|Year : 2022 | Volume
| Issue : 2 | Page : 116-121
Randomized trial of bolus ephedrine or mephentermine for maintenance of arterial pressure and fetal outcome during spinal anesthesia for the cesarean section
Thomas S Linette, T Gurumurthy
Department of Anaesthesia, Father Muller Medical College, Kankanady, Mangalore, Karnataka, India
|Date of Submission||16-May-2021|
|Date of Acceptance||11-Apr-2022|
|Date of Web Publication||02-Sep-2022|
Dr. T Gurumurthy
Department of Anaesthesia, Father Muller Medical College, Kankanady, Mangalore - 575002, Karnataka
Source of Support: None, Conflict of Interest: None
Background and Aims: Spinal anesthesia remains the preferred choice for cesarean deliveries, but hypotension is one of the common complications which may have detrimental effects on both the mother and fetus. In this study, we compared the efficacy and adverse effects of bolus doses of ephedrine hydrochloride and mephentermine sulfate administered intravenously to treat spinal-induced hypotension and the fetal outcomes through Apgar scores and umbilical cord blood gas analysis in the lower segment cesarean section. Material and Methods: In this prospective, randomized, double-blind study, 60 patients undergoing the lower segment cesarean section (LSCS) under spinal anesthesia were randomized into two groups of 30 each using computer-generated random numbers which were kept in an opaque envelope. Patients were pre-loaded with Ringer's lactate solution 10 ml/kg before the spinal anesthesia. Hypotension was defined as the fall in systolic blood pressure of less than or equal to 20% of the baseline or systolic blood pressure of less than 90 mmHg. Whenever hypotension occurred, patients in group E (ephedrine) received a bolus dose of ephedrine 6 mg intravenous and patients in group M (mephentermine) received a bolus dose of mephentermine 6 mg intravenous. Intra-operative recording included maternal hemodynamic parameters and the number of bolus doses of study drugs required to treat maternal hypotension and the adverse effects of study drugs. The Apgar score and umbilical cord blood gas values were recorded. Data were analyzed by analysis of variance test, Student's t-test, and Chi-square test. A P value of < 0.05 was considered as significant. Results: There was a statistically significant (p < 0.05) increase in systolic and mean arterial blood pressure at the second min and fourth min after administration of ephedrine in group E compared to mephentermine in group M. The systolic blood pressure at the second min in the ephedrine group was 114.3 ± 12.06, whereas in the mephentermine group, it was 106.10 ± 8.41 and was statistically significant (p < 0.05). At the fourth min, the systolic blood pressure in the ephedrine group was 115.03 ± 8.87, whereas in the mephentermine group, it was 108.46 ± 8.10 and was statistically significant (p < 0.05). There was a transient increase in heart rate immediately after administration of spinal anesthesia. The mean number of bolus doses of vasopressor consumption was 2.4 (14.4 mg) in the ephedrine group and 2 (12 mg) in the mephentermine group. The umbilical cord blood gas analysis and Apgar scores were similar in both the groups. Three patients (10%) developed bradycardia in the mephentermine group compared to the ephedrine group (0%). The incidence of nausea (13.3% vs 3.3%) and vomiting (10% vs 1%) was higher in the ephedrine group compared to the mephentermne group, and it was not statistically significant (p > 0.05). No significant differences were observed in the umbilical arterial blood pH and Apgar scores. Conclusion: In conclusion, after hypotension, ephedrine and mephentermine administration as bolus doses are equally efficacious in preventing spinal-induced hypotension in patients undergoing the cesarean section and are associated with similar neonatal outcomes.
Keywords: Ephedrine, mephentermine, neonatal outcome, spinal hypotension, vasopressors
|How to cite this article:|
Linette TS, Gurumurthy T. Randomized trial of bolus ephedrine or mephentermine for maintenance of arterial pressure and fetal outcome during spinal anesthesia for the cesarean section. J Obstet Anaesth Crit Care 2022;12:116-21
|How to cite this URL:|
Linette TS, Gurumurthy T. Randomized trial of bolus ephedrine or mephentermine for maintenance of arterial pressure and fetal outcome during spinal anesthesia for the cesarean section. J Obstet Anaesth Crit Care [serial online] 2022 [cited 2023 Feb 5];12:116-21. Available from: https://www.joacc.com/text.asp?2022/12/2/116/355346
| Introduction|| |
Spinal anesthesia is the most popular among the regional anesthesia techniques for the cesarean section. Compared to any other anesthetic technique, it is not devoid of complications, with the most common being hypotension, which may adversely affect both the mother and fetus.
Commonly used methods to prevent or treat such hypotension include pre-loading/co-loading with fluids, avoidance of aortocaval compression, lower limb compression/elevation, and administration of vasopressor drugs. Various vasopressors, for example, ephedrine, mephentermine, methoxamine, metaraminol, phenylephrine, angiotensin 2, dopamine, and dobutamine, have been studied for this purpose. However, no drug has been proved to be entirely satisfactory.,
Among the vasopressors, ephedrine is the most commonly recommended drug to treat spinal-induced hypotension. It has both α and β agonist action, but indirect action is more prominent because of the release of norepinephrine from sympathetic nerve endings. It increases the blood pressure by β1 receptor stimulation with an increased heart rate and cardiac contractility. The advantages of ephedrine include familiarity, long history, and low propensity for uteroplacental vasoconstriction. Ephedrine, however, has limited efficacy, is difficult to titrate, causes maternal tachycardia, and depresses fetal pH and base excess.
Mephentermine also has a mixed α and β receptor agonist action with both direct and indirect effects because of the release of norepinephrine and epinephrine. Its use in hypotension after a neuraxial blockade in obstetrics is because of its ability to increase the blood pressure by augmenting the cardiac output. However, it may cause a decrease in uterine blood flow, which may result in fetal hypoxia. Mephentermine is commonly used in India for the management of spinal-induced hypotension. Nonetheless, there is a paucity of information on its use as well as its comparison with other vasopressors regarding safety and efficacy.
In the present study, we compared the efficacy of a bolus dose of ephedrine hydrochloride and mephentermine sulfate administered intravenously to treat spinal-induced hypotension and the fetal outcomes in the lower segment cesarean section. The primary outcome was to study the efficacy of ephedrine and mephentermine for the management of hypotension following spinal anesthesia in the mother and the neonatal outcomes in terms of umbilical cord blood gas analysis and Apgar scores. The secondary outcome was to evaluate the incidence of side effects of ephedrine and mephentermine.
| Materials and Methods|| |
This randomized clinical trial was conducted after obtaining approval from the institutional ethics committee. It was registered with the Clinical Trial Registry of India (CTRI/2018/05/014238). The study was conducted on 60 women aged between 20 and 40 years, weighing 45–75 kg and with a height of 145–160 cm, belonging to ASA physical status 1 and 2 with a singleton pregnancy scheduled for the elective lower segment cesarean section (LSCS) under the sub-arachnoid block (SAB). The exclusion criteria are pregnancy-induced hypertension (PIH), obesity, pre-existing hypertension, cardiovascular diseases, cerebrovascular diseases, gestational diabetes, evidence of fetal anomalies, and contraindications to spinal anesthesia. The study protocol was explained to the patients in detail in their own language, and informed written consent was taken. Ethics committee approval obtained dated 11.10.2017.
A detailed pre-anesthetic evaluation was performed to rule out the exclusion criteria. Routine investigations of hemoglobin, blood urea, serum creatinine, bleeding and clotting time, and blood sugar level were performed. Patients were asked to fast overnight and given tablet ranitidine 150 mg orally the night before surgery. On the day of surgery, all patients were pre-medicated with injection ranitidine 50 mg and metaclopramide 10 mg given intravenously 1 hour before the surgery.
On arrival to the operating room, patients were randomly allocated into two groups of 30 patients each using computer-generated random numbers which were kept in an opaque envelope. The patients in group E received a bolus of ephedrine hydrochloride 6 mg intravenous, and the patients in group M received a bolus of mephentermine sulfate 6 mg intravenous. The study drugs were administered during spinal anesthesia by an anesthesiologist who did not further participate in the study. All observations were recorded by an anesthesiologist who was unaware of the group to which the patient belonged.
In the operating room, an intravenous line was established with 18 G cannulas. The standard monitors of pulse oximetry, non-invasive blood pressure (NIBP), and electrocardiogram (ECG) were connected to the patient. The heart rate (HR), systolic blood pressure (SBP), diastolic blood pressures (DBP), and mean arterial blood pressure (MAP) were recorded. An average of three readings at the time interval of 2 minutes was considered as the baseline value. Patients were pre-loaded with Ringer's lactate 10 ml/kg over a period of 20 min prior to the surgery, and then the infusion rate was reduced to 4 ml/kg/hr as the maintenance fluid.
Under aseptic precaution, lumbar puncture was performed by a mid-line approach with 25 G quincke spinal needles at the L3–L4 intervertebral space. After confirming free flow of the clear cerebrospinal fluid, 2 ml (10 mg) of 0.5% w/v hyperbaric bupivacaine hydrochloride (Sensorcaine) was administered over 10–15 secs. The time of injection was recorded, and the patient was turned supine immediately. A wedge was placed under the right buttock to facilitate left uterine displacement. Oxygen was administered at a rate of 5 liters/minute by facemask until clamping of the umbilical cord. The level of sensory block was assessed by the pinprick method using 22 G hypodermic needles every minute until it reached the T5 dermatome level after administration of SAB; then, the surgery was allowed to begin. The time from the sensory blockade to skin incision, uterine incision, and the extraction of the baby was recorded.
Hypotension was defined as the fall in systolic blood pressure of less than or equal to 20% of the baseline or systolic blood pressure of less than 90 mmhg.
The hemodynamic parameters of heart rate, SAB, DAB, and MAP were recorded at the time of onset of hypotension, and a bolus of the study drug was administered intravenously. Subsequently, the hemodynamic parameters were recorded at every 2 minutes for 20 min and then every 5 minutes up to 30 minutes. Whenever hypotension occurred, a bolus dose of the vasopressor drug was repeated, and the total number of bolus doses required was recorded.
Bradycardia was defined as the pulse rate of less than or equal to 50 beats/minute and was treated with injection atropine 0.6 mg intravenously. The number of episodes of nausea and vomiting and any other adverse events was recorded. Nausea and vomiting were treated with ondansetron 4 mg intravenous.
After extraction of the baby before the first breath section of the umbilical cord was double-clamped for blood gas analysis of umbilical vessels. Then, 20 IU of oxytocin was administered immediately after the delivery of the baby by infusion over a period of 30 minutes. A pH of the umbilical blood sample less than 7.2 was considered as fetal acidosis. Apgar scores at the first and fifth minutes of birth were recorded, and an Apgar score of less than 7 was considered as low.
Power analysis calculated from the reference article suggested that a sample size of 30 patients per group was required to get the power of study to 80% with a 0.05 level of significance, a confidence interval of 95%, and an alpha error of 0.05. The quantitative data are represented as mean ± standard deviation (SD). The qualitative data are presented as frequency and percentage. Categorical data are represented as the number of patients. The hemodynamic parameters and the number of bolus doses of study drugs were compared using Student's t-test and Chi-square test. The P value <0.05 was considered significant. The adverse effect profile was compared with Fischer's exact test. The statistical software SPSS version 23 was used to analyze the data.
| Results|| |
The demographic data and operative details are shown in [Table 1]. There was no significant difference (p > 0.05) between the two groups with respect to age, weight, and height. There was no statistically significant difference regarding operative details, that is, the time interval between SAB and the delivery of the baby (SAB-D) and between uterine incisions and delivery (UI-D). The maximum sensory block level attained was T4 and T5 in both the groups. The maximum sensory level of T4 was 9 (30%) versus 10 (33.3%) and that of T5 was 21 (70%) versus 20 (66.7%) in group E and group M, respectively, and was not statistically significant. The time of onset of hypotension was similar in both the groups; it was 2.6 ± 1.38 minutes in group E and 2.4 ± 1.60 minutes in group M.
There was a fall in SBP, DBP, and MAP after the administration of the sub-arachnoid block in both the groups. However, there was a significant (p < 0.05) increase in SAB and MAP at the second and fourth minutes in group E compared to group M [Figure 1] and [Figure 2] after the administration of the vasopressor drug. The systolic blood pressure was (114.3 ± 12.06 vs 106.10 ± 8.41) at the second minute and (115.03 ± 8.87 vs 108.46 ± 8.10) at the fourth minute in group E and group M, respectively [Table 2], whereas the diastolic blood pressure increased only at the second minute (67.93 ± 9.12 vs 62.87 ± 7.35) in group E compared to group M.
The baseline heart rate was similar in both the groups. There was a transient increase in heart rate immediately after the administration of SAB [Figure 3], and it was statistically not significant. After the administration of the vasopressor, there was no significant change in heart rate throughout the study period.
The number of bolus doses of the vasopressor required in both the groups to maintain the blood pressure was comparable and was not statistically significant (p > 0.05). The number of bolus doses of the vasopressor required in group E and group M was 5 (16.7%) versus 3 (10%) for a single bolus dose, 11 (36.7%) versus 6 (20%) for two bolus doses, and 13 (43.3%) vs. 15 (50%) for three bolus doses. One patient in group E required a maximum of six bolus doses of the vasopressor.
The incidences of side effects in both groups were found to be comparable and were not statistically significant. Four patients (13.3%) in Group E developed nausea compared to one patient (3.33%) in Group M. Three patients (3%) in Group E compared to one patient in group M developed vomiting. The incidence of bradycardia was observed in 3 (10%) in group M, whereas bradycardia was not observed in group E. The bradycardia was managed successfully by atropine 0.6 mg intravenous. There was no significant difference (p > 0.05) with regard to side effects of drugs between the two groups.
The Apgar scores at the first minute and fifth minute were good in both the groups [Table 3]. No significant differences were observed in the umbilical arterial and venous blood pH, pO2, and pCO2 between both the groups.
| Discussion|| |
The incidence of hypotension was reported to be as high as 85% in patients undergoing the elective cesarean section under spinal anesthesia. Hypotension during spinal anesthesia for cesarean delivery can have detrimental effects on both the mother and neonate.,
The mechanism of action of mephentermine is similar to that of ephedrine. It is an alpha as well as beta adrenergic receptor agonist. It acts both directly and indirectly by releasing noradrenaline from storage sites. The effect on beta receptors is more prominent than that on alpha receptors.
Hypotension has been variously defined as a decrease in SBP of 30 mmHg, a decrease of 20% below the baseline pressure, or an absolute value of <100 mmHg. In the present study, we defined hypotension as a decrease in the systolic blood pressure of more than 20% of the baseline value or less than 90 mmHg. This was based on the fact that the percentage decrease in placental perfusion is related to the percentage decrease in the maternal arterial pressure and not to the absolute decrease in pressure. In the current study, there was a fall in systolic, diastolic, and mean arterial blood pressure in both groups following spinal anesthesia. Hypotension could be because of sympathectomy caused by local anesthetic drugs used for SAB. Sympathectomy reduces the peripheral vascular resistance, venous return, and cardiac output. Aortocaval compression because of the weight of the gravid uterus and sympathetic hyperactivity seen during pregnancy also contribute to the hypotension., In our study, there was a significant increase in systolic, diastolic, and mean arterial blood pressure after administering bolus doses of the study drugs in both groups. However, there was a significant (p < 0.05) increase in SBP and mean arterial pressure at the second min and fourth min after administration of ephedrine as compared to mephentermine. The SBP was (114 ± 12.6 vs 106.10 ± 8.41) at the second min and at the fourth min (115.03 ± 8.87 vs 108.46 ± 8.10) in group E and group M. The reason for this could be that ephedrine has a peak effect within 2–5 min, whereas mephentermine has an average of 5 minutes.
In the present study, the mean vasopressor dose required to maintain the arterial pressure from hypotension to the baseline value was 14.4 mg in group E and 12 mg in group M. Ganeshanavar et al. reported an increase in systolic, diastolic, and mean arterial blood pressure at the second, fourth, and sixth min after administration of study drugs, that is, ephedrine and mephentermine, and the mean dose of drugs required to maintain the blood pressure from hypotension to the baseline value was 9.56 ± 4.62 mg in the ephedrine group and 9.78 ± 4.01 mg in the mephentermine group, and it was not significant. Similar observations were made by Dua et al., whereas the study conducted by Kansal et al. found that there were no significant changes in SBP and mean arterial pressure throughout their study period. This could have been probably because of the protocol of administration of drugs followed in their study. They administered the study drug by continuous infusion instead of bolus doses, and they concluded that intravenous infusion of the vasopressor is associated with better control of arterial pressure and fewer maternal side effects compared to intra-muscular administration.
The results of our study indicate that baseline heart rates were comparable in both the groups. The heart rate was increased in both the groups at the onset of hypotension and remained on the higher side throughout the study period [Figure 3]. Regarding heart rate, many investigators have reported similar results in their studies.,,, The increase in the heart rate could be because of the beta adrenergic effect of both ephedrine and mephentermine.
In the present study, the average requirement of vasopresor bolus doses was ephedrine 2.4 (14.4 mg) and mephentermine 2 (12 mg) to maintain the blood pressure within 20% of the baseline. In both the groups, the maximum number of boluses required was 3. Only one patient (3.3%) in the ephedrine group required six bolus doses.
Regarding the assessment of neonatal outcomes, Armstrong et al. recommended umbilical cord blood gas analysis as the gold standard to assess the newborn status in their study. In the present study, both Apgar scores and umbilical cord blood gas analysis were used to assess the fetal outcome. We defined fetal acidosis as an umbilical cord blood pH less than 7.2. On analyzing the data from umbilical cord blood [Table 3], there was no significant difference in the mean umbilical cord blood pH, pO2, and pCo2 between the two groups. Surprisingly, Ralston et al. had reported a decrease in uterine blood flow by 20% with mephentermine as compared to no change with ephedrine affecting neonatal outcomes with the use of mephentermine, thus indicating that ephedrine has a better safety profile than mephentermine. However, our study showed that both drugs were equally safe in terms of fetal outcome.
With regard to side effects, the incidence of nausea and vomiting was higher in patients who were administered ephedrine as compared to mephentermine, but it was not statistically significant (p > 0.05). The etiology of nausea and vomiting could be multi-factorial. Most commonly, it is caused because of hypoperfusion of the chemoreceptor trigger zone because of hypotension. It could also be because of the side effect of ephedrine itself.
In the present study, bradycardia was observed in three (10%) patients in the mephentermine group compared to none in the ephedrine group. However, Kansal et al. reported in their study that bradycardia occurred in one patient (3.33%) in the ephedrine group compared to two patients (6.66%) in the mephentermine group. This difference was however not statistically significant. The bradycardia could be because of the loss of cardio-accelerator nerve functions because of an SAB level above T5.
Thus, in this study, it was found that both the vasopressors were effective in managing spinal-induced hypotension when given as bolus doses. Even the neonatal outcomes were comparable in both the groups, which suggest that both the drugs can be safely used in the management of hypotension after SAB. The incidence of side effects was less prevalent and comparable between both the groups.
One of the limitations of this study was a relatively low sample size to assess other adverse effects of these two drugs. Also, there is a dearth of studies on the vasopressor of choice during emergency cesarean sections, and hence, it would be prudent to conduct further research in high-risk pregnancies and emergency cesarean sections.
In conclusion, in this study, ephedrine and mephentermine administration as bolus doses are equally efficacious in preventing spinal-induced hypotension in patients undergoing the cesarean section and are associated with similar neonatal outcomes.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]