European Journal of Cardiovascular Medicine

Caesarean section is most common operation performed worldwide [1]. Spinal anaesthesia is commonly used anaesthetic technique for caesarean section [2]. Hypotension is frequent immediate complication of Spinal anaesthesia for caesarean section. Hypotension after spinal anaesthesia for caesarean section is defined when systolic blood pressure [SBP] decreases to ≤ 100 mmHg or 20% decreased from baseline reading [3]. Hypotension occurred after spinal anaesthesia is due to sympathetic blockade which control vascular smooth muscle tone and is exaggerated by physiological changes in pregnancy. The incidence of hypotension is as much as 55-90% amongst mothers posted for caesarean section [4]. The fall in blood pressure causes nausea, vomiting, and dizziness. Severe and sustained hypotension may compromise utero-placental blood flow which may result foetal acidosis and ultimately neonatal depression. Maternal SBP of 80 mmHg for 5 min is almost always associated with hypoxic foetal bradycardia5. No single measure has been proven to   eliminate hypotension during spinal anaesthesia for caesarean section3. Prevention of hypotension during caesarean section following spinal anaesthesia includes intravenous fluid loading, left lateral uterine displacement and use of vasopressor [5]. Vasopressor, causing an increase in systemic vascular resistance (SVR) and mean arterial pressures (MAP), have traditionally been used for the management and prevention of neuraxial anaesthesia-induced hypotension with variable success6. Phenylephrine, a pure α 1 agonist, is considered as the first line agent for the treatment of hypotension during caesarean section [6]. But its use is reported to be associated with baroreceptor-triggered, vagally mediated, dose-dependent bradycardia and vasoconstriction in venous capacitance vessels causing increased venous resistance, leads to decrease preload and so reduced cardiac output8. These may raise concern about adverse maternal and neonatal outcomes [6]. Norepinephrine, a potent α 1 agonist with mild β 1 >> β 2 agonistic property has recently attracted attention in obstetric anaesthesia for this purpose. It antagonizes the reflex bradycardia β 1 mediated chronotropic action and reduced venous resistance mediated through weak β 2 relaxing effects on large capacitance vessels, there by not hampering preload and cardiac output (CO). So, use of Norepinephrine provides more stable maternal haemodynamic and so utero-placental perfusion. A number of studies comparing Norepinephrine and Phenylephrine in various doses have been done recently [7].

Study Type and Design: An institution based Comparative Prospective study.

Study place: Operation theatre of Department of Gynaecology & Obstetrics, Murshidabad Medical College & Hospital, Berhampore, West Bengal.

Study Period: One and half year (February 2023 – May 2024) after getting permission from Institute Ethics Committee (IEC) and approval of The West Bengal University of Health Sciences (WBUHS).

Work plan:

Preparatory Phase: -1st August to 31th October.

1. Selection of topic.
2. Protocol formation.
3. Permission was taken from the Institutional

Ethical Committee.

Data collection and data entry phase: -1st February 2023 to 31st March 2024.

Data analysis and interpretation: -1st April 2024 to 30th April 2024

Report writing and presentation: -1st May 2024 to 31st May 2024.

Sample size: 30

Inclusion criteria:

Patients in the age group of 18 - 35 years, height >140cm to <180cm with single term pregnancy, ASA ll scheduled for elective caesarean section were included in the study.

Exclusion criteria:

1. Multiple Pregnancy
2. Cardiovascular and cerebrovascular disorders.
3. Hypertensive disorder of pregnancy.
4. Diabetes Mellitus
5. Hepato-renal disorders.
6. Obesity (B.M.l. >35 kg/m2)
7. Contraindication to spinal anaesthesia.
8. Allergy or Hypersensitivity to the drugs under study.
9. Foetal abnormalities.

Study equipment:

1. Multichannel Monitor.
2. 18 G IV cannula and infusion set for fluid therapy.
3. Ringer lactate & Normal saline infusion.
4. 2,5, 10 cc Syringe.
5. 25 G Quincke's Spinal Needle.
6. Cotton swab
7. Table pin for testing the level of sensory block.
8. Anaesthesia machine, drugs and necessary equipment for airway and hemodynamic management.
9. Drugs like
10. Lignocaine 2% for local infiltration of injection site.
11. Povidone iodine 5% solution.
12. Tab Pantoprazole 40 mg.
13. Inj Metoclopramide (10 mg).
14. Ondansetron (4 mg/2ml) ampoule
15. Atropine (0.6 mg/1ml) ampoule
16. 5% Hyperbaric Bupivacaine 4ml ampoule
17. Norepinephrine (4mg/2ml) ampoule
18. Phenylephrine (10mg/1ml) ampoule
19. Oxytocin (5 IU/1ml) ampoules
20. Heparinised syringe.
21. Resuscitative drugs and instruments
22. Monitoring scale:
    1. Modified Bromage Scale
    2. The level of sensory block was assessed using pin-prick test.

Statistical analysis:

Collected Data were checked for consistency and completeness. The data were entered into MS Excel spreadsheet and analysis was done using the Statistical Package for Social Sciences (SPSS) version 21 (IBM Corp, Armonk, NY, USA). Descriptive analysis was done in the form of proportion for categorical variables, mean or median for continuous variables. Data were checked for normal distribution using tests for normality and non-parametric test was performed accordingly. The difference between proportions was analyzed using Chi square test; p value of less than 0.05 was considered statistically significant.

Table: 1. Base line hemodynamic parameters distribution of study subjects

Table: 2. Study subjects’ distribution as per Norepinephrine and Phenylephrine   infusions

Figure: 1. Comparison of baseline hemodynamic parameters at different time interval within both comparative groups receiving Norepinephrine and Phenylephrine infusions (n=30)

Figure: 2. Mean Heart rate trend within both comparative group of receiving Norepinephrine and phenylephrine infusions (n=30)

Figure: 3. Comparison of Mean Systolic Blood Pressure at different time interval within both comparative groups receiving Norepinephrine and Phenylephrine infusions(n=30)

Mean baseline haemodynamic parameters (HR, SBP, DBP, MAP) of the both groups were put on the table. Although difference in SBP, DBP and MAP were not statistically significant but   HR among the group was statistically significant.

Requirement infusions was higher for the Phenylephrine infusions group subjects than the Norepinephrine infusions group subjects, and which was not statistically significant. The mean (SD) infusions required for Norepinephrine group subjects was 3.033(0.7063) and for Phenylephrine infusions group subjects was 3.267(0.6798).

Caesarean delivery is most commonly performed procedure at obstetric operation theatre. Spinal anaesthesia is choice for caesarean section unless contraindicated. Most common immediate side effect is hypotension and requires prompt management to avoid maternal and neonatal adverse effects. Minimum required amount of local anaesthetic, slow intrathecal injection, left lateral uterine displacement and vasopressor are used in order to prevent and management of hypotension.

Phenylephrine is the gold standard drug for restoring maternal blood pressure under spinal anaesthesia. But most common side effect of Phenylephrine use is maternal bradycardia which reduced cardiac output and may jeopardize utero- placental circulation and possibility of adverse neonatal outcome. There is search for alternative suitable vasopressor drug. There are several studies regarding the use of   Norepinephrine in obstetric anaesthesia for restoring maternal blood pressure following spinal anaesthesia during caesarean section with promising results 9-13. The present study was conducted for comparison of total minute’s infusions of Norepinephrine or Phenylephrine required for management of hypotension during spinal anaesthesia for caesarean section and also to compare the maternal outcomes.

In this study we diluted and loaded in an identical coded 50ml syringe (labelled vasopressor) for infusions of Norepinephrine 4 µg/ml and Phenylephrine 50 µg/ml.  Patients in the Group NE was treated with 4 µg/min of Norepinephrine and Group PE was treated with 50 µg/min of   Phenylephrine equipotent intravenous infusions after sub-arachnoid block when SBP dropped < 100mmHg or below 80% of baseline. Various vasopressors have been used to manage hypotension after spinal anaesthesia.

The vasopressor may be given as intermittent boluses or as an infusion for treatment of maternal hypotension after spinal anaesthesia. Norepinephrine and Phenylephrine infusions allow tighter blood pressure control with less intervention required by Anaesthesiologist. Phenylephrine infusions are found to be better than boluses. Though the use of intermittent boluses drug may be feasible in poor resource settings where infusion pumps are not available or are only available in limited numbers. Another advantage of   Norepinephrine use is cheaper than Phenylephrine.

The significant findings of the present study:

• In the present study, we observe that intraoperative Systolic Blood Pressure (SBP) of receiving Phenylephrine infusions were high than Norepinephrine infusions group patients although it was not statistically significant. This was probably due to the lowest dose of Norepinephrine being used through peripheral vein as a potent vasoconstrictor.
• In the present study we observed that the intraoperative mean heart rate (HR) was more among the subjects receiving Norepinephrine (Gr NE) than the patients receiving Phenylephrine (Gr PE), and the difference was statistically significant. Although no incidence of bradycardia observed in both groups. Phenylephrine is pure α 1 agonist whereas Norepinephrine has mild β1 adrenergic properties in addition to its’ potent α 1 agonistic action. Thus, Norepinephrine antagonizes the incidence of bradycardia in Gr NE and intraoperative heart rate were higher in the group NE compared to group patients.
• In this study, we observed that the total minutes infusions of drug required for management of hypotension was higher Phenylephrine group of patients than the Norepinephrine group, and the association was not statistically significant.
• The present study we found that the maternal side effects like nausea, vomiting or dizziness were more among the patient receiving Phenylephrine than Norepinephrine, although this difference of proportions was not statistically significant.

The significant findings of the present study are hereby discussed with other similar studies done with similar

objectives and sample composition as far as possible:

Mofeed A et al [8] on 2018 conducted a study on “prophylaxis or treatment of spinal hypotension during caesarean delivery: phenylephrine versus norepinephrine boluses”

They selected 100 parturient for prophylaxis to prevent hypotension as group PE (Phenylephrine 100µg IV bolus) and group NE (Norepinephrine 8µg IV bolus).

They found that,

• There were no statistically significant differences among groups as regards baseline SBP, intraoperative SBP, except first episode of decrease of SBP.
• The incidence of bradycardia was significantly higher in PE (prophylaxis and treatment) groups (24 and 12%) but did not occur in NE group (0%).

In our study,

• There were no statistically significant differences among both groups regarding baseline SBP, intraoperative SBP, except SBP at 55 and 60minutes difference were statistically significant.
• Mean heart rate was high among the Norepinephrine receiving subjects than the Phenylephrine receiving subjects and the difference was statistically significant.

So, finding of our study correlates with this study.

Puthenveettill N et al [9] on 2019 conducted a study on “comparison of norepinephrine and phenylephrine boluses for the treatment of hypotension during spinal anaesthesia for caesarean section- a randomised controlled trial”

They randomly selected 50 elective parturient into two group.

Group P had been administered phenylephrine 50μg and Group N had been administered 4 μg of norepinephrine as intravenous boluses.

They observed,

• Similar findings in intra- operative SBP but they found it statistically And

• Requirement of vasopressor for Group N was 1.40 ± 0.577 and Group P was 2.28 ± 1.061 and P = 0.001
• Incidence of bradycardia for Group N vs Group P were 4% vs 20% and P = 0.192
• Maternal side effect such as nausea, vomiting and shivering were comparable between the groups.

In our study,

• Almost similar findings were observed in both initial intra-operative SBP and SBP was high within the study group receiving Phenylephrine infusions than the group receiving Norepinephrine infusions at 55 and 60 minutes and the difference were statistically significant.
• Mean requirement of vasopressor Phenylephrine (3.267±0.679) was almost equal of Norepinephrine (3.033 ± 0.706) and which was not statistically significant (p= 0.197).
• Mean heart rate was high among the Norepinephrine receiving patients than the Phenylephrine receiving patients and the difference was statistically significant. So, chance of bradycardia was less for norepinephrine group subjects.

Sharkey AM et al [10] on 2019 conducted study on “comparison of intermittent intravenous boluses of phenylephrine and norepinephrine to prevent and treat spinal induced hypotension in caesarean deliveries: randomized controlled trial”

They selected PE group for 100 µg phenylephrine bolus and NE group for 6 µg norepinephrine bolus.

They found that, Incidence of bradycardia was lower in the Norepinephrine group compared with that in the Phenylephrine group (10.7% vs 37.5%; P< .001).

In our study, Mean heart rate was high among the Norepinephrine receiving subjects than the Phenylephrine receiving subjects and the difference was statistically significant. So, finding of our study correlates with this study.

Goel Kanika et al [11] on 2021 studied on “comparison of norepinephrine and phenylephrine infusions for maintenance of haemodynamics following subarachnoid block in lower segment caesarean section”

They selected 200 parturients as group A and group B to administer variable rate, manually controlled infusions of phenylephrine and norepinephrine to maintain 100% baseline SBP.

They observed that, Lower SBP during initial 6 minutes after spinal anaesthesia and experienced ≥1 episode of hypotension in group A vs group B was 13% vs 9%. Incidence of bradycardia was significantly higher in Phenylephrine group (16%) than the Norepinephrine group (1%). Intra-operative nausea, vomiting and maternal vasopressor consumption were comparable among both the groups.

In our study, Episode of hypotension and drug requirement of Phenylephrine group (3.267± 0.679) were more than Norepinephrine group (3.033± 0.706). Mean heart rate was high among the Norepinephrine receiving subjects than the Phenylephrine receiving subjects and the difference was statistically significant. So, finding of our study correlates with this study.

Ngaan kee et al [11] on 2015 conducted study on “Randomized double- blinded comparison of norepinephrine and phenylephrine for maintenance of blood pressure during spinal anesthesia for caesarean delivery”

They observed that,

• Equipotent dose of Norepinephrine had similar efficacy to Phenylephrine in heart rate (HR) maintenance.
• There was no significant difference in the incidence of nausea vomiting (P=0.67) between the Norepinephrine (6.1%) and Phenylephrine groups (3.8%).

In our study,

Mean heart rate was well maintained with equipotent dose of norepinephrine.

So, finding of our study correlates with this study.

Warwick D et al [12] on 2017 conduct a study on “A random- allocation graded dose -response study of Norepinephrine and Phenylephrine for treating hypotension during spinal anaesthesia for caesarean delivery”

Healthy 180 patients undergoing spinal anaesthesia for elective caesarean delivery received a single bolus of norepinephrine in one of six different doses ranging from 4 to 12 µg or phenylephrine in one of six different doses ranging from 60 to 200 µg to treat the first episode of hypotension.

They found that, ED50 values (dose giving a 50% response) were norepinephrine 10 µg (95% CI, 6 to 17 µg) and phenylephrine 137 µg (95% CI, 79 to 236 µg). They had shown that the relative potency of Norepinephrine: Phenylephrine when given as intravenous bolus for treatment of obstetric hypotension under spinal anaesthesia was estimated to be 13.1 µg (95% CI, 10.4 to 15.8 µg).

In our study, Mean required Norepinephrine infusions was 3.033± 0.706 minutes for Group NE (each minute NE infusion=4µg). Mean required Phenylephrine infusions was 3.267± 0.679 minutes for Group PE (each minute PE infusion=50µg). So, requirement of Norepinephrine was almost equal to Phenylephrine.

Finding of our study correlates with this study.

1. N. Onwochei et al [13] on 2017 studied on “Norepinephrine intermittent intravenous boluses to prevent hypotension during spinal anaesthesia for caesarean delivery”. They administered intermittent Norepinephrine bolus of either patient 3, 4,5,6,7, or 8 µg every time their systolic blood pressure (SBP) fell to below 100% of baseline to maintain SBP at or above 80% of baseline.

They observed that, the ED90 and 95% Confidence interval (CI) of Norepinephrine was 5.49 µg for intermittent iv boluses for treatment of hypotension during caesarean delivery under spinal anaesthesia, was not associated with adverse outcome like nausea, vomiting, hypertension (SBP > 120% of baseline), bradycardia (<50 bpm), upper sensory level of anaesthesia to ice cold and umbilical artery and vein blood gases.

In our study, Norepinephrine infusions was 4 µg/minute and adverse effect like nausea, vomiting, dizziness was 6.67% and Phenylephrine infusions was 50 µg/minute and adverse effect was 13.33%. This difference was not statistically significant. So, finding of our study correlates with this study.

We conclude that, intraoperative heart rate was observed to be higher in patients receiving norepinephrine compared to those receiving phenylephrine. Despite this difference, norepinephrine and phenylephrine demonstrated similar efficacy in maintaining hemodynamic stability during spinal anesthesia for cesarean sections. However, patients receiving phenylephrine required higher infusion rates to achieve the desired hemodynamic control. Additionally, the incidence of maternal side effects such as nausea, vomiting, and dizziness was more frequent among those receiving phenylephrine compared to those administered norepinephrine. These findings suggest that while both agents are effective in managing hemodynamics during spinal anesthesia, norepinephrine may offer a preferable side effect profile and potentially lower infusion requirements. Overall, norepinephrine could be considered a viable alternative to phenylephrine, particularly for its comparable efficacy and potentially reduced incidence of adverse maternal effects.

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