Phenylephrine, a potent α-agonist vasopressor, has become the preferred choice for managing hypotension during cesarean sections with spinal anesthesia due to its rapid action and better preservation of fetal acid-base balance compared to ephedrine. However, its drawback includes reflex bradycardia and reduced cardiac output.^1-3 Recently, norepinephrine has emerged as an alternative due to its α-adrenergic effects and weak β-agonist action. Studies have shown its effectiveness in maintaining blood pressure (BP) and improving heart rate (HR) and cardiac output compared to phenylephrine, particularly in healthy pregnant patients undergoing electivecesareansections.^4-6Yet, there's a  gap in research regarding its use in pregnant women, who often have compromised uteroplacental circulation. Therefore, this study aimed to compare bolus doses of phenylephrine and norepinephrine in managing hypotension during cesarean sections in pregnant women under spinal anesthesia. The primary goal was to assess neonatal outcomes, focusing on umbilical artery pH, while secondary objectives included other umbilical cord blood gas variables, Apgarscores, maternal hemodynamic changes, vasopressor requirements, and maternal complications. It was hypothesized that both phenylephrine and norepinephrine would yield similar neonatal outcomes

This randomized, double-blinded study was conducted at our hospital, focusing on pregnant women with singleton pregnancies undergoing cesarean sections under spinal anesthesia. The written informed consent obtained from all participants,adhering to consolidated standards of reporting trials statement.

A total of 94 patients experiencing hypotension after subarachnoid block were included. Exclusion criteria encompassed various medical conditions and contraindications. Patients were randomized into two groups: phenylephrine or norepinephrine, administered intravenously for treating hypotension.

The study employed rigorous blinding methods, and data collection included baseline assessments,spinal anesthesia administration,monitoring of vital signs,and administration of vasopressor boluses as needed.

Hypotension and reactive hypertension were defined based on blood pressure thresholds,with bradycardia managed accordingly. Umbilical cord blood samples were collected for analysis, and Apgarscores were recorded post-delivery.Sample size was calculated based on umbilical artery pH variability, with statistical analyses conducted using SPSS 21 software

StatisticalAnalysis

The data were analyzed using SPSS 21 statistical software. Unpaired t-tests were utilized to assess demographic parameters, baseline hemodynamic parameters, hypotensive and hypertensive values, baby birth weight, and fetal acid-base status. Mann-Whitney tests we re employed to compare period of gestation, number of previous pregnancies, height of block, episodes of hypotension, number of boluses used, and neonatal Apgar scores. Pearson Chi- square or Fisher's exact tests were conducted to analyze the severity of pre-eclampsia, incidence of bradycardia, maternal complications, and fetal acidosis between the two groups. Given the variation in time to delivery among patients, intergroup trends for heart rate (HR) and systolic blood pressure (BP) following spinal injection and vasopressor administration were examined using a mixed model analysis,selecting the best covariance structure based on Akaike's information criterion. A significance level of P < 0.05 was adopted for statistical significance

Patient demographic characteristics and block height were similar in both groups (Table 1). About 40.2% of patients in the phenylephrine group and 42.5% in the norepinephrin e group underwent cesarean sections before 37 weeks of gestation, resulting in an overall preterm delivery rate of 41.4%. Most patients received antihypertensive medication, mainly oral or intravenous labetalol. The number of patients with severe pre-eclampsia and those receiving magnesium sulfate prophylaxis was comparable between the two groups (Table 2).

Here'sasummaryofthepatientcharacteristicspresentedinTable1:

• Age, bodyweight, height, and period of gestation were similar between the phenylephrine and norepinephrine groups, with p-values greater than 0.05.
• The number of previous pregnancies was also comparable between the two groups, with no statistically significant difference observed (p = 0.168).
• The height of spinal block, measured in thoracic dermatomes, showed no significant difference between the groups (p = 0.417).

Overall,the patient characteristics between the phenylephrine and norepinephrine groups were similar, indicating a balanced distribution of baseline characteristics in the study population. The Apgar scores at 1 and 5 minutes and the birth weights of the infants were similar in both groups (Table 2). Only one neonate in the norepinephrine group had an Apgar score less than 7 at 1 minute, whereas none in the phenylephrine group had such a score.

 Table2-Umbilical cord blood gas parameters and other neonatal parameters

Table 2 presents the hemodynamic parameters, including baseline values, occurrences of hypotensive episodes, instances of bradycardia, and administered vasopressor boluses. Both groups exhibited comparable heart rates (HR) and baseline as well as hypotensive and hypertensive systolic bloodpressures (BP).There were no significant differences between the two groups in terms of maternal arterial blood gas parameters, including pH, PCO2, HCO3, and base excess, as indicated by the p-values (> 0.05).

• Maternal arterial partial pressure of oxygen(PO2)showed a trend towards being higher in the norepinephrine group, but this difference was not statistically significant (p = 076).
• Fetal acidosis rates (definedasApH<7.2)were similar between the phenylephrine and norepinephrine groups (p = 0.693).
• Venous blood gas analysis showed statistically significant differences in venous PO2 and venous oxygen saturation between the two groups, with higher values observed in the norepinephrine group (p = 0.003 and p = 0.001, respectively).
• There were no significant differences between the groups in terms of Apgar scores at1 minute and 5 minutes, indicating similar neonatal outcomes (p > 0.05).
• Baby birth weight was similar between the two groups(p=531).

Overall,the study suggests that both phenylephrine and norepinephrine have similar effects on maternal arterial blood gas parameters and neonatal outcomes when used for treating postspinal hypotension during caesarean section in pre-eclampsia patients. However, there were differences in venous blood gas parameters,with norepinephrine associated with higher venous PO2 and oxygen saturation.

In the phenylephrine group, 7 patients experienced three episodes of hypotension, 11 patients had two episodes, and the

remaining 17 patients had only one episode. Conversely, in the norepinephrine group,2 patient encountered eight episodes of hypotension,2 patients had five episodes, 3 patients experienced four episodes, 6 patients had three episodes, and 15 patients had two episodes. The rest (17 patients) experienced only one episode of hypotension.

The median [IQR] number of boluses administered for the first hypotensive episode was 1 [1 to 1] in both groups. However, the phenylephrine group exhibited a statistically significant higher requirement compared to the norepinephrine group(Table3).Here's a summary of the data presented in the table 3:

• Baseline systolic and diastolic blood pressure (BP), baseline heart rate (HR), hypotensive value,and hypertensive value were comparable between the phenylephrine and norepinephrine groups, with p-values greater than 0.05.
• The number of hypotensive episodes was significantly lower in the phenylephrine group compared to the norepinephrine group (p = 0.014).
• Similarly, the number of boluses required for the treatment of the first hypotensive episode was significantly lower in the phenylephrine group compared to the norepinephrine group (p = 0.011).
• The total number of boluses given was similar between the two groups(p=411).
• There were no episodes of bradycardia after vasopressor use in the norepinephrine group, while one episode was reported in the phenylephrine group. However, this difference was not statistically significant (p = 1.000).

Overall, while baseline blood pressure and heart rate were similar between the two groups, phenylephrine was associated with fewer hypotensive episodes and required fewer boluses for treatment compared to norepinephrine. There were no significant differences in the total number of boluses given or the occurrence of bradycardia episodes after vasopressor use between the two groups.

Specifically, one patient in the phenylephrine group required seven boluses, two patients needed six boluses, two patients received three boluses, and five patients were administered two boluses to manage the initial hypotensive episode. In contrast, no patient in the norepinephrine group required more than two boluses. Nonetheless, the total number of vasopressor boluses used did not differ significantly between the two groups (Table 3).

Hypotension occurred at varying times post-spinal injection. As our primary objective was to compare the effects of the two vasopressors, it was crucial to also evaluate HR and BP trends after vasopressor administration.Values upto 9minutes after vasopressor administrationwere compared.HR was consistently lower in the phenylephrine group,while systolic BP remained comparable between both groups at most time points. Only one patient in the phenylephrine group experienced bradycardia,which was managed with glycopyrrolate administration.None of the patients in the norepinephrine group developed bradycardia or other cardiac complications following vasopressor administration.

Only one patient in each group reported experiencing nausea,which resolved with the treatment of  hypotension and did not necessitate any additional specific treatment.There were no reports of other complications, such as vomiting or dizziness, in either of the two groups

The outcomes of our study in pregnant women receiving either phenylephrine or norepinephrine for postspinal hypotension treatment revealed comparable primary outcomes, particularly umbilical artery pH, between the two groups. Despite a higher incidence of hypotensive episodes with norepinephrine, no significant differences were observed in secondary outcomes such as Apgar scores, total vasopressor bolus requirements, incidence of bradycardia,and maternal complications. Furthermore,subgroup analysis  of severely pregnant women did not reveal statistically significant differences in any primary or secondary outcomes.

The international consensus statement on vasopressor use for post spinal hypotension management advocates prophylactic vasopressor infusion. However, due to pre-eclamptic patients' lower hypotension incidence and greater vasopressor sensitivity,prophylactic infusion might not be optimal. Therefore, our study opted for vasopressor boluses in line with the consensus

The parameters of umbilical arterial and venous blood gas analysis were similar between the two groups, except for lower venous partial pressure of oxygen and venous oxygen saturation in the phenylephrine group. Although there's a chance of a Type I statistical error due to multiple comparisons of cord blood variables, phenylephrine, being apureα-agonist drug,can decrease uteroplacental blood flow through vasoconstriction, potentially reducing uteroplacental perfusion and oxygen delivery. Ngan Kee et al. found, while comparing phenylephrine and norepinephrine for maintaining blood pressure during elective caesarean delivery under spinal anesthesia, that umbilical artery blood gases showed no difference, but umbilical venous pH and oxygen content were lower in the phenylephrine group compared to the norepinephrine group. However, no adverse neonatal outcomes have been associated with phenylephrine use. Numerous studies have reported similar neonatal outcomes, including umbilical cord blood gases and Apgar scores, whether phenylephrine or norepinephrine was administered for preventing postspinal hypotension during elective caesarean section in healthy parturients.

Even though phenylephrine and norepinephrine were administered in equivalent doses in this study, the phenylephrine group required a significantly higher number of boluses to treat the first hypotensive episode compared to the norepinephrine group. Conversely, the norepinephrine group experienced a greater number of hypotensive episodes. Consequently, the overall requirement for vasopressors was similar in both groups.The median[interquartile range] total number of vasopressor boluses used was 2 [1 to 3] in both the phenylephrine and norepinephrine groups. This corresponded to a dose requirement of 100 [50 to 150] μg for phenylephrine and 8 [4 to 12] μg for norepinephrine.

In this study, the blood pressure changes observed during the study period were statistically similar in both the phenylephrine and norepinephrine groups. Similar findings have been reported in previous studies conducted in pregnant women during elective caesarean sections in healthy parturients, whether using intermittent boluses for treating hypotension or continuous infusions for preventing postspinal hypotension.^4-6

Heart rates in our study were lower in patients receiving phenylephrine compared to those receiving norepinephrine, both after spinal injection and after vasopressor administration. However, only one patient in the phenylephrine group developed bradycardia. Reflex bradycardia is a known adverse effect of phenylephrine due to its predominant vasoconstrictive action.

Based on our observations, we conclude that administering phenylephrine (50 μg) and norepinephrine (4 μg) as intravenous bolus doses for treating postspinal hypotension in pre- eclampsia patients undergoing caesarean section results in similar neonatal and maternal outcomes. Both medications are equally effective in treating hypotension in this context.

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