European Journal of Cardiovascular Medicine

Spinal anaesthesia (SA) is one wonder in the field of regional anaesthesia, providing a proper analgesia and it inculcates a maternal new born tie by letting the mother see her baby just after birth, by maintaining her consciousness during the whole surgery [1,2]. One of the common side effects of spinal anaesthesia is hypotension.  In obstetric spinal hypotension, compromised placental perfusion raises the concerns of foetal acidosis, hypoxia, and postnatal neurological injury. Without prophylactic vasopressors, post spinal hypotension affects nearly 60% of women during caesarean delivery [5]. Spinal anaesthesia for elective caesarean is associated with a higher incidence of foetal acidosis when compared to epidural or general anaesthesia. The increased incidence of foetal acidosis associated with spinal anaesthesia is likely to be secondary to maternal hypotension, or to be a side effect of drugs used in the prevention or treatment of hypotension [6,7]. Providing proper drugs, combination of drugs [3,4,5] and ratio of combined drugs to the patients, and the process of proper preloading and co loading also plays a major role in preventing hypotension.

 In study use of methoxamine and metaraminol (α-adrenergic vasopressors) increases uterine vascular resistance and decreases uterine blood flow, ephedrine (α-adrenergic and β-adrenergic) did not reduce uterine blood flow despite drug-induced increases in maternal arterial blood pressure.  In more recent trials, Phenylephrine (α-adrenergic agonist) in treatment of neuraxial induced hypotension or as a prophylactic infusion at the time of spinal placement is not only effective in preventing hypotension, but also is associated with less foetal acidosis and base deficit than use of ephedrine. At present, phenylephrine is the first line drug for maternal hypotension, [3,4] and the efficacy and safety of its use is still under research. Phenylephrine can cause reflexive decrease in maternal heart rate and cardiac output.

Norepinephrine has weak β-adrenergic receptor agonist activity in addition to potent α-adrenergic receptor activity and therefore may be suitable for maintaining blood pressure with less negative effects on heart rate and cardiac output compared with phenylephrine [8,9]. In spite of, number of studies going in this evergreen part, there were limited studies on the effect of pharmacological events to prevent and manage the maternal hypotension of spinal anaesthesia in elective caesarean section and its effects on foetus [10]. In our study we compared the effectiveness of infusion Phenylephrine and infusion Norepinephrine in elective caesarean section and their efficacy in maintaining maternal haemodynamic and its effects on new born.

A prospective single blind parallel group randomized controlled study was conducted at Gynaecology and Obstetrics OT complex of Calcutta National Medical College and Hospital, Kolkata, West Bengal, India during February 2019 to August 2020 after getting the approval from the Institutional Ethics Committee.

2.1 INCLUSION CRITERIA: Obstetrics patients aged between 18 to 40 years with a singleton pregnancy and gestational age more than or equal to 36 weeks undergoing elective caesarean section with ASA physical status-I to II and Mallampati score-I to II who gave consent for spinal anaesthesia were included in the study.

2.2 EXCLUSION CRITERIA: Patient with co-morbidities, Mallampati score-III and IV, ASA physical status- ≥III, allergy to any study medication, any spine deformities, intake of anticoagulants, contraindication to spinal anaesthesia, weight less than 50 kg or more than 100 kg, height less than 140 cm or more than 180 cm, presence of mesenteric or peripheral vascular thrombosis, patients who are about to undergo emergency caesarean section for any foetus related complications such as anticipated foetal anomalies and metabolic errors in foetus.

Total 80 pregnant patients were randomly allocated into 2 groups, Group P (phenylephrine) received 40 patients and Group N (norepinephrine) received 40 patients. After getting the written informed consent from mothers, all relevant history and physical examination completed and routine laboratory investigations checked. Fasting time was 8 hours for all before caesarean section and acid aspiration prophylaxis provided to all with H2 antagonist IV 30 minutes before surgery.

The anaesthesia workstation, circuit, oxygen supply sources, reserve oxygen, laryngoscope were checked and kept in proper functioning state. Face mask, endotracheal tubes and emergency drugs were kept in hand.

Baseline systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) and heart rate (HR) were recorded as the mean of 3 consecutive preoperative measurements taken 5 minutes apart, 1 hour before arrival in OT. All patients had a peripheral intravenous cannulation (18G) placed in upper limb and received 500ml ringer lactate over 15-20 minutes. When the patients had arrived at the OT, routine monitors were attached. FHS was auscultated by obstetrician.

The patients were explained about the procedure of spinal anaesthesia and reassured. Proper antiseptic dressing was done with betadine and rectified spirit and draped. The intervertebral space was palpated and local anaesthetic 2ml of 2% lignocaine was injected and intradermal wheal was raised in the better palpated intervertebral space either L2-L3 or L3-L4.

A standardized spinal anaesthetic consisting of hyperbaric (0.5%) bupivacaine 10-12 mg and fentanyl 20 mcg was administered by a 25-gauge spinal needle (Quinckes needle) in sitting position at L2-L3 or L3-L4 intervertebral space. After intrathecal injection patients were placed in supine position and table tilted 15 degrees to provide left uterine displacement. The spinal sensory level was tested bilaterally to ensure a T4 dermatomal level before surgical incision.

The study infusion medication was started at the same time when cerebrospinal fluid was obtained, immediately before injection of spinal medications. Study drugs were administered via syringe pump connected to peripheral intravenous line through small bore tubing. Phenylephrine was infused @ 100mcg/ml/hr to group P and noradrenaline was infused @ 6 mcg/ml/hr to group N to maintain SBP within 80% within of the baseline value and HR within 60-100 beats/min.

If hypotension would occur i.e., SBP< 20% of the baseline the patient would receive rescue boluses of iv phenylephrine 50- 100mcg. When HR dropped below 50/min, injection atropine 0.6mg was given iv bolus. Those who had nausea or emesis Injection ondansetron 4mg iv bolus was given. After delivery of the baby, 10units oxytocin was given slow iv and blood from umbilical cord was collected and sent for ABG analysis at 0 and 5 minutes. APGAR score was recorded in 0 min and 5min after birth. After the operation the mother was shifted to the post-operative care unit. Hemodynamic and any side effects if present were observed for 4 hours.

STATISTICAL EVALUATION:

Sample size for the study was calculated on basis of incidence of hypotension as primary outcome measure. Total number of patients 80 was obtained taking power to be 80% and type 1 error probability to be 5%. Sample size calculation has been done using nMaster 2.0 (Department of Biostatistics, CMC Vellore 2011) software.

Results obtained from sample collection were entered in Microsoft Excel and statistical analysis were done using IBM SPSS Python version 25.

 The parametric test employed for finding the significance in the study is the independent sample students T test.

The variables explored were t score, the single and two tailed significance values which were compared with the critical value by corresponding degree of freedom and alpha standard taken as 0.05. With 95% confidence interval P value less than the standard 0.05 was considered as significant to reject nulls hypothesis.

Levene’s test for equality of variances and student’s independent sample T test were used for equality of means between groups and variables over time. Means, SD, SE were also explored. Standard error bar containing line graph of means were used for pictorial representation of the variables in two groups (N and P).

For parametric data included in the study, the analogous Mann Whitney U test was employed.

Figure 1. Histogram showing age distribution in study subjects

The above shown histogram depicts the age distribution of the subjects taken for study in both the groups. The mean age varies around 25 years with a SD of 4.1.

Table 1: Demographic data

It can be seen that there is no significant statistical difference in weight and height in the two groups of patients

Table 2: Comparison of systolic blood pressure (SBP) in both the groups

At 6, 9, 12, 15, 25, 30, 35, 40, 45, 50 minutes and at 3.5 hours, it showed a significant difference between groups. Group N had a mean SBP which was comparatively higher than group P over time and is statistically significant with a p value of <0.05.

Table 3: Comparison of diastolic blood pressure (DBP) in both the groups

Comparing both groups not much of clinically significant variation of DBP was noticed, but a statistical significance at 3, 6, 12, 15, 25, 30, 40, 45, 60 minutes and at 3 hours with p value <0.05 was there.

Table 4: Comparison of mean blood pressure (MBP) in both the groups

Statistically significant P value (<0.05) at 3, 6, 9, 12, 40, 45, 60 minutes and at 3 hours noticed when comparing mean blood pressure in two groups.

Table 5: Comparison of pulse rate (PR) in both the groups

A statistical significance between two groups at 6, 9, 15, 20, 35, 40, 50, 55 minutes and at 2, 3, 4 hours with p value <0.05. Clinically significant variation of PR was not much in both groups.

Table 6: Comparison of PH, Lactate, and HCO3 in both the groups

Statistical significance pH changes at 0 and 5 minutes for Group N and Group P was there. Group P had statistically significant higher 0 minutes lactate levels than Group N. Group P had statistically significant lower Hco3 compared to Group N.

Table 7: Comparison of Apgar score in both the groups

There is no clinical as well as statistical difference or association, since the p values are >0.05 for Groups N and Group P at 0- and 5-minutes APGAR scores.

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Spinal Anaesthesia is one of the important means of delivering painless caesarean section. It is a “single-shot” technique with an obvious endpoint of visual CSF return and provides a rapid onset of dense anaesthesia. Spinal anaesthesia is also associated with the least absorption of local anaesthetic into the maternal circulation and thus least foetal exposure. The disadvantage is that there is no way to extend its action in single shot technique.

Prophylaxis and treatment of hypotension after spinal anaesthesia is a combination of proper patient positioning, fluids, and vasopressor support. Crystalloid administration has been considered the first line treatment for hypotension. Studies suggested superiority of co-loading to preloading with 500 to 1000 ml crystalloid.

 However intravenous fluid administration whether preloading or co loading did not prove to be sufficient to prevent maternal hypotension. As a result, vasopressors came into the field. Ideal vasopressor would be reliable and easy to use, has rapid onset, short duration of action, easily titrable, can be used prophylactically and lack any adverse maternal and foetal effect. Various vasopressors like ephedrine, phenylephrine, noradrenaline, metaraminol and mephentermine have been used to prevent spinal induced hypotension in caesarean section ^[53] 

 Phenylephrine is considered as the gold standard nowadays for SA induced hypotension in LSCS surgeries, but it causes maternal bradycardia. Many studies are still on the run for newer ideas regarding usage of vasopressor for spinal hypotension [54], of which one emerged out drug is Norepinephrine. Norepinephrine is usually considered as a vasopressor of choice in septic shock and it mostly is effective in maintaining MAP over long duration.

Norepinephrine has been introduced recently as a drug for SA related hypotension and has been studied extensively. Many studies show the efficacy of Norepinephrine in reducing the multiple episodes of hypotension occurring in the mother following neuraxial blockade, either through continuous infusions or as intermittent boluses. Its efficacy has also been compared with that of phenylephrine. This topic remains an enigma.

In the past decades, the efficacy of the types of anaesthesia like GA, SA, Epidural were studied through foetal blood gas analysis. In our study we have compared two novel drugs, Phenylephrine and Norepinephrine.

We administered the two drugs by continuous infusion at a fixed dose of 100ug/ml/hr for Group P and 6 ug/ml/hr for Group N immediately after the spinal anaesthesia is given. And we have analysed its efficacy by studying the foetal blood gas analysis done via new born umbilical artery blood sample ^[55]. The variables taken for consideration are Foetal pH, Hco3, Lactate and APGAR scores at 0 and 5 minutes along with maternal SBP, DBP, MBP, PR throughout the surgery.

Initial fall of BP varied but the throughout the maintenance phase, during the surgery and for four hours post-operative period the SBP, MBP was significantly stable in N group compare to P group. Intermittent rescue boluses were required for some patients but not more than 3 doses were required in either of the groups.

During the surgery there have been noted BP rise above the expected value, which warranted gradual tapering for some time period varying from (1-3 minutes) for Group P and (1-5 minutes) for Group N. Thereby showing the requirement for Phenylephrine was more intra operatively than Noradrenaline.

Out of 40 subjects receiving norepinephrine, 11 complained of nausea and 1 had vomiting and out of 40 subjects receiving phenylephrine, 15 complained of nausea and 9 had vomiting. A single bolus of Injection ondansetron 4mg relieved nausea and vomiting in all the affected patients. Significant vomiting noticed in those receiving phenylephrine. However, none of these patients had hypotension associated with the episodes of nausea and vomiting.

National Institute for Health and Care Excellence (NICE) guideline ensures the proper safe routine ABG analysis in case of suspected foetal distress ^[56]. In our study we have used foetal blood gas analysis as an outcome predictor in evaluating the two drugs. Foetal ABG analysis done at 0 and 5 minutes of birth showed demonstrable statistical significance in pH, Hco3, lactate between groups but very little clinical significance could be noted. No big variations were also noted in the APGAR score at both times.

Thus, we had an idea that the prophylactic infusion of Norepinephrine had an equal potency as well as efficacy in maintaining the intra-operative BP as well as HR, compared to that of Phenylephrine.

Till date the use of norepinephrine was generally limited to the setting of intensive care and cardiac anaesthesia. Given this lack of familiarity, the shift toward use of norepinephrine in obstetric domain will be challenging. Local vasoconstriction and tissue injury from norepinephrine extravasation is also a potential safety concern which necessitates large bore intravenous access and dilution of norepinephrine solutions. Almost all the published studies norepinephrine has been found to be more effective in terms of maintaining maternal heart rate and cardiac output and associated with low incidence of nausea and vomiting.

Doherty et al suggested that there were no clinical benefits when phenylephrine was administered as an infusion compared to bolus. In our study we were using phenylephrine as maintenance infusion throughout the surgery. There were no frequent needs of intermittent rescue boluses during the surgery.

Hasanin et al concluded that Norepinephrine when used at rates 0.05- 0.075/kg/min infusion during the surgery effectively reduced the intra operative spinal hypotension. Our study had similar outcome.

Onwochei et al showed that norepinephrine when used at fixed dose of 6 ug/ml/hr (ED90) as an infusion was able to reduce any hypotensive episodes during the surgery. We employed the same dose of 6 ug/ml/hr infusion in our study and the outcomes were identical.

Warwick et al in their study comparing norepinephrine and phenylephrine in obstetric spinal anaesthesia concluded that norepinephrine was effective in reducing any episodes of hypotension when compared to phenylephrine, our study in accordance with this study.

There were some limitations of the present study. Most of the published studies have done more elaborate haemodynamic monitoring with the help of non-invasive cardiac output monitor. Some studies have shown norepinephrine and phenylephrine infusions via computer controlled, microprocessor based closed loop vasopressor delivery system and have claimed better precision in blood pressure control and higher cardiac output for the mother, and better cord pH. They have compared cardiac output, cardiac index, stroke volume and systemic vascular resistance in the two groups, but in the present set up non-invasive cardiac output monitor was not feasible.

Prevention of hypotension after spinal anaesthesia in caesarean section is similar with phenylephrine and noradrenaline infusion but noradrenaline is better in terms of maintaining heart rate. Even though major clinical difference cannot be ascribed in maternal hemodynamic parameters, there is a statistically significant hemodynamic preservation with noradrenaline. Noradrenaline infusion shows a reduced levels of lactate CI (1.1-0.6) and the pH values varying around (7.27), with a CI (0.04-0.08), which are in accordance with aim of the study, that is a p value less than 0.05 with a CI of 95%. Thus, maternal haemodynamic parameters are better maintained with infusion noradrenaline.

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