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E:/Biomedica Vol.23 Jul. – Dec. 2007/Bio-10 (A) COMPARISON OF NEFIDIPINE WITH SOLBUTAMOL Department of Obstetrics and Gynaecology, Fatima Jinnah Medical College / Sir Ganga Ram Hospital, Lahore This study was carried out to evaluate the tocolytic efficacy for prolongation of pregnancy with oral nifidipine in comparison to solbutamol, and to evaluate side effects of nefidipine. It was an interventional study and was performed for a period of one year in Sir Ganga Ram hospital, and in the department of obstetrics and gynaecology, Fatima Jinnah Medical College. Sixty women were enrolled in this study. A questionnaire was filled for each patient. Once random-ised the women received oral nifedipine or intravenous solbutamol in recommended dosage for acute tocolysis. Measurements of maternal pulse, blood pressure and foetal heart rate were re-corded for upto 24 hours and compared over the treatment course. Outcome measures were prolongation of pregnancy as a result of tocolysis and recorded in hours and days, along with maternal and foetal side effects. Delivery was deferred for 48 hours, 3 to 7 days and more than 7 days in 30%, 6.66% and 3.33% respectively in nifedipine group compared with 26.66%, 3.33% and 3.33% of women respectively in solbutamol group (no significant difference P > 0.05). Ma-jor maternal and foetal side effects were significantly less common in nifedipine group (0%) than in solbutamol group (13.33%) P value = 0.05. Nifedipine is almost as effective as solbuta-mol in suppressing preterm labour. Its use is associated with less frequent side effects. Preterm labour is everyday’s obstetrical problem. obstetricians indicate a high usage of tocolysis for The ‘early’ baby requires intensive medical atten- preterm labour, but evidence that this treatment tion, which taxes our limited neonatal services. confers overall benefit is still lacking. Betamime- The earlier the delivery before completion of ges- tics are now, correctly, being abandoned in favour tation the greater the risk to the newborn. Onset of of nifedipine, which has superior tocolytic proper- labour after 24 weeks and before 37 weeks of the gestation is labelled as preterm labour.1 The inci- The main problem with preterm labour is our dence of preterm birth has remained unchanged lack of progress in the successful management of for years at about 8 - 10% per anum and prematu- this condition. We as clinicians need to reassess rity remains the leading cause of neonatal morta- our approach to this problem because preterm la- lity accounting for 70-85% of all neonatal deaths, bour is not a disease, but an event, that may result so the prevention and treatment of preterm labour from multiple independent pathways. The appro- is a central issue in pregnancy care.2 The percent- ach requires a close collaboration between clini- age of perinatal deaths in Pakistan due to prema- cians and researchers in order to make significant progress in this difficult area and ultimately imp- Premature infants are at great risk for making rove outcome.6,7 Improvements in tocolysis with it imperative to make efforts to stop the preterm the recent introduction of new therapeutic agents labour. Management of threatened preterm labour have led to a tendency away from prescribing beta includes: managing treatable predisposing factors of preterm labour and tocolysis. There are many In this study beta sympathomimetic agent (so- tocolytic agents that are under consideration all lbutamol) the standard group of drugs was com- over the world. The prevention of preterm labour pared with the newer agent nifedipine as a tocoly- by tocolytic agent aims to prolong pregnancy suffi- ciently to administer glucocorticoids and arrange transfer of women to a center with neonatal inten- The perfect tocolytics do not exist however the The study was conducted from March 2006 to large number of significant and occasionally po- April 2007. It was carried out in Sir Ganga Ram tentially life threatening side effects of beta sym- Hospital, Lahore, in the department of obstetrics pathomimetic agents if used inappropriately, have and gynaecology, Fatima Jinnah Medical College. prompted the search for other tocolytic agents wi- Sixty women were included in the study, meeting th their own foetomaternal side effects. Surveys of shop score calculated. If the contractions persisted • The pregnant women presenting with preterm or was a change in bishop score the women were labour between 28 to 35 weeks of gestation. randomised to receive either nifedipine or intrave- nous solbutamol. In this way two groups were for- med including women on alternate basis that is in group 1 women received nifedipine (i.e. patient no. 1,3,5) and in group 2 received intravenous solbu- In group 1 patients meeting inclusion and exclus- • Maternal or foetal condition necessitating im- ion criteria and after assessment by senior medi- cal officer destined to receive tocolytic therapy we- • treatment with another tocolytic agent in pre- re included. Data were entered in standardised proforma and filled as the treatment proceeded. The women receive nifedipine therapy after initial • in cases of solbutamol cardiac patients. hydration, sedation, corticosteroid and antibiotic A 10 mg capsule of adalat was given every 20 – 30 minutes for the first hour sublingually. If con- tractions had not decreased in strength or frequ- The two tocolytic agents were used for the two ency after one hour dose repeated till contractions comparative groups. The whole information inclu- stopped maximum upto 4 hours then 60–90 mg/ ding baseline data, drug used and the outcome day of slow release nifedipine depending on uter- measures were filled in the proforma, nifedipine was used (calcium channel blocker) as capsule • Continuous foetal heart rate was monitored. adalat 10 mg. For beta antagonist (solbutamol) in- • Maternal pulse and blood pressure was recor- travenous ventolin injections were used. On ordi- ded every ten minute for up to 30 to 60 minu- nal data chi square test was applied to calculate p tes thereafter half hourly for 12 hours. value and on numerical data student t test was ap- • Blood samples for complete blood and high va- Treatment was carried out until contractions Methodology In this experimental study sixty women who pre- had completely subsided, usually this happened sented at Sir Ganga Ram hospital with preterm la- within 24 to 48 hours or when treatment fails. End bour and met inclusion and exclusion criteria, we- point of treatment was delivery in hours or days re included from March 2006 to April 2007. from the start of tocolytic therapy and was consi- Preterm labour was defined as three or more dered successful if delivery was deferred for at contractions per 30 minutes or serial change in bi- least 48 hours. The women remained admitted for shop score as assessed by senior medical officer. at least 72 to 96 hours after tocolysis and were Informed consent was taken from women, WHO then discharged and oral dose given for one week were randomly selected to receive either glyceryl and advise follow up untill delivery. Side effects trinitrate patch or solbutamol infusion on altern- were observed and recorded, they included mater- ate basis after assessment by a senior medical offi- nal hypotension, headache, flushing, and foetal he- The protocol of assessment consisted of: • Assessment of duration and frequency of palp- In group 2 pregnant women received tocolytic the- rapy in the form of beta sympathomimetic agent • Cervical examination in order to calculate bi- solbutamol (ventolin). Thirty women were rando mised to receive solbutamol infusion that was star- The women then prophylactically received: a ted at a rate of 50 micrograms per minute i.e. 8 1000 ml intravenous infusion of 0.9 % saline or ampules of solbutamol injection (4 mgm) per 500 ringer lactate over 30 - 60 minutes, sedation injec- ml of 0.9% normal saline infusion at 8 drops per tion beta methasone 12mg intra-muscular, antibio- minute (0.5 ml/ min). The dose was increased by tic cover augmentin / ampicillin. A second cervical 15 microgram per 30 minute up to a maximum of examination was then performed and uterine cont- 300 microgram per minute or until contractions ractions were assessed by the same doctor and bi- stopped or unacceptable side effects appear. COMPARISON OF NEFIDIPINE WITH SOLBUTAMOL AS TOCOLYTIC AGENTS The effective tocolytic dose was maintained for fidipine tocolysis was successful (delivery delayed 12 hours and then tapered over 2 to 4 hours. Treat- > 48 hours) in 9 women (30%). Delivery was de- ment was considered successful if delivery was de- layed for 3 to 7 days in 2 women (6.66%) and be- ferred for 48 hours. Women in whom beta agonists yond 7 days in 1 woman (3.33%). Failure of tocoly- failed were not treated with an alternate drug. Wo- sis occurred in 18 women (60%). Solbutamol to- men in whom quiescence was maintained beyond colysis was successful {delivery delayed for > 48 72 hours were discharged and instructed to conti- hours} in 8 women (26.66%). Delivery was delayed nue bed rest and follow up. Monitoring was done for 3 to 7 days in 1 woman (3.33%) and beyond 7 as in GTN therapy group and chest auscultation days in 1 woman (3.33%). Tocolysis was unsuc- was also performed on hourly basis. Side effects cessful in 19 patients (66.66%). There were no sig- were carefully recorded which included maternal nificant differences in the two groups as regard the tachycardia, pulmonary oedema, headache, tremo- delay in delivery for more than 48 hours, 7 days or urs, palpitations, chest discomfort, ECG changes, beyond (P value more than 0.05). This information hypotension and foetal heart rate changes. group but all other side effects were more common In baseline data the maternal variables are; age, and subjectively more troublesome in solbutamol parity, history of preterm delivery, gestational age group. Statistically minor side effects were recor- at presentation, bishop score at presentation and ded in 13 women (43.33%) in nifidipine group and at randomisation in two groups under study. 19 women (63.33%) in the other group. No major The statistical tests used for the baseline data side effects seen in nifedipine group but there was are students t test for maternal age, gestational age need to stop treatment in 4 women (13.33%) due at presentation, bishop score at presentation and to heart rate more than 130 beats per minute and at randomisation. Students t test is applied after chest pain – (P value = 0.05 so it is significant). In calculating mean and standard deviation for each GTN group side effects subsided in a few hours variable. Chi square test is used for parity and his- and did not necessitate any special measures (Ta- tory of preterm delivery after calculating percenta- ble 3). In statistical analysis, P value less than or ges in two groups. P value for each variable bet- equal to 0.05 is considered statistically signifi- ween two groups is calculated and given in results In outcome measures variables are: delivery within 48 hours, from 3 to 7 days and beyond 7 This study shows that nifedipine is an effective to- days. The side effects of the two drugs are also in- colytic agent compared to beta agonist and it cau- cluded and Chi square test is applied on these vari- ses fewer side effects and less haemodynamic com- ables to calculate the P value for each variable. The promise. In order to evaluate critically the effect of results are given in Tables 2, and 4. Degree of free- nifedipine we included women with objective evi- dom for t test is taken as n – 2 and for chi-square dence of change in bishop score or persistent ute- rine contractions after supportive measures for more than one hour. Success of tocolysis was de- fined as delay of labour for at least 48 hours, to A total of 60 women were included in the study allow enhancement of foetal lung maturity with and were randomised to receive nefidipine (n=30) glucocorticoids. Using these criteria successful to- or solbutamol (n=30) and followed up till delivery. colysis was achieved in 40% of women treated with There was no difference in P value > 0.05 in nifedipine. There is growing interest in calcium base line data for nifedipine compared with sal- channel blockers as a potentially effective and well butamol group. Table 1 presents base line data or tolerated form of tocolysis. Studies suggest that characteristics on admission in two groups. Ni- nifedipine drugs may be effective tocolytic agents Table 1: Characteristics of women in preterm. Table 2: Prolongation of pregnancy with tocolytic therapy. labour, calcium channel blo-ckers are preferable to other ulations of calcium channel blockers on maternal and continuation due to severe Table 3: Side effects of the drugs. beta agonist but with a fewer side effects. There is a need for further clinical trials to establish an un- equivocal evidence base for tocolysis, which requ- ires placebocontrolled trials, and for comparative trials to identify the agent with superior character- istics. So, it is suggested that oral nifedipine may be promising as a safe, effective means for toco- Ahmed K, Malik A, Yusuf W. Perinatal morbidity side effects and complications. The ability to pro- and mortality in cases of preterm labour, an ante- long pregnancy by inhibiting uterine contractions grade study conducted at lady willingdon hospital, bwas similar to beta agonist in this study.11 The limitations of this study were that nifedip- 2. Kolben M, Maritus J. Prevention and treatment of ine or its metabolites levels were not measured in preterm labour. Geburtshilfe und Frauenheilkunde maternal or foetal blood. Fetal monitoring with electronic foetal monitoring alone was done. Fa- 3. Rana S. Maternal and perinatal mortality. In: Rana cilities of Doppler artery studies for feto placental S. Obstetrics and perinatal care for developing blood flow and foetal blood sampling to measure counteries. Islamabad Pakistan: Saf publications, calcium channel blockers levels were not available. Furthermore, foetus was followed till delivery and 4. Greenfield P J, Lamont R F. The contemporary use after birth any effect of drugs on neonate immedi- of tocolytics. Curr Obstet Gynaecol 1999; 10 (4): ately and later on were not studied. The rapid and effective action obtained with the nifedipine, its 5. King JF. Tocolysis and preterm labour. Curr Opin simplicity of administration and safety suggest that prospective randomised comparison of nife- 6. McNamara HM. Problems and challenges in the dipine with established therapy or placebo should management of preterm labour. BJOG 2003; 110 be carried out in larger study populations. This study clearly showed that solbutamol has a prono- 7. Lamont RF. Looking to the future. BJOG 2003; 110 unced effect on maternal and foetal cardiovascular systems than nifedipine. Nifedipine excellent saf- 8. King JF, Flenady VJ, Papatsonis DN, Dekker GA, ety record it might be an alternative to beta agonist Carabane B. Cochrane Database Sys Rev. 2003; (1): for preterm labour and could make a major contri- bution to the management of preterm labour. 9. Giles W, Bisits A. The present and future of toco- This study Concludes that nifedipine is a lysis. Best Pract Res Clin Obstet Gaenecol 2007; 23: useful tocolytic agent comparable in efficacy to COMPARISON OF NEFIDIPINE WITH SOLBUTAMOL AS TOCOLYTIC AGENTS 10. Coomarasamy A, Knox EM, Gee H, Song F, Khan 11. Tan TC, Devendar K, Tan LK, Tan HK. Tocolytic KS. Effectivenes of nifedipine versus atosiban for treatment for the management of preterm labour: a tocolysis in preterm labour; a metaanalysis with n systematic review. Singapore Med J2006; 47 (5): indirect comparison of randomized trials. BJOG

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