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The place of ethacridine lactate for mid-trimester M.T.P. (Multicentric study) VN Purandare, Veena Mhatre, Usha R Krishna, SG Gogate, Kusum C Gupta, UK Sheth, Aruna KhatuDepartment of Obstetrics & Gynaecology,and Pharmacology, K.E.M Hospital & Seth .G.S.Medical College, Parel, Bombay 400012, India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 614418
Ethacridine Lactate is a safe abortifacient with about 80% success and hardly any side effects. The incidence of retained placenta is 16%. The extra-amniotic injection is a technically simple procedure and can be carried out even between 13-15 weeks of pregnancy when intraamniotic injection is difficult. Its bactericidal properties minimise the danger o f post-abortal infection. It can be used in certain medical conditions like hypertension, bronchial asthma where hypertonic saline and prostaglandin are contraindicated.
With the liberalization of abortion laws in many parts of the world, the demand for a new, reliable and safe method for the termination of midtrimester pregnancy has become more pressing. The methods described decades ago and long forgotten, have been brushed up and are being used again. Extra-amniotic route has been of increasing interest of late because it eliminates amniocentesis, thereby obviating the need to delay medical termination of pregnancy till sixteen weeks. However, the efficacy of the procedure varies with the agent used. Extra-ovular instillation of 0.1 per cent Ethacridine Lactate solution is commonly used by Japanese obstetricians as a safe and effective method for therapeutic abortions in midpregnancy. The use of Ethacridine Lactate dates from 1949, but more extensive studies have been carried out only recently by Manabe [7] since 1969.
Ethacridine Lactate is a derivative of acridine, a yellow dyestuff with antiseptic action. It has been used as 0.05 to 0.2 per cent solution locally as an antiseptic. The 0.1 per cent solution which is used for inducing abortion is free of renal and cardiac toxicity, and is well handled and easily excreted. Manabe [7] claims that the solution, in dilution of 0.1%, is safe even when injected intravenously so that there is no danger of intravasation when injected in extra-ovular space. Oxytocic action of Acridine derivatives has been demonstrated in cats. Lewis [6] using human uterine muscle strip in perfusion experiment has shown that it has oxytocic effect on human myometrial strips.
Preliminary study of 30 cases with extra-amniotic ethacridine lactate (0.1%) was carried out in the K. E. M. Hospital with almost 87% success rate. After the completion of preliminary trial, the study was planned on multicentric basis, and carried out. A total of 155 subjects had volunteered for this multicentric trial for midtrimester termination of pregnancy. A Foley's catheter, of diameter 14 F was selected for primigravida and of diameter 16 F for multigravida. Under proper aseptic precautions, it was introduced gently through the cervix into the lower uterine segment. The balloon was then inflated with 5 ml. of normal saline. A slight traction was applied to the catheter after inflation of the balloon. 100 ml. of ethacridine lactate, either as 0.1 per cent or 0.15 per cent solution was injected along with 300 mgm of Spartein Sulfate, extra-amniotically, by means of the indwelling Foley's catheter. This was given in the form of a drip over a period of 10 minutes. The catheter was withdrawn after 4 hrs. The concentration of the drug used for a particular patient was decided by randomized allocation cards. No antibiotics were given prophylactically. Patients' vital signs (temperature, pulse, blood pressure and respiration etc.) were monitored throughout the procedure.
Thirty patients were studied to find out the metabolic changes after the injection of ethacridine. The blood samples were taken (1) before the injection (2) after the abortion (3) six weeks after the injection. The patients were divided into three groups. 1. Blood coagulation studies + Haemogram. 2. Renal Function Tests+Haemogram 3. Liver Function Tests+Haemogram The following tests were carried out for coagulation studies: 1. Pro thrombin time. 2. Partial thromboplastin time. 3. Thrombin time. 4. Platelet aggregation. 5. Platelet adhesiveness. 6. Plasma fibrinogen. 7. Platelet count. 8. Euglobulin clot lysis time (ECLT) . Haemogram included: (1) Haemoglobin (2) Packed cell volume (3) W.B.C. Total and differential (4) E.S.R. Kidney function tests included(1) Blood urea nitrogen (2) Blood urea (3) Plasma creatinine. Liver function tests included- (1) S.G.O.T. (2) S.G.P.T. (3) Total bilirubin (4) Direct bilirubin (5) Alkaline phosphatase (6) Pseudocholinesterase. The methods for all the above investigations were those given in the standard Text books of Clinical Biochemistry.
[Table 1] shows the distribution of the cases according to gestation weeks. Almost 33% of the patients were in 13-14 weeks' gestation where intra-amniotic injection is technically difficult. Average gestation weeks were 16.25. [Table 2] shows that there is hardly any difference between 0.1% and 0.15% solution groups, as far as success rate and induction abortion interval are concerned. Almost 80% have aborted successfully, without requiring the second procedure. There were hardly any side effects observed with ethacridine in comparison with prostaglandins, where gastrointestinal side effects is a frequent occurrence [Table 3]. The surgical evacuation for incomplete 3rd stage always poses a problem for all second trimester M.T.Ps. The incidence of incomplete abortions was lower with extra-amniotic ethacridine than with that of hypertonic saline and prostaglandins. This is important because excessive blood loss is often associated with partially separated, retained placenta. Though the sepsis has contributed to 3-5% of the cases, it was considerably higher at one of the centres. Therefore, it may not be related to the method.
There was one case of rupture uterus in this series with 0.15% concentration. This patient was a 25 year old, parous patient with a gestation week of 20. Inspite of the strong uterine contractions, the cervix failed to dilate. While under observation, at 77 hours, patient developed shock which was out of proportion to bleeding. A rupture of the uterus was suspected. After resuscitation of the patient, an exploratory laparotomy was carried out. On exploration, a left sided broad ligament hematoma, 18-20 cm. in diameter was observed. The foetus and the blood clots were removed from this hematoma. The uterine tear was too extensive to suture. The total hysterectomy was carried out. 700 ml. of blood were given. Postoperative recovery was uneventful.
There was one death in this series, which occurred on the 29th post-abortal day. This patient was readmitted to the medical side in one of the peripheral hospitals with severe anaemia (Hb-3 gm The blood picture showed depression of the bone marrow. Inspite of doing repeated external punctures, bone marrow could not be obtained. She developed hyperpyrexia, respiratory tract infection and expired. The success rate was almost the same in all these abortifacients. [Table 4]. As far as induction abortion interval was concerned, 15 methyl PGF 2α, a, single shot 920 µgm extra-aminotically had induced abortions faster than other agents. The most important point as mentioned earlier, was that the incidence of incomplete abortions, was minimum in the ethacridine group. [Table 5] shows the analysis of failure cases and various ways and means by which ultimately the pregnancies were terminated. Blood Coagulation Studies There was no significant change except 1. In one case there was a change in Partial Thromboplastin time from 55 sec. to 2. In one case there was a change in platelet aggregation from 108 sec. to 3. In one case there was a change in platelet count from 203,000/c.mm. after 6weeks after the injection. Renal function tests There was a slight increase in B.U.N., blood urea and plasma creatinine in a few cases but they were within normal limits. Liver Function Tests No significant changes were found in Liver Function Tests.
Manabe [7] reviewed the work of various Japanese authors. He advocated 50 ml. of the solution to be injected through No. 12 Nelaton Catheter, along with the catheter in situ. In 1971, Nabriski [9] used a metal catheter in extra-amniotic space for injection of ethacridine lactate. The volume injected by him varied from 500-700 ml. The underlying principle was pure mechanical action giving rise to the success rate of 94%. Later in 1973, Ingemanson [5] of Sweden compared the combination of Ethacridine Lactate and the rubber catheter with extra-amniotic hypertonic saline injection. He reported the success rate of 94% in 72 hours as against 74% in that of saline group. In 1975, Himmelmann [4] reported 200 cases of extra-amniotic ethacridine lactate in the dosage of 10 ml. per gestation week, maximum upto 150 ml. The catheter was withdrawn after 24 hours. The success rate was reported to be 80% with a low complication rate. Martin [8] combined the immediate uterotonic property of prostaglandins and the delayed oxytocic response of ethacridine lactate. During the first hours, 750 µgm of PGF 2α were supplemented and the catheter was withdrawn after 12 hours, giving rise to the success rate of 75%. In India, Anjaneyulu et al [1] from Poona reported the success rate of 81.4%, in 72 hours. Inspite of the widespread use of ethacridine lactate for midtrimester abortion in Japan, the precise mechanism involved has never been studied. Manabe [7] suggested that extra-amniotic injection of ethacridine lactate causes mechanical stimulation of the uterus. Extensive detachment of the membranes can stimulate the uterus and precipitate the abortion. The catheter left in the extra-ovular space itself plays the role of stimulating the uterine contractions. [2] Oxytocic action of acridine derivatives has been demonstrated as sustained uterine contractions in cats. In 1969, Manabe [7] reported that disruption of placental functions is not the cause of the rise in uterine contractility. Serial urinary steroid levels did not show significant fall during the course of treatment. He also observed that foetuses born to late midtrimester cases, were alive. Gustavii [3] suggested that extra-ovular procedures act by releasing lysosomal enzymes within the decidual cells. He observed that damage to decidual lysosomes is followed by the synthesis and releases of prostaglandins, resulting in uterine contractions and finally abortion. Cervical tear is one of the problems in midtrimester terminations. In one study of 600 second trimester terminations with saline and prostaglandins, the incidence was 1%. [10] All these tears were in the posterior lip of the cervix, occasionally extending to the posterior wall of the lower uterine segment. These patients had no extra bleeding or hypotension suggesting cervical or uterine injuries. Therefore, it is recommended that each patient should be examined after the abortion to exclude the possibility of visible or palpable cervical injury. Nebriski [9] reported 2 (4%) cases of cervical tears with 0.1% ethacridine lactate in the dose of 150 ml ' lunar month extra-amniotically. 90% patients were supplimented with oxytocin. In our study, there was only one case with cervical tear giving an incidence of 0.82%. Blood biochemistry of the patients revealed that ethacridine has minimal side effects such as changes in Partial Thromboplastin time, platelet count and aggregation. There was also a small insignificant rise in the levels of BUN, and plasma creatinine. All these did not pose any problems in the treatment.
We thank Dr. C. K. Deshpande for allowing us to use the Hospital Data. We also thank all the contributors for their kind co-operation. We thank Shri Amrut Modi of Unichem Laboratories for the supply of Ethacridine Lactate (Unacredil) and World Health Organisation for financial help.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]
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