PROSPECTIVE RANDOMISED COMPARATIVE STUDY OF EFFICACY OF COMBINATION OF TRANEXAMIC ACID AND ETHAMSYLATE BY ORAL AND INTRAVENOUS ROUTES IN RELATION TO CONTROL OF BLEEDING IN CARDIAC SURGERIES. Dissertation submitted to THE TAMILNADU DR. M.G.R. MEDICAL UNIVERSITY In partial fulfilment for the award of the degree of DOCTOR OF MEDICINE IN ANAESTHESIOLOGY BRANCH X INSTITUTE OF ANAESTHESIOLOGY AND CRITICAL CARE MADRAS MEDICAL COLLEGE CHENNAI - 600003 MAY 2019 CERTIFICATE This is to certify that the dissertation titled, “PROSPECTIVE RANDOMISED COMPARATIVE STUDY OF EFFICACY OF COMBINATION OF TRANEXAMIC ACID AND ETHAMSYLATE BY ORAL AND INTRAVENOUS ROUTES IN RELATION TO CONTROL OF BLEEDING IN CARDIAC SURGERIES” submitted by Dr. HEMALATHA R V in partial fulfilment for the award of the degree of Doctor of Medicine in Anaesthesiology by the Tamil Nadu Dr. M.G.R. Medical University, Chennai., is a bonafide record of the work done by her in the INSTITUTE OF ANAESTHESIOLOGY AND CRITICAL CARE, Madras Medical College and Rajiv Gandhi Government General Hospital, during the academic year 2016-2019. Prof. Dr. ANURADHA SWAMINATHAN Prof. Dr. JAYANTHI. R M.D., D.A., M.D., FRCP (Glasg) The Director, The Dean, Institute of Anaesthesiology & Critical Care, Madras Medical College, Madras Medical College, Government General Hospital, Government General Hospital, Chennai – 600 003. Chennai – 600 003. CERTIFICATE BY THE GUIDE This is to certify that the dissertation entitled, “PROSPECTIVE RANDOMISED COMPARATIVE STUDY OFEFFICACY OF COMBINATION OF TRANEXAMIC ACID AND ETHAMSYLATE BY ORAL AND INTRAVENOUS ROUTES IN RELATION TO CONTROL OF BLEEDING IN CARDIAC SURGERIES” submitted by Dr. HEMALATHA R V, in partial fulfilment for the award of the degree of Doctor of Medicine in Anaesthesiology by the Tamil Nadu Dr. M.G.R. Medical University, Chennai., is a bonafide record of the work done by her in the INSTITUTE OF ANAESTHESIOLOGY AND CRITICAL CARE, Madras Medical College and Rajiv Gandhi Government General Hospital, during the academic year 2016-2019. Prof.Dr.VELLINGIRI, MD, DA. Professor of Anaesthesiology, Institute of Anaesthesiology and critical care, Rajiv Gandhi Govt. General Hospital, Madras Medical College, Chennai - 600 003. DECLARATION I hereby, solemnly declare that this dissertation titled “PROSPECTIVE RANDOMISED COMPARATIVE STUDY OF EFFICACY OF COMBINATION OF TRANEXAMIC ACID AND ETHAMSYLATE BY ORAL AND INTRAVENOUS ROUTES IN RELATION TO CONTROL OF BLEEDING IN CARDIAC SURGERIES”, is a bonafide record of the work done by me in the INSTITUTE OF ANAESTHESIOLOGY AND CRITICAL CARE, Madras Medical College and Rajiv Gandhi Government General Hospital, during the academic year 2016-2019 under the guidance of Prof.Dr.VELLINGIRI M.D., D.A., Professor of Anaesthesiology, Institute of Anaesthesiology and critical care, Rajiv Gandhi Govt. General Hospital, Madras Medical College, Chennai- 600 003 and submitted to The Tamil Nadu Dr. M.G.R. Medical University, Guindy, Chennai – 32, in partial fulfilment of the requirements for the award of the degree of M.D. Anaesthesiology (Branch X), examinations to be held on April 2019. I have not submitted this dissertation previously to any university for the award of degree or diploma. Place : Chennai Dr. HEMALATHA R V Date : URKUND.COM PHOTO PLAGIARISM CERTIFICATE This is to certify that this dissertation work titled “PROSPECTIVE RANDOMISED COMPARATIVE STUDY OF EFFICACY OF COMBINATION OF TRANEXAMIC ACID AND ETHAMSYLATE BY ORAL AND INTRAVENOUS ROUTES IN RELATION TO CONTROL OF BLEEDING IN CARDIAC SURGERIES” of the candidate Dr.HEMALATHA R V with registration number 201620008 for the award of M.D. in the branch of ANAESTHESIOLOGY. I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion 91 pages and the result shows 13 percentage of plagiarism in the dissertation. Prof. Dr.VELLINGIRI, M.D., D.A., Professor of Anaesthesiology, Institute of Anaesthesiology and critical care, Rajiv Gandhi Govt. General Hospital, Madras Medical College, Chennai - 600 003. ACKNOWLEDGEMENT I am extremely thankful to Prof. Dr. JAYANTHI. R, M.D., FRCP (Glasg)., Dean, Madras Medical College & Rajiv Gandhi Govt. General Hospital, for her permission to carry out this study. I am immensely grateful to Prof. Dr.ANURADHA SWAMINATHAN, M.D., D.A., Director, Institute of Anaesthesiology and Critical Care, Madras Medical College & Rajiv Gandhi Govt. General Hospital for her concern and support in conducting this study. I am extremely grateful and indebted to my guide Prof. DR. VELLINGIRI, M.D., D.A., Professor of Anaesthesiology, Institute of Anaesthesiology and critical care, Rajiv Gandhi Govt. General Hospital, for his concern, inspiration, meticulous guidance, expert advice and constant encouragement in preparing this dissertation. I am extremely thankful to my co-guide Dr. RAVI M.D., for his guidance and expert advice in carrying out and shaping this study. I am very grateful to express my sincere gratitude to the Professors, Institute of Anaesthesiology & Critical Care, for their constant motivation and valuable suggestions. I am extremely thankful to the Assistant Professors especially Dr. SENTHIL KUMAR.V. M.D., Dr.GANESH. A. M.D., Dr. RAMYA. N, D.A, Dr. ASHA. A. M.D., for their guidance and expert advice in carrying out this study. I am thankful to the Institutional Ethics Committee for their guidance and approval of this study. My sincere thanks to the statistician who played an important role in my study. I am thankful to all my colleagues, family and friends for their moral support, help and advice in carrying out this dissertation. Last but not the least; I thank all the parents of the patients for willingly submitting their children for this study. Above all I pay my gratitude to the Lord Almighty for blessing me to complete this work. CONTENTS S.NO TOPIC PAGE NO. 1 INTRODUCTION 1 2 AIM OF THE STUDY 2 3 PHARMACOLOGY OF TRANEXAMIC ACID 3 4 PHARMACOLOGY OF ETHAMSYLATE 7 5 REVIEW OF LITERATURE 11 6 MATERIALS AND METHODS 15 7 OBSERVATION AND RESULTS 25 8 DISCUSSION 77 9 SUMMARY 89 10 CONCLUSION 91 11 BIBLIOGRAPHY 12 ANNEXURES INTRODUCTION INTRODUCTION Bleeding after cardiac surgery is a major complication that affects 18% of patients undergoing cardiac surgery. Subsequent transfusion of blood and blood products puts the patient at risk for transfusion reactions and transfusion acquired infections. The mechanism of bleeding is subclinical induction of fibrinolysis and platelet receptor damage. These changes are induced by activation of factor XII caused by contact with CPB circuit, initiating a systemic inflammatory response involving coagulation cascade, fibrinolysis and compliment activation. Also, hypothermia during CPB causes reversible platelet membrane dysfunction, inhibition of coagulation factors and disordered fibrinolysis. The antifibrinolytic tranexamic acid and platelet stabilising ethamsylate when used in combination helps reduce post operative bleeding. This study aims at comparing the efficacy of oral versus intravenous combination of the above said drugs in controlling blood loss. 1 AIM OF THE STUDY AIMS & OBJECTIVES To know the effect of tranexamic acid in reducing intraoperative and postoperative blood loss in patients undergoing cardiac valve replacement surgeries. The secondary purpose of the study is 1. To know the requirement of transfusion intraoperatively and post operatively. 2. To study the effect of drug on haematocrit change after surgery. 3. To compare the cost effectiveness of the 2 groups. 2 PHARMACOLOGY OF TRANEXAMIC ACID PHARMACOLOGY OF TRANEXAMIC ACID It is an antifibrinolytic agent with the chemical name Trans-4-(aminomethyl) cyclohexane carboxylic acid. pH = 6.5 – 8.0 EMPERICAL FORMULA = C8H15NO2 MOLECULAR WEIGHT = 157.2 STRUCTURAL FORMULA MECHANISM OF ACTION: o It is a synthetic lysine derivative that inhibits fibrinolysis by blocking the lysine binding sites on plasminogen. o It is a competitive inhibitor of plasminogen activation and at higher concentrations, a non- competitive inhibitor of plasmin. This action is similar to that of epsilon-aminocaproic acid but tranexamic acid is 10 times more potent. 3 o In concentrations of upto 10mg/ml it has no effect on platelet counts, clotting time or clotting factors in whole blood. But in concentrations of 10mg/ml to 1g/ml it prolongs thrombin time. PHARMACOKINETIC AND PHARMACODYNAMICS: Plasma protein binding is almost equal to 3% and mainly binds to plasminogen mainly and does not bind to albumin. The half life of intravenous dose of 1g is 2hours. The antifibrinolytic concentration remains in different tissues for 17hours and in serum for upto 7-8hours. Volume of distribution is about 9 to 12 L. Elimination is mainly via glomerular filtration. Renal clearance is 110 – 116ml/min and more than 95% of the drug is excreted in urine unchanged. Following administration of drug intravenously at the dose of 10mg/kg body weight, excretion is almost 90% at 24hours. 4 Tranexamic acid can cross the placenta and it is secreted into the breast milk at a concentration of 1/100th of plasma concentration. INDICATIONS: I. MEDICAL: Hereditary angioneurotic edema[1] Upper gastro intestinal bleeding.[2,3] Reversal of drug induced bleeding (eg., TPA, Dabigatran, Rivaroxaban, Fondaparinux induced bleeding). Menorrhagia.[4,5] II. ELECTIVE SURGERY Oral surgeries[6,7] Obstetrics and gynaecology surgeries for treatment of menorrhagia and post partumhaemorrhage[8,9,10] Cardiac surgeries: