European Journal of Cardiovascular Medicine

In elective caesarean sections, spinal anaesthesia is the most commonly utilized anaesthesia technique, except for cases involving laboring mothers and significant fetal distress requiring general anaesthesia ^[1]. The interruption of sympathetic nerves caused by spinal anaesthesia results in decreased peripheral vascular resistance and often leads to inadequate blood volume, which increases the likelihood of hypotension ^[2]. If hypotension is not addressed promptly, it can result in placental hypoperfusion, jeopardizing the fetal acid-base balance ^[3]. Various strategies are employed to manage hypotension, including adjusting the anesthetic dosage, altering the surgical position, prehydrating or cohydrating with fluids, and administering vasoactive medications ^{[4], [5], [6]}.

At present, phenylephrine is advised as the primary vasopressor for addressing hypotension during caesarean deliveries performed with spinal anaesthesia ^{[[7], [8], [9]]}. In comparison to ephedrine, which was previously the first-choice medication, phenylephrine leads to less fetal metabolism stimulation because it has lower permeability across the placenta, thereby enhancing the pH and base excess in the umbilical cord blood ^[10]. Recent studies on phenylephrine have primarily concentrated on its intravenous application for the prevention or treatment of hypotension ^[8,11].

Phenylephrine, an α1-adrenergic agonist, is expected to mitigate the reduction in systemic vascular resistance caused by spinal anaesthesia and has been shown to be both safe and effective when administered in bolus intravenous doses to patients having a Caesarean section.¹² Additionally, phenylephrine is considered safe for use via the intramuscular route in healthy non-pregnant individuals, including older adults, at doses of 0.15 mg/kg (up to a maximum of 10 mg). However, there is a lack of extensive studies regarding the administration of phenylephrine via the intramuscular route for preventing hypotension during spinal anaesthesia in Caesarean sections.^13,14

Therefore, we aimed to conduct a study to evaluate the effects of 2 mg of phenylephrine compared to 4 mg of phenylephrine and normal saline (as a placebo) administered via the intramuscular route immediately following the induction of spinal anaesthesia. Our research will focus on hemodynamic stability, the need for rescue intravenous vasopressor therapy, and neonatal outcomes as measured by the Apgar score at 1 and 5 minutes.

Objectives:

1. To evaluate and compare hemodynamic parameters including heart rate (HR), mean arterial pressure (MAP), respiratory parameters including rate (RR) and SPO2 with epidural magnesium sulfate vs dexmedetomidine vs normal saline during the postoperative period.
2. To compare the duration of postoperative analgesia.
3. To compare the incidence of postoperative complications including nausea, vomiting, respiratory depression, pruritus, hypotension, bradycardia and sedation.

Study Design:    It is a randomized, double blinded, prospective, placebo controlled comparative study.

Study area: The Pre-operative room, Gynaecological operation theatre, Post anaesthesia care unit (PACU) of Dr PSIMS & R. 

Study Period: January 2019 to September 2019.

Study population: Patients with ASA physical status 1 or 2, undergoing elective caesarean section at term pregnancy under spinal anaesthesia at Konaseema institute of medical sciences, Amalapuram.

Sample size:

Minimal sample size of my study is 27 using the formula

Zα = 1.65 with 95% confidence limit (one tail) Zβ = 1.28 with 90% power

P = (P1+P2) /2

P1= incidence of hypotension in control group (70%) P2 = incidence of hypotension (assumed around 30%)

Taking 20% error into account, actual sample size was taken as 32.

SAMPLE DESIGN:

All the antenatal mothers (n=96) were divided into three groups according to sample size.

Group A (n=32): received 2mg i.m phenylephrine (1ml) with 1ml normal saline (total 2ml).

Group B (n=32): received 4mg i.m phenylephrine (2ml)

Group C (n=32): received 2ml 0.9% normal saline. All the drugs were given intramuscularly.

Inclusion Criteria:

1. Patients with term pregnancy
2. Posted for elective caesarean section under spinal anaesthesia.
3. Age between 18-40 yrs
4. Weight 40-75 kgs.
5. Height 5 feet or more
6. ASA physical status grade 1 or 2

Exclusion criteria:

1. a) Refusal to spinal anaesthesia
2. b) Any other contraindication to spinal anaesthesia
3. c) Patients with previous hypertensive disorders
4. d) Pregnancy induced hypertension
5. e) Patients with diabetes, kidney disease
6. f) Patient with known cardiac disease

Ethical consideration: Institutional Ethical committee permission was taken before the commencement of the study.

Study tools and Data collection procedure:

All study medications were administered by an anaesthesiologist not involved in the care of the patient or collection of data. A second anaesthesiologist blinded to the identity of the study medication managed the patient by giving rescue vasopressor as needed and collected all the data in relation to the code of the patient.

STUDY TOOLS

1. Boyle’s machine with continuous central uninterrupted oxygen supply.
2. IV cannula, transfusion set, IV fluids,
3. Hyperbaric Bupivacaine (0.5%), Inj. Fentanyl citrate, spinal needle (26G), disposable syringe (2cc, 5cc)
4. Sterile dressing draping set for spinal technique.
5. 2% Lignocaine for local infiltration.
6. Phenylephrine (diluted in various dilution – one syringe 100 mcg/ml for rescue bolus and in other syringe 2mg/ml for prophylactic intramuscular injection)
7. Multichannel monitor-NIBP, HR, SPO2, continuous ECG, pulse oxymeter, alcohol swabs.

PARAMETERS MEASURED: DEMOGRAPHIC PARAMETERS:

These parameters were measured in the pre-anaesthetic check-up. Age Weight Height Gravida

CLINICAL PARAMETERS:

1. Noninvasive blood pressure (NIBP) monitoring starting from 10 minutes before anaesthesia to 6 hours post operatively – SBP, DBP, MAP.
2. Heart rate by continuous ECG monitoring.
3. Dermatomal sensory level checked by alcohol-soaked cotton swab test.
4. Duration of surgery.
5. Apgar score at 1 min and at 5 min after birth.
6. Number of bolus rescue dose of i.v. phenylephrine (100mcg) required for each group.

STUDY PROCEDURE:

A day before the scheduled operation the patients were visited preoperatively in their wards for preanaesthetic check-up. A thorough clinical history was obtained. They were physically examined, general survey, systemic examination, airway assessment was done thoroughly with special focus on Modified Mallampati classification, mouth opening, neck movement, thyromental distance to find out any possibility of difficult intubation. Any patient with anticipated difficult intubation was excluded from the study. Laboratory investigations were reviewed. Prior history of any surgery or anaesthetic problems was also noted. The patients were explained about the procedure of study and were counselled about the potential complications of both surgery and anaesthesia. All queries and doubts were answered to get their confidence and support. No sedative was used to allay her anxiety as it could cause respiratory depression of the baby. They were advised to take tablet ranitidine (150mg) before dinner and not to take any oral feed after 9pm on the night before surgery.

On the morning of the surgery preparation of the operative room (OR) was done meticulously. Boyle’s anaesthesia machine was checked. Appropriate size endotracheal tubes, working laryngoscope with medium and large size blades, stylet and working suction apparatus were kept ready before the procedure. Emergency drug tray consisting of atropine, adrenaline was kept ready. After obtaining written informed consent, 96 women of ASA grade 1 or 2 undergoing elective caesarean section under spinal anaesthesia were taken up for the study. After shifting the patient in the operation table all the monitors (ECG, pulse oxymetry, NIBP) were attached. Average value of SBP (systolic blood pressure) and HR (heart rate) of the last 2 readings before operation (within 10 minutes) was taken as the baseline SBP & HR. Then according to the body weight of the patient 10ml/kg ringer’s lactate infusion was given as preload to all patients 20-30 minutes before operation80,81,82. The patients were randomized by a coded, opaque, scaled envelope technique into 3 groups-group A, B and C. All the necessary aseptic precaution of spinal technique was maintained each time. Before introducing spinal needle, the local skin was infiltrated with 1-2ml of 2% lignocaine in every case. Subarachnoid block was given in L3-L4 space in sitting position through midline approach by injecting 2ml of 0.5% hyperbaric bupivacaine and fentanyl 25mcg (total volume 2.5ml) when free flow of CSF was evident using a 26G Quincke’s spinal needle. After spinal injection patient was made supine and the tablet was tilted 150 left laterally. Intramuscular injections were given according to the code of the patient in the left vastus lateralis muscle immediately after the subarachnoid block. Group A received phenylephrine 2mg, group B received phenylephrine 4mg and group C received 2ml 0.9% normal saline as placebo. Time of anaesthesia was taken as time zero. Level of spinal block was checked with alcohol swab 5 minutes after intrathecal injection. Duration of the operation was monitored. Continuous blood pressure & EGG monitoring was done. From the time zero up to first 10 minutes SBP, HR were monitored every 2 minutes, then up to 1-hour measurements were done every 5 minutes. Then in the post operative period monitoring was done every 30 minutes for 6 hours. Bolus 100mcg phenylephrine i.v. was used as rescue vasopressor for the treatment of hypotension whenever SBP was less than 100 mm of Hg. Time of delivery was noted and after delivery of the baby oxytocin 10 mg i.m. injection was given to each mother in her left deltoid muscle. Apgar score monitoring was done at 1 min and again at 5 min after birth of the neonate in each group.

Statistical analysis:

Data were collected and compiled in excel sheets and analyzed using different statistical methods like tables and various charts etc. For descriptive statistics mean, median, standard deviation, simple proportion etc. were estimated. To test statistical significance tests like simple chi-square, chi-square for trend, Kruskal-Wallis non parametric test, Relative risk with 95% Confidence Interval, ANOVA with Post Hoc (LSD) test, were adopted. Data were analyzed at 95% confidence level i.e. p<0.05 was considered acceptable. For the purpose of data analysis, SPSS 16 version was used.

Table-1: Distribution of participant groups as per age, weight, height and gravid (N=96).

* Kruskal - Wallis non parametric test done

Table - 2: Distribution of participant groups according to preoperative heart rate, SBP and highest level of sensory block.

* Kruskal -Wallis non parametric test done

The above table shows that the study groups were not different in respect to the preoperative heat rate, Systolic blood pressure and height of block.

Table - 3: Distribution of study groups as per the reading of SBP within first 10mins of drug administration

*Not applicable

Three were statistically significant differences in SBP among the groups at observation level of 2,8 and 10mins. After the administration of medicine and the difference were significant mainly between Gr.C Vs A& B.

Table - 4: Distribution of groups according to the occurrence of hypotension within first 10mins after drug administration.

Statistical tests between Gr. A & B. showed X2=1.24,0.2661051; RR (95%CI) = 1.57 (0.70-3.54)

The above table has been constructed for better understanding of previous table and indicates that the gr. A & B were comparable in respect to the events of hypotension. However, they were found to differ significantly from gr.C in this respect.

Three groups differed in SBP in the observations at 15,25 and 30th min. interval after the administration of medicine. Average heart rate was found to be significantly higher in Gr.A compared to that of Gr.B.&C.

The gr. A&B were found to be different from the gr. C so far as the occurrence of hypotension and the difference was statistically robust. However, the difference between group A and group B was not statistically strong enough to refute the conclusion that they were similar at least in regard to the occurrence of the event of hypotension during this phase of the experiment.

Table - 5: Distribution of study groups as per the level of post-op SBP up to 6 hrs. after surgery.

The mean SBP was found to be different between the groups at different level of observations after the surgical manoeuver. The differences were statistically significant except at 60 min., 2 hours, 4.5 hours and 5 hours point of observations after the caesarean section.

Table - 6: Distribution of study groups as per HR during post-op period up to 6 hrs.

HR was revealed to differ across the groups at 1.5, 2.0, 4.0, 4.5 and 5.0 hours points of observations. However, the incidence of tachycardia/bradycardia didn’t happen whatsoever in any groups.

All the patients were observed up to 6 hours postoperatively and it was found that there were 38, 16, 87 episodes of hypotension in group A, B and C respectively. The rate of occurrence of hypotension was estimated to be 1.19, 0.50,2.71 per patient in gr. A, B and C respectively. It clearly shows the superiority of group B over group A & group C.

Table - 7: Distribution of participants requiring at least one dose of rescue drug (N=96).

The analysis in the above table depicts the difference among the groups in respect to the requirement of at least one dose of rescue medicine as indicated by the value of Chi-sqaure and RR which stated the superiority of Gr.B over the Gr. A & C and again Gr.A over the Gr. C (as per the values of RR).

Table - 8: Distribution of participants in various groups requiring more than one repeat dose of rescue drug (N=96).

Gr.A Vs Gr.C: Chi-square at df 1 = 15.27, 0.0000932; RR (95% CI) = 4.75 (1.82- 12.41)

This table is to judge the status of the groups in respect of their requirement of repeat dose(s) of rescue medicine to manage the event(s) of hypotension, if any, developed during the period of observations. It showed the best position of gr.B in this connection.

Regarding the requirement of repeat dosesit was found that 14 repeat doses were required by 10 patients in group A with an average of 1.4 per patient, 3 repeat doses were required by 3 patients in group B with an average of 1 per patient and 59 repeat doses were required by 27 patients in group C with an average of 2.18 per patient.

From tables (20,21,22,23& 24) it can be derived that the total requirement of rescue phenylephrine was highest in group C (87 doses = 87mg), lowest in group B (16 doses = 16 mg) and requirement in group A was in between other two groups (38 doses = 38mg).

Table no-9: Distribution of different groups according to the Apgar score after birth at 1 min and at 5 min (N=96) .

The table shows that Apgar score, a predictor of neonatal wellbeing was not different among the groups at 1st and 5th min after birth.

Overall Comparisons

Test of equality of survival distributions for the different levels of group.

The survival analysis (the Survival function followed by statistically robust Chi-square reading) clearly depicted the superiority of gr.B over other 2 groups. As the event of interest i.e occurrence of hypotension followed by administration of rescue medicine (for the first time) didn’t happen after 180mins level of observation, that’s why survival and hazard analysis was done considering this point of observation as the end point.

In our study we used prophylactic intramuscular phenylephrine (2 mg, 4 mg) instead of phenylephrine infusion. The reason being that there is dose-dependent decrease in heart rate associated with a continuous infusion of phenylephrine during spinal anaesthesia for caesarean delivery which is associated with a reduction in maternal cardiac output and this may be dangerous to mother as well as fetus.55 But this has not been reported when phenylephrine was used intramuscularly. In 1992 Korkuschko OW et al found that phenylephrine can be given safely up to 0.15mg/kg via the i.m. route.13 Pharmacokinetic studies have suggested that the peak effect of i.m phenylephrine or ephedrine is 10-15 mins after i.m administration.¹⁵

However, giving i.m vasopressor before a spinal anaesthetic is more controversial because of concerns about reactive hypertension and adequacy of placental perfusion if subarachnoid block fails.¹⁶ We justified delaying the administration of i.m vasopressors until the induction of subarachnoid block. This was the same method used by B.T Ayorinde et al in 2001.

The present study evaluated the efficacy of different doses of intramuscular (i.m.) phenylephrine in preventing spinal anesthesia-induced hypotension in pregnant mothers undergoing cesarean delivery. The findings highlight significant differences in hemodynamic stability among the three groups, with Group B (intermediate dose) demonstrating the most favorable outcomes compared to Groups A (higher dose) and C (control/no prophylaxis).

Comparability of Study Groups

The baseline demographic and clinical characteristics—age, weight, height, gravidity, BMI, ASA-PS, preoperative heart rate, systolic blood pressure (SBP), and spinal blockade level—were comparable across all groups (p > 0.05). This homogeneity ensures that any observed differences in hemodynamic responses were likely due to the intervention rather than confounding variables.

Early Hemodynamic Stability (0-10 Minutes)

Group B (intermediate dose) and Group A (higher dose) exhibited significantly higher SBP at the 2nd, 8th, and 10th minutes compared to Group C (control) (p < 0.05). The 4th and 6th-minute values were comparable across groups, likely due to the vasoconstrictive effect of rescue intravenous (i.v.) phenylephrine administered to counteract hypotension.

Hypotension incidence was highest in Group C (65.63%), followed by Group A (34.37%), and lowest in Group B (21.88%). The relative risk (RR) of hypotension was significantly higher in Group C (RR 6.82) compared to Group B, reinforcing the protective effect of prophylactic phenylephrine.

Mid-Observation Period (15-30 Minutes)

Group C continued to show significantly lower SBP compared to Groups A and B (p < 0.05), with the most pronounced difference between Group B and Group C. Hypotension incidence remained lowest in Group B (15.62%), followed by Group A (31.25%), and highest in Group C (62.50%). Group B demonstrated superiority over Group C (RR 4.00), though no significant difference was observed between Groups A and B (p = 0.140).

Late Observation Period (35-60 Minutes)

Group B maintained the best hemodynamic stability, with only 3.12% experiencing hypotension, compared to 18.75% in Group A and 53.12% in Group C. Group B was significantly superior to Group C (RR 17.00, p = 0.000), while Group A also performed better than Group C (RR 2.83, p = 0.004). No significant difference was found between Groups A and B (p = 0.04), suggesting that the higher dose (4 mg) did not provide additional benefit over the intermediate dose (2 mg).

Our findings align with Sen et al.¹⁷ (2013), who reported that higher doses of phenylephrine did not offer additional protection against hypotension compared to lower doses. However, unlike their study, we did not observe hypertensive episodes, possibly due to differences in dosing regimens or patient selection.

Prophylactic i.m. phenylephrine (2 mg) is effective in reducing spinal hypotension without increasing hypertension risk. Higher doses (4 mg) do not confer additional benefits, supporting the use of moderate dosing to minimize side effects. Group B (2 mg) demonstrated the most consistent hemodynamic stability, making it a preferable choice for prophylaxis.

The present study evaluated the efficacy of different doses of intramuscular (i.m.) phenylephrine in preventing spinal anesthesia-induced hypotension in pregnant mothers undergoing cesarean delivery. The findings highlight significant differences in hemodynamic stability among the three groups, with Group B (intermediate dose) demonstrating the most favorable outcomes compared to Groups A (higher dose) and C (control/no prophylaxis).

Comparability of Study Groups: The baseline demographic and clinical characteristics—age, weight, height, gravidity, BMI, ASA-PS, preoperative heart rate, systolic blood pressure (SBP), and spinal blockade level—were comparable across all groups (p > 0.05). This homogeneity ensures that any observed differences in hemodynamic responses were likely due to the intervention rather than confounding variables.

Early Hemodynamic Stability (0-10 Minutes): Group B (intermediate dose) and Group A (higher dose) exhibited significantly higher SBP at the 2nd, 8th, and 10th minutes compared to Group C (control) (p < 0.05). The 4th and 6th-minute values were comparable across groups, likely due to the vasoconstrictive effect of rescue intravenous (i.v.) phenylephrine administered to counteract hypotension. Hypotension incidence was highest in Group C (65.63%), followed by Group A (34.37%), and lowest in Group B (21.88%). The relative risk (RR) of hypotension was significantly higher in Group C (RR 6.82) compared to Group B, reinforcing the protective effect of prophylactic phenylephrine.

Mid-Observation Period (15-30 Minutes): Group C continued to show significantly lower SBP compared to Groups A and B (p < 0.05), with the most pronounced difference between Group B and Group C. Hypotension incidence remained lowest in Group B (15.62%), followed by Group A (31.25%), and highest in Group C (62.50%). Group B demonstrated superiority over Group C (RR 4.00), though no significant difference was observed between Groups A and B (p = 0.140).

Late Observation Period (35-60 Minutes): Group B maintained the best hemodynamic stability, with only 3.12% experiencing hypotension, compared to 18.75% in Group A and 53.12% in Group C. Group B was significantly superior to Group C (RR 17.00, p = 0.000), while Group A also performed better than Group C (RR 2.83, p = 0.004). No significant difference was found between Groups A and B (p = 0.04), suggesting that the higher dose (4 mg) did not provide additional benefit over the intermediate dose (2 mg).

Post-Operative Hemodynamic Stability:

Group B (2 mg phenylephrine) maintained significantly better SBP in the post-operative period compared to Group C (placebo), with hypotensive episodes occurring in only 6.25% of Group B versus 37.50% in Group C (RR 6.00, p = 0.002). Group A (4 mg phenylephrine) did not show a statistically significant advantage over Group C (p = 0.280), aligning with findings by B.T. Ayorinde et al., who reported similar outcomes between a 2 mg phenylephrine group and placebo. No significant differences were observed at 60 min, 2 hours, 4.5 hours, and 5 hours, suggesting that the prophylactic effect of phenylephrine diminishes over time.

Rescue Phenylephrine Requirements: The time to first rescue vasopressor administration was similar across all groups (p = 0.140), indicating that prophylactic phenylephrine delays but does not entirely prevent hypotension, consistent with previous studies. Group B required the fewest rescue doses (13 mothers, 40.63%), compared to Group A (24 mothers, 75%) and Group C (28 mothers, 87.50%). Group B was superior to both Group A (RR 0.54, p = 0.005) and Group C (RR 0.46, p = 0.000), reinforcing the optimal efficacy of 2 mg phenylephrine. No significant difference was found between Group A and Group C (p = 0.20), suggesting that 4 mg phenylephrine does not offer a clinically meaningful advantage over placebo, corroborating findings by B.T. Ayorinde et al.

Our findings align with George Ronald B et al.¹⁶ (2010), who determined the ED90 of intravenous phenylephrine for treating spinal hypotension to be 150 mcg. Our use of 100 mcg i.v. bolus phenylephrine as rescue therapy was based on the lower confidence interval of their study, ensuring efficacy while minimizing overdose risk. Similar to Indu Sen et al. (2013), we found that higher doses of phenylephrine (4 mg) did not provide additional benefits over lower doses (2 mg), though unlike their study, we observed no hypertensive episodes, possibly due to differences in administration timing or patient selection.

In a study Dyer RA, Reed AR et al (2009) reported that co-administration of phenylephrine and oxytocin obtunded the decrease SVR, increase HR and CO effect of oxytocin.²⁰ Though we did not measure the cardiac output but the slower heart rate (without bradycardia) throughout the observational period may be due to the opposite effects of phenylephrine and oxytocin which was administered following delivery of the baby.

Kaplan-Meier survival analysis between the three groups shows chance of survival (i.e less chance of hypotension) was highest in group B and lowest in group C, group A is midway between other 2 groups. In another way Kaplan-Meier analysis shows that group C had maximum hazards of hypotension than the other two groups.

Previously in 1997 Brooker RF, Butterworth JF 4th et al showed that phenylephrine was significantly effective in restoring systolic blood pressure but was associated with a decrease in heart rate and decrease in cardiac output compared to epinephrine.²¹ Dyer et al in 2009 found that phenylephrine reduces maternal cardiac output in comparison to ephedrine.²⁰ In 2010 Stweart A, Fernando et al also concluded that infusing higher concentration of phenylephrine reduces maternal cardiac output.²² We did not measure the effect of phenylephrine on CO and derived systemic vascular resistance index (SVRI) in our study.

In conclusion, our findings indicate that administering intramuscular phenylephrine at a dosage of 4mg helps to decrease both the occurrence and intensity of hypotension following spinal anaesthesia in caesarean sections when compared to 2 mg of phenylephrine or placebo. Prophylactic administration of phenylephrine at 2mg lowers the severity of hypotension but does not affect its incidence in comparison to placebo. Both dosages of prophylactic phenylephrine, 2mg and 4mg, lead to a reduced need for rescue vasopressors when matched against the use of placebo. The use of intramuscular phenylephrine does not correlate with any negative neonatal outcomes as measured by the Apgar score.

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