Ulinastatin & Continuous hemodiafiltration The Impact of Inhibiting Cytokines on Circulation after Cardiac Surgery Susumu Ishikawa, MD Associate Professor.

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Presentation transcript:

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

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

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

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

Introduction

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

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

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

Stress Stress Monocyte ・ Macrophage Neutrophil Cell/Organ Injury MOFCytokines InternalUlinastatin ExternalUlinastatin Elastase (Timing/Dosage) (Timing/Dosage) Effects of Ulinastatin Replacement Therapy Replacement Therapy (Supplement) (Supplement)

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

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

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

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

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

Patients & Methods No. of Patients: 12 (Jan 2007~) * Exclusion: chronic renal failure, sepsis * Exclusion: chronic renal failure, sepsis circulatory assist device 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 MVP/R 3, AVR 3 CPB time : 286 ± 32 ( ) min. Dialyzer : polysulfone membrane (SH 1.3, Tore Co.Ltd., Japan) (SH 1.3, Tore Co.Ltd., Japan)

Circulation before CHDF mean ± SE Range mean ± SE Range SBP (mmHg) 96 ± HR ( /min) 101 ± CI (L/min/m 2 ) 2.9 ± CVP (mmHg) 11 ± SPAP (mmHg) 32 ± SVRI (dynes ・ sec ・ cm -5 ・ m 2 ) 1452 ± UV (ml/4hrs) 169 ±

Systemic Blood Pressure (SBP) mmHg * * * * p< ± 5 120± 5

Urine Volume ml * * * p< ±75 371±108

Serum IL-6 Concentration Pg/dl * p<0.05 * * 717± ±92

Serum IL-8 Concentration Pg/dl * * p< ±31 53±10

Systemic Vascular Resistance Index dynes ・ sec ・ cm-5 ・ m2 **** ** ** p< ± ±198

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

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

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

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

Serum Ulinastatin Concentration Preop. after CPB POD P<0.01 P<0.05

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

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

Serum Concentration of Polymorphonuclear elastase (PMNE) μ ｇ /dl * * * p<0.05

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

Respiratory Index * * * p<0.05

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

Comparison of Ulinastatin & Aprotinin

Suppression of intracellular elastase activity Ulinastatin Aprotinin

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

Recovery from Shock 2.Urine Volume (normal range: Urine Volume ≥ 50mL/hr) 74.0% Ulinastatin (n=52) Dosage 10,000unit x 3 / 3days Aprotinin (n=51) Dosage 20,000unit x 3 / 3days

Recovery from Shock 3. Serum Creatinin P <0.05 (mg/dl)

Effects of Ulinastatin in Other Organs - Summary of previous reports-

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

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

3. Liver –post hepatic resection- IL-6 (pg/ml) IL-6 (pg/ml) Pre-Albumine (mg/dl) Pre-Albumine (mg/dl) UST ntrol Control UST Control Preop. POD Miyazaki K. 2000

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

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

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

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

If you may have any questions concerning Today’s lecture Visiting Teikyo University Traveling in Japan Please let me know ! Ishikawa S, Tokyo → CTS net

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