Susumu Ishikawa, MD Associate Professor of Surgery, Teikyo University, Tokyo, Japan

1. 24th Korean Society for Thoracic & Cardiovascular Surgery Ulinastatin & Continuous hemodiafiltrationThe Impact of Inhibiting Cytokines on Circulation after Cardiac Surgery Susumu Ishikawa, MD Associate Professor of Surgery, Teikyo University, Tokyo, Japan

2. Teikyo University Hospital Located at the center of Tokyo city 2,000 beds in Total

3. Background • Systemic inflammatory responses after cardiac surgery using cardiopulmonary bypass (CPB) may be responsible for the postoperative organ dysfunction. • Therefore, over-induction of cytokines and polymorphonuclear elastase (PMNE) should be prevented especially in critical patients.

4. Today’s Contents Clinical Study 1. Mechanical removal of cytokines by continuous hemodiafiltration (CHDF) 2. Pharmacological suppression of cytokines by Ulinastatin (a protease inhibitor)

5. Introduction

6. Cardiopulmonary Bypass Controlled Shock Cardiac Surgery & Organ Dysfunction Systemic Inflammatory Responses Cytokine induction, Leukocyte activation Acute circulatory failure

7. CPB Time and Cytokine Interleukin 8 (IL-8) Granulocyte Elastase μg /L Pg/ml 6,000 4,000 2,000 * * P<0.01 90 70 50 30 ■ : CPB > 120 min. ▲ : CPB < 120 min. Preop. AfterCPB POD1 POD3 POD6 CPB time (min.) Hurunaga H, 1995 Doi H, 1988

8. Ulinastatin: A Protease Inhibitor (Urinary Trypsin Inhibitor) Features 1) exists naturally in the human body. 2) plays an important role in host defense during stress. Synthesis in Human Body Neutrophil Neutrophil Antecedent Elastase Liver Ulinastatin Interαtripsin inhibitor (MW 67,000) ・Ulinastatin antecedent (IαTI ) is produced mainly in Liver. ・During stress, IαTI is influenced by activated Neutriphil Elastase, changing into Ulinastatin.

9. Effects of Ulinastatin Stress External Ulinastatin Cell/Organ Injury MOF Monocyte・Macrophage Cytokines Internal Ulinastatin Neutrophil Elastase (Timing/Dosage) ReplacementTherapy (Supplement)

10. Dose-dependent Effect of Ulinastatin- Experiments using shock models- (LPS induced peritonitis) Ulinastatin Neutrophil elastase Free radical Ulinastatin Ulinastatin Kato K. 1995 Dose-dependent suppression of inflammatory responses LPS: lipopolysaccharide

11. Indications of Ulinastatin 1．Acute circulatory failure hemorrhagic shock, bacterial shock, traumatic shock, febrile shock 2. Acute pancreatitis includinｇ traumatic acute pancreatitis after operation endoscopic retrograde pancreatography Same as the indication in Japan

12. 1. Mechanical Removal of Cytokines by CHDF- Clinical Study - Continuous Hemodiafiltration

13. Background We sometimes experience the circulatory improvement after the initiation of CHDF. Why ??

14. Objective • Prolonged CPB sometimes causes postoperative circulatory collapse especially in critical patients. • The efficacy of CHDF on the circulation was evaluated focusing on the inflammatory reactive substances.

15. Patients & Methods No. of Patients: 12 (Jan 2007~) * Exclusion: chronic renal failure, sepsis circulatory assist device Age : 67 ± 2 (57-85) years M/ F : 11/ 1 Operation : CABG 3, Acute aortic dissection 3, MVP/R 3, AVR 3 CPB time : 286 ± 32 (171 -552) min. Dialyzer : polysulfone membrane (SH 1.3, Tore Co.Ltd., Japan)

16. Circulation before CHDF mean ± SE Range SBP (mmHg) 96 ± 5 57 - 85 HR ( /min) 101 ± 6 95 - 147 CI (L/min/m2) 2.9 ± 0.1 2.4 - 3.4 CVP (mmHg) 11 ± 1 6 - 16 SPAP (mmHg) 32 ± 2 21 - 39 SVRI (dynes・sec・cm-5・m2) 1452 ±153 1007 - 2206 UV (ml/4hrs) 169 ± 44 10 - 550

17. Systemic Blood Pressure (SBP) mmHg 120± 5 * * * 96 ± 5 * p<0.05

18. Urine Volume ml 371±108 * * 69±75 * p<0.05

19. Serum IL-6 Concentration Pg/dl 717±152 353±92 * * * p<0.05

20. Serum IL-8 Concentration Pg/dl 86±31 53±10 * * p<0.05

21. Systemic Vascular Resistance Index dynes・sec・cm-5・m2 1898±198 ** ** ** 1452±153 ** p<0.01

22. Summary 1 Continuous hemodiafiltration removed inflammatory cytokines and improved systemic circulation.

23. 2. Pharmacological Suppression of Cytokines by Ulinastatin- Clinical Trial -

24. Patients & Methods Group Ulinastatin Control p (n=7) (n=8) Age (yr) 65 ± 5 65 ± 3 NS Operation CABG 3 3 AVR 3 2 MVR 1 3 CPB time (min) 165 ± 16 191 ± 15 NS Ao-clamp time (min) 88 ± 10 99± 12 NS

25. Protocol in the Ulinastatin Group Dosage 1) CPB priming solution : 600,000 U 2) Addition to CPB : 300,000 U (just before the removal of aortic cross-clamping) 3) After Surgery : 300,000 U/day (5days) Each amp.(2ml) contains : Ulinastatin 100,000 U

26. Serum Ulinastatin Concentration P<0.01 P<0.05 Preop. after CPB POD 1 2 5

27. Serum IL-6 Concentration Pg/dl * * * p<0.05

28. Serum IL-8 Concentration Pg/dl * * * p<0.05

29. Serum Concentration of Polymorphonuclear elastase (PMNE) μｇ/dl * * * p<0.05

30. Correlation between IL-8 & PMNE- Maximum Levels after Cardiac Surgery- r = 0.556, p<0.05 Sato Y, Ishikawa S, 2000

31. Respiratory Index * * p<0.05 *

32. Summary 2 Urinastatin reduces the overinduction of cytokines and PMNE during cardiac surgery

33. Comparison of Ulinastatin & Aprotinin

34. Suppression of intracellular elastase activity Ulinastatin Aprotinin

35. Recovery from Shock 1. Improvement of Blood pressure(normal range: systolic ≥ 100mmhg) 86.5% Ulinastatin (n=52) Aprotinin (n=51) Yamamura H, 1984

36. Recovery from Shock 2.Urine Volume (normal range: Urine Volume ≥ 50mL/hr) 74.0% Ulinastatin (n=52) Dosage10,000unit x 3 / 3days Aprotinin (n=51) Dosage 20,000unit x 3 / 3days

37. Recovery from Shock3.Serum Creatinin (mg/dl) P <0.05

38. Effects of Ulinastatinin Other Organs - Summary of previous reports-

39. Lung- A-aDO2 after Cardiac Surgery - A-aDO2 *p<0.05 mmHg 400 300 200 100 * ■ Control □ Ulinastatin * Before CPB After surgery Bingyang J, 2007

40. 2. Kidney –Renal Function after Cardiac Surgery- Serun creatinine N-Acetyl-β-D-Glucosaminidase (urine) mg/dl *p<0.05 *p<0.05 2.0 1.5 1.0 0.5 0 Control Ulinastatin Control Ulinastatin * * * POD POD Ueki M, 1995

41. IL-6(pg/ml) Pre-Albumine(mg/dl) 3. Liver –post hepatic resection- 180 100 50 0 25 20 15 10 5 0 UST Control UST Control Preop. POD 1 3 7 14 Preop. POD 1 3 7 14 Miyazaki K. 2000

42. Prevention of Organ Failure - Our Strategy in Cardiac Surgery- Case Critical Severe Usual Mechanical Intraoperative Hemodialysis Postoperative CHDF Pharmacological Intraoperative ◎ ◎ Postoperative ◎ ◎ ◎ (Ulinastatin, 300,000 U/day)

43. Conclusion • Urinastain and CHDF suppressed acute-phase reactive substances and improved systemic circulation after cardiac surgery. • Perioperative active suppression of inflammatory cytokines improves the surgical outcome especially in critical patients.

44. New Buildings of Teikyo University Hospital Cardiovascular Center will open in April, 2009.

45. Welcome to Japan Kyoto : Tradition Mt. Fuji : Scenery Tokyo Disney Land : Fantasy

46. If you may have any questionsconcerningToday’s lectureVisiting Teikyo UniversityTraveling in Japan Please let me know ! Ishikawa S, Tokyo → CTS net

47. 또, 여러분을 만날 수 있는 것을 기대하고 있습니다.