A double blinded, randomised, interventional, placebo controlled study was conducted from July 2013 to September 2013 in Obstetrics and Gynaecology operation theatre of a tertiary teaching hospital. Institutional Ethics Committee approval letter no. F78/Pr/COMJNMH/I.E.C/42/(27) dated 26/04/2013. CTRI registration no. CTRI/2014/11/005218 dated 21/11/2014.

A power analysis was performed by assuming 70% incidence of hypotension in the control group and revealed that a sample size of 26 patients in each group shall have 90% power to detect a 35% reduction in the incidence of hypotension, with Type I error probability (α) of 0.05 and 10% of dropout [9]. Total sample size was 104 subjects.

After obtaining Institutional Ethics Committee’s approval, total 104 pregnant women between 18-30 years, American Society of Anaesthesiologists (ASA) physical status I or II, weight 50-90 kg, height 145-165 cm, having uncomplicated singleton pregnancy beyond 36 weeks, scheduled to have elective caesarean section under spinal anaesthesia were recruited for this study.

Subjects with foetal malpresentation, Pregnancy Induced Hypertension (PIH), hypertensive or resting BP≥160/90 mmHg before surgery, cardiac disease, systemic illness (renal disease, diabetes mellitus, coagulation disorder etc), chronic medications were excluded from the study.

After obtaining written informed consent, subjects were randomly (computer generated random numbers) allocated, where every subject had a chance to get allocated in any group, to receive 0.9% normal saline solution (Group A), or 1 mg of IM phenylephrine (Group B) or 2 mg of IM phenylephrine (Group C), or 3 mg of IM phenylephrine (Group D).

All medication with phenylephrine was made up to 2 mL with 0.9% saline. All patients were managed by an anaesthesiologist who was blind to the identity of the study medication.

No premedication was given to the study patients. Before spinal anaesthesia, 18 gauge IV catheter was introduced in the vein of left forearm of each patient. After that 500 mL IVF Ringer lactate was infused over 15 minutes as preloading. Then Ringer lactate infusion was continued throughout the operation and one hour after the operation at a rate of 4 mL/kg/hr through infusion pump.

Non Invasive Blood Pressure (NIBP), Electrocardiography (ECG) and pulse oximetry were attached for monitoring the BP, HR and O₂ saturation. Baseline SBP, DBP, MBP, HR were recorded. Then, patients were placed in sitting position and after antiseptic dressing and draping, a 25 gauge spinal needle was inserted in L2-3 or L3-4 vertebral inter-space, spinal anaesthetic agent, hyperbaric bupivacaine 0.5%, 2.5 mL was administered intrathecally.

Thereafter, patients were placed supine with left lateral uterine displacement at 15° angle. The IM injection of the study medication was given into the lateral aspect of the right thigh. Then, SBP, DBP, MBP, HR were recorded at three minutes interval throughout the surgery (average time for surgery was 27-30 minutes) (in the present study the average time was 27 minutes) and 10 minutes interval for one hour after surgery [4].

Hypotension was defined as SBP of <90 mmHg or fall of MBP more than 25% from the baseline MBP. Patients who met either criterion were treated with rescue IV bolus dose of phenylephrine 100 mcg. The same dose was repeated in three minute interval if both SBP and MBP would not increase above the threshold levels. Treatment with IV atropine 0.6 mg was given if bradycardia (defined as HR<50 bpm) occured, and if required repetition of the same dose in six minute interval. Subsequently no increase above the threshold level after two rescue dose (either phenylephrine or atropine, or both), the patient was excluded from the study. After delivery of the shoulders of the baby, patients received 5 IU of oxytocin by slow IV.

Efficacy parameters were assessed through the data of SBP, MBP, DBP. Any changes in ECG, HR or any other adverse events were also noted in detail.

Statistical analysis was done only after the completion of Case Record Form (CRF) of the last subject.

Data were represented as mean±SEM. Categorical data were compared between groups by Fisher’s exact test. As the data could not pass the normality test, numerical data between the groups were analysed by Kruskall-Wallis (nonparametric) test, whereas within the group were analysed by Friedman’s ANOVA (nonparametric) followed by Dunn’s Multiple Comparison test as post hoc test. All analyses were two tailed and p<0.05 was taken to be statistically significant.

A total of 104 subjects were randomised during the period of July 2013 to September 2013. Out of 104, 102 completed the study as per protocol, two subjects were excluded from the study as to hypotension was not controlled by rescue medications in (Group A) and needed different medications. There were 24 subjects in Group A (placebo treated group), whereas 26 subjects each in Group B (phenylephrine 1 mg IM), Group C (phenylephrine 2 mg IM) and Group D (phenylephrine 3 mg IM) [Table/Fig-1].

[Table/Fig-1]:

CONSORT flow diagram.

The subjects in all groups had comparable demographic profiles, laboratory parameters and baseline efficacy parameters [Table/Fig-2].

There were significant changes of SBP in Group A over different time points (compared to the baseline), whereas in Group D, the SBP was maintained (least variability) throughout the surgery except in SBP-8, (p<0.05), and also throughout one hour of postoperative period. Group C had less fluctuation than Group B in respect of SBP [Table/Fig-3].

The same results were seen in case of DBP [Table/Fig-4], and MBP [Table/Fig-5]. Group D had the least variability [decrease DBP was seen in DBP-8 (p<0.001), and DBP-9 (p<0.01)] followed by Group C, then Group B.

HR in all groups was steadily maintained in intraoperative as well as first one hour of postoperative period (p>0.05) [Table/Fig-6]. In HR, all groups were comparable, and there was no significant difference in comparison to baseline in all four groups.

Incidence of hypotension [Table/Fig-7] was frequently seen in Group A over different time points, least incidence was observed in Group D.

Group D was better than Group A (p<0.001), Group B (p<0.001) and Group C (p<0.007) in respect of total amount of rescue medication requirement. So, Group D required least amount of rescue medication which is statistically significant [Table/Fig-8,9].

Another analysis was done in respect of how many subjects received rescue medications, it was seen that Group D was better than Group A (p<0.001), Group B (p<0.0002) and Group C (p 0.0019), as to least number of subjects in this group received rescue medication. [Table/Fig-10,11].

Nausea and vomiting were the only adverse effects observed in the patients under study. Here, Group D was better than Group A (p<0.001) and Group B (p=0.0006) but comparable with Group C (p 0.41). Subjects of Group D had least incidence of nausea and vomiting [Table/Fig-12,13]. There was no episode of raised BP or bradycardia observed in the present study.

This study reports that 3 mg IM phenylephrine (Group D) is more effective to prevent the spinal anaesthesia induced hypotension in elective caesarean section than other different doses of phenylephrine (1 mg in Group B and 2 mg in Group C). We have not designed our study to include 4 mg of IM phenylephrine. Recent studies observed that haemodynamic control can be achieved with increasing dose of IM phenylephrine [5,6,8]. In another recent study it was observed that infusion regimen required a higher total dose of phenylephrine to maintain maternal arterial blood pressure at baseline during the predelivery period [10].

Subjects who received 3 mg of IM phenylephrine, hypotensive episodes were minimal among them, consecutively they received minimal amount of rescue medication. In a clinical trial 4 mg and 2 mg phenylephrine was administered to patients to evaluate the reduction of hypotension under spinal anaesthesia, it was observed that the incidence of hypotension was 25% in 4 mg group and 46.66% in group 2 mg. In this study it was concluded that preemptive IM phenylephrine 4 mg reduces the severity of spinal anaesthesia induced hypotension [6].

In a recent study it was observed that prophylactic administration was associated with a higher incidence of hypertension and bradycardia, but in the present study there was no episode of hypertension or bradycardia [7].

Subjects who received 3 mg IM phenylephrine had least incidence of nausea and vomiting than other groups. Recent meta-analytic technique also suggested that the risk of nausea or vomiting was reduced by almost 80% in the women receiving α-agonists [11].

Use of IV phenylephrine for correcting spinal anaesthesia induced hypotension is well established [11]; however, giving IM phenylephrine before spinal anaesthesia is more controversial due to risks of phenylephrine induced hypertension with or without bradycardia if spinal anaesthesia fails. We justified delaying the administration of IM phenylephrine until induction of spinal anaesthesia.

The timing of IM drug administration to achieve optimum efficacy is mostly unpredictable. Pharmacokinetic studies shows that the peak effect of IM phenylephrine is 10-15 minutes after administration [12]. The onset of subarachnoid block is seen within minutes, initially there were the episodes of hypotension; however, 3 mg IM phenylephrine decreased the frequency and incidence of hypotensive episode thereafter.

It was not possible to administer phenylephrine before spinal anaesthesia, because if there was failure of spinal anaesthesia, the patient would be suffering from phenylephrine induced hypertension with or without bradycardia.

The present study had some limitation like effect of phenylephrine on foetus was not assessed (umbilical arterial cord pH for foetal acidosis, APGAR score), higher dose group (4 mg IM or above) was not included in this study, drug concentration was not measured.

To conclude, it can be said that prophylactic 3 mg IM phenylephrine is effective and safe to reduce the incidence of spinal anaesthesia induced hypotension in caesarean section with minimal adverse effect.

Further study will be needed with larger population (without the above limitations) to detect the ideal IM dose of phenylephrine that will be maximally effective for the prevention of spinal anaesthesia induced hypotension, with minimal adverse effect.