European Journal of Cardiovascular Medicine

Subarachnoid block has established itself as one of the most popular techniques for lower limb and lower abdominal surgeries. It is easy to administer, gives profound muscle relaxation and very good analgesia in the affected area with fast recovery, and less nausea and vomiting in the immediate post-operative period as compared to general anesthesia1. In obstetrics, it offers a fast, profound, high-quality sensory and motor block in women undergoing cesarean sections1. Its advantage in obstetric patients are, avoidance of airway complications, complications associated with a full stomach and limits the neonatal drug transfer associated with general anesthesia2,3. SAB procedure however, is not without its inherent side- effects and risks and is frequently accompanied by hypotension. The incidence of hypotension has been reported to be as high as 80-85 % in patients undergoing elective cesarean section under spinal anesthesia. Systolic hypotension higher than 20% to 30% of patients’ baseline blood pressure can causenausea, vomiting, dizziness, low level of consciousness and can compromise uterine blood flow and fetal circulation leading to fetal hypoxia and acidosis2. The choice of the most effective management strategy for SAIH during caesarean section continues to be one of the main challenges in obstetric anaesthesia3. Strategies to minimize hypotension include use of vasopressors to cause vasoconstriction of the peripheral circulation eg; phenylephrine, ephedrine, mephentermine.   All these drugs cross placenta to variable extent & have implications on both mother & fetus3,4.  Norepinephrine, a potent α-agonist and a weak β-agonist, commonly used in septic shock has been showing promising results in many studies for SAIH with respect to maternal haemodynamic stability. So the present study was conducted to compare intravenous norepinephrine and mephentermine for maintenance of blood pressure during spinal anaesthesia for caesarean section.

The primary objective was number of intravenous bolus doses of norepinephrine or mephenteramine required to treat spinal induced hypotension. And secondary objective wasto note maternal complications shivering, headache vomiting/nausea and local tissue ischemia and to compare the effect of drugs on the fetus in both the groups (APGAR score at 1min & 5min).

Following approval by the board of studies, Department of Anaesthesiology and ethical committee clearance from this institution, the study was conducted in J N Medical College & Hospital on 60 pregnant females undergoing lower segment caesarean section under subarachnoid block. It was a Prospective Randomized Double-Blinded Study. It was conducted between year 2020-2022.The study was approved by the institutional review board and the hospital's ethics committee. Its CTRI registration number was CTRI/2022/10/046224

SAMPLE SIZE CALCULATION

By using the openepi.com version 3, based on the mean and standard deviation of a previous study, with 95% power of study5 , an alpha error of 0.05, and a 95% confidence interval, the sample size was determined to be 50 (25 in each group). Considering a 10% attrition rate, a total of 60 patients (30 in each group) are considered for the study.

Equipotency: As per the electronic search, norepinephrine and mephentermine have not been compared much for the management of SAIH, thus potency ratio of them is uncertain. So equipotent doses were derived on the basis of the evidence available in the literature.

Different bolus doses of norepinephrine (4-10 ug) had been used in spinal-induced hypotension during caesarean section5.(Mephentermine doses used 6mgand Norepinephrine doses used 6 ug6).

Equipotency derived :

v  100 ug phenylephrine is equivalent to 6 ug norepinephrine6

v  100 ug phenylephrine is equivalent to 6 mg of mephentermine7

v  A thorough pre-anaesthetic evaluation of parturients was conducted. Patients were randomly assigned to one of two groups using random numbers generated from www.random.org.

v  The parturients were divided into two groups of 30 each:

·         Group M – received 1ml intravenous bolus of 6 mg/ml mephentermine

·         Group N – received 1ml intravenous bolus of 6 ug/ml norepinephrine.

v  SNOSE (sequentially numbered, opaque, sealed envelopes) was used as concealment method.

v  Parturient were premedicated inj. Metoclorpromide 10mg i.v. and i.v pantaprazole 40mg.In addition to an existing line a wide bore intravenous cannula preferrably in the non-dominant arm was secured.(All patients will have two i.v. access, one for fluid and one for drugs.)

v  In 15 degree tilted supine position ASA Standard non-invasive monitors were attached, baseline SBP,MAP& HR was measured .(avg of 3 readings was noted at 1 minute interval with a difference of not more than 10% as baseline8).

·         USAP, parturients were given SAB in the L3-L4 or L4-L5 intervertebral space in sitting position using 25G spinal needle9, clear CSF flow were observed, 0.07mg/cm of 0.5%inj. bupivacaine Heavy was given7.

·         They were administered 10 ml/kg Ringer Lactate over 10 minutes as soon as CSF was tapped (co-loading).10,11

·         Following this parturient was put in the supine position with wedge under right hip.

·         Supplemental oxygen was given at 5L/min

·         The highest level of sensory block was assessed by the pin prick method and the level of motor blockade was assessed by modified bromage scale, 5mins after subarachnoid block

·         SBP, MAP & HR were recorded every minute after SAB till delivery of baby and every 5 minutes thereafter until surgery was completed.12

All solutions were prepared under strict aseptic technique using 0.9% normal saline. Anesthesiologist not participating in the study diluted and loaded the drug in identical coded 10ml syringe.

v  Mephentermine – 6mg in 1 ml as IV bolus. (1ml = 30mg. 2ml diluted in10ml NS to make 6mg/ml)

v  Norepinephrine – 6 microgram in 1ml (1.5ml of norepinephrine=1500 mcg. 1.5 ml diluted in 250 ml of NS to make 5.96 mcg=6mcg /ml)

GROUP M received i.v. bolus mephentermine 6mg, and  

GROUP N received i.v. bolusnor epinephrine 6 ug, for maintenance of blood pressure during spinal anaesthesia for caesarean section.

An anaesthesiologist posted in ot used the vasopressor-labeled syringe to treat hypotension and collected the data for analysis. The patient and investigator were blinded to the vasopressor used.

After delivery of baby 3U of oxytocin was given as a slow IV bolus followed by 3 units three times (repeated at 3 min intervals) if there was no uterine contraction. It was followed by oxytocin infusion at 3IU per hour/ 0r 100ml/hour (15 unit in 500ml) 13

v  Use of uterotonics other than oxytocin was noted.

v  Incidence of hypotension, reactive hypertension, bradycardia, bradycardia requiring treatment, tachycardia, and number of boluses of both drugs were recorded.

ü  Hypotension was defined as any fall in SBP >20% of baseline9.

ü  Reactive Hypertension was defined as a SBP elevation of > 20% of the preoperative value 3.

ü  Bradycardia was defined as any fall in heart rate <60 bpm.9Inj. Atropine 1mg (ACLS guideline 2020) was given if there is any bradycardia.

ü  Tachycardia is considered as any rise in heart rate >20% of baseline.7,8

ü  Nausea is a diffuse sensation of unease and discomfort, often perceived as an urge to vomit14.

v  Maternal complications like nausea/vomiting, headache, shivering and local tissue ischemia in the limb in which drug is given were noted.

v  Newborn APGAR scores at 1 and 5 minutes.

v  FAILED SAB: as per institutional protocol.

STATISTICAL TOOLS EMPLOYED

The data entry was done in the Microsoft EXCEL spreadsheet and the final analysis was done with the use of Statistical Package for Social Sciences (SPSS) software, IBM manufacturer, Chicago, USA, ver 25.0. The values were represented in number (%), and mean± standard deviation, results were analyzed by student’s paired t-test and chi-square test and Mann-Whitney Test.

Table 1:-Comparison of number of drug boluses between group M and N.

• Mann Whitney test, ^* Fisher's exact test

Proportion of patients with number of drug boluses: - 4, 5, 6, 7 was significantly higher in group N as compared to group M. (4:- 3.33% vs 0% respectively, 5:- 36.67% vs 0% respectively, 6:- 50% vs 0% respectively, 7:- 13.33% vs 0% respectively). The proportion of patients with the number of drug boluses: - 1, 2, 3 was significantly lower in group M as compared to group N. (1:- 0% vs 36.67% respectively, 2:- 0% vs 56.67% respectively, 3:- 0% vs 6.67% respectively). (P-value<0.0001). The mean number of patients with a number of drug boluses: - 4,5,6,7 was significantly higher in group N as compared to group M (P<0.0001). Group N mean was 5.77 ± 0.68 which was significantly higher as compared to group M mean which was 1.7± 0.6.

The median (25th-75th percentile) of the number of drug boluses in group N was 6(5-6) which was significantly higher as compared to group M (2(1-2)). (P-value<.0001)

Table 2: Comparison of APGAR score at 1 minute between group M and N.

^* Fisher's exact test

No significant difference was seen in APGAR score at 1 minute (p value=0.145)(6.47 ± 1.01 vs 6.83 ± 0.65), and at 5 minutes (p-value 0.254) (8.3 ± 1.32 vs 8.77 ± 0.9) between group M and group N.

Table 3:-Comparison of maternal complications between group M and N.

^* Fisher's exact test, ^†Chi-square test

Proportion of patients with maternal complications: Vomiting was significantly higher in group N as compared to group M. (46.67% vs 13.33% respectively, p value=0.01)) Distribution of maternal complications:- Headache, Shivering, Local tissue ischemia was comparable between group M and N. (Headache:-30% vs 10% respectively (p value=0.104), Shivering:- 33.33% vs 16.67% respectively (p value=0.136), Local tissue ischemia:- 0% vs 0% respectively) (p-value=0.104).

The distribution of age (years) was comparable between group M and group N. Duration of surgery was 50.93minutes in group M and 51.83 minutes in group N,Skin incision to delivery time (in minutes)was 9.67 in group M and 9.77 in group N, all these parameters were comparable and showed no significant difference between them as their P-value came out to be >0.05 like various previous studies by PJ Shah8, Fauzia Shifaat, Gagandeep et al, the difference in baseline parameters was insignificant (P >0.05).

In our study, it was found that significantly more boluses of norepinephrine were required to manage SAIH compared to mephentermine as we can see in table-1, i.e; the proportion of patients with a number of drug boluses:-4, 5, 6, 7 was significantly higher in group N as compared to group M. (4:- 3.33% vs 0% respectively 5:- 36.67% vs 0% respectively, 6:- 50% vs 0% respectively, 7:- 13.33% vs 0% respectively). The proportion of patients with a number of drug boluses:- 1, 2, 3 was significantly lower in group M as compared to group N. (1:- 0% vs 36.67% respectively, 2:- 0% vs 56.67% respectively, 3:- 0% vs 6.67% respectively), (p-value <0.0001).Mean bolus dose required in group N was 5.77±0.68 which was significantly higher than mean dose in group N which was 1.7±0.6. (p value <0.0001). From this, we can infer that the majority of patients(47%) required  6 boluses of drug in group N, while in group M majority of patients(28%) required 2 boluses of drug  (p-value <0.0001). This was similar to a previous study done by PJ Shah, who found that the maximum number of parturients required three boluses of norepinephrine to treat SAIH in group N as compared to single bolus of mephentermine in group M8. More number of drug boluses in the norepinephrine group could be explained bythe faster onset of action and shorter half-life of norepinephrine. Norepinephrine has a relatively shorter duration of action of 5-10 minutes as compared to mephentermine, which has a duration of action of 30 minutes15. It is well established that neonatal outcome can be assessed using APGAR score at 1st and 5th minute and umbilical cord blood pH values at the time of delivery. Vasopressors used to treat spinal induced hypotension may alter metabolic effect of the fetus due to placental crossing.

In the present study, it was found that the Distribution of APGAR score at 1 and 5 minute was comparable between group M and N with (p value=0.145)(6.47 ± 1.01 vs 6.83 ± 0.65) at 1 minute, and at (p-value 0.254) (8.3 ± 1.32 vs 8.77 ± 0.9) at 5 minutes between group M and group N, which was similar to the study done by PJ shah et al in 2020, where the APGAR score at the 1st and 5th minute was comparable between the groups and no statistical difference was observed (p=0.91)8. A similar study was done by Gurudutt C L et al in 2015 to compare intravenous boluses of phenylephrine, ephedrine and mephentermine and found no statistically significant difference in the APGAR score at 1st and 5th min among all three groups9. The major difference between our study and the above studies was that they compared other fetal parameters, like umbilical pH. However, a study done by M Mohtacomparing phenylephrine and norepinephrine found that there was no statistically significant difference with respect to umbilical pH,pO2, pco2 in both groups, so we avoided fetal sampling.

Pregnant women exhibit an increased level of sympathetic activity compared to parasympathetic activity. Sympatholysis therefore leads to a higher degree of peripheral vasodilatation and a predominance of parasympathetic activity, consequently reducing the venous return and cardiac pre-load, and resulting in bradycardia, nausea and vomiting16. In the present study it was found that the proportion of patients with maternal complications like Vomiting was significantly higher in group N as compared to group M, which might be related to hypotensive episodes. (46.67% vs 13.33% respectively (p value=0.01)) while the distribution of other maternal complications like Headache, Shivering and local tissue ischemia was comparable between groups M and N. (Headache:-30% vs 10% respectively (p value=0.104), Shivering:- 33.33% vs 16.67% respectively (p value=0.136), Local tissue ischemia:- 0% vs 0% respectively) (p value=0.104).

Norepinephrine-induced vasoconstriction and skin necrosis is another concern for norepinephrine application in obstetric anaesthesia, where a peripheral rather than central vein is commonly used. Chen D et al observed skin color, an indicator of peripheral vascular constriction, and they found the incidence of pale skin was relatively low and similar among groups17. In addition, Ngan Kee et and Onwochei et al. suggested that norepinephrine is safe for local tissue perfusion since norepinephrine is diluted before use and administered in a running fluid for a relatively short duration, thus reducing the risk of tissue ischemia18. Further, an equal potency of norepinephrine infusion or bolus has a theoretically similar vasoconstrictive potency as the currently used phenylephrine, so that risk should be no different to that posed by phenylephrine. Furthermore, a previous study showed spinal anaesthesia increases skin perfusion and that this effect is not counteracted by norepinephrine application. Collectively, results suggest norepinephrine likely has no adverse effect on local tissue perfusion in patients with spinal anaesthesia for commonly used infusion or bolus doses. Commercially available norepinephrine does not specify that norepinephrine needs to be given centrally, indicating only that it should be via a large vein, preferably antecubital. Similar to our study, the study done by PJ Shah also included maternal adverse effects as a secondary outcome; however, they found no difference between the norepinephrine and mephentermine groups. This contrasts with our study, in which there was a significant difference in the incidence of nausea/vomiting between the mephentermine group and the norepinephrine group.

Thus rejecting our null hypothesis.

LIMITATIONS OF THE STUDY

1.      There were several limitation in our study like:

2.      The study was conducted at a single centre.

3.      Small number of patients were included in the study so larger studies are required to confirm our observation.

4.      Percentage response of the drug to correct hypotension was not included as the parameter for comparison in the present study.

5.      In our study we had limited the study duration till the delivery of the baby that should be extended till the passing off effect of SAB.

After completion of the study and analysing various findings in our study; following conclusions can be drawn that more boluses of norepinephrine are required compared to mephentermine. When compared to mephentermine, norepinephrine displays a similar safety profile in neonates, as the APGAR score was not affected by SAIH in our patients. Maternal complications were comparable except vomiting which was more in norepinephrine group

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