Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
Journal of Obstrectic Anaesthesia and Critical Care
Search articles
Home Print this page Email this page Small font size Default font size Increase font size Users Online: 1110

 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 8  |  Issue : 1  |  Page : 29-34

A comparative study of phenylephrine and ephedrine combination to ephedrine and phenylephrine alone for maintenance of blood pressure for caesarean delivery and their effects on foetal acid base status


Department of Anaesthesiology, King George's Medical University, Lucknow, Uttar Pradesh, India

Date of Web Publication13-Apr-2018

Correspondence Address:
Dr. Reetu Verma
Department of Anaesthesiology, King George's Medical University, Lucknow, Uttar Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joacc.JOACC_17_16

Rights and Permissions
  Abstract 


Introduction: Spinal anaesthesia is the preferred technique for caesarean section. Around 80% of which is complicated by maternal hypotension. Vasopressors are currently the treatment of choice for spinal-induced hypotension but these may individually have significant maternal or foetal side effects. Aim: To compare ephedrine and phenylephrine infusion with ephedrine and phenylephrine combination for preventing the hypotension in patients undergoing emergency caesarean section under spinal anaesthesia. Materials and Methods: A prospective randomized double blind study of 90 parturients beyond 32 weeks of pregnancy for caesarean section under spinal anaesthesia. Assuming a potency ratio of 80:1 ephedrine to phenylephrine, the patients were divided into the following three groups: Group E - received infusions of ephedrine 8 mg/ml, Group P - received infusions of 100 mcg/ml phenylephrine and Group E + P received infusion of ephedrine 4 mg/ml + phenylephrine 50 mcg/ml. A predefined algorithm was used to adjust the infusion rate according to the systolic blood pressure (SBP). After spinal injection, SBP, diastolic blood pressures (DBP), heart rate (HR) were recorded every one minute until the cord was clamped. Also, the vasopressor infusion rates were collected till clamping of umbilical cord in each group. Foetal parameters were analyzed from umbilical blood gas. Results: The incidence of hypotension was significantly higher in ephedrine group. The mean rate of infusion was higher for group E (P < 0.05). The foetal metabolism measured by mean pH, was significantly higher in group P(P > 0.05) as compared to others. Complications of bradycardia were observed in 30% of patients receiving phenylephrine. Conclusions: Combination of both phenylephrine and ephedrine is efficacious for spinal-induced hypotension with least maternal or foetal side effects.

Keywords: Ephedrine, foetal acid base status, phenylephrine


How to cite this article:
Singh R, Verma R, Bhatia V K, Chaudhary AK, Chandra G. A comparative study of phenylephrine and ephedrine combination to ephedrine and phenylephrine alone for maintenance of blood pressure for caesarean delivery and their effects on foetal acid base status. J Obstet Anaesth Crit Care 2018;8:29-34

How to cite this URL:
Singh R, Verma R, Bhatia V K, Chaudhary AK, Chandra G. A comparative study of phenylephrine and ephedrine combination to ephedrine and phenylephrine alone for maintenance of blood pressure for caesarean delivery and their effects on foetal acid base status. J Obstet Anaesth Crit Care [serial online] 2018 [cited 2019 Dec 12];8:29-34. Available from: http://www.joacc.com/text.asp?2018/8/1/29/230057




  Introduction Top


Regional anaesthesia is the preferred anaesthetic technique for caesarean section nowadays. It avoids the maternal risks of general anaesthesia such as aspiration of gastric contents and difficulty with airway management.[1] Though it confers greater safety for the mother compared with general anaesthesia, common limitation of spinal anaesthesia is hypotension due to sympathetic blockade that may also affect the foetus leading to acidosis. Maternal bradycardia should be avoided at all cost as it accentuates the observed haemodynamic effects.

The incidence of hypotension in spinal anaesthesia is 80% without any prophylactic measures.[2] Vasopressor drugs has been observed to be more effective than crystalloid solution or placebo in preventing spinal anaesthesia-induced hypotension.[3] An appropriate vasopressor in obstetrics should be efficacious, having less maternal effects other than increasing blood pressure, easy to use, minimum direct and indirect foetal effects, cost effective and should be easily available. However, the widely available and commonly used drugs for which the safety data is available are ephedrine and phenylephrine.

Ephedrine is an indirectly acting sympathomimetic drug having α and β-adrenergic actions and increases blood pressure with minimal effect on utero-placental blood flow. It has been proposed that ephedrine crosses the placenta and increases foetal catecholamine concentrations. It acts on foetal β1 receptors, increasing oxygen consumption and lactate concentration.[4] The propensity of ephedrine to cause maternal tachycardia and depress foetal pH and base excess has resulted in suggestions to eliminate or drastically limit its use.[5]

Phenylephrine is a short-acting potent α 2 agonist; it causes vasoconstriction and increases both SBP and DBP counteracting the vasodilatation due to neuraxial anaesthesia. It is considered as a first line vasopressor for management of spinal induced hypotension during caesarean section.[6] It is efficacious and is associated with less foetal acidosis compared with ephedrine. However, the use of phenylephrine is associated with reflex bradycardia which is deleterious to both the mother and the foetus.[7]

A newer idea of using a combination of both has been tried. The physiologic rationale for adding phenylephrine to ephedrine is to increase the α/β-agonist activity ratio. The positive chronotropic and inotropic effects of ephedrine may be useful to counter the reflex decreases in heart rate and cardiac output that phenylephrine may induce. Previous studies done by Mercier et al., Das et al., and Saravanan et al. have made an attempt to add ephedrine to phenylephrine infusion.[8],[9],[10] It is proposed in this study that combination will allow us to use lesser amounts of each drug thereby avoiding their complications, hence we have compared the ephedrine and phenylephrine infusion with ephedrine and phenylephrine combination for preventing hypotension in patients undergoing emergency caesarean section under spinal anaesthesia. Primary outcome measure was incidence of hypotension and secondary outcome measures were rate of infusion signifying the amount of drug to maintain a stable SBP, the side effects of these drugs on the mother like bradycardia, tachycardia, nausea and vomiting etc., and their effects on foetus.


  Materials and Methods Top


After getting institutional ethics committee approval a randomized double-blind study was conducted on patients admitted in Gynaecology and Obstetrics department of KGMU over a period of one year (July 2014–June 2015). Three groups comprising of at least 30 patients in each group with women aged between 18 to 40 years, ASA grade 1 and 2 with uncomplicated singleton pregnancy beyond 32 weeks for emergency caesarean section under spinal anaesthesia were eligible for this study. Parturient with comorbidities, in labour, with known allergy to the study drug, non-consenting and those converted to general anaesthesia were excluded.

After a complete pre-anaesthetic check-up an informed consent was obtained from all the patients. An 18-gauge intravenous (IV) cannula was inserted into a forearm vein and connected to a crystalloid for pre loading @ 15 ml/kg. Patients received IV premedication with ranitidine -50 mg; metoclopramide- 20 mg. Standard non-invasive monitors were applied and baseline values of heart rate (HR), blood pressure (BP), electrocardiogram (Ecg) and oxygen saturation (Spo2) were recorded. Under aseptic condition a 23/25 gauge spinal needle was inserted at L3–4 or L4–5 vertebral interspace and hyperbaric 0.5% bupivacaine (10 mg) and fentanyl 15 μg was injected intrathecally. Patient was then returned to supine position with 15 left lateral tilt. After induction of spinal anaesthesia, vasopressor infusion started at the rate of 40 ml/h in all patients. Patients were randomly distributed using a computer generated random table into the following three groups: Group E - received infusions of ephedrine 8 mg/ml, Group P - received infusions with 100 mcg/ml phenylepherine, Group E + P - received infusions ephedrine 4 mg/ml + phenylephrine 50 mcg/ml. The infusions were prepared separately in a 50-ml syringe and were given to the emergency anaesthesia team to observe the effect. The observing team remained blinded to the drug. The different anaesthesiologist prepared and supplied the drug as per randomization number and was not related to data collection, monitoring or conduct of anaesthesia. Assessors were blinded to group allocation, patient profile and the study drugs.

A predefined algorithm was used to adjust the infusion rate according to the SBP. This rate was maintained if SBP remained within 90–110% of baseline. The rate of infusion was halved (20 ml/h) if SBP was more than 110%. The infusion was stopped if SBP was increased to more than 120% of baseline value and restarted at 40 ml/h if SBP decreased back to between 90% and 110%. The rate was doubled (80 ml/h) if SBP was decreased to between 80% and 90% of baseline. Hypotension (SBP less than 80% of baseline) was treated with IV 6 mg ephedrine bolus.

Upper level of sensory block was observed after 5 minutes of spinal injection and every 5 minutes thereafter till 30 minutes by bilateral loss of pinprick discrimination. Surgery was started only after upper level of sensory block reached T5. After spinal injection, data [SBP, DBP, HR] were taken every 1 minute until cord clamping. Data of vasopressor administration were collected till clamping of umbilical cord. Bradycardia (maternal HR less than 50 beats per minute) if associated with hypotension was treated with 0.6 mg IV atropine. Bradycardia, if clinically tolerable and not associated with maternal hypotension, was treated by stopping the infusion temporarily. The incidence of maternal tachycardia (HR >100 beats/min) and reactive hypertension (increase in systolic pressure above baseline by 20%) were recorded. The time of induction of spinal anaesthesia, uterine incision and delivery were recorded. At the delivery of anterior shoulder of baby, oxytocin 5 units was given by slow IV injection followed by a 10-unit infusion in 500 ml 0.9% normal saline by slow infusion. Any complications observed during spinal anaesthetic technique such as nausea, vomiting or dizziness were also recorded. No nausea was given grade 0, nausea with no vomiting as grade1 and nausea and vomiting as grade 2. Arterial blood sample were obtained from a double-clamped segment of umbilical cord and analysed within 10 min. Apgar scores at 1, 5 and 10 min were determined by the attending paediatrician who was unaware of group assignment.

Sample size was calculated according to the previous study which showed the incidence of hypotension as 4% in group P and 24% in group E.[11] Assuming to have at least 80% power and an alpha error of 0.05 and design effect of 20, sample size calculated was 26. The study was done till 30 patients were recruited in each group. Data were summarized as Mean ± SD. Groups were compared by one way analysis of variance (ANOVA) and the significance of mean difference between the groups was done by Tukey's post hoc test. Groups were also compared by two factor repeated measure ANOVA using general linear models (GLM) and the significance of mean difference within and between the groups was done by Tukey's post hoc test. Discrete (categorical) groups were compared by Chi-square (χ2) test. A two-sided (α= 2) P value less than 0.05 (P < 0.05) was considered statistically significant. All analyses were performed on STATISTICA software (Windows version 6.0).


  Results Top


The demographic profile and clinical features (block height at 5 min, block height at 15 min, induction-delivery time and uterine incision delivery time) were comparable between three groups [Table 1] and [Table 2].
Table 1: Basic characteristics of three groups

Click here to view
Table 2: Clinical features of three groups

Click here to view


The mean SBP in all three groups shows similar trend at all periods; decrease from 0 min to 3 min and then increase gradually till end. Comparing the mean SBP of three groups showed significantly lower mean SBP in group E as compared to respective baseline SBP. Group P and Group E+P showed insignificant difference in the values [Figure 1].
Figure 1: Mean SBP of three groups during spinal anaesthesia

Click here to view


[Figure 2] compares the mean HR between the three groups, and show significantly lower HR of group P as compared to respective level of group E. Similarly, the mean HR of group P also lowered significantly (P < 0.05 or P < 0.01) as compared to respective level of group E+P. Between group E and group E+P mean HR at all periods did not differ significantly (P > 0.05).
Figure 2: Mean HR of three groups during spinal anaesthesia

Click here to view


The mean rate of infusion depicts the total amount of drug infused and it is statically higher for group E as compared to the other two groups. Group P and Group E+P shows almost similar trends with insignificant difference meaning that they are equally efficacious [Figure 3].
Figure 3: Mean rate of infusion of three groups during spinal anaesthesia

Click here to view


The foetal metabolism was measured in terms of the umbilical cord blood gas analysis [Table 3]. Apgar scores differed insignificantly in all three groups, increased linearly and similarly with time. Mean PO2 did not differ (P > 0.05) between the groups. The mean pH of group P was found to be significantly (P < 0.01) different and higher as compared to group E+P and group E. Addition of ephedrine caused significantly lower pH values. The mean base excess did not differ (P > 0.05) between group E and group P but lower mean base excess of group E+P as compared to both group E and group P.
Table 3: Secondary outcome measures – foetal and acid base status

Click here to view


[Table 4] shows the complications in the study. Incidence of hypotension was significantly higher in Group E (P < 0.05). Bradycardia was seen in 30% patients of Group P, 11% of which required treatement with atropine. Other complications of nausea, vomiting and rebound hypertension were seen with Group E.
Table 4: Complications related to the three groups

Click here to view



  Discussion Top


In our study, we compared the ephedrine and phenylephrine infusion with ephedrine and phenylephrine combination for preventing hypotension in patients undergoing emergency caesarean section under spinal anaesthesia and observed that incidence of hypotension requiring rescue boluses was least in combination group. Mercier et al. and Cooper et al. had also observed the same in their studies.[8],[12]

The other outcome variables were a stable maternal haemodynamic and rate of infusion of drugs which signify the amount of drug infused and the total amount of drug required to maintain maternal perfusion. Earlier studies have proven that the percentage decrease in placental perfusion is related to the percentage reduction in maternal arterial pressure and not to the absolute reduction in pressures.[11] So active intervention to prevent spinal induced hypotension was considered in this study, pharmacological method being the preferred choice. Contrary to earlier practices the role of boluses for the prevention of spinal induced hypotension has been challenged as it has been observed with rapid shoot-ups and unpredictable responses.[7] Steady perfusion pressure benefits both the mother and the foetus. So, infusion of drugs helps maintain this goal in a better manner. As invasive monitors for cardiac output measurement were not used, we measured SBP and HR as surrogate markers of cardiac output and tissue perfusion. Appreciating that the mean arterial pressure is a better indicator of tissue perfusion, we have used SBP as a clinically useful endpoint on which our therapy was based and most of the earlier studies have used SBP as primary outcome.[12],[13] Various potency ratios have been tried but 80:1 (ephedrine: phenylephrine) has been found to be most effective for controlling spinal induced hypotension.[10] So in our study we have used this ratio.

In our study, we observed that the mean rate of infusion was significantly higher in group E as compared to other groups. That means larger amount of ephedrine is required to prevent spinal-induced hypotension. Cooper et al. also observed the same in their study.[12] We also observed that mean SBP was significantly lower in ephedrine group. Odagme et al. also established the supremacy of phenylephrine over ephedrine regarding prevention of maternal hypotension during caesarean section under spinal anaesthesia.[14]

Complications are unavoidable with use of any drugs. Risk benefit ratio should always be weighed with use of all drugs. In our study, we observed that incidence of tachycardia and hypotension was significantly higher in ephedrine group. Reactive hypertension was occasionally found in ephedrine group, which was clinically insignificant. Maternal bradycardia was a significant complication observed in our study in phenylephrine group. Reason for which could be the reflex activation of vagal autonomic fibres to the heart.[15],[16] Ngan Kee et al. and Stewart et al. have studied different phenylephrine infusion rates in their study that demonstrated dose-related reductions in heart rate.[17],[18] But dose reduction compromises the basic aim for maintaining stable maternal SBP. In our study, we have observed that incidence of bradycardia was 0% in combination group, whereas in a study conducted by Das et al. where they have used the 33:1 potency ratio, it was found to be 9%.[9] But overall incidence of maternal bradycardia in their study was less in the combination group. So, combination helps combat the side effects of individual drugs and achieve a comparable stable haemodynamic providing a good perfusion to the mother and foetus. An insignificant complication of nausea and vomiting was seen in 20% of patients in group E compared to none in group P and group E+P. Maternal nausea occurred despite having good systolic pressure (within 20% of baseline) and so can be attributed to side effect of ephedrine.

The drugs used to treat maternal hypotension may have an affect the foetus too. Ephedrine, which crosses the placental barrier, is proposed to act on β receptors and increase the metabolism.[16] The secondary outcomes of foetal well being were measured via Apgar score, and foetal arterial blood gas sampling. Umbilical cord blood gas and pH provide an indication of the fetal condition immediately before delivery, and might therefore be more useful than Apgar scores when assessing perfusion and the impact of vasopressors on the foetus.[11] Apgar scores did not differ significantly in the three groups indicating that the drugs had no effect on it. Foetal metabolism can be directly estimated by measuring levels of epinephrine and norepinephrine in the blood.[16] Indirect parameters that can be measured include blood gas analysis, blood pH values or base excess levels.[16],[17],[18],[19],[20],[21] We analysed the values of Po2, Pco2, pH, Hco3 levels. Po2 and Pco2 differed insignificantly in our study. The pH of three groups ranged from 7.21–7.44 with significantly different and higher mean pH of group P and group E+P as compared to group E [Table 1]. The pH values remain in the near normal range but difference in group P is significant and highest compared to other groups. This can be due to ephedrine in groups E and E+P, which crosses placental barrier and is proposed to cause increase in metabolism. Furthermore, the base excess of the groups showed similar trends. Similar trends in value were shown in other studies too.[8],[11]{Table 1}

Our study took place in emergency settings and the indications for caesarean section can have an effect on the foetus apart from the drugs being used. This can be a limitation to our study. For that we suggest the use of direct parameters to measure foetal metabolism in contrast to indirect ones used in our study. Other limitation can be sample size for which large randomized study be carried on larger population.

We can conclude that ephedrine is less efficacious in terms of providing a stable maternal SBP and is associated with significant maternal hypotension and foetal acidosis. Both phenylepherine alone or phenylepherine with ephedrine are equally efficacious for blood pressure control but phenyepherine alone is associated with significant maternal side effects like bradycardia. A combination allows us to use less amount of drug individually thereby decreasing its side effects with equally efficacious control of spinal-induced hypotension.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hawkins JL, Koonin L, Palmar S. Anesthesia-related deaths during obstetrics delivery in United States. Anaesthesia 1997;86:277-84.  Back to cited text no. 1
    
2.
Riley ET, Cohen SE, Rubenstein AJ, Flanagan B. Prevention of hypotension after spinal anaesthesia for caesarean section: 6% hetastarch versus lactated Ringer's solution. Anaesth Analg 1995;81:838-4.  Back to cited text no. 2
    
3.
Tsen LC. Anesthesia for cesarean delivery. In: Chestnut DH, editor. Chestnut's Obstetrics Anesthesia. 5th ed. Philadelphia: Elsevier; year p. 581.  Back to cited text no. 3
    
4.
Gournay VA, Roman C, Rudolph AM. Effect of beta adrenergic stimulation on oxygen metabolism in fetal lamb. Pediatr Res 1999;45:432-6.  Back to cited text no. 4
    
5.
Riley ET. Spinal anaesthesia for Caesarean delivery: Keep the pressure up and don't spare the vasoconstrictors. Br J Anaesth 2004;92:459-61.  Back to cited text no. 5
    
6.
Ngan Kee WD. Prevention of maternal hypotension after regional anaesthesia for caesarean section. Curr Opin Anesthesiol 2010;23:304-9.  Back to cited text no. 6
    
7.
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 caesarean delivery. Anaesth Analg 2010;111:1221-9.  Back to cited text no. 7
    
8.
Mercier FJ, Riley ET, Frederickson WL, Roger-Christoph S, Benhamou D, Cohen SE. Phenylephrine added to prophylactic ephedrine infusion during spinal anesthesia for elective Caesarean section. Anesthesiology 2001;95:668-74.  Back to cited text no. 8
    
9.
Das S, Mukhopadhyay S, Mandal M, ManSekhar S, Basu R. A comparative study of infusions of phenylephrine ephedrine and phenylephrine plus ephedrine on maternal haemodynamics in elective caesarean section. Indian J Anaesth 2012;55;578-83.  Back to cited text no. 9
    
10.
Saravanan S, Kocarev M, Wilson RC, Watkins E, Columb MO, Lyons G. Equivalent dose of ephedrine and phenylephrine in the prevention of post-spinal hypotension in caesarean section. Br J Anaesth 2006;96:95-9.  Back to cited text no. 10
    
11.
Ngan Kee WD, Khaw KS, Tan PE, Ng FF, Karmakar MK. Placental Transfer and Fetal Metabolic Effects of Phenylephrine and Ephedrine during Spinal Anaesthesia for Caesarean Delivery. Anaesthesiology 2009;111:506-12.  Back to cited text no. 11
    
12.
Cooper DW, Carpenter M, Mowbray P, Desira WR, Ryall DM, Kokri MS. Fetal and maternal effects of phenylephrine and ephedrine during spinal anesthesia for Caesarean delivery. Anesthesiology 2002;97:1582-90.  Back to cited text no. 12
    
13.
Prakash S, Pramanik V, Chellani H, Salhan S, Gogia AR. Maternal and neonatal effects of bolus administration of ephedrine and phenylephrine during spinal anaesthesia for caesarean delivery: A randomised study. Int J Obstet Anesth 2010;19:24-30.  Back to cited text no. 13
    
14.
Odagme MT, Fyneface-Ogan S, Mato CN. Prophylactic infusions of Phenylephrine and Ephedrine during combined Spinal Epidural Spinal Anaesthesia for Caesarean Section: A Comparative Study. J Anesth Clin Res 2013;4:357.  Back to cited text no. 14
    
15.
Thomas DG, Robson SC, Redfern N, Hughes D, Boys RJ. Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anesthesia for Caesarean section. Br J Anaesth 1996;76:61-5.  Back to cited text no. 15
    
16.
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 caesarean delivery. Anesth Analg 2002;94:920-6.  Back to cited text no. 16
    
17.
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. 17
    
18.
Stewart A, Fernando R, McDonald S, Hignett R, Jones T, Columb M. The dose-dependent effects of phenylephrine for elective cesarean delivery under spinal anesthesia. Anesth Analg 2010;111:1230-7.  Back to cited text no. 18
    
19.
Ngan Kee WD, Lau TK, Khaw KS, Lee BB. Comparison of metaraminol and ephedrine infusions for maintaining arterial pressure during spinal anesthesia for elective caesarean section. Anesthesiology 2001;95:307-13.  Back to cited text no. 19
    
20.
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. 20
    
21.
Ngan Kee WD, Lee A, Khaw KS, Ng FF, Karmakar MK, Gin T. A randomized double-blinded comparison of phenylephrine and ephedrine combinations given by infusion to maintain blood pressure during spinal anesthesia for caesarean delivery: Effects on fetal acid-base status and hemodynamic control. Anesth Analg 2008;107:1295-302.  Back to cited text no. 21
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]


This article has been cited by
1 Vasopressor drugs for the prevention and treatment of hypotension during neuraxial anaesthesia for Caesarean delivery: a Bayesian network meta-analysis of fetal and maternal outcomes
Preet M. Singh,Narinder P. Singh,Matthew Reschke,Warwick D.Ngan Kee,Arvind Palanisamy,David T. Monks
British Journal of Anaesthesia. 2019;
[Pubmed] | [DOI]



 

Top
 
 
Search
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)  

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1177    
    Printed59    
    Emailed0    
    PDF Downloaded214    
    Comments [Add]    
    Cited by others 1    

Recommend this journal