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ORIGINAL ARTICLE
Year : 2018  |  Volume : 12  |  Issue : 2  |  Page : 446-451  

Study comparing phenylephrine bolus and infusion for maternal hypotension and neonatal outcome during cesarean section under spinal anesthesia


Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, India

Date of Web Publication14-Jun-2018

Correspondence Address:
Dr. Jeetendra Kumar Bajaj
Department of Anaesthesia and Intensive Care, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aer.AER_23_18

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   Abstract 

Background: Phenylephrine(PE) bolus and infusion have been compared for post spinal hypotension and neonatal effects during cesarean section(CS) under spinal anesthesia(SA). Aim: The primary aim of this study was to compare bolus doses of 50μg of PE with a fixed infusion rate of 50 μg/min of the same drug given prophylactically. The secondary aim was to study the neonatal outcome and side effects with the two regimes. Settings and Design: This prospective,randomized,comparative study was conducted in the department of Anesthesia in a tertiary care teaching hospital. Materials and Methods: This study was conducted on 100 normotensive women undergoing CS under SA. The patients were randomized into two groups of 50 each. Group A received bolus of 50 μg PE after the systolic BP(SBP) fell by 20% from the baseline and Group B received a prophylactic infusion of 50 μg/min PE. The changes in heart rate (HR), BP and side effects were compared till delivery. The neonatal APGAR scores were compared at 1 and 5 minutes and an umbilical artery sample was sent for blood gas analysis. Statistical Analysis: Categorical variables were shown in number and percentage. Normally distributed continuous variables were presented as mean ± SD and compared using unpaired t-test. Non normally distributed continuous variables were displayed as median and were compared using Mann-Whitney test. A P value of <0.05 was considered significant. Results: In group A, the HR was higher than in group B throughout the monitoring period. (P < 0.001). In group A, SBP trend showed a fall of more than 20% from the base line in 44 patients. The mean fall in SBP was -28.06 ± 5.3 mmHg% in Group A while in group B the mean fall in SBP was only -0.44 ± 4.3mmHg%. Nausea and vomiting was less in group B. There was no difference in APGAR or neonatal acidosis on ABG. Conclusion: There was a tighter control of BP in the infusion group vs. the bolus group while the neonatal outcome was similar in both the groups.

Keywords: Cesarean section, postspinal hypotension, phenylephrine infusion


How to cite this article:
Choudhary M, Bajaj JK. Study comparing phenylephrine bolus and infusion for maternal hypotension and neonatal outcome during cesarean section under spinal anesthesia. Anesth Essays Res 2018;12:446-51

How to cite this URL:
Choudhary M, Bajaj JK. Study comparing phenylephrine bolus and infusion for maternal hypotension and neonatal outcome during cesarean section under spinal anesthesia. Anesth Essays Res [serial online] 2018 [cited 2020 Apr 3];12:446-51. Available from: http://www.aeronline.org/text.asp?2018/12/2/446/230451


   Introduction Top


Spinal anesthesia (SA) is the technique of choice for cesarean section (CS).[1] However, it is accompanied by maternal hypotension which can have an incidence as high as 70%–80% when pharmacological prophylaxis is not used.[2] Hypotension, after SA for CS, is defined when the systolic blood pressure (SBP) decreases to <100 mmHg or to >20% less than baseline readings.[3] The fall in blood pressure causes nausea, vomiting, and lightheadedness, and when severe and sustained, it can impair uterine and intervillous blood flow. This ultimately results in fetal acidosis and neonatal depression. Maternal SBP of 80 mmHg for 5 min almost always results in hypoxic fetal bradycardia.[4]

Measures which have been described to prevent hypotension after SA include fluid preload, left lateral tilt, and use of vasopressors.[4] However, a Cochrane review from 2006 concluded that no single intervention has been proven to eliminate postspinal hypotension.[5] Among the vasopressors, ephedrine (a mixed α- and β-agonist) was previously recommended as the drug of choice in obstetrics, but there is now increasing evidence that this agent has the propensity to decrease fetal pH and base excess.[6],[7] Phenylephrine, a pure α-agonist, is currently considered as the preferred drug to use in hypotension due to SA in CS.

However, the American Society of Anesthesiologists (ASA) Practice Guidelines for Obstetric Anesthesia published in 2016 suggest that either intravenous (IV) ephedrine or phenylephrine may be used for treating hypotension during neuraxial anesthesia.[8] They recommend that in the absence of maternal bradycardia, phenylephrine should be considered because of improved fetal acid–base status in uncomplicated pregnancies. The Association of Anaesthetists of Great Britain and Ireland (AAGBI) consensus statement published in 2018 by Kinsella et al. recommends a variable rate prophylactic infusion of phenylephrine immediately after the intrathecal injection.[9]

The present study was started earlier than the guidelines published by ASA and AAGBI. We used our departmental protocols of preloading and standard dose of bupivacaine and fentanyl as an additive for the subarachnoid block. We hypothesized that a fixed infusion dose of phenylephrine is better than the therapeutic boluses given reactively to maintain maternal hemodynamic stability. The primary aim of this study was to compare reactive bolus doses of 50 μg of phenylephrine with a fixed infusion rate of 50 μg/min of the same drug given prophylactically. The secondary aim was to study the neonatal outcome and side effects with the two regimens.


   Material and Methods Top


The study was conducted as a prospective randomized, comparative study of 100 physical status ASA Classes I and II parturients who were scheduled for elective or emergency CS under subarachnoid block in a tertiary care teaching hospital. The study was conducted between 2015 and 2016 after approval by the ethics committee of the institution and informed consent. Inclusion criteria were age between 18 and 40 years, height between 150 and 170 cm, body mass index <30 kg/m,2 and singleton pregnancies. Exclusion criteria were preexisting or pregnancy-induced hypertension, prenatal fetal distress, significant cardiovascular, respiratory, neurological, and coagulation disorders [Figure 1].
Figure 1: Consort diagram of patients' recruitment

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A double-blind, placebo-controlled trial of four fixed rate infusion regimens of phenylephrine was conducted by Allen et al., in 2010.[10] This study observed that 3 (15%) of 20 patients in the 50 μg infusion group had one or more episodes of hypotension compared with 16 (80%) of 20 in the control group (P< 0.0001). Taking these values as reference, the minimum required sample size with 95% power of the study and 5% level of significance is 9 patients in each study group. However, in a pilot study, we estimated the fall in SBP may be less than the targeted 20%, and thus, a total of 50 patients in each group were recruited to compensate for potential subject loss.

Randomization was done using a computer-generated table of random numbers placed in sealed, opaque envelopes. Patients were allocated to one of the two groups A and B using a block randomization technique with a block size of 10, i.e., for every ten patients randomized, five received therapeutic bolus and other five received prophylactic infusion.

Patients were premedicated with injection ranitidine 50 mg IV 1 h before the surgery or as soon as the decision to perform CS was made. On arrival to the operating room, monitors were connected, and heart rate, oxygen saturation (SpO2), and noninvasive blood pressure (NIBP) were measured. The NIBP was measured three times and the least systolic value was taken as the baseline value. An IV line was started using 18G cannula and patients were preloaded with 500 ml of Ringer's lactate over 10 min and subsequently continued at 7 ml/kg/h. A subarachnoid block was given in the sitting position using a 25-G lumbar puncture needle in the L2–L3 or L3–L4 intervertebral space ensuring all aseptic precautions. Injection fentanyl 10 μg was added to 10 mg of 0.5% bupivacaine (heavy) with an insulin syringe (total volume 2.1 ml), and the mixture was injected intrathecally. After administration of subarachnoid block, patients were placed supine with left uterine displacement.

Group A patients received phenylephrine 50 μg IV bolus after significant hypotension developed, i.e., fall in SBP ≥20% of basal value and bolus was repeated if necessary. Group B patients received prophylactic phenylephrine 50 μg/min infusion through a syringe pump (B Braun Infusomat ) started immediately after the administration of subarachnoid block. The infusion was continued till the delivery of the baby and was stopped if SBP rose to >20% of baseline.

Level of sensory block was assessed by checking for the loss of cold sensation using alcohol swab bilaterally. NIBP was measured at 2 min interval and the time at which hypotension developed was noted. Six patients who did not develop targeted hypotension in Group A after SA were excluded from the analysis. The incidence of side effects such as bradycardia, nausea, and vomiting (Grade: 0–2) was noted. After delivery, blood sample was obtained from the umbilical artery and sent for analysis of pH, pO2, pCO2, standard bicarbonate, and base excess (Radiometer ABL9). Appearance, pulse, grimace, activity, and respiration (APGAR) score was assessed at 1 and 5 min after the delivery.

Statistical analysis

Categorical variables were presented in number and percentage (%), and normally distributed continuous variables were presented as mean ± standard deviation with 95% confidence interval (CI) of mean and nonnormally distributed continuous variables were presented as median (interquartile range) with 95% CI of median. Normality of data was tested by Kolmogorov–Smirnov test. If the normality was rejected, then nonparametric test was used. Normally distributed quantitative variables were compared using unpaired t-test and nonnormally distributed quantitative variables were compared using Mann–Whitney test. The incidence of nausea and vomiting was compared using Chi-square test. P < 0.05 was considered statistically significant. The data were entered into MS Excel spreadsheet and analysis was done using the Statistical Package for Social Sciences version 21 (IBM Corp, Armonk, NY, USA).


   Results Top


The two groups of patients were comparable with respect to age, sex, and weight [Table 1]. The hemodynamic changes were monitored and analyzed in both the groups till the delivery of the baby. The baseline heart rate was comparable between the groups. In the bolus group, the heart rate was higher than in the infusion group throughout the monitoring period [Table 2] and the change in the heart rate was statistically significant between the two groups (P< 0.001).
Table 1: Demographic details

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Table 2: Heart rate trend

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The baseline SBP was comparable between the two groups. In group A, systolic BP trend showed a fall in BP of >20% from the baseline at about 6 min when bolus 50 μg was administered in 44 patients [Table 3]. The mean percentage fall in SBP was −28.06 ± 5.3 mmHg %. No patient required a second bolus dose of phenylephrine, while in the infusion group, the mean percentage fall in SBP was only − 0.44 ± 4.3 mmHg% [Table 4]. The mean total dose of phenylephrine infused was 585 ± 54 μg till delivery of the baby. The diastolic BP and mean arterial pressure also showed a similar trend in both the groups.
Table 3: Trend of systolic blood pressure

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Table 4: Percentage change in systolic blood pressure

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The incidence of nausea and vomiting was 12% in the bolus group and 6% in the infusion group [Table 5].
Table 5: Incidence of nausea and vomiting

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APGAR scores at 1 and 5 min were compared between the two groups, and the difference was statistically insignificant with P = 0.830 and 0.254, respectively [Table 6]. Umbilical artery sample was taken after delivery, and none of the babies had a pH <7.2 [Table 7]. The median pH difference between the two groups was not statistically significant, the P value being 0.544. The median umbilical artery pO2 was 18.2 (15.5–22.1) mmHg and 19.25 (16.7–21.8) mmHg in both the groups, respectively, and was not statistically significant. The median pCO2 was 44.35 (41.9–46.4) mmHg in Group A and 42.0 (39.8–45.5) mmHg in Group B. Median serum HCO3 was 23.35 (22.0–24.3) mmol/l in the bolus group and 22.6 (22.7–23.7) mmol/l in the infusion group. Similarly, the median base excess was not significantly different in the two groups being −2.0 (−3.05–−0.95) mmol/l and −2.15 (−3.3–−1.5) mmol/l, respectively.
Table 6: Appearance, pulse, grimace, activity, and respiration scores

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Table 7: Umbilical artery blood gas analysis

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   Discussion Top


The mechanism of hypotension after SA for CS was thought to be related to aortocaval compression and its detrimental effect on venous return, cardiac filling, and cardiac output. This led to a reliance on IV fluid preloading, which has now been shown to have limited efficacy. The emphasis has now changed toward proactive and liberal administration of vasopressors.[11] These directly counter the primary physiological derangement induced by the sympathetic block: arteriolar vasodilation and decreased systemic vascular resistance.[12] Ephedrine was previously recommended as vasopressor of choice, but phenylephrine has been shown to have greater efficacy, lower placental transfer, and a smaller propensity to depress fetal pH.[13]

The optimal dosing regimen and the optimal method of administration for phenylephrine are controversial. Although the use of intermittent boluses is a simple technique, there has been much interest in the use of titrated continuous infusions. Ngan Kee et al[14]in 2004 published a study describing prophylactic infusion of IV phenylephrine for the prevention of hypotension during SA for cesarean delivery.[10] The results of this study showed that umbilical artery pH was greatest and the incidence of nausea and vomiting was smallest when phenylephrine was titrated with the aim of maintaining maternal BP at 100% of baseline compared with <90% or <80% baseline.[10]

The same authors in 2005 showed that hypotension was virtually eliminated by the combination of a high-dose phenylephrine infusion and rapid IV crystalloid cohydration.[15] Patients who received cohydration with the phenylephrine infusion had greater hemodynamic stability compared with patients who received maintenance fluid and required less phenylephrine to maintain their blood pressure. This technique had no adverse effect on neonatal outcome and a low incidence of maternal nausea and vomiting.[15]

Some authors have performed meta-analyses on various studies which had used ephedrine and phenylephrine bolus and infusion on maternal and fetal effects. Habib [16] analyzed 21 studies and Veeser et al.[17] pooled 20 studies and concluded that ephedrine was associated with lower umbilical cord pH and more nausea and vomiting in women undergoing lower segment CS.

Unlike fixed-dose infusions used by the previous authors, Siddik-Sayyid et al.[18] compared variable rate phenylephrine infusions versus rescue boluses and found that in the infusion group SBP was maintained closer to baseline with less nausea/vomiting.

Heesen et al.[19] performed a systematic review of 21 randomized trials of prophylactic phenylephrine. They found that the relative risk of hypotension with a phenylephrine infusion was lower than an ephedrine infusion and nausea/vomiting was reduced. They commented that the use of prophylactic infusions does expose those patients who are not prone to hypotension to phenylephrine unnecessarily, but there was no evidence that hypertension, bradycardia, or neonatal endpoints were affected. Our results are similar to this meta-analysis.

Prophylactic bolus doses have also been used by various workers. Lee et al.[4] used prophylactic bolus doses of 1 μg/kg, 1.5 μg/kg, and 2.0 μg/kg phenylephrine in low-dose SA. They found an incidence of 37% hypotension with 1.5 μg/kg which needed to be treated with rescue 100 μg phenylephrine. Kuhn et al.[20] gave phenylephrine initial bolus of 0.25 μg/kg and infusion of 0.25 μg/kg/min. They monitored cardiac output and concluded that phenylephrine prevented hypotension primarily by restoring systemic vascular resistance and did not cause hypertension or a clinically relevant reduction in cardiac output.

Body weight-adjusted (0.5 mg/kg/min) infusion of phenylephrine has been used by Mwaura et al.[21] They reported that this resulted in a lower incidence of hypotension versus a fixed-rate (37 mg/min) infusion (18.6% vs. 35.2%). Although adjusting dose according to weight makes pharmacological sense, many clinicians prefer to use titrated nonweight-adjusted infusions for simplicity.

In the consensus statement by AAGBI, Kinsella et al.[9] recommend a variable rate prophylactic infusion of phenylephrine to be started at 25–50 μg/min immediately after the intrathecal injection. They state that in clinical practice, if a bolus of vasopressor is administrated, when a low blood pressure is recorded, it leads to a delay in the effect of the treatment. In comparison, a prophylactic infusion started immediately after the spinal and titrated to blood pressure and pulse rate is more effective in preventing maternal hypotension.

Our results prove the hypothesis that the fixed infusion regimen is better than the therapeutic bolus group in maintaining maternal hemodynamic stability.

The primary outcome of our study was that 50 μg/min infusion maintains a tight control of SBP compared to reactive 50 μg bolus of phenylephrine. The secondary outcome was that none of the parameters such as APGAR or uterine artery blood gas analysis which indicate neonatal acidosis reached statistical significance. The side effects such as nausea and vomiting were significantly higher in the therapeutic bolus group.

In our study, we have kept the preloading volume to fixed 500 ml over 10 min and thereafter at 7 ml/kg/h which is as per our hospital protocol. The dose of hyperbaric bupivacaine was 10 mg, and 10 μg fentanyl was used as an additive. This was as per our departmental protocol for patients who are 150–170 cm tall and it was found to be adequate in achieving a level of at least T6. The dose of phenylephrine in the bolus and infusion groups was decided based on the studies by previous workers. We found that in the group receiving reactive bolus dose of phenylephrine (50 μg) when there was a significant fall in SBP (20%), it was restored with a single dose. In the group receiving prophylactic infusion of phenylephrine (50 μg/min) started immediately after the administration of SA, there was minimal fall in the blood pressure and none of the patients needed a rescue dose. It was observed that the maternal heart rate in the bolus group remained higher after 2 min than in the phenylephrine infusion group. The absence of reflex bradycardia in both the groups in our study could be explained by the low 50 μg dose of phenylephrine which we have used compared to other authors who have used 100 μg.[14] The high incidence of hypotension in some other studies can be attributed to a higher dose of bupivacaine that the authors have used.[18]

The limitation of our study is that only one 50 μg dose of reactive bolus phenylephrine has been studied and compared with infusion instead of multiple weight-adjusted or titrated doses. This was done for the sake of simplicity for clinical use and because we did not monitor intra-arterial pressure. Blinding of the researcher cannot be done as manual interventions are needed to treat episodes of hypotension.


   Conclusion Top


The results of this study suggest that phenylephrine, when given as a prophylactic infusion, leads to a significantly better control of postspinal hypotension during CS and lesser intraoperative maternal side effects such as nausea and vomiting. When used in the dose of 50 μg/min, it does not lead to any reflex bradycardia or reactive hypertension. The APGAR scores and fetal acid–base status did not show any evidence of acidosis which was similar to the bolus regimen.

The present study has been conducted in normotensive patients. Further studies are needed in hypertensive parturients and in the presence of preexisting fetal distress to clarify whether there is a significant benefit of phenylephrine infusion over therapeutic bolus. As stated by Kinsella et al., the efficacy of prophylactic boluses and variable rate infusions also needs further research.[9]

In future, automated smart pumps to deliver vasopressors in response to maternal physiologic variables are on the horizon.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
   References Top

1.
Carvalho B, Dyer RA. Norepinephrine for spinal hypotension during cesarean delivery: Another paradigm shift? Anesthesiology 2015;122:728-30.  Back to cited text no. 1
    
2.
Mercier FJ, Augè M, Hoffmann C, Fischer C, Le Gouez A. Maternal hypotension during spinal anesthesia for caesarean delivery. Minerva Anestesiol 2013;79:62-73.  Back to cited text no. 2
    
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Bimbach DJ, Browne IM. Anesthesia for obstetrics. In: Miller RD, editor. Miller's Anesthesia. 7th ed. Philadelphia: Churchill Livingstone; 2010. p. 4758.  Back to cited text no. 3
    
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Lee JE, George RB, Habib AS. Spinal-induced hypotension: Incidence, mechanisms, prophylaxis, and management: Summarizing 20 years of research. Best Pract Res Clin Anaesthesiol 2017;31:57-68.  Back to cited text no. 4
    
5.
Cyna AM, Andrew M, Emmett RS, Middleton P, Simmons SW. Techniques for preventing hypotension during spinal anaesthesia for caesarean section. Cochrane Database Syst Rev 2006;18:CD002251.  Back to cited text no. 5
    
6.
Lee A, Ngan Kee WD, Gin T. A quantitative, systematic review of randomized controlled trials of ephedrine versus phenylephrine for the management of hypotension during spinal anesthesia for cesarean delivery. Anesth Analg 2002;94:920-6.  Back to cited text no. 6
    
7.
Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS, et al. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for cesarean delivery. Anesthesiology 2002;97:1582-90.  Back to cited text no. 7
    
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Practice guidelines for obstetric anesthesia: An updated report by the American Society of Anesthesiologists Task Force on Obstetric Anesthesia and the Society for Obstetric Anesthesia and Perinatology. Anesthesiology 2016;124:270-300.  Back to cited text no. 8
    
9.
Kinsella SM, Carvalho B, Dyer RA, Fernando R, McDonnell N, Mercier FJ, et al. International consensus statement on the management of hypotension with vasopressors during caesarean section under spinal anaesthesia. Anaesthesia 2018;73:71-92.  Back to cited text no. 9
    
10.
Allen TK, George RB, White WD, Muir HA, Habib AS. A double-blind, placebo-controlled trial of four fixed rate infusion regimens of phenylephrine for hemodynamic support during spinal anesthesia for cesarean delivery. Anesth Analg 2010;111:1221-9.  Back to cited text no. 10
    
11.
Ngan Kee WD. The use of vasopressors during spinal anaesthesia for caesarean section. Curr Opin Anaesthesiol 2017;30:319-25.  Back to cited text no. 11
    
12.
Dyer RA, Biccard BM. Ephedrine for spinal hypotension during elective caesarean section: The final nail in the coffin? Acta Anaesthesiol Scand 2012;56:807-9.  Back to cited text no. 12
    
13.
Ngan Kee WD, Khaw KS. Vasopressors in obstetrics: What should we be using? Curr Opin Anaesthesiol 2006;19:238-43.  Back to cited text no. 13
    
14.
Ngan Kee WD, Khaw KS, Ng FF, Lee BB. Prophylactic phenylephrine infusion for preventing hypotension during spinal anesthesia for cesarean delivery. Anesth Analg 2004;98:815-21.  Back to cited text no. 14
    
15.
Ngan Kee WD, Khaw KS, Ng FF. Prevention of hypotension during cesarean delivery: An effective technique using combination phenylephrine infusion and crystalliod cohydration. Anesthesiology 2005;103:744-50.  Back to cited text no. 15
    
16.
Habib AS. A review of the impact of phenylephrine administration on maternal hemodynamics and maternal and neonatal outcomes in women undergoing cesarean delivery under spinal anesthesia. Anesth Analg 2012;114:377-90.  Back to cited text no. 16
    
17.
Veeser M, Hofmann T, Roth R, Klöhr S, Rossaint R, Heesen M. Vasopressors for the management of hypotension after spinal anaesthesia for elective caesarean section. Systematic review and cumulative meta-analysis. Acta Anaesth Scand 2012;56:810-6.  Back to cited text no. 17
    
18.
Siddik-Sayyid SM, Taha SK, Kanazi GE, Aouad MT. A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses versus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery. Anesth Analg 2014;118:611-8.  Back to cited text no. 18
    
19.
Heesen M, Kölhr S, Rossaint R, Straube S. Prophylactic phenylephrine for caesarean section under spinal anaesthesia: Systematic review and meta-analysis. Anaesthesia 2014;69:143-65.  Back to cited text no. 19
    
20.
Kuhn JC, Hauge TH, Rosseland LA, Dahl V, Langesæter E. Hemodynamics of phenylephrine infusion versus lower extremity compression during spinal anesthesia for cesarean delivery: A randomized, double-blind, placebo-controlled study. Anesth Analg 2016;122:1120-9.  Back to cited text no. 20
    
21.
Mwaura L, Mung'ayi V, Kabugi J, Mir S. A randomised controlled trial comparing weight adjusted dose versus fixed dose prophylactic phenylephrine infusion on maintaining systolic blood pressure during caesarean section under spinal anaesthesia. Afr Health Sci 2016;16:399-411.  Back to cited text no. 21
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]


This article has been cited by
1 Update on Vasopressors for Cesarean Delivery
Stephen Ramage,Sarah Armstrong,Roshan Fernando
Current Anesthesiology Reports. 2019;
[Pubmed] | [DOI]



 

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