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Abstract
Introduction
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ORIGINAL ARTICLE
Year : 2021  |  Volume : 22  |  Issue : 2  |  Page : 136-142
 

A randomized, double-blinded comparative study of phenylephrine infusion and norepinephrine infusion for the prevention and treatment of spinal anesthesia-induced hypotension in elective and emergency cesarean deliveries


1 Department of Anaesthesiology, Pramukhswami Medical College, Bhaikaka University, Karamsad, Gujarat, India
2 Department of Central Research Services, Bhaikaka University, Karamsad, Gujarat, India

Date of Submission23-Jan-2021
Date of Decision19-Apr-2021
Date of Acceptance08-Jul-2021
Date of Web Publication29-Sep-2021

Correspondence Address:
Dr. Sanket Hirenbhai Mehta
H-88, Yogidarshan Society, Opposite Manjalpur Township No. 2, Near Sai Chokdi, Manjalpur, Vadodara - 390 011, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/TheIAForum.TheIAForum_9_21

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  Abstract 


Context and Aims: Among vasopressors used to treat postspinal hypotension (PSH) in cesarean sections (CS), phenylephrine (PE) is the preferred drug at present but reflex bradycardia and thus reduction in cardiac output still pose a concern. Norepinephrine (NE), with its better pharmacological properties, may be a better alternative to overcome this risk. Hence, we did this study intending to compare both the drugs.
Materials and Methods: A double-blinded, randomized, controlled trial (RCT) was carried out on 70 patients, 35 in each group-group P (PE) and group N (NE) undergoing CS, to compare and evaluate the efficacy of both drugs for preventing and treating PSH. Patients in Group P and Group N were given intravenous infusion of PE at the rate of 50 μg/min and NE at the rate of 2.5 μg/min, respectively, after the intrathecal injection of bupivacaine. The number of intermittent bolus doses required, heart rate, and mean arterial pressure (MAP) at predefined intervals were noted.
Results: The incidence of hypotension calculated from the number of bolus doses required was lower in Group N than in Group P for the initial 15 min (P < 0.05). The incidence of bradycardia and vomiting was higher in Group P but were not statistically significant, while the incidences of nausea (P = 0.004) and oxygen requirement (P = 0.03) were statistically significantly higher in Group P.
Conclusion: This study suggests that NE infusion is superior to PE infusion when used in the potency ratio of 20:1, to prevent and treat PSH in CS, with a lesser number of side effects.


Keywords: Cesarean section, norepinephrine, phenylephrine, postspinal hypotension, spinal anesthesia, vasopressors


How to cite this article:
Berawala PK, Mehta SH, Chaudhari MS, Shinde MK. A randomized, double-blinded comparative study of phenylephrine infusion and norepinephrine infusion for the prevention and treatment of spinal anesthesia-induced hypotension in elective and emergency cesarean deliveries. Indian Anaesth Forum 2021;22:136-42

How to cite this URL:
Berawala PK, Mehta SH, Chaudhari MS, Shinde MK. A randomized, double-blinded comparative study of phenylephrine infusion and norepinephrine infusion for the prevention and treatment of spinal anesthesia-induced hypotension in elective and emergency cesarean deliveries. Indian Anaesth Forum [serial online] 2021 [cited 2021 Dec 7];22:136-42. Available from: http://www.theiaforum.org/text.asp?2021/22/2/136/326986





  Introduction Top


Hypotension occurs after spinal anesthesia (SA) in obstetric patients due to sympathetic blockade and compression of inferior vena cava by gravid uterus decreasing venous return.[1] Maternal hypotension can lead to serious sequelae, including hypoxia, nausea, vomiting, cardiovascular instability, decreased uteroplacental circulation, depressed APGAR scores, and fetal acidosis.[2] Currently, phenylephrine (PE) is the preferred first-line vasopressor in maintaining blood pressure (BP) during SA.[3] Being a potent alpha-1-receptor agonist, its use is associated with reflex bradycardia and reduction in cardiac output (CO). This may be a concern in a compromised fetus. Norepinephrine (NE) being a potent alpha-adrenergic agonist with weak beta-adrenergic agonist activity can be an effective alternative as a vasopressor with less tendency to cause reflex bradycardia.[4],[5],[6] As catecholamines undergo a break down in the placenta, the safety of the fetus is also not a concern.[6],[7],[8] As there is a scarcity of data in the literature supporting the use of NE in the form of a continuous infusion, we decided to do a comparative study of the effects of NE and PE infusions on fetomaternal outcomes by preventing and treating postspinal hypotension (PSH) in cesarean sections (CS).


  Materials and Methods Top


Ethics

The present study was carried out after the Institutional Ethics Committee approval and registration in the Clinical Trials Registry-India (CTRI) (CTRI/2020/09/027704). All the selected patients were explained in detail about the purpose, procedure of the study, and possible side effects of the drugs being used as well as the procedure of SA. They were shown the letter of information on the study. The written informed consent for the study and SA was taken in the local vernacular language. The nil by mouth status was confirmed.

Study design

It was a double-blinded RCT study where randomization was done by the computer software WinPepi-generated randomization table [Figure 1].
Figure 1: Consort flow diagram depicting the study process

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Inclusion criteria

American Society of Anesthesiologists Grade (ASA) II and III patients undergoing elective and emergency CS were included in the study.

Exclusion criteria

Gestational age <36 weeks, multiple pregnancies, severe pregnancy-induced hypertension, eclampsia, epilepsy, diabetes mellitus, cardiac diseases, patient refusing for SA, and contraindications for SA were excluded from the study.

A multipara monitor (having electrocardiogram, SpO2, and noninvasive BP) was attached to the patient and baseline parameters such as heart rate (HR), systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP) were obtained.

Drug preparation

Group N– Injection NE 1 ml (=2000 μg), diluted up to 8 ml of normal saline (NS), to make 250 μg/ml. We took 0.5 ml of this solution and diluted up to 50 ml NS to make 2.5 μg/ml. The initial rate was set at 60 ml/h [Figure 2].
Figure 2: Commercially available preparation of injection norepinephrine

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Group P – Injection PE 1 ml (=10000 μg/ml), diluted up to 10 ml of NS, to make 1000 μg/ml. We took 2.5 ml of that and diluted up to 50 ml NS to make 50 ug/ml. The initial rate was set at 60 ml/h [Figure 3].
Figure 3: Commercially available preparation of injection phenylephrine

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All the participants were assigned a serial number 1−70 and divided into Group N or P as per the randomization protocol. The serial number of the participant with the group written against the number was placed in an opaque envelope which was opened and drug prepared accordingly by a third party anesthesiologist as described above. In all patients, 18G intravenous (IV) access was secured, monitors were attached, intrathecal injection of injection bupivacaine (heavy) 2−2.4 ml was given in the sitting position after which immediately supine-left lateral 15° tilt position was given along with co-loading of ringers lactate (RL) at the rate of 10 ml/kg body weight. Patients were given an IV infusion of the study drug at 60 ml/h immediately after SA. The level to be achieved of SA was T4.

The baseline values of HR, SBP, DBP, and MAP were recorded. The same parameters were monitored at zero (at the time of giving SA), 2, 4, 6, 8, 10, 15, 20, 30, 45, and 60 min after SA. Hypotension (SBP <20% of baseline value) was intervened by an incremental dose of 1 ml bolus of the study drug. HR <60 beats/min was treated by IV glycopyrrolate 0.2 mg. Immediately, after the delivery of the baby, the infusion dose was tapered gradually from 60 ml/h to 40 ml/h. The drug was immediately discontinued in the cases where arrhythmia occurred. The drug was tapered before the delivery of the baby when there was an increase in SBP >20% of baseline by decreasing the rate of infusion from 60 ml/h to 40 ml/h in both groups. APGAR score of the neonate was noted at 1 and 5 min.

Statistics

The incidence of hypotension was reported between 2.5% and 37.5% in the PE group from various studies. In the absence of reliable regional estimates, a 30% incidence of hypotension was assumed. An absolute reduction of 25% was considered clinically important. For this reduction, a sample of size 36 was required per group to achieve 80% power allowing for 5% type I (alpha) error. Considering the nature of the study, we did not expect any dropouts. Considering the time duration of the study (3 months), we expected about 80–85 eligible participants.[8],[9],[10] To maintain a proper priory randomization plan, 70 eligible participants were considered and divided into two groups of 35 each. This sample size was calculated using Stata 14.2 software (StataCorp LLC4905 Lakeway DriveCollege Station, Texas 77845-4512USA). Data were expressed as mean and standard deviation. The analysis of the data for the various parameters was done using the Student's unpaired t-test for the quantitative data and Chi-square test for the qualitative data using Stata 14.2 software.

P < 0.05 was considered statistically significant.


  Results Top


The mean age and weight of patients in Group P and Group N were showing a statistically significant difference. The mean height in both groups was comparable with no statistically significant difference [Table 1].
Table 1: Demographic profile

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On comparison of all the mean baseline parameters, apart from mean HR, all other parameters were comparable in both the groups. Mean HR was found to be less in the patients in Group N as compared to the patients in Group P with a statistically significant difference [Table 2].
Table 2: Mean baseline hemodynamics

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The mean total time from induction to delivery and mean total time of vasopressor administration was comparable in both groups, with no statistically significant difference [Table 3].
Table 3: Mean comparable time intervals for both groups

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The incidence of hypotension in the first 15 min after induction was 2.86% and 20.02% in Group N and Group P, respectively. The total number of intermittent bolus doses needed in the first 15 min and 60 min was lesser in Group N as compared to Group P with a statistically significant difference [Table 4]-.
Table 4: Incidence of hypotension in both groups (total number of intermittent bolus doses required) in first 15 min

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There was no statistically significant difference seen in the APGAR scores in the neonates from both groups at 1 and 5 min [Table 5].
Table 5: Assessment of APGAR score

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The comparison of mean difference of HR from baseline was not significant between the two groups initially up to 4 min after which it was significantly higher in Group P than in Group N [Table 6].
Table 6: Mean difference of heart rate from baseline AT different time intervals

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There were lesser incidences of complications in patients of Group N as compared to Group P. Nausea and a requirement of oxygen supplementation was statistically significantly more in Group P. We observed no incidence of pale skin which may occur due to local extravasation of vasopressors in any of the patients of both the groups [Table 7].
Table 7: Perioperative complications

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  Discussion Top


At present, ephedrine, PE, and NE are three commonly used vasopressors during CS.[11] Ephedrine has a slow onset, causes reactive hypertension, tachyphylaxis, has high placental transfer and stimulation of fetal metabolism and fetal acidemia, collectively make it an inferior choice compared to PE.[2] Thus, PE is at present the first-line vasopressor in obstetric PSH,[2] and its superiority in this context has been experimented with different dosing regimens.[12],[13] PE is a pure α-adrenergic receptor agonist with no β-adrenergic receptor activity thus causes arteriolar vasoconstriction to increase SVR and MAP, reflexively leading to a dose-dependent decrease of HR, in turn, decreasing CO.[14] In venous capacitance vessels, such vasoconstriction may increase venous return; however, venous resistance also increases, thus limiting venous return to the heart.[15] Whereas NE has weak β-receptor agonist activity in addition to α-adrenergic agonist activity hence is less likely to decrease HR and CO, making it a better alternative to PE. However, these data still need to be confirmed in an obstetric spinal parturient. Both NE and PE are catecholamines that do not readily cross the placenta. NE provided better maintenance of HR compared to PE in most trials. Monitoring of maternal HR can be used as a surrogate for CO if the CO cannot be monitored.[16]

Based on previous studies using NE and/or PE to prevent and treat PSH in CS either as a bolus or as a continuous iv infusion, we considered the 1:20 potency ratio to be the standard in our study.[4],[6],[7],[9],[17],[18],[19],[20]

The results of the study suggest that in the demographic data, there is a statistically significant difference in the mean age and weight of the patients of both groups. However, these differences were clinically nonsignificant. There was no statistically significant difference in the mean height of the patients of both groups.

Among the mean baseline hemodynamic parameters, there was a statistically significant difference in mean baseline HR of both groups. However, as we have defined the bradycardia as HR <60 beats/min and not a percentage decrease, these findings are clinically nonsignificant.

The differences in the meantime of induction to delivery and the total time of vasopressor administration were statistically nonsignificant. These results indicated that in most of the parturients, the babies were delivered as well as the infusions of the concerned drugs were stopped within 10 min of intrathecal injection of local anesthetic.

The incidence of hypotension calculated from the numbers of bolus doses required in both the groups was lower in Group N than in Group P for the initial 15 min with the statistical significance of P = 0.002. The incidence of hypotension in the first 15 min after induction was 2.86% and 20.02% in Group N and Group P, respectively. A total of 34 patients from 35 patients in Group N required no boluses at all and only 1 patient required 1 bolus dose. Whereas 28 patients from 35 patients in Group P required no bolus doses at all, 6 patients requiring 1 bolus dose and 1 patient requiring 3 bolus doses-thus collectively making 9 episodes of hypotension within initial 15 min in Group P.

Similar results were found in Puthenveettil et al. 2019[10] double-blinded RCT study in which the requirement of the boluses of similar drugs with slightly different concentrations (PE 50 μg, NE 4 μg) for the treatment of PSH was lower in Group N than in Group P with statistical significance of P = 0.001.

Sharkey et al. in their double-blinded RCT in 2018[9] found out that the incidence of hypotension was higher in patients receiving PE 100 μg than those receiving NE 6 μg as a preventive bolus although not statistically significant (P > 0.05).

In an open-label RCT done by Vallejo et al. in 2017[21] the results yielded were showing no statistically significant difference between the number of rescue boluses required for incidence of hypotension in both the similar groups.

The maternal central blood volume increases after baby delivery due to autotransfusion.[22] Our study is slightly different from other similar studies done in the past as, unlike other studies, we have continued the infusion of both vasopressors after baby delivery and have tapered down the infusions to 40 ml/h in both groups. The reason for this is that sudden stoppage of vasopressor infusion can lead to the episodes of hypotension as the duration of action of both vasopressors are short and the concentration used in our study is very low. There is a persistent autonomic spinal blockade even after baby delivery which continues to cause hypotension. To reduce the blood loss and contract the uterus, oxytocin is started which induces a brief, but significant, decrease in maternal BP due to peripheral vasodilatation.[23] Furthermore, there may be blood loss even after baby delivery due to various causes such as longer duration of the procedure, adhesions, atonic PPH, DIC, etc.

Similarly, the numbers of patients requiring bolus doses in both the groups to treat the episodes of hypotension were lower in Group N than in Group P for a total of 60 min time duration with the statistical significance of P = 0.045. The incidence of hypotension over 60 min after induction was 14.26% and 51.43% in Group N and Group P, respectively. A total of 30 patients from 35 patients in Group N required no bolus dose at all, 4 patients required 1 bolus dose and 1 patient required 2 bolus doses. Whereas, 17 patients from 35 patients in group P required no boluses at all, 13 patients requiring 1 bolus dose, 4 patients required 2 bolus doses and 1 patient requiring 3 bolus doses.

These results suggest that NE infusion is superior to PE infusion when used in the potency ratio of 20:1 (PE 50 μg/min and NE 2.5 μg/min) to prevent and treat PSH in elective or emergency CS.

Nausea, the requirement of oxygen supplementation was statistically significantly more in Group P. We observed no incidence of pale skin which may occur due to local extravasation of vasopressor in any of the patients of both groups.

NE-induced vasoconstriction and skin necrosis is another concern for NE application in obstetric anesthesia, where a peripheral rather than central vein is commonly used.[22] Ngan Kee et al.[4],[17] and Onwochei et al.[6] suggested that NE is safe for local tissue perfusion since NE is diluted before the use and administered in a running fluid for a relatively short duration, thus reducing the risk of tissue ischemia. Further, an equal potency of NE infusion or bolus has a theoretically similar vasoconstrictive potency as the currently used PE, so that risk should be no different to that posed by PE. A previous study showed that SA increases skin perfusion and that this effect is not counteracted by NE application.[24] Collectively, the results suggest that NE likely has no adverse effect on local tissue perfusion in patients with SA for commonly used infusion or bolus doses. None of the patients of our study had extravasation during vasopressor infusion administration and hence no pallor or skin necrosis had occurred.

APGAR score at 1 and 5 min of the neonates showed no statistically significant difference between the groups. This might have happened because all the participants in our study were healthy without any pregnancy-related complications and intraoperative were maintaining hemodynamic parameters due to continuous vasopressor infusions.

In Puthenveettil et al. 2019[10] double-blinded RCT study, the incidence of nausea/vomiting and the APGAR score at 1 and 5 min of life did not show any statistically significant difference in both the groups.

Sharkey et al. in their double-blinded RCT in 2018[9] found out that there was a statistically significant difference between the groups for the incidence of bradycardia with a P value being 0.001. They had used 100 μg PE bolus when SBP was less than the baseline value. This suggests that they had used more dose of PE than our study and in bolus form which may lead to a higher incidence of bradycardia. There was no statistically significant difference in patients experiencing nausea and vomiting as well as the APGAR score at 1 and 5 min between the groups.

In an open-label RCT done by Vallejo et al. in 2017,[21] the result yielded were showing no statistically significant difference in the incidence of bradycardia and nausea as well as the APGAR score. There was a statistically significant difference in the number of patients experiencing emesis with a P < 0.001.

The table of mean difference of HR from baseline in both the groups suggests that at any given moment in the study, the change in HR was more in Group P with the absolute value of mean HR being lower than the baseline. Although this difference was statistically significant at the 6th, 8th, 10th, 15th, 20th, and 30th min with a P < 0.001 and not significant initially up to 4 min and at 30th min. This suggests that PE causes more fluctuation in the maternal HR (which is the indirect indicator of maternal CO) than NE and thus more stable maintenance of HR and CO can be achieved with NE than PE.

Limitations of the study

We used vasopressor infusion to maintain SBP near baseline without monitoring the maternal CO which is the direct indicator of feto-maternal circulation. We studied healthy normal parturients which may affect some of the results of the study positively. The neonatal outcome was solely represented by APGAR score which can be misleading, and other fetal parameters such as uterine arterial pH should be included in the study to find out fetal acidosis.

Further scope of the study

Future researches should be directed toward high-risk pregnancies to establish more potent results about both the vasopressors and their efficacy and safety. Direct monitoring of maternal CO, direct invasive BP monitoring, and fetal blood gas analysis should be taken into consideration for better and more transparent results. A larger population should be studied to find out the hemodynamic stability indicated by the maintenance of hemodynamic parameters to the baseline. The commercial preparation available for injection NE contains the active form of NE 1 mg/ml, whereas the tartrate is 2 mg/ml. Future studies can be directed toward finding out the potency ratio of the active form rather than the tartrate.


  Conclusion Top


Our results show that when given as an IV infusion at a potency ratio of 20:1 of NE and PE, the former is better in preventing and treating the PSH in parturients undergoing elective and emergency CS. Furthermore, the fall in HR from baseline is lesser in patients receiving NE which indicates more stable maintenance of HR, and thus, indirectly CO with NE. There are lesser incidences of nausea, vomiting, and oxygen supplementation with NE. The neonatal outcome indicated by the APGAR score is similar with both drugs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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

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



 

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