European Journal of Cardiovascular Medicine

In elective caesarean section, subarachnoid block is preferred, as it avoids the common risks associated with general anaesthesia, such as difficulty in intubation, aspiration and side effects of general anaesthetics on the foetus[1]. But in 60-70% of the cases, maternal hypotension due to preganglionic sympathetic block occurs and it lead to adverse maternal outcomes like dizziness, nausea and vomiting, etc. Also, reduced placental perfusion increases the risk of hypoxia, fetal acidosis and postnatal neurological injury. Hence, effective prevention and management of maternal hypotension has great clinical significance.[2,3]

Various methods have been investigated alone and in combination for both its prevention and treatment. Left uterine displacement can be done to decrease the effects of aortocaval compression. Leg elevation alone has not been shown to decrease the incidence of hypotension. Even though pre-hydration or preloading is commonly administered, it shows controversial results. Hence, a vasopressor is commonly used, as nonpharmacological methods have poor outcome in managing spinal hypotension.[4]

Ephedrine, phenylephrine, and recently norepinephrine are the most commonly used vasopressors. Maternal tachycardia and neonatal acidosis are the common adverse effects associated with ephedrine.[5] The current gold standard vasopressor used for the prevention and treatment of maternal hypotension in subarachnoid block is phenylephrine, which is a potent alpha-adrenergic receptor agonist. Phenylephrine can reduce maternal heart rate and decrease in cardiac output. The reflex slowing of heart rate, which is a surrogate marker of cardiac output, may result in compromised uteroplacental perfusion, resulting in a compromised foetus.[6] 

Norepinephrine is a potent α-adrenergic agonist, but also has weak β-adrenergic agonist activity. It is metabolised by monoamine oxidase and catechol-O-methyltransferase to vanillylmandelic acid and has a half-life of 1 to 2 minutes. It increases or maintains heart rate, blood volume, cardiac output and increases arterial blood pressure.[7] Another  advantage of the use of norepinephrine is that it is cheaper than phenylephrine. Also, no ischaemic complications in the limbs were reported by its use through a peripheral vein.[8]  The vasopressor can be given as intermittent bolus doses or infusion for the management of spinal hypotension. Advantage of infusion over bolus dose is that it allows tighter blood pressure control with less intervention. The use of intermittent boluses of the drug may be feasible in poor-resource settings where infusion pumps are not available or in limited availability.[8]

The ideal infusion dose of norepinephrine seems to be 5-10 µg/kg/hr for reducing the incidence of hypotension and better hemodynamic stability in spinal anaesthesia induced caesarean section. Doses above 10 µg/kg/hr have been reported to be associated with higher incidence of hypertension.[2] So, in search for the ideal dose of norepinephrine infusion in spinal hypotension in caesarean section, we compared the doses of 5 µg/kg/hr, 8 µg/kg/hr and 10 µg/kg/hr.

A randomized controlled study was conducted in the Department of Anaesthesiology, Regional institute of medical sciences (RIMS), Imphal, Manipur from May 2022 to June 2024 consisting of 120 eligible patients totally. The permission of the Research Ethics Board, RIMS, Imphal, Manipur was obtained before initiating the study. Study was also registered in the Clinical Trial Registry of India registration (CTRI/2023/08/056943). Informed written consent were taken from all patients. Inclusion criteria include age between 18 to 50 years undergoing elective caesarean section and ASA (American Society of Anaesthesiology) category I or II. Exclusion criteria include history of allergy to local anaesthetic agent and/or study drugs, bleeding disorders (Von Willebrand disease, ITP, platelet count <50000/microliter, prothrombin time >14 seconds, and INR >1.5), local site infection, spinal deformity, cardiorespiratory diseases, renal disorders, neurological deficit and parturient with pre-eclampsia or any hypertensive disorders. The study groups were divided into four, named group A, group B, group C and group D. The total sample size was 120 (30 patients in each group) based on the study conducted by Chen et al[2]. Patients were allocated by using block randomization chart. Group A patients received norepinephrine 5μg/kg/h as intravenous infusion, group B patients received norepinephrine 8μg/kg/h as intravenous infusion, group C received norepinephrine 10μg/kg/h as intravenous infusion and group D received normal saline as intravenous infusion. In the operating room, standard monitoring including electrocardiography, pulse oximetry, and non-invasive blood pressure monitoring were established. Baseline systolic blood pressure (SBP), mean blood pressure (MBP), diastolic blood pressure (DBP), heart rate (HR), were recorded. All measurements were continuously recorded every 2 mins till 10 mins and then every 5 mins until the end of surgery. An upper limb vein was cannulated with a 18G intravenous catheter. To avoid possible influence on the measurements, the monitoring module was placed on the other arm. Lactated Ringer’s solution was loaded intravenously at the rate of 15ml/kg. Patient was placed in the left lateral position. Spinal anaesthesia was performed with a 25 G Quincke needle at the L3–4 interspace. After confirming the cerebrospinal fluid, 2 ml of 0.5% hyperbaric bupivacaine was administered. Block level was assessed by pin prick with a 25G hypodermic needle and controlled within T4–6. If the anaesthesia level becomes higher than T4, the case was excluded from analysis. If blood loss exceeds 500 ml, the case was also excluded from analysis. Immediately after intrathecal injection, the study medication was started at 1ml/kg/hr using an infusion pump. In the three norepinephrine groups, the infusion dosage regimens were 5μg/kg/h, 8μg/kg/h and 10μg/kg/h, respectively in group A, group B and group C. In the control group, patients received normal saline infusion at the same rate. A rescue bolus of 10μg norepinephrine from the bolus syringe was used to treat hypotension which is defined as a 20% decrease in systolic blood pressure from baseline. After delivery of the baby, 10 U of oxytocin was given as a slow infusion. Incidence of hypotension, bradycardia, tachycardia and hypertension were noted. When hypertension occurs, the infusion was stopped. Bradycardia (heart rate < 50 beats/min) was treated with 0.6 mg atropine. Tachycardia was defined as HR >120 beats per minute. Hypertension was defined as a 20% increase in systolic blood pressure from baseline and its incidence as a result of norepinephrine infusion will be noted. Norepinephrine consumption before delivery and during the surgery was recorded. Adverse effects including shivering, vomiting, peripheral vascular constriction, bradycardia, hypertension and hypotension were recorded. Incidences of dizziness, nausea or vomiting due to maternal hypotension were noted. Age, weight, height, duration of surgery and obstetric data (parity, indication of caesarean section) of all the patients were noted. Apgar score at 1 and 5 minutes were recorded along with the umbilical vein blood gases. Foetal acidosis was defined as pH <7. At the end of surgery all patients were shifted to post-anaesthetic care unit for routine follow up care. All data was entered in a pre-designed Proforma. Data collected was checked for completeness and consistency. Data was entered in Statistical Package for the Social Sciences (SPSS) version 26.0 for Windows (Armonk, NY: IBM Corp; 2020) for analysis. Descriptive data was summarised in mean, standard deviation, frequency and percentage. Continuous data was analysed with student ‘t’ test and ANOVA test. Chi-square test was used for categorical data, whichever is appropriate.

The study protocol was completed in all the enrolled patients. The demographic parameters such as age, weight, height and duration of surgery in the four groups are comparable and statistically not significant, as shown in table 1

Table 1. Distribution and comparison of age, weight, height and duration of surgery of the study participants between the groups (N= 120)

The dermatomal block distribution after the administration of spinal anaesthesia in the study groups are comparable, as shown in table 2

Table 2. Dermatomal block distribution of the study participants between the groups (N= 120)

Table 3 shows that there was significant difference in the incidence of hypotension before delivery among the study groups with group (D) recording maximum incidence of hypotension and was statistically significant.

Table 3: Distribution of the study participants according to incidence of hypotension before delivery between the groups (N= 120)

Table 4 also shows there was significant difference in the incidence of hypotension after delivery among the study groups with group (D) recording maximum incidence of hypotension and was statistically significant.

Table 4: Distribution of the study participants according to incidence of hypotension after delivery between the groups (N= 120)

The distribution and comparison of haemaodynamic parameters in the four groups at different time points are shown in Figure 1,2,3 and 4.

Figure 1: Comparison of the systolic blood pressure at various time in different groups (N=120)

Figure 2: Comparison of the diastolic blood pressure at various time in different groups (N=120)

Figure 3: Comparison of the mean arterial pressure at various time in different groups (N=120)

Figure 4: Comparison of the heart rate at various time in different groups (N=120)

Intergroup comparison of SBP, DBP and MAP shows less significant changes between Group A,B and C at all time points, even though significant changes were observed when study groups (A,B,C) were compared with  control group (D). Maximum changes were observed in between group C and group D.

Table 4 shows incidence of nausea and vomiting were comparable among the study groups and not statistically significant.

Table 4: Distribution of the study participants according to incidence of nausea/ vomiting between the groups (N= 120)

Table 5 shows incidence of shivering were comparable among the study groups and not statistically significant. The foetal parameters were within the normal range for the groups and there were no incidences of foetal acidosis.

Table 5: Distribution of the study participants according to incidence of shivering between the groups (N= 120)

Spinal anaesthesia can lead to occurrence of hypotension. This is mostly associated with reduced blood flow to the uterus and low placental perfusion, which can lead to acidosis and hypoxemia in the fetus. Spinal anaesthesia may also affect fetal heart rate and reduce intervillous blood flow. Hypotension in the mother can also lead to nausea and vomiting. Pharmacological management of hypotension especially vasopressors are extensively used[9]. Faster onset of action, cheaper, easy availability, and not adversely affect the mother and fetus are the important characteristics for ideal vasopressor[10].

Given the increasing concerns about phenylephrine, which is a gold standard vasopressor recommended for treating maternal spinal-induced hypotension, there is consideration of an alternative: norepinephrine. The concern arises from phenylephrine’s potential to slow heart rate, compromise uteroplacental perfusion, and potentially impact fetal outcomes. Norepinephrine, which is relatively weak in its agonistic activity at beta-adrenergic receptors, may be used as a substitute for phenylephrine. This study is one among the few studies that have compared the intravenous infusion doses of norepinephrine required to treat spinal anaesthesia induced hypotension.

In our study, the mean age of the study participants was 28.5 (5.5) years. The median age of the study participants was 28 years with a minimum of 18 years and a maximum of 39 years. Also the mean age between the group were comparable. Duration of surgery was comparable among all the groups and was statistically not significant. Highest block level attained was also comparable between study groups and control groups and it was statistically not significant.

Our primary outcome was the occurrence of post spinal hypotension defined as decreased SBP by 20% or more

compared with the baseline reading. This definition is the most commonly used definition in similar  studies[11,12,13,14]. In our study, we included a control group (Group D) that did not receive prophylactic vasopressor administration. In this group, rescue boluses of norepinephrine were given as required to treat any episodes of hypotension that occurred. Control group was included in the study to define a baseline comparator to evaluate the efficacy of norepinephrine infusion. In a study conducted by Chen et al[2], they compared 5µg/kg/hr, 10µg/kg/hr and 15 µg/kg/hr with control group. In our study we chose 5µg/kg/hr, 8µg/kg/hr and 10µg/kg/hr as study groups as higher concentration have higher incidence of hypertension. We observed that occurrence of hypotension was significantly higher in the control group (Group D) compared to study groups and was statistically significant. Occurrence of hypotension was higher in group A which was infusion of norepinephrine 5µg/kg/hr compared to group B and group C which was infusion of norepinephrine 8µg/kg/hr and 10µg/kg/hr respectively. Studies conducted by Chen et al[2], Ngan kee et al[14] also reported this finding.

In our study, decrease in heart rate was observed in two patients in group C, which was transient and recovered without use of atropine. It was statistically not significant. Similar finding was reported by study conducted by Ngan kee et al[11]. We also observed occurrence of tachycardia were comparable among study groups and control group and it was statistically not significant. Occurrence of hypertension was comparable between study groups and control groups and it is statistically not significant. Group C (10µg/kg/hr) recorded higher occurrence of hypertension among study groups but it was statistically not significant. Study conducted by Chen et al [2] also recorded this observation.

Ngan Kee et al[12] were the first to report norepinephrine used in caesarean delivery to maintain blood pressure during spinal anaesthesia in 2015. They recorded that that norepinephrine produced better heart rate and cardiac output with similar anti-hypotension effect compared with phenylephrine by computer-controlled infusion. Vallejo et al[15] compared 6µg/kg/hr of phenylephrine and 3µg/kg/hr of norepinephrine in preventing hypotension followed by spinal anaesthesia for elective caesarean delivery; proportion of patients who required rescue vasopressor boluses was similar between groups, so he considered norepinephrine as an alternative to phenylephrine.

The concerns about the necrosis due to administration of norepinephrine through peripheral veins was present. However, when norepinephrine is administered in dilute concentrations its vasoconstriction is similar to the most commonly used phenylephrine concentration. When IV fluid is infused constantly via a large bore catheter, the risk of peripheral administration of phenylephrine is likely minimal and insertion of central venous line and arterial line is unwarranted[15].

In our study, the adverse effects like shivering, nausea and vomiting were comparable between study groups and control group and was statistically not significant. Study conducted by Chen et al[2], Ngan kee et al[14], Hasnanin et al[16] also recorded similar results. Significantly lower side effects with norepinephrine. In our study foetal parameters between the two groups which include umbilical pH, PCO2, PO2, lactates, APGAR1 and APGAR5 were comparable. Similar findings were reported in studies conducted by Puthenveettil et al[8], Chen et al[2]. There was no foetal acidosis in study groups as well as control groups.

Our study has the advantage of being a randomized and double-blinded study. However, the limitations were unavailability of advanced hemodynamic monitors for cardiac output measurement, and non-inclusion of parturient with cardiac morbidities. All our patients were scheduled for elective and not emergency caesarean sections. Study can be extrapolated to non-parturient with different type of surgery under spinal anaesthesia.

Prophylactic norepinephrine infusion doses of 10 µg/kg/hr recorded lower incidence of hypotension as compared with other groups receiving either normal saline or norepinephrine infusion of 5µg/kg/hr and 8µg/kg/hr. Thus, prophylactic infusion doses of norepinephrine 10µg/kg/hr can be used to prevent spinal anaesthesia induced hypotension in patients undergoing elective lower segment caesarean section.

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2.             Chen D, Qi X, Huang X, Xu Y, Qiu F, Yan Y, Li Y. Efficacy and Safety of Different  Norepinephrine Regimens for Prevention of Spinal Hypotension in Cesarean Section: A Randomized Trial. Biomed Res Int. 2018 23;2018:2708175.

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4.             Nazir I, Bhat MA, Qazi S, Buchh VN, Gurcoo SA. Comparison between  phenylephrine and ephedrine in preventing hypotension during spinal anesthesia for caesarean section. J Obstet Anaesth Crit Care. 2012;2:92-7.

5.             Hassabelnaby YS, Hasanin AM, Adly N, Mostafa MMA, Refaat S, Fouad E, et  al. Comparison of two Norepinephrine rescue bolus for Management of Post Spinal Hypotension during Cesarean Delivery: a randomized controlled trial. BMC Anesthesiol. 2020 17;20(1):84.

6.             Goel K, Luthra N, Goyal N, Grewal A,  Taneja A. Comparison of norepinephrine and phenylephrine infusions  for maintenance of haemodynamics following subarachnoid block in  lower segment caesarean section. Indian J Anaesth 2021;65:600-5.

7.             Andrade PA, Ortiz YM, Gamon AA. Norepinephrine and Etilefrin as prevention of maternal      hypotension in cesarean section under spinal anesthesia. Revista Científica  Ciencia Médica. 2018 ;21( 1 ):68-77.

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9.             Lirk P, Haller I, Wong CA. Management of spinal anaesthesia-induced hypotension for caesarean delivery: a European survey. EJA. 2012 Sep 1;29(9):452-3.

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11.          Siddik-Sayyid SM, Taha SK, Kanazi GE, Aouad MT. A randomized controlled trial of variable rate phenylephrine infusion with rescue phenylephrine boluses versus rescue boluses alone on physician interventions during spinal anesthesia for elective cesarean delivery. Anesth Analg. 2014;118(3):611-8.

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13.          Vallejo MC, Attaallah AF, Elzamzamy OM, Cifarelli DT, Phelps AL, Hobbs GR, et al. An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery. Int J Obstet Anesth. 2017;29:18-25.

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16.          Hasanin AM, Amin SM, Agiza NA, Elsayed MK, Refaat S, Hussein HA, et al.  Norepinephrine Infusion for Preventing PostspinalAnesthesia Hypotension during  Cesarean Delivery: A Randomized Dose-finding Trial. Anesthesiology. 2019;130(1):55-62.