Ulinastatin & Ulinastatin & Continuous hemodiafiltrationContinuous hemodiafiltration

The Impact of Inhibiting Cytokines on The Impact of Inhibiting Cytokines on

Circulation after Cardiac SurgeryCirculation after Cardiac Surgery

Susumu Ishikawa, MDSusumu Ishikawa, MD

Associate Professor of Surgery, Associate Professor of Surgery,

Teikyo University, Tokyo, JapanTeikyo University, Tokyo, Japan

2424thth Korean Society for Thoracic & Cardiovascular Surgery Korean Society for Thoracic & Cardiovascular Surgery

Teikyo University HospitalTeikyo University Hospital

LocatedLocated

at the centerat the center

of Tokyo cityof Tokyo city

2,000 beds in Total 2,000 beds in Total

BackgroundBackground

Systemic inflammatory responses after Systemic inflammatory responses after

cardiac surgery using cardiopulmonary cardiac surgery using cardiopulmonary

bypass (CPB) may be responsible for the bypass (CPB) may be responsible for the

postoperative organ dysfunction. postoperative organ dysfunction.

Therefore, over-induction of cytokines and Therefore, over-induction of cytokines and

polymorphonuclear elastase (PMNE) should polymorphonuclear elastase (PMNE) should

be prevented especially in critical patients. be prevented especially in critical patients.

Today’s ContentsToday’s Contents

Clinical StudyClinical Study

1. Mechanical removal of cytokines 1. Mechanical removal of cytokines

by continuous hemodiafiltration by continuous hemodiafiltration (CHDF)(CHDF)

2. Pharmacological suppression of cytokines 2. Pharmacological suppression of cytokines

by Ulinastatin by Ulinastatin (a protease inhibitor)(a protease inhibitor)

IntroductionIntroduction

Cardiac Surgery & Organ DysfunctionCardiac Surgery & Organ Dysfunction

Cardiopulmonary BypassCardiopulmonary Bypass

Controlled ShockControlled Shock

Systemic Inflammatory ResponsesSystemic Inflammatory Responses Cytokine induction, Leukocyte activationCytokine induction, Leukocyte activation

Acute circulatory failure

CPB Time and CytokineCPB Time and Cytokine

Granulocyte ElastaseGranulocyte Elastase

μg /L

6,000

4,000

2,000

CPB time (min.)

Interleukin 8 (IL-8)Interleukin 8 (IL-8)

Pg/ml

90

70

50

30

Preop. AfterCPB POD1 POD3 POD6

■ : CPB > 120 min.▲ : CPB < 120 min.

* ** *

P<0.01P<0.01

Hurunaga H, 1995Hurunaga H, 1995 Doi H, 1988Doi H, 1988

Ulinastatin: A Protease InhibitorUlinastatin: A Protease Inhibitor (Urinary Trypsin Inhibitor)

Antecedent Neutrophil Neutrophil

Elastase

LiverLiverUlinastatin

FeaturesFeatures 1) exists naturally in the human body. 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 BodySynthesis in Human Body

・・ Ulinastatin antecedent (IαTI ) is produced mainly in Liver.Ulinastatin antecedent (IαTI ) is produced mainly in Liver.・・ During stress, IαTI is influenced by activated Neutriphil During stress, IαTI is influenced by activated Neutriphil 　　 Elastase, changing into Ulinastatin.Elastase, changing into Ulinastatin.

Interαtripsin inhibitor(MW 67,000)(MW 67,000)

StressStress

MonocyteMonocyte ・・ MacrophageMacrophage

NeutrophilNeutrophil

Cell/Organ InjuryCell/Organ Injury

MOFMOF

CytokinesCytokines

InternalInternalUlinastatinUlinastatin

ExternalExternalUlinastatinUlinastatin

ElastaseElastase

(Timing/Dosage)(Timing/Dosage)

Effects of UlinastatinEffects of Ulinastatin

ReplacementReplacement TherapyTherapy (Supplement)(Supplement)

Dose-dependent Effect of UlinastatinDose-dependent Effect of Ulinastatin- Experiments using shock models-- Experiments using shock models-

Ulinastatin

(LPS induced peritonitis)(LPS induced peritonitis)

Neutrophil elastaseNeutrophil elastase

Ulinastatin Ulinastatin

Free radicalFree radical

Kato K. 1995Kato K. 1995

Dose-dependent suppression Dose-dependent suppression of inflammatory responsesof inflammatory responses

LPS: lipopolysaccharideLPS: lipopolysaccharide

Indications of UlinastatinIndications of Ulinastatin

11 ．． Acute circulatory failureAcute circulatory failure 　　　　　　　　　　 hemorrhagic shock, bacterial shock, hemorrhagic shock, bacterial shock,

　　　　　　　　 traumatic shock, febrile shocktraumatic shock, febrile shock

2. 2. Acute pancreatitisAcute pancreatitis

includinincludin ｇ ｇ traumatic traumatic

acute pancreatitis after operation acute pancreatitis after operation

endoscopic retrograde pancreatographyendoscopic retrograde pancreatography

Same as the indication in Japan

1. Mechanical Removal of 1. Mechanical Removal of Cytokines by CHDFCytokines by CHDF

- Clinical Study -- Clinical Study -

Continuous Hemodiafiltration

BackgroundBackground

We sometimes experience We sometimes experience

the circulatory improvement after the circulatory improvement after

the initiation of CHDF.the initiation of CHDF.

Why ??Why ??

ObjectiveObjective

Prolonged CPB sometimes causes postoperative Prolonged CPB sometimes causes postoperative

circulatory collapse especially in critical patients.circulatory collapse especially in critical patients.

The efficacy of CHDF on the circulation was The efficacy of CHDF on the circulation was

evaluated focusing on the inflammatory evaluated focusing on the inflammatory

reactive substances.reactive substances.

Patients & MethodsPatients & MethodsNo. of Patients: 12 No. of Patients: 12 (Jan 2007~)(Jan 2007~)

* Exclusion: chronic renal failure, sepsis* Exclusion: chronic renal failure, sepsis

circulatory assist devicecirculatory assist device

Age : 67 Age : 67 ±± 2 2 (57-85)(57-85) years years M/ F : 11/ 1M/ F : 11/ 1Operation : Operation : CABG 3, Acute aortic dissection 3,CABG 3, Acute aortic dissection 3,

MVP/R 3, AVR 3MVP/R 3, AVR 3

CPB time : 286 CPB time : 286 ±± 32 32 (171 -552)(171 -552) min. min.Dialyzer : polysulfone membrane Dialyzer : polysulfone membrane (SH 1.3, Tore Co.Ltd., Japan)(SH 1.3, Tore Co.Ltd., Japan)

Circulation before CHDFCirculation before CHDF mean mean ± ± SE RangeSE Range

SBP SBP (mmHg)(mmHg) 96 96 ±± 5 57 - 85 5 57 - 85HR HR ( /min)( /min) 101 101 ±± 6 95 - 147 6 95 - 147CI CI (L/min/m(L/min/m22)) 2.9 2.9 ±± 0.1 2.4 - 3.4 0.1 2.4 - 3.4CVP CVP (mmHg)(mmHg) 11 11 ±± 1 6 - 16 1 6 - 16SPAP SPAP (mmHg)(mmHg) 32 32 ±± 2 21 - 39 2 21 - 39SVRI SVRI (dynes(dynes ・・ secsec ・・ cmcm-5-5 ・・ mm22) ) 1452 1452 ±±153 1007 - 2206 153 1007 - 2206 UV UV (ml/4hrs)(ml/4hrs) 169 169 ±± 44 10 - 550 44 10 - 550

Systemic Blood Pressure (SBP)Systemic Blood Pressure (SBP)

70

80

90

100

110

120

130

140

Pre-CHDF CHDF 4h 8h 12h

SBP

mmHg

**

*

* p<0.05

96 ± 596 ± 5

120± 5120± 5

Urine VolumeUrine Volume

0

100

200

300

400

500

600

Pre-CHDF

CHDF4h

8h 12h

urine/4hrs

mlml

****

* * p<0.05p<0.05

69±7569±75

371±108371±108

Serum IL-6 ConcentrationSerum IL-6 Concentration

0100200300400500600700800900

1000

Pre-CHDF CHDF 4h CHDF12 h

IL-6

Pg/dl

* p<0.05

**

**

717±152717±152

353±92353±92

Serum IL-8 ConcentrationSerum IL-8 Concentration

0

20

40

60

80

100

120

Pre-CHDF CHDF 4h CHDF 12 h

IL-8

Pg/dl

**

* p<0.05

86±3186±31

53±1053±10

Systemic Vascular Resistance IndexSystemic Vascular Resistance Index

1000

1200

1400

1600

1800

2000

2200

2400

Pre-CHDF

CHDF 4h 8h 12h

SVRI

dynesdynes ・・ secsec ・・ cm-5cm-5 ・・ m2m2

**** ********

** p<0.01** p<0.01

1452±1531452±153

1898±1981898±198

Summary 1 Summary 1

Continuous hemodiafiltrationContinuous hemodiafiltration

removed inflammatory cytokines removed inflammatory cytokines

and improved systemic circulation.and improved systemic circulation.

2. Pharmacological Suppression 2. Pharmacological Suppression of Cytokines by Ulinastatinof Cytokines by Ulinastatin

- Clinical Trial -- Clinical Trial -

Patients & MethodsPatients & Methods

Group Ulinastatin Control p Group Ulinastatin Control p (n=7) (n=8)(n=7) (n=8)

Age Age (yr)(yr) 65 ± 5 65 ± 3 NS 65 ± 5 65 ± 3 NS

Operation CABG 3 3Operation CABG 3 3

AVR 3 2AVR 3 2

　　　　　　　 　　　　　　　 MVR MVR 1 31 3

CPB time CPB time (min)(min) 165 ± 16 191 ± 15 NS 165 ± 16 191 ± 15 NS

Ao-clamp time Ao-clamp time (min) (min) 88 ± 10 99± 12 NS 88 ± 10 99± 12 NS

Protocol in the Ulinastatin GroupProtocol in the Ulinastatin Group

Dosage Dosage

1) CPB priming solution : 600,000 U1) CPB priming solution : 600,000 U

2) Addition to CPB : 300,000 U2) 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 UEach amp.(2ml) contains : Ulinastatin 100,000 U

Serum Ulinastatin ConcentrationSerum Ulinastatin Concentration

Preop. after CPB POD 1 2 5Preop. after CPB POD 1 2 5

P<0.01

P<0.05P<0.05

Serum IL-6 ConcentrationSerum IL-6 Concentration

0

20

40

60

80

100

120

140

Before CPB After surgery

ControlUlinastatin

Pg/dl

* p<0.05

*

*

Serum IL-8 ConcentrationSerum IL-8 Concentration

0

2

4

6

8

10

12

14

16

18

Before CPB After surgery

ControlUlinastatin

Pg/dl

* p<0.05

*

*

Serum Concentration of Serum Concentration of Polymorphonuclear elastase (PMNE)Polymorphonuclear elastase (PMNE)

0200400600800

100012001400160018002000

Before CPB After surgery

ControlUlinastatin

μ ｇ /dl

*

*

* p<0.05

Correlation between IL-8 & PMNECorrelation between IL-8 & PMNE- Maximum Levels after Cardiac Surgery-- Maximum Levels after Cardiac Surgery-

r = 0.556, p<0.05

Sato Y, Ishikawa S, 2000Sato Y, Ishikawa S, 2000

Respiratory IndexRespiratory Index

0

0.5

1

1.5

2

2.5

Preop. POD 1 POD 2

ControlUlinastatin

*

** p<0.05

Summary 2Summary 2

Urinastatin Urinastatin

reduces the overinduction of cytokines reduces the overinduction of cytokines

and PMNE during cardiac surgeryand PMNE during cardiac surgery

Comparison of Comparison of Ulinastatin & AprotininUlinastatin & Aprotinin

Suppression of Suppression of intracellular elastase activityintracellular elastase activity

0

50

100

150

control 500 3000

cyto

toxi

city

(%

)

0

50

100

150

control 500 3000

cyto

toxi

city

(%

)

Ulinastatin Aprotinin

Recovery from Shock Recovery from Shock 1. Improvement of Blood pressure1. Improvement of Blood pressure

(normal range: systolic ≥ 100mmhg)(normal range: systolic ≥ 100mmhg)

86.5%

Ulinastatin (n=52) Ulinastatin (n=52) Aprotinin (n=51)Aprotinin (n=51)

Yamamura H, 1984

Recovery from Shock Recovery from Shock 2.Urine Volume 2.Urine Volume

(normal range: Urine Volume ≥ 50mL/hr)(normal range: Urine Volume ≥ 50mL/hr)

74.0%

Ulinastatin (n=52)Ulinastatin (n=52) Dosage 10,000unit x 3 / 3days

Aprotinin (n=51)Aprotinin (n=51) Dosage 20,000unit x 3 / 3days

Recovery from ShockRecovery from Shock 3.3. Serum Creatinin Serum Creatinin

P <0.05

(mg/dl)

Effects of Ulinastatin Effects of Ulinastatin in Other Organs in Other Organs

- Summary of previous reports-- Summary of previous reports-

1.1. LungLung- A-aDO2 after Cardiac Surgery -- A-aDO2 after Cardiac Surgery -

Before CPB After surgery

■ Control □ Ulinastatin

400

300

200

100

mmHg A-aDO2A-aDO2 * p<0.05

*

*

Bingyang J, 2007Bingyang J, 2007

2. Kidney 2. Kidney –Renal Function after Cardiac Surgery-–Renal Function after Cardiac Surgery-

POD POD

2.0

1.5

1.0

0.5

0

mg/dl

*

*

* p<0.05 * p<0.05

*ControlUlinastatin

ControlUlinastatin

Ueki M, 1995Ueki M, 1995

Serun creatinineSerun creatinine N-Acetyl-N-Acetyl-ββ-D-Glucosaminidase (urine)-D-Glucosaminidase (urine)

3. Liver 3. Liver –post hepatic resection-–post hepatic resection-

IL-6IL-6 (pg/ml)(pg/ml) Pre-AlbuminePre-Albumine (mg/dl)(mg/dl)

USTControlntrol

USTControl

180180

100100

5050

00

Preop. POD 1 3 7 14 Preop. POD 1 3 7 14

2525

2020

1515

1010

55

00

Miyazaki K. 2000Miyazaki K. 2000

Prevention of Organ Failure Prevention of Organ Failure - - Our Strategy in Cardiac Surgery-Our Strategy in Cardiac Surgery-

Case Critical Severe UsualCase Critical Severe Usual Mechanical Mechanical Intraoperative Hemodialysis Intraoperative Hemodialysis Postoperative CHDFPostoperative CHDF

Pharmacological Pharmacological Intraoperative Intraoperative ◎ ◎◎ ◎ Postoperative Postoperative ◎ ◎ ◎◎ ◎ ◎

(Ulinastatin, (Ulinastatin, 300,000 U/day300,000 U/day))

ConclusionConclusion

Urinastain and CHDF suppressed acute-phase Urinastain and CHDF suppressed acute-phase

reactive substances and improved systemic reactive substances and improved systemic

circulation after cardiac surgery. circulation after cardiac surgery.

Perioperative active suppression of inflammatory Perioperative active suppression of inflammatory

cytokines improves the surgical outcome cytokines improves the surgical outcome

especially in critical patients.especially in critical patients.

New Buildings of New Buildings of Teikyo University HospitalTeikyo University Hospital

Cardiovascular Center will open in April, 2009.Cardiovascular Center will open in April, 2009.

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