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ORIGINAL ARTICLE
Year : 2023 | Volume
: 13
| Issue : 1 | Page : 17-23
A randomised comparative study to compare the prophylactic use of phenylephrine and norepinephrine in caesarean delivery under spinal anaesthesia
C V Soabir Ali, Jeetendra Kumar Bajaj
Department of Anaesthesia, Vardhman Mahavir Medical College and Safdarjung Hospital, New Delhi, Delhi, India
Correspondence Address:
Dr. C V Soabir Ali
S/O- ALI CV Chittakath Variyathazhath House, Punnathala (P. O), Malappuram District, Kerala – 676 552
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/JOACC.JOACC_12_22
Background: To compare the efficacy and safety of prophylactic intravenous infusions of phenylephrine (0.1 μg/kg/min) and norepinephrine (NE) (0.05 μg/kg/min) for the management of maternal hypotension under spinal anesthesia for cesarean delivery. Methods: A prospective randomized comparative interventional study was conducted on 100 pregnant patients who underwent elective/emergency cesarean section under the sub-arachnoid block. The study patients were randomly allocated into two equal groups comprising of Group P (n = 50): who received phenylephrine 0.1 μg/kg/min infusion prophylactically and Group N (n = 50): who received norepinephrine 0.05 μg/kg/min infusion prophylactically. The data of outcome measures were compared among the two groups by SPSS ver 21.0. Results: A significant difference was seen in the incidence of bradycardia between groups P and N (20% vs 4%, P value = 0.028). The blood pressure was significantly higher in Group N (systolic-120.5 vs 104 mm of Hg, P = 0.026; diastolic-66 vs 61 mm of Hg, P = 0.019). Group N patients had no complications whereas Group P patients experienced nausea (8%) and vomiting (4%), P = 0.027. Neonatal outcomes in terms of Appearance, Pulse, Grimace, Activity, and Respiration (APGAR) score and umbilical arterial/venous blood gases were similar among the two groups (P > 0.05). Conclusion: In conclusion, the study results show that NE is better in maintaining the hemodynamic parameters (BP and HR) during spinal anesthesia for cesarean delivery with minimal side effects. It can be suggested that NE may be advantageous in pregnancies especially those complicated with pregnancy-induced hypertension.
Keywords: Bradycardia, caesarean, hypotension, spinal anaesthesia
Against the WHO recommendation of 10-15% ideal incidence of cesarean sections, India has witnessed an alarming increase in the cesarean sections in both public (3.6-44.5%) and private (23.6%-82.7%) facilities as per the NFHS-5 data.[1] The adequate institutionalized care for the women undergoing cesarean sections demands adequate anesthesia with minimal side effects. The sub-arachnoid block is the anesthetic technique of choice for elective/emergency cesarean section as it is easy to perform, provides a rapid onset, dense surgical block, and is not associated with a maternal or fetal risk of toxicity to local anesthetics.[2]
Despite adequate fluid loading, hypotension poses a major concern subsequent to spinal anesthesia with reported occurrence in up to 80% of cases.[3] It is detrimental to both mother and the baby because of maternal nausea, vomiting, utero-placental hypoperfusion, fetal distress, and acidosis;[4] thus, necessitating prompt management.
Traditionally, it has been managed by fluid loading and vasopressor drugs such as ephedrine and phenylephrine.[5] An ideal vasopressor to manage hypotension secondary to spinal anesthesia must have high efficacy with minimal continuous dose and must not cross the placenta.[6] Ephedrine became outdated because of its property to cross the placenta and cause fetal acidosis.[7] Among the two, phenylephrine is short-acting and is the drug of choice as it causes minimal fetal acidosis. The continuous infusion of phenylephrine has been preferred over the bolus dose as it provides better hemodynamic stability.[8] But the effectivity is guarded by the occurrence of "baroreceptor-mediated bradycardia" and a fall in cardiac output.[4],[9]
Recently, norepinephrine (NE) has been considered an effective alternative to phenylephrine whereby the side effects are significantly less.[10],[11]
NE, on account of its combined alpha-adrenergic and beta-adrenergic action, prevents the fall in heart rate and cardiac output while maintaining an increase in maternal blood pressure.[12],[13]
Puthenveettil et al. (2019)[14] showed that boluses of NE required to prevent hypotension are significantly less than boluses of phenylephrine. In another study on assessment of the graded dose-response, 100 μg bolus of phenylephrine was found to be equivalent to 8 μg of NE in controlling the maternal hypotension.[15] Another study from the same author reported that a computer-controlled infusion of NE 5 μg/ml was significantly more effective in controlling blood pressure than phenylephrine 100 μg/ml.[16]
However, all the previous trials have obviated the need for further comparative trials to determine the better potency, efficacy, safety, dosage, and mode of infusions among the two drugs. This has been mainly because there have been different results with the bolus, intermittent bolus, continuous infusions, and intermittent infusions at different doses. To date different doses and ED90[17] have been proposed for both drugs but no specific guidelines have been laid down.
The present study was conducted with an aim to compare the efficacy and safety of prophylactic intravenous infusions of phenylephrine (0.1 μg/kg/min) and NE (0.05 μg/kg/min) for the management of maternal hypotension under spinal anesthesia for cesarean delivery.
The primary objective of the study was to compare falls in maternal blood pressure and to quantify the rescue boluses needed for both groups. The secondary objectives were to compare fetal acid-base status and APGAR scores at 1 and 5 minutes.
MethodsA prospective randomized comparative interventional study was conducted in the department of a tertiary care hospital on 100 pregnant patients of physical status American Society of Anaesthesiologists grade II with height 150 to 170 cm, who underwent elective/emergency cesarean section under sub-arachnoid block. Patients with significant coagulopathies, pregnancy-induced hypertension/essential hypertension, history of significant systemic disorders (cardiovascular, respiratory, or central nervous system), and other contra-indications for spinal anesthesia were excluded.
The sample size calculation of the study was based on the previous study by Vallejo et al.,[11] in 2016 where both phenylephrine and NE have been compared, and a sample size of 47 per group was required to detect at least mean difference of 20 in systolic blood pressure (SBP) and HR with SD 30 with a power of 90% at the 5% significance level.
The study patients were randomly allocated into two equal groups as shown in [Flow Diagram 1].
Group P (n = 50): who received phenylephrine 0.1 μg/kg/min infusion prophylactically.
Group N (n = 50): who received NE 0.05 μg/kg/min infusion prophylactically.
Randomization
Simple randomization was done into two groups using sealed, opaque envelopes comprising groups P or N. Each patient picked up one envelope, and the group was allocated accordingly. Neither the patient nor the doctor was blinded to the allocated group.
After satisfying the eligibility criteria, written informed consent was obtained from the patients. The institutional ethical committee clearance was obtained before starting the study (IEC/VMMC/SJH/Thesis/October/2018-110, dated 30.10.2018).
The demographic and anthropometric characteristics of the patients were recorded. Patients were premedicated with inj. Ranitidine 50 mg iv 1 hour before the surgery. Heart rate, oxygen saturation, and three reading of blood pressure (BP) were measured and the lowest one of the SBP was taken as the baseline value. The cycling time of the SBP was kept at 2 minutes. An IV line was secured using an 18G cannula and patients were preloaded with 500 ml of Ringer's lactate over 10 mins and thereafter continued at 7 ml/kg/hr.
Subarachnoid block was given by midline/paramedian approach in the sitting/lateral position with a 25G lumbar puncture needle at L2- L3 or L3 – L4 intervertebral space by 10 mg of Bupivacaine (heavy) +10 μg fentanyl. Patients were placed supine and a wedge was placed below the right flank. Supplemental oxygen was given through a face mask till the delivery of the baby. Heart rate, BP, oxygen saturation, and electrocardiography were monitored.
In group A, infusion of phenylephrine at 0.1 μg/kg/min was immediately started after giving sub-arachnoid block by using a syringe infusion pump. The infusion was continued till the delivery of the baby unless SBP was greater than 20% of baseline in which case it was stopped. Recording of any incidence of hypotension was noted, which was defined as a fall in BP ≥20% of basal value. If there were two readings of low blood pressure, we administered a "rescue" intravenous bolus dose of 50 mcg phenylephrine and were repeated if needed.
In group N, infusion of NE at 0.05 μg/kg/min was immediately started after giving sub-arachnoid block similarly to the group P. The infusion was continued till the delivery of the baby in a similar way as done in group P. The rescue bolus in this group was 4 μg of NE. When patients developed bradycardia, which was defined as HR ≤50 bpm with associated hypotension, then Inj. Atropine 0.6 mg IV was given and repeated if necessary.
The duration of skin incision, uterine incision, duration of surgery, time of delivery from subarachnoid block (SAB), and level of the block were noted. The specific outcome measures included changes in the heart rate, blood pressure, and oxygen saturation at 2-minute intervals from pre-operative levels till 16 minutes after installation.
For the neonates, the APGAR score was measured at 1 min and 5 mins after the delivery. At delivery 1 ml of the umbilical artery and venous blood were obtained and sent for blood gas analysis as well. Any complications arising out during anaesthesia was recorded. The data of outcome measures were compared among the two groups by SPSS ver 21.0.
Statistical analysis
The data presentation was done in tables and graphs. From the raw data, number (percentage -%), mean (± standard deviation), and median (interquartile range) with 95% CI were derived by using Statistical Package for the Social Sciences, IBM manufacturer, Chicago, USA version 21.0. Unpaired t-test, Chi-square test, and Mann–Whitney test were employed for intergroup comparison. P <0.05 was considered statistically significant.
ResultsThe two groups were comparable in terms of age, weight, height, and duration of surgery. Compared to Group P, Group N achieved earlier uterine incision following SAB (7 vs 8 minutes, P = 0.03). However, time of delivery from SAB (10 vs 11 minutes, P = 0.488); duration of skin incision (3 vs 4 minutes, P = 0.2) and level of block achieved was comparable in Group N and P. [Table 1]
The HR showed a decreasing trend in both groups and reached comparable values at 2-16 minutes (P > 0.05) [Figure 1]. A significant difference was seen in the incidence of bradycardia between groups P and N (20% vs 4%, P value = 0.028).
SBP showed a decreasing trend in both the groups in the initial period except for a significant increase in Group N leading to significantly high values at 14 minutes (120.5 vs 104 mm of Hg, P = 0.026) [Figure 2]. Similarly, DBP also showed a decreasing trend in both the groups in the initial period except for a significant increase in Group N leading to significantly high values at 8 minutes (66 vs 61 mm of Hg, P = 0.019) [Figure 3]. Concurrently, Mean arterial pressure was high in Group N at 8-12 minutes in comparison to Group P [Figure 4]. There was no significant difference in the oxygen saturation at the follow up intervals (P > 0.05) [Figure 5].
Overall the changes in the hemodynamic parameters were mild with no overt and no significant difference was seen in the distribution of the number of boluses of vasopressors between group P and N (P value = 0.803).
Group N patients had no complications whereas Group P patients experienced nausea (8%) and vomiting (4%), P = 0.027. Neonatal outcomes in terms of APGAR score and umbilical arterial/venous blood gases were similar a mong the two groups (P > 0.05) [Table 2].
DiscussionThe results of the index study showed that in comparison to phenylephrine, NE had better efficacy for maintaining mean blood pressure without causing a fall in heart rate during spinal anesthesia (SAB) for cesarean delivery. This can be ascribed to the combined mild "β-adrenergic activity" and potent "α-adrenergic receptor activity" that helps in exhibiting similar vasopressor effects as phenylephrine but with less undesirable negative chronotropic effects.
Typically, during spinal anesthesia in delivery, due to a fall in vascular resistance (BP), there is a compensatory mechanism to increase heart rate and cardiac output.[18] As management of spinal-induced hypotension, phenylephrine became popular.[18],[19] However, it came to notice that it exhibits dose-response relationship in terms of decreasing HR rather than a response to falling BP, which may adversely affect uteroplacental perfusion. In addition, side effects of Nausea and vomiting showed a graded increase with the dose of phenylephrine.[20] Due to this, NE was found to be advantageous as it has direct chronotropic and reflex negative chronotropic effects with an overall neutral effect on HR.[21]
We found that continuous infusions of NE hold superiority over phenylephrine in preventing significant hypotension and bradycardia. Our findings were in line with the previous studies,[9],[14],[15],[17] that showed the superiority of NE over phenylephrine. Ngan Kee et al.,[16] also showed a greater increase in CO and HR with NE possibly due to the positive chronotropic effects and effect on venous return. NE causes constriction of the capacitance vessels without increasing vascular resistance, thereby maintaining the venous return and cardiac output.[22],[23] This mechanism becomes very important in the parturients who experience both bradycardia and hypotension, as it may favor the maintenance of uteroplacental perfusion. Puthenveettil et al.,[14] also showed a higher incidence of bradycardia with phenylephrine as compared to NE.
Interestingly, though absolute values of the umbilical artery and venous pH and oxygen content were higher in the NE group, statistically, there was no significant difference (P > 0.05). This was in contrast to the study by Ngan Kee et al.,[16] who showed a higher umbilical venous pH and oxygen content in the NE group which was related to higher placental blood flow and consequent oxygen delivery. But in their study, this association was prone to type I statistical error due to the small differences. Other parameters of umbilical arterial and venous were comparable among the two groups in Ngan Kee et al.,[16] as was seen in our study. Nevertheless, it may be suggested that NE may hold an advantage in pregnancies complicated with pregnancy-induced hypertension where maintenance of uteroplacental circulation may be the primary aim of the spinal anesthesia drug.
NE was first evaluated formally in obstetric patients in 2015[16] and since then its use in the clinical settings has increased to an extent that phenylephrine has become a second-line drug because of an altered mechanism of BP control whereby it fails to control cardiac output and heart rate.[24],[25]
We used NE at a concentration of 0.05 μg/kg/min against phenylephrine at a concentration of 0.1 μg/kg/min according to the estimated potency ratio of 20:1.[26] It is possible that the potency ratio needs further changes to increase or maneuver the effects of Phenylephrine as it shows a significant dose-response effect. Ngan Kee et al.,[16] found that the median infusion rate required for maintaining BP was greater in the NE group, thereby suggesting that the true potency ratio for NE: PE for maintaining BP may be less than 20:1.
We administered both drugs as continuous infusions. Since NE has a faster onset of action with a short duration compared to phenylephrine, it holds advantageous in titrated infusions, whereas vasopressors such as phenylephrine may be better given in intermittent boluses.[14]
The side effects of nausea and vomiting were found to be more with Phenylephrine which may be due to a higher incidence of bradycardia. In the study by Puthenveettil N et al.,[14] the side effects of nausea/vomiting and shivering were comparable and even the incidence of bradycardia was comparable among the two groups. Nausea and vomiting become troubling for the parturients as they are nauseous throughout the pregnancy and thus NE holds significance in this aspect.
Limitations of the study
The study suffered from the limitations of not evaluating different doses of the drugs or the intermittent infusions of phenylephrine. Also, there was a potential bias of non-matching values of HR and BP at the baseline before anesthesia among the two groups.
ConclusionIn conclusion, the study results show that NE is better in maintaining the hemodynamic parameters (BP and HR) during spinal anesthesia for cesarean delivery with minimal side effects. Neonatal outcomes in terms of APGAR score and umbilical arterial/venous blood gases were similar. It can be suggested that NE may be advantageous in pregnancies especially those complicated with pregnancy-induced hypertension.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Research involving human participants and/or animals
None
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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