Comparison of potency of ephedrine and mephentermine for prevention of post-spinal hypotension in caesarean section.
The dosages and potency of intravenous mephentermine for prevention of post-spinal hypotension are not available in English literature This study was designed to determine the minimum effective dose ([ED.sub.50]) of mephentermine and to compare its potency with that of ephedrine for prevention of post-spinal hypotension in parturients undergoing caesarean section. Dixon's up-down method of sequential allocation was used for vasopressor doses Following administration of spinal anaesthesia, patients received a prophylactic infusion with 50 mg infused over a period of 30 minutes as the initial dose and dose intervals of 5 mg; of either cohedrine or mephentermine The [ED.sub.50] of cohedrine was 25.0 mg (95% CI 15.5 to 40.4 mg). For mephentermine, the up-down method was abandoned due to the success of the minimum dose possible but the [ED.sub.50] appeared to be less than 5 mg In conclusion, the minimum effective dose of mephentermine is much less than that of ephedrine for prevention of post-spinal hypotension. Another trial with a lower starting dose and smaller dose interval of mephentermine is required to determine the potency ratio of mephentermine and ephedrine
Key Words: ephedrine, mephentermine, caesarean section, hypotension, post-spinal hypotension
Mephentermine, a sympathomimetic amine having [alpha]- and [beta]-adrenergic agonist actions, is commonly used in India as a vasopressor for prevention and treatment of hypotension following spinal anaesthesia. However, in most parts of the world, until recently ephedrine has been the drug most used for this purpose for many decades. According to a survey of practice published in 2001, ephedrine was the sole vasoconstrictor selected by 95.2% consultant obstetric anaesthetists in the U.K.(1). The doses of ephedrine required for prevention and treatment of hypotension are well described in the literature (2-5). However, there is a paucity of information on the use of mephentermine. The various dosage regimens mentioned for treatment of hypotension using mephentermine are 30 mg intravenously (IV) (6), 30 to 45 mg IV (7) and 6 mg IV boluses (8). In our earlier study (9), we have shown that mephentermine is as efficacious as ephedrine for treatment of hypotension in pregnant females receiving subarachnoid block for lower segment caesarean section. In that study, we used both the vasopressors in similar doses, assuming the two to be equipotent. Other investigators have also compared similar doses of ephedrine and mephentermine for treatment of hypotension'. However, the literature does not mention a prophylactic IV dose of mephentermine and there are no studies comparing the minimum effective dose of this drug with that of ephedrine for prevention of post-spinal hypotension. Hence, the present study was carried out in an effort to determine the minimum effective dose ([ED.sub.50]) of mephentermine and to compare its potency with that of ephedrine for prevention of hypotension in parturients undergoing caesarean section under spinal anaesthesia.
MATERIALS AND METHODS
Following institutional ethics committee approval, this prospective, randomised, double-blind study was carried out by sequential allocation of doses of each vasopressor.
After obtaining written informed consent, the study was conducted in 46 ASA I or II females aged 18 years or more and having term, uncomplicated, singleton pregnancy who underwent elective caesarean section under subarachnoid block.
Patients suffering from diabetes, pregnancy-induced hypertension, cardiovascular disease, cerebrovascular diseases, autonomic neuropathy, spinal deformities, other neurological diseases, infections in the lumbar area, coagulation abnormalities, hypovolaemia due to any cause and systolic blood pressure (SBP) less than 100 mmHg were excluded from the study.
All patients were anaesthetised using subarachnoid block with bupivacaine and all received an infusion of vasopressor to prevent hypotension. Height and weight of the patients were measured during a pre-anaesthetic visit and participants were asked to fast overnight. All received ranitidine 150 mg orally the night before and ranitidine 50 mg and metoclopramide 10 mg IV one hour before surgery. In the operating theatre, baseline values for maternal SBP and heart rate (HR) were recorded as the average of three readings, with the patients lying supine with a standard sized wedge under the right buttock. An IV line was established and Ringer lactate solution 10 ml/kg administered over a period of 10 to 15 minutes for preloading. Thereafter, the fluid infusion rate was reduced to 4 ml/kg/h. Lumbar puncture was performed by midline approach with the patient in the left lateral position, using a 25 gauge Quincke spinal needle inserted at the [L.sub.2]-[L.sub.3] or [L.sub.3]-[L.sub.4] vertebral interspace. A volume of 2.2 ml of hyperbaric 0.5% bupivacaine was injected in patients of height greater than 150 cm, as is the routine practice in our institution. The volume of bupivacaine was reduced to 2 ml for those 150 cm or less. The patient was then immediately turned supine, a wedge placed under her right buttock and the prophylactic infusion of vasopressor was started. Oxygen was administered by clear facemask throughout the procedure. The upper level of sensory block was assessed in midline by pin prick using a sterile 26 gauge needle. The aim was to achieve a minimum sensory block of T6. Any patient whose block failed to reach this level was withdrawn from the study and that dose of vasopressor was repeated for the next patient. Monitoring included continuous electrocardiogram, HR, non-invasive blood pressure and pulse oximetry. Heart rate and SBP were recorded at the time of spinal drug injection and then every two minutes until delivery of the baby.
The patients were randomly allocated to the Ephedrine group' or 'Mephentermine group' by using a sealed envelope technique. The first patient in either group received a dose of 50 mg. The dose of vasopressor was diluted to 20 ml with normal saline and the infusion was started at a rate of 40 ml/h using an Emco Infusor 850 syringe infusion pump (Emco Meditek Pvt Ltd, Mumbai, India). The initial dose and the dose interval were chosen based on previous literature about ephedrine (10), making the assumption that the two vasopressors are equipotent. Hypotension was defined as a reduction in SBP of [greater than or equal to]20% from baseline value or an absolute value of < 100 mmHg, which ever was higher. If hypotension occurred during the study period, the particular dose of vasopressor was considered as ineffective and the next successive patient received a dose increased by 5 mg in that group. On the other hand, if hypotension was prevented, this dose was deemed effective and the dose for the next patient was decreased by 5 mg. The observer assessing the efficacy of these drugs was blinded to the nature of vasopressor infusion. Hypotension was treated with bolus doses of ephedrine 5 mg IV, repeated as required, irrespective of the group. Whenever SBP exceeded the baseline value, the infusion rate was decreased in steps of 4 ml/h. Thus, the aim was to maintain SBP between hypotension value and baseline value. The study continued until the time of delivery or 30 minutes, whichever was earlier.
Any maternal complications during the study period were noted and appropriately managed.
Statistical analysis was performed using Statistical Package for SPSS version 13.0. Student's unpaired t-test and Mann Whitney U-test were used to compare demographic and other characteristics in the two groups. The data for these characteristics are presented as mean (SD) or median (range).
It was decided to base the sample size on previous literature of the up-down method of Dixon, according to which at least six independent pairs of patients with no hypotension/hypotension (response/no response pairs) should provide reliable estimates of minimum effective dose of vasopressor ([ED.sub.50]) (11). This method was used to calculate the minimum effective dose with 95% confidence intervals in the ephedrine group. However, in the mephentermine group, the unanticipated pattern of response made it impossible to fulfill this criterion.
The two groups were comparable with respect to age, weight, height, parity, baseline HR, baseline SBP and subarachnoid block to delivery interval (Table 1).
The sequences of dose against patient for ephedrine and mephentermine are shown in Figures 1 and 2 respectively. In the ephedrine group, 22 patients were studied to fulfill the requirement of at least six independent response/no response pairs for up-down analysis (Figure 1). On the other hand, this requirement could not be fulfilled in the mephentermine group. As evident from Figure 2, following an initial uninterrupted string of successes in this group, a failure occurred at the dose of 25 mg and thus the first response/no response pair was formed. This was again followed by another string of successes until the dose of 10 mg resulted in the next failure and hence the second response/ no response pair. However, there were consecutive successes after this and the 14th patient received a dose of 5 mg, which was also successful in preventing hypotension. The dose could not be reduced any further since the dose interval itself was 5 mg and hence this was the minimum dose possible in this group. Therefore, the procedure of sequential allocation of doses had to be abandoned and it was decided to manage 10 cases with the same dose of 5 mg, irrespective of the outcome. Of these 10 patients, hypotension occurred in only two patients, therefore 5 mg was effective in 80%. Twenty-four patients were studied in this group, with one excluded because the height of block failed to reach T6. The sequences for the 23 patients are shown in Figure 2.
The [ED.sub.50] of ephedrine was 25.0 mg (95% CI 15.5 to 40.4 mg), as calculated by the formula of Dixon and Massey (12). The [ED.sub.50] of mephentermine could not be calculated; however, it appears to be less than 5 mg as the dose of 5 mg of mephentermine was successful in preventing hypotension in 80% of cases.
In one patient in each group, HR increased to more than 130 beats/minute during the study period. Four patients in mephentermine group had one or more readings of heart rate below 60 beats/minute, but none of these patients required treatment with vagolytic agents.
[FIGURE 1 OMITTED]
[FIGURE 2 OMITTED]
The rate of infusion of vasopressor needed to be reduced in 11 patients in the mephentermine group due to SBP overshooting the baseline value, whereas it was reduced in only three patients in the ephedrine group. In these 11 patients in the mephentermine group, the peak SBP values were 10 to 32 mmHg higher than the respective baseline SBP values. The rate of mephentermine infusion was reduced from 40 ml/h to 36 ml/h in three patients, 32 ml/h in one, 28 ml/h in two, 24 ml/h in one, 20 ml/h in three and to 16 ml/h in one patient. On the other hand, three patients in the ephedrine group showed a peak rise in SBP of 11 to 31 mmHg above the respective baseline SBP values. The rate of ephedrine infusion was decreased to 28 ml/h in two patients and 16 ml/h in one patient.
One patient in the ephedrine group complained of nausea and chest pain. This patient had hypotension and required two bolus doses of ephedrine 5 mg. Shivering occurred in one patient in the mephentermine group.
Mephentermine has been in use in India to treat and prevent hypotension for a number of decades. However, there is a paucity of literature regarding the dose requirements or its relative potency compared with other vasopressors.
In 1978, Lauckner et al used mephentermine 30 mg IV to treat hypotension in pregnant females', whereas the drug information by Wyeth(r), India gives a dose of 30 to 45 mg intramuscularly for prevention and 30 to 45 mg IV for treatment of post-spinal hypotension (7). Other doses used are 6 mg boluses (8) and a 5 mg bolus followed by an infusion (9). In our institution, the routine bolus dose used for treatment of post-spinal hypotension is 3 to 5 mg, repeated as required. However, an IV dose of mephentermine for prophylaxis of hypotension is not mentioned in literature.
The mechanism of action of ephedrine and mephentermine is similar. Both drugs have [alpha]- as well as [beta]-adrenergic agonist actions and act both directly and indirectly at adrenergic nerve endings. Effect on [beta]-receptors is more prominent than that on [alpha] receptors. Despite similar actions, the trials comparing efficacy and potency of these two vasopressors have yielded conflicting results. During early years, mephentermine was reported to be as potent as ephedrine with respect to its effect on total vascular and venous resistance in the perfused foreleg of the dog (13), whereas it was found to be more potent than other agents including ephedrine for restoring the contractility of depressed and hypodynamic isolated frog heart (14). Only a few clinical studies have compared these two vasopressors. Sahu et al (8) compared 6 mg bolus doses of ephedrine and mephentermine following onset of hypotension and observed similar requirements for both drugs for maintenance of arterial pressure during caesarean section. In our previous study, we also assumed the two vasopressors to be equipotent and used similar infusion rates in both groups to treat hypotension (9). The two drugs were found to be equally efficacious for treatment of hypotension. However, the potency ratio of mephentermine and ephedrine for prevention of hypotension has never been studied in human beings. Considering the above facts, the present study was designed to determine the ED so of mephentermine and to compare its potency with that of ephedrine for prevention of hypotension in term obstetric patients undergoing caesarean section under subarachnoid block.
The [ED.sub.50] of ephedrine found by the sequential allocation method in this study was 25.0 mg (95% CI 15.5 to 40.4 mg). This is much less than the value reported by Saravanan et al who found it to be 43.3 mg (95% CI 39.2 to 47.3 mg) using a similar technique of sequential allocation (10). The lower requirement of ephedrine in our study could be a result of differences in the methodology. Our target sensory level after subarachnoid block was T6 in contrast to T5 used by Saravanan et al. Moreover, we preloaded our patients with Ringer lactate 10 ml/kg prior to administration of subarachnoid block, whereas Saravanan and co-workers commenced a normal saline 500 ml infusion and then started the regional technique. Fluid preloading can influence vasopressor requirements, although its importance has been challenged (15). Fluid loading prior to obstetric spinal anaesthesia remains a widespread practice (1). We chose to administer a volume of 10 ml/kg as volumes greater than this have no apparent benefit. Park et al compared 10, 20 and 30 ml/kg of crystalloid preload and found no significant alteration in maternal haemodynamics or ephedrine requirement with the higher volumes (16).
In the mephentermine group we achieved an unanticipated success with the lowest possible dose in the sequence and thus could not fulfil the criteria of making six pairs of response/no response. The calculation of [ED.sub.50] for this group using Dixon's method was also not possible. Therefore, 10 cases were conducted with this minimum dose and the response (no hypotension) was seen in eight out of 10 cases, indicating that the [ED.sub.50] of mephentermine is likely to be less than 5 mg as an infusion given over 30 minutes.
We based the dose interval of ephedrine, i.e. a 5 mg increment or decrement in total dose for each patient, depending on the presence or absence of hypotension respectively in the previous patient, on earlier literature (10). A similar dose interval was adopted for mephentermine since both drugs were assumed to be equipotent. However, based on the results of this study, wherein mephentermine appears to be more potent than ephedrine, we consider that prophylaxis with mephentermine needs to be investigated using a lower starting dose and smaller dose intervals.
Besides difference in potency, another explanation for the apparently lower requirements of mephentermine compared to ephedrine is the difference in their half-lives. The half-life of ephedrine is three to six hours (17,18), whereas that of mephentermine is 17 to 18 hours (19). Although the duration of the infusion was only eight to 24 minutes and seven to 30 minutes in the ephedrine and mephentermine groups respectively, the significantly longer half-life of mephentermine could be a factor in reducing its dose requirement.
In conclusion, the minimum effective dose of mephentermine appeared much less than that of ephedrine for the prevention of hypotension in parturients undergoing caesarean section under spinal anaesthesia. However, further studies are required to confirm this and to estimate a potency ratio for these vasopressor drugs.
Address for reprints: Dr M. Mohta, 28-B, Pocket-C, SFS Flats, Mayur Vihar Phase--III, Delhi 110096, India.
Accepted for publication on February 22, 2008.
(1.) Burns SM, Cowan CM, Wilkes RG. Prevention and management of hypotension during spinal anaesthesia for elective caesarean section: a survey of practice. Anaesthesia 2001; 56:794-798.
(2.) Loughrey JPR, Walsh E, Gardiner J. Prophylactic intravenous bolus ephedrine for elective caesarean section under spinal anaesthesia. Fur J Anaesthesiol 2002; 19:63-68.
(3.) Vercauteren MP, Coppejans HC, Hoffmann VH, Mertens E, Adriaensen HA. Prevention of hypotension by a single 5-mg dose of ephedrine during small-dose spinal anesthesia in prehydrated cesarean delivery patients. Anesth Analg 2000; 90:324-327.
(4.) Thomas DG, Robson SC, Redfern N, Hughes D, Boys RJ. Randomized trial of bolus phenylephrine or ephedrine for maintenance of arterial pressure during spinal anaesthesia for Caesarean section. Br J Anaesth 1996; 76:61-65.
(5.) Ngan Kee WD, Lau TK, Khaw KS, Lee BB. Comparison of metaraminol and ephedrine infusions for maintaining arterial pressure during spinal anesthesia for elective cesarean section. Anesthesiology 2001; 95:307-313.
(6.) Lauckner W, Schwarz R, Retzke U. Suitability of mephentermine for the management of arterial hypotension in pregnancy. Zentralblatt fur Gynakologie 1978; 100:217-221.
(7.) Mephentine--prescribing information. From: http://www. wyethindia.com Accessed September 2007.
(8.) Sahu D, Kothari D, Mehrotra A. Comparison of bolus phenylephrine, ephedrine and mephentermine for maintenance of arterial pressure during spinal anaesthesia in caesarean section-a clinical study. Indian Journal of Anaesthesia 2003; 47:125-128.
(9.) Kansal A, Mohta M, Sethi AK, Tyagi A, Kumar P. Randomised trial of intravenous infusion of ephedrine or mephentermine for management of hypotension during spinal anaesthesia for caesarean section. Anaesthesia 2005; 60:28-34.
(10.) Saravanan S, Kocarev M, Wilson RC, Watkins E, Columb MO, Lyons G. Equivalent dose of ephedrine and phenylephrine in the prevention of post-spinal hypotension in caesarean section. Br J Anaesth 2006; 96:95-99.
(11.) Dixon WJ. The up-and-down method for small samples. Journal of American Statistical Association 1965; 60:967-978.
(12.) Dixon WJ, Massey FJ. Introduction to statistical analysis, 4th ed. New York: McGraw Hill 1983. p 426-441.
(13.) Zimmerman BG, Abboud FM, Eckstein JW. Comparison of the effects of sympathomimetic amines upon venous and total vascular resistance in the foreleg of the dog. J Pharmacol Exp Ther 1963; 139:290-295.
(14.) Glassman JM, Seifter J. The effect of mephentermine on hypodynamic and arrhythmic isolated frog hearts. J Pharmacol Exp Ther 1954; 112:364-373.
(15.) Jackson R, Reid JA, Thorburn J. Volume preloading is not essential to prevent spinal-induced hypotension at caesarean section. Br J Anaesth 1995; 75:262-265.
(16.) Park GE, Hauch MA, Curlin F, Datta S, Bader AM. The effects of varying volumes of crystalloid administration before cesarean delivery on maternal hemodynamics and colloid osmotic pressure. Anesth Analg 1996; 83:299-303.
(17.) Westfall TC, Westfall DP. Adrenergic agonists and antagonists. In: Brunton LL, Lazo JS, Parker K, eds. Goodman & Gilman's The pharmacological basis of therapeutics, 11th ed. New York: McGraw Hill 2006. p. 237-295.
(18.) Berlin I, Warot D, Aymard G, Acquaviva E, Legrand M, Labarthe B et al. Pharmacodynamics and pharmacokinetics of single nasal (5 mg and 10 mg) and oral (50 mg) doses of ephedrine in healthy subjects. Fur J Clin Pharmacol 2001; 57:447-455.
(19.) Lieberman DE. Adrenergic agents. In: Dart RC, ed. Medical Toxicology, 3rd ed. Philadelphia: Lippincott Williams and Wilkins 2004. p. 542-559.
M. MOHTA *, D. AGARWAL ([dagger]), L. K. GUPTA ([double dagger]), A. TYAGI ([section]), A. GUPTA ([double dagger]), A. K. SETHI **
Department of Anaesthesiology and Critical Care University College of Medical Sciences and Guru Teg Bahadur Hospital, Delhi, India
* M.B., B.S., M.D., M.A.M.S., Reader.
([dagger]) M.B., B.S., M.D., Specialist.
([double dagger]) M.B., B.S., M.D., Senior Resident.
([section]) M.B., B.S., M.D., D.N.B., M.N.A.M.S., Reader.
** M.B., B.S., M.D., D.A., Professor and Head.
TABLE 1 Demographic and other characteristics shown as mean (SD) or median (range) Ephedrine Mephentermine (n= 22) (n= 23) Age (y) 26.3 (3.5) 25.0 (2.9) Height (cm) 155.6 (4.8) 153.6 (3.7) Weight (kg) 57.4 (7.3) 58.1 (9.6) Parity 1 (0-5) 1 (0-3) Baseline heart rate (beats/min) 94.3 (11.8) 93.2 (16.8) Baseline SBP (mmHg) 124.6 (11.5) 125.5 (11.1) Spinal-delivery interval (min) 13.4 (4.6) 14.1 (5.7) SBP= systolic blood pressure.