta S, Bhardwaj N, Kumar P. Exploring novel infusion regimens of phenylephrine during spinal anesthesia for caesarean delivery: The effects on hemodynamic control and fetal acid-base status. J Obstet Anaesth Crit Care 2016;6:86-91

How to cite this URL:
Muzaffar SN, Jain K, Samanta S, Bhardwaj N, Kumar P. Exploring novel infusion regimens of phenylephrine during spinal anesthesia for caesarean delivery: The effects on hemodynamic control and fetal acid-base status. J Obstet Anaesth Crit Care [serial online] 2016 [cited 2017 May 24];6:86-91. Available from: http://www.joacc.com/text.asp?2016/6/2/86/191602


  Introduction Top


Hypotension following spinal anesthesia (SA) produces unpleasant maternal symptoms such as nausea, vomiting, and light headedness, and if severe and sustained, an impairment of the uterine and intervillous blood flow can result in fetal hypoxia, acidosis, and neonatal depression.[1],[2] Thus, it is important to maintain maternal hemodynamics and uteroplacental perfusion following spinal anesthesia for caesarean section. Many trials comparing phenylephrine and ephedrine for management of hypotension during spinal anesthesia for caesarean section have shown favorable umbilical cord pH values with phenylephrine.[3],[4],[5] In this nonrandomized, double-blinded, comparative prospective study, we compared infusions of phenylephrine in three different ratios. The primary objective of this study was to compare the effects of different infusion regimens on maternal systolic blood pressure (SBP) and heart rate (HR), with the secondary objective of evaluating the effects of these infusion regimens on umbilical cord blood gases.


  Materials and Methods Top


Approval was obtained from the ethical committee of our institute, and a written informed consent was taken from 90 American Society of Anaesthesiologist physical status (ASA) I, nonlaboring parturients scheduled for elective caesarean section under spinal anesthesia. These patients were nonrandomly allocated to one of the three groups. We excluded patients who had hypertension (SBP ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mm Hg), cardiovascular or cerebrovascular disease, known fetal anomaly, contraindications to spinal anesthesia, or signs of onset of labor. Patients received aspiration prophylaxis premedication (ranitidine and metoclopramide). Standard noninvasive monitoring was applied in the operation theatre. They were rested in left-tilted supine position for several minutes, during which blood pressure (BP) was measured every 1–2 min. Baseline SBP and HR were noted as the mean of these three readings. Standard monitoring was done (including noninvasive blood pressure, electrocardiography, and pulse oximetry) by a multichannel monitor (Datex Omeda S5/avance, GE Health Care, Hilsenski, Russia). Electrocardiography monitoring, HR, and oxygen saturation readings were monitored continuously whereas NIBP recordings were taken at 1-min intervals beginning 1 min after intrathecal injection and continued until delivery of the baby.

No intravenous (IV) prehydration was given. We then inserted a 16-gauge IV cannula under local anesthetics infiltration into a forearm vein and connected this using a wide-bore infusion set to a 500 ml bag of warmed lactated Ringer's solution, which was given by high pressure bag as co-loading. Spinal anesthesia was induced in the left lateral position using a 26G-quincke needle at L3–4 or L4–5 vertebral interspace and hyperbaric 0.5% bupivacaine (10 mg) and fentanyl (20 µg) were injected intrathecally by an anesthesiologist. Patients were then repositioned in the tilted supine position. Hemodynamic data were recorded by another anesthesiologist at 1-min intervals. If there was any unexpected value of BP (large swing) record, we repeated NIBP before titration of phenylephrine dose.

Each group received a titrated IV infusion of a solution containing one of three different infusions of phenylephrine. The vasopressor solutions were prepared in identical 50 mL syringes by another investigator. Immediately after intrathecal injection, a 50 µg bolus of IV phenylephrine was administered and a prophylactic IV phenylephrine infusion of 100 µg/min, 80 µg/min, or 60 µg/min was initiated at a rate of 60 ml/h using a syringe pump (Graseby 3500 Anaesthesia pump, Graseby Medical Ltd., Watford, Herts, UK). Before attaching the infusion line, it was primed with a bolus through the syringe driver. The infusion and IV fluid lines were connected to IV cannula using a three-way connector. In order to maintain maternal BP at near-baseline levels, a predefined algorithm was used: (a) rate of infusion was maintained (60 ml/h) if BP remained within 90–110% of the baseline; (b) rate of infusion was halved (30ml/h) if BP increased to 110–120% of the baseline; (c) infusion was stopped if BP increased to more than 120% of the baseline; (d) rescue bolus of 50 µg phenylephrine IV was given if BP decreased to less than 90% of the baseline. Hypotension was defined as SBP <90% of the baseline reading and hypertension was defined as SBP >110% of the baseline. The infusion was discontinued following delivery of the baby. The total dose of phenylephrine along with number of boluses required were recorded. Bradycardia (HR <50 bpm) associated with SBP greater than baseline was treated by stopping the phenylephrine infusion, and bradycardia associated with SBP less than baseline values was treated by IV atropine 0.6 mg. Any episode of nausea or vomiting was recorded and graded using a 4-point scale: (0 = none, 1 = mild nausea, 2 = nausea requiring treatment, 3 = vomiting). Nausea or vomiting with a score of 2 or 3 was treated with IV ondensetron if unrelated to hypotension or not corrected by phenylephrine boluses alone. Additional data included co-loading time, time of induction, skin incision time, uterine incision time and induction–delivery time, neonatal weight, and umbilical arterial and venous blood samples from a doubled-clamped segment of cord for immediate measurement of blood gases (using Bayer Rapid LAB 855 gas analysis machine). A pH of less than 7.20 was defined as fetal acidosis. APGAR score at 1 and 5 min after the delivery were also noted.

Statistical analysis

Statistical evaluation was done using the Statistical Package for the Social Sciences version 17.0 (SPSS Inc., Chicago, IL, USA). Group comparisons between different dosage schedules of phenylephrine were used, and various quantitative variables were analyzed using one-way analysis of variance (ANOVA) (for independent variables) and repeated-measure ANOVA (for dependent variables). Repeated-measure ANOVA compared the effects of time trends (serial HE and SBP), as well as time trend × vasopressor dose group interaction. Post-hoc analyses were carried out using Tukey's honestly significantly difference (for one-way ANOVA) and Bonferroni's correction for multiple comparisons of time trend data (repeated HR and SBP values) in repeated-measure ANOVA. Nonparametric Kruskal–Wallis test was used to compare time related variables and other non-normally distributed quantitative variables across three doses of phenylephrine used during spinal anesthesia. Qualitative variables (e.g., number of times boluses of vasopressor was needed or patients with or without episodes of hypotension, etc.) were compared using Chi-square test and Fisher exact test. All tests were two-tailed, and P value of 0.05 was considered to be significant. The sample size was estimated considering that the SBP would be improved by 20% with phenylephrine continuous infusion. Twenty-six patients in each group were needed to demonstrate a 20% change in SBP between two groups with an alpha error of 0.05 and 80% power.


  Results Top


The present study was conducted in 90 patients scheduled for elective caesarean section under spinal anesthesia. They were nonrandomly divided into three groups. Of these, 86 completed the study protocol; 1 patient was excluded from group A because of anxiety leading to raised BP readings; and 2 patients were excluded from groups B and C each because of protocol violations (conversion of SA to general anesthesia). In Group A (n =29), patients received phenylephrine infusion at 60 µg/min, patients in Group B (n =28) received phenylephrine infusion at 80 µg/min, and in group C, patients (n =28) received phenylephrine infusion at 100 µg/min. In all groups, co-loading was done and patients in all the three groups received similar amount of fluids. Phenylephrine infusion was started immediately after intrathecal injection. Patient characteristics, the upper level of sensory anesthesia, surgical times, and the amount of IV fluid given up to the time of uterine incision were comparable in all three groups [Table 1].
Table 1: Patient characteristics, induction-delivery time, and co-loading time

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Hemodynamic changes are described in [Table 2] and [Figure 1] and [Figure 2]. In group A, 10 (34.4%) patients had hypotension compared to 2 (7.1%) patients in group B and 4 (14.2%) patients in group C. The incidence of hypotension was significantly higher in group A as compared to group B (P = 0.01) and C (P = 0.03). No significant difference in the incidence of hypotension was found between groups B and C. The minimum SBP achieved in group A was 106 ± 16 mmHg compared to 116 ± 12 mmHg in group C (P = 0.02). However, group B (116 ± 13 mmHg) and C (116 ± 12 mmHg) had comparable values of minimum SBP. The number of additional boluses of phenylephrine given in the three groups was 0.8 ± 1.4 µg, 0.1 ± 0.6 µg, and 0.2 ± 0.7 µg, respectively. The patients in group A received more boluses than those in group B and group C (P < 0.05). The number of boluses administered were comparable between groups B and C. The incidence of hypertension was significantly higher in group C (n = 26; 92.8%) as compared to group A (n = 3; 10.3%) (P = 0.000) and B (n = 22; 78.5%), respectively. No significant difference in the incidence of hypertension was found between groups B and C. Maximum increase in SBP was seen in group C (156.6 ± 18.9) as compared to group A (133 ± 12; P = 0.000) and group B (145 ± 15; P = 0.01). The increase was also more in group B compared to group A (P = 0.01). Of note, no patient received anticholinergic drugs that may have caused an exaggerated increase in SBP. The incidence of bradycardia was significantly higher in group C as compared to group A (P = 0.01). No significant difference in the incidence of bradycardia was found between groups A and B and also between the groups B and C. A minimum HR of 55 ± 10 was seen in group C (P = 0.001) as compared to 68 ± 17 and 61 ± 12 in groups A and B, respectively. No patient complained of nausea/vomiting or had sedation in any group during the intraoperative observation period. To maintain SBP closer to the baseline values, the infusion pump settings had to be halved in 1 patient in group A as compared to 17 patients in group B and 23 patients in group C. Similarly, the infusion pump settings had to be stopped in 1 patient in group A compared to 10 patients in group B and 25 patients in group C. The mean cumulative dose of phenylephrine (in µg) given up to the time of uterine incision was 939 ± 256, 1049 ± 301, and 1288 ± 447, respectively in groups A, B, and C. Large total doses of phenylephrine were administered overall in the infusion groups B and C to maintain target BP.
Table 2: Incidence of hypotension, hypertension, and bradycardia

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Figure 1: Intraoperative systolic blood pressure (mean ± SD) shows blood pressure recordings from baseline to 15 min after induction

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Figure 2: Intraoperative heart rate (mean ± standard deviation)

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Neonatal effect is shown in [Table 3]. The mean umbilical arterial pH was similar and comparable in all the three groups. However, the mean umbilical venous pH showed higher mean values in group A as compared with group C (P = 0.025). The umbilical venous pH values were comparable between groups A and B as well as between groups B and C. The mean umbilical arterial and venous pH was not less than 7.20 in any group. All the three groups were also comparable in umbilical arterial and venous base deficit, standard bicarbonate, partial pressure of oxygen and carbon dioxide, and oxyhemoglobin saturation values. APGAR scores were not less than 7 in any group at 5 min.
Table 3: Umbilical cord gases

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  Discussion Top


Hypotension has been variously defined in different studies as reduction in arterial pressure of 20% below the baseline or by 30 mmHg below the baseline or SBP <100 mmHg. The incidence of hypotension is reported to be 50–80% depending upon the definition of hypotension used and other factors such as position of the patient, intravascular fluid loading, and dose of intrathecal local anesthetics.[6],[7],[8] Further, it has been shown that uteroplacental perfusion is affected more by a percentage reduction in maternal blood pressure rather than by an absolute reduction in blood pressure.[8] Recent studies have demonstrated that phenylephrine infusion effectively maintains maternal blood pressure during spinal anesthesia for caesarean delivery.[4],[5] These studies reported that the best phenylephrine infusion regimen is the one which maintains maternal SBP at near-baseline values. Using this strategy, Kee et al. maintained a tight control of BP near the baseline values by starting a high dose infusion of phenylephrine (100 µg/min) and reported better maternal (less nausea, vomiting) and neonatal outcomes (higher umbilical artery pH) in these patients. However, the authors concluded that, although phenylephrine appeared safe from the fetal perspective, it caused maternal bradycardia and hypertension.[6] In another study, authors reported that prophylactic infusion of phenylephrine (100 µg/min) maintained hemodynamic stability but was associated with a small incidence of hypotension.[7] This was probably because, in this study, authors followed a rigid protocol for maintaining infusion which permitted only a fixed rate of drug to be administered. The authors felt that a regimen that allowed a more flexible approach such as one which did not completely stop the infusion or that allowed small boluses to be given when the infusion was restarted may have further reduced or completely eliminated hypotension. Therefore, further investigations with variable dose regimens, which also result in better hemodynamic stability, would be of interest. Hence, we designed this study to compare three different phenylephrine infusion regimens along with a rapid crystalloid co-hydration during SA for caesarean delivery. The efficacy of combining simultaneous rapid crystalloid infusion (co-hydration) with a high dose phenylephrine infusion was also studied by Kee et al. who concluded that this was the only technique till date which was effective in virtually eliminating hypotension.[9] We initiated the phenylephrine infusion following a bolus soon after intrathecal injection and titrated it according to a predetermined algorithm to maintain baseline BP (90–110%). This method of drug administration where infusion is started prophylactically before the onset of reduction in BP has been shown to be more superior to withholding the treatment till BP falls. Our infusion protocol used a basic “on–off” algorithm that was designed to be simple and easy to use. This “on–off” algorithm has previously been used by Kee et al. in their studies.[9]

In our study, the dosing regimens for phenylephrine were selected on the basis of initial work with the use of phenylephrine in clinical practice. Hall et al. reported that a 10 µg/min phenylephrine infusion with a 20 µg bolus regimen to less effective than ephedrine infusion in their study.[10] Hypotension was defined as BP less than 80% of the baseline. They found that there was a high incidence of hypotension in all the groups. The authors felt that the incidence of hypotension could be decreased if infusion rates were increased before BP fell below 80% of the baseline. Mercier et al. added phenylephrine to ephedrine infusions to have better control of maternal BP following SA.[11] Hypotension was defined as BP less than 80% of baseline or a reduction in BP of less than 100 mmHg in this study. There was a 50% reduction in the incidence of hypotension with the addition of phenylephrine to ephedrine. Cooper et al. started infusion of phenylephrine at 33 µg/min and increased or decreased as necessary to maintain baseline BP. They considered <80% as hypotension. Using this definition, the authors reported an incidence of hypotension as 48% in this group, with a mean infusion rate of 40 µg/min.[5] Therefore, we chose the lowest infusion regimen of phenylephrine as 60 µg/min, and compared its efficacy with higher dose infusion regimens of 80 µg/min (not studied previously) and 100 µg/min (used by Kee et al. in their previous studies [3],[4],[6],[7]).

In our study, we found that, in group A, parturients had more hypotension as compared groups B and C. On the other hand, we also found that the incidence of hypertension was higher in groups B and C as compared to group A. To maintain the BP in the target range, infusion pump settings had to be frequently altered in groups B and C. Minimal alterations were required in group A. The incidence of bradycardia was also higher in groups B and C as compared to group A. As bradycardia was not associated with hypotension, and in most patients, HR increased after stopping phenylephrine infusion, the decrease in HR most likely reflected a physiological baroreceptor reflex. In addition, there was no detrimental effect on neonatal outcome which indicates that low HR is well tolerated if maternal BP is maintained at baseline levels. Similar to our study, other studies with higher dose of phenylephrine (100 µg/min) have also observed a high incidence of hypertension and bradycardia in patients undergoing cesarean delivery following SA. Kee et al. titrated phenylephrine infusion of 100 µg/min to maintain SBP values at 100% of the baseline values (group 100); they reported the incidence of hypertension and bradycardia as 21 and 8%, respectively.[6] In another study, varying combinations of phenylephrine and ephedrine were given by infusion to maintain BP during spinal anesthesia for caesarean delivery. The authors reported a trend toward higher BP and slower HR with increasing doses of phenylephrine, with maximum incidence with 100 µg/min infusion (50 and 13%, respectively).[12] In another study, Kee et al. combined the technique of a high dose phenylephrine infusion (100 µg/min) with a rapid crystalloid co-load, and reported the incidence of hypertension and bradycardia as 47 and 1.8%, respectively.[9] In addition, they had to frequently alter infusion pump settings, which the authors felt was distracting. The higher incidence of hypotension in group A in our study can be explained since we defined hypotension as SBP <90% of the baseline in contrast to <80% of the baseline in previous studies. These episodes were probably of no clinical significance as both maternal and fetal outcomes were unaffected and no patient required any rescue medication to treat hypotension other than phenylephrine. It is noteworthy that, despite the administration of a large total dose of phenylephrine in all the groups, the fetal acid-base status and clinical condition of neonates were not affected. Previous reports, in which the authors used similar infusion regimens, also did not find any adverse neonatal effects despite similarly used large doses of phenylephrine.[6],[7] The mean umbilical arterial (UA) and venous (UV) pH was >7.20 in all the groups. The base deficit was also similar among all the three groups. This finding is reassuring and provides evidence for the safety of using phenylephrine in all doses used in our study. APGAR scores were also good for all newborn infants, and none required tracheal intubation and ventilation or intensive care in the immediate post-delivery period. The results of our present study suggest that a prophylactic infusion of phenylephrine at lower doses between 60 µg/min and 80 µg/min immediately after the induction of spinal anesthesia for caesarean delivery is effective in reducing the incidence, frequency, and severity of hypotension in addition to reducing the incidence of side effects such as hypertension and bradycardia in the mother. Moreover, less manual titrations of infusion pump settings will be required at such doses.

The limitations of our study was that we titrated the phenylephrine infusions according to maternal BP whereas concurrent measurement of cardiac output would probably have yielded more useful information; this is difficult to perform in routine clinical practice. Similarly, use of direct intra-arterial pressure monitoring may facilitate accurate maintenance of blood pressure without major fluctuations; however, this is difficult to justify in routine ASAI cases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Tsen LC, Boosalis P, Segal S, Datta S, Bader AM. Hemodynamic effects of simultaneous administration of intravenous ephedrine and spinal anesthesia for caesarean delivery. J Clin Anesth 2000;12:378-82.  Back to cited text no. 1
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2.
Datta S, Alper MH, Ostheimer GW, Weiss JB. Method of ephedrine administration and nausea and hypotension during spinal anesthesia for caesarean section. Anesthesiology 1982;56:68-70.  Back to cited text no. 2
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3.
Ngan Kee WD, Khaw KS, Lee BB, Lau TK, Gin T. A dose response study of prophylactic intravenous ephedrine for the prevention of hypotension during spin al anesthesia for caesarean delivery. Anesth Analg 2000;90:1390-5.  Back to cited text no. 3
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Lee A, Ngan Kee WD, Gin T. A quantitative, systemic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anaesthesia for caesarean section. Anesth Analg 2002;94:920-6.  Back to cited text no. 4
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5.
Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS. Fetal and maternal effects of phenylephrine and ephedrine during spinal anaesthesia for caesarean delivery. Anesthesiology 2002;97:1582-90.  Back to cited text no. 5
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6.
Ngan Kee WD, Khaw KS, Ng FF. Comparison of phenylephrine infusion regimens for maintaining maternal blood pressure during spinal anaesthesia for caesarean section. Br J Anaesth 2004;92:469-74.  Back to cited text no. 6
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7.
Ngan Kee WD, Khaw KS, Ng FF. Prophylactic phenylephrine infusion for preventing hypotension during spinal anaesthesia for caesarean section. Anesth Analg 2004;98:815-21.  Back to cited text no. 7
    
8.
Macarthur A, Riley E T. Obstetric Anesthesia Controversies: Vasopressor Choice for Postspinal Hypotension During Cesarean Delivery. Int Anesthesiol Clin 2007;45:115-32.  Back to cited text no. 8
    
9.
Ngan Kee WD, Khaw KS, Ng FF. Prevention of hypotension during spinal anesthesia for cesarean delivery: An effective technique using combination phenylephrine infusion and crystalloid cohydration. Anesthesiology 2005;103:744-50.  Back to cited text no. 9
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10.
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.  Back to cited text no. 10
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11.
Mercier FJ, Riley ET, Frederickson WL, Roger-Christoph S, Benhamou D, Cohen SE. Phenylephrine added to prophylactic ephedrine infusion during spinal anaesthesia for elective cesarean section. Anesthesiology 2001;95:668-74.  Back to cited text no. 11
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12.
Ngan Kee WD, Khaw KS, Ng FF. A randomized double-blinded comparison of phenylephrine and ephedrine infusion combinations to maintain blood pressure during spinal anesthesia for caesarean delivery: The effects on fetal acid-base status and hemodynamic control. Anesth Analg 2008;107:1295-302.  Back to cited text no. 12
    


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