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CLINICAL TYPES OF HEPATORENAL SYNDROME (HRS). Type-2 HRS. Type-1 HRS. 6. 5. Cefotaxime. 4. Therapeutic paracentesis. 3. Creatinine (mg/dL). Encephalopathy Jaundice. 2. 1. 0. -6. -4. -2. 0. 1. 2. 3. Months. Weeks. DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS. Type-2. Type-1.

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CLINICAL TYPES OF

HEPATORENAL SYNDROME (HRS)

Type-2 HRS

Type-1 HRS

6

5

Cefotaxime

4

Therapeutic

paracentesis

3

Creatinine (mg/dL)

Encephalopathy

Jaundice

2

1

0

-6

-4

-2

0

1

2

3

Months

Weeks


DIFFERENCES BETWEEN TYPE-1 AND TYPE-2 HRS

Type-2

Type-1

Renal failure

Moderate and steady

Severe and progressive

Setting

Non-azotemic cirrhosis

Type-2 HRS

Onset

Spontaneous

Precipitated

Consequence

Refractory ascites

Terminal hepatorenal failure

Survival

Months

Days


HRS. SURVIVAL

1.0

Median survival

0.8

Type-1

15 days

Type-2

150 days

0.6

Probability

Type-2

0.4

p<0.0001

0.2

Type-1

0.0

0

100

200

300

400

500

600

Days


TIME-COURSE OF THE CIRCULATORY, NEUROHORMONAL

AND RENAL FUNCTION ABNORMALITIES IN CIRRHOSIS

No Ascites

Ascites

Degree of splanchnic

arterial vasodilation

Time

Hyperdinamic circulation

 RAAS, SNS and sodium retention

ADH and hyponatremia

HRS


CARDIOVASCULAR HEMODYNAMICS IN 8 PATIENTS

DEVELOPING TYPE-1 HRS AFTER SBP

At SBP diagnosis

SBP-HRS

MAP (mmHg)

83±7

73±8*

PRA (ng/mL.h)

18±11

28±12*

SVR (dyn.s/cm-5)

1137±220

1268±320

CO (L/min)

5.7±0.9

4.6±0.7*

* p<0.02

Ruiz del Arbol et al., Hepatology 2002


CARDIOVASCULAR HEMODYNAMICS

IN 12 PATIENTS DEVELOPING TYPE-1 HRS*

Baseline

Type-1 HRS

p

MAP (mmHg)

84±2.6

70±2.3

<0.001

PRA (ng/mL.h)

12.9±2.6

25.8±3.4

<0.01

NE (pg/mL)

735±69

1385±99

<0.001

SVR (dyn.s/cm-5)

1099±81

1211±97

NS

CO (L/min)

5.8±0.2

4.6±0.3

<0.01

RAP (mmHg)

7±0.8

5±0.5

<0.01

PCP (mmHg)

8.7±1

6.5±1

<0.01

HR (bpm)

86±5

84±4

NS

* baseline measurements: 9±1 months prior HRS

Ruiz del Arbol et al., Hepatology 2005


REGIONAL CIRCULATORY CHANGES IN CIRRHOSIS

80

0.9

* p<0.05

p<0.001

0.8

60

0.7

Resistive index middle cerebral artery

Brachial blood flow (mL/min)

40

*

0.6

*

0.5

20

0.4

0

H

NA

A

HRS

H

NA

A

Maroto et al., Hepatology 1993

Guevara et al., Hepatology 1998

Healthy subjects (H), cirrhotic patients without ascites (NA),

with ascites (A) and with hepatorenal syndrome (HRS)


CHANGES IN HEPATIC HEMODYNAMICS

ASSOCIATED WITH TYPE-1 HRS

HVPG IN PATIENTS DEVELOPING

TYPE-1 HRS AFTER SBP

HBF IN PATIENTS DEVELOPING

TYPE-1 HRS

30

1000

p<0.05

25

800

HVPG (mmHg)

Hepatic blood flow (mL/min)

20

600

15

400

At SBP

diagnosis

After SBP

resolution

Baseline

Type-1

HRS

Baseline measurements:

9±1 months prior HRS

Ruiz del Arbol et al., Hepatology 2002

Ruiz del Arbol et al., Hepatology 2005


INCIDENCE OF RELATIVE ADRENAL INSUFFICIENCY*

IN CIRRHOTIC PATIENTS (n=20) WITH SEPTIC SHOCK

Non-cirrhotic patients

10-40%

Cirrhotics Child B

25%

Cirrhotics Child C

75%

* Diagnostic criteria:

- baseline cortisol <9 mg/dL

- increase in cortisol after ACTH <9 mg/dL

- peak cortisol <20 mg/dL

Fernández et al. (unpublished)


TYPE-I HRS AS A PART OF A MULTIORGAN FAILURE

Spontaneous bacterial peritonitis

or other precipitating event

Adrenal

dysfunction

Increase in arterial vasodilation

Decrease in cardiac output

A-II, NE, ADH

­ resistance to

portal venous flow

Regional arterial

vasoconstriction

Kidneys

HRS

Aggravation of

portal hypertension

Brain

Encephalopathy

Liver

Liver failure


EFFECT OF VASOCONSTRICTORS

(Ornipressin and Terlipressin)

PLUS I.V. ALBUMIN IN TYPE-1 HRS

Baseline

(n=15)

Day 7

(n=9)

Day 14

(n=7)

MAP (mmHg)

70±8

77±9

79±12

PRA (ng/mL.h)

15±15

2±3

1±1

NE (pg/mL)

1257±938

550±410

316±161

Creatinine (mg/dL)

3±1

2±1

1±1

GFR (mL/min)

9±1

25±2.5

41±1.5

Guevara et al., Hepatology 1998; Uriz et al., J Hepatol 2000


SERUM CREATININE BEFORE AND AFTER

TREATMENT OF TYPE-1 HRS (11 cases)

WITH TERLIPRESSIN PLUS ALBUMIN

5

4

3

Serum creatinine (mg/dL)

2

1

0

1 day

1 month

Baseline

After treatment

Ortega et al., Hepatology 2002


TREATMENT OF HRS WITH VASOCONSTRICTORS

AND ALBUMIN (Group 1) AND STANDARD MEDICAL

THERAPY (Group 2). REVIEW OF 18 STUDIES

Group 1

(n=154)

Group 2

(n=137)

MCFS*

(n=99)

Reversal of HRS

61.7%

2.9%

58%

HRS recurrence

20%

-

-

Survival 1 month

41.6%

3%

40%

Survival 3 months

30%

0%

22%

Liver transplantation

12.3%

-

13%

* Multicenter French Study


TREATMENT OF TYPE-1 HRS

WITH TERLIPRESSIN PLUS

I.V. ALBUMIN vs TERLIPRESSIN

Terlipressin +

albumin (n=13)

Terlipressin

(n=8)

Complete response

10

2

Survival >1 month

12

2

OLT

5

0

Ortega et al., Hepatology 2002


TIPS IMPROVES CIRCULATORY AND RENAL

FUNCTION IN TYPE-1 HRS (7 patients)

After treatment

Baseline

Day 7

Day 30

Renin (ng/mL/h)

18±5

6±2

3±1

NE (pg/mL)

1257±187

853±102

612±197

Creatinine (mg/dL)

5.0±0.8

3.7±1.0

1.8±0.4

GFR (mL/min)

9±4

11±5

27±7

Guevara et al., Hepatology 1998


CIRCULATORY SUPPORT WITH I.V. ALBUMIN IN PATIENTS

WITH SBP. EFFECT ON ARTERIAL BLOOD VOLUME

*

*

9

*

8

* p<0.05

7

6

5

PRA (ng/mL.h)

4

3

2

1

0

1

3

6

9

Days

Cefotaxime + albumin

Cefotaxime

Sort et al., N Engl J Med 1999


CIRCULATORY SUPPORT WITH I.V. ALBUMIN

IN PATIENTS WITH SBP. EFFECT ON HRS

DEVELOPMENT AND HOSPITAL MORTALITY

Cefotaxime

(n=63)

Cefotaxime +

albumin (n=63)

Resolution of infection

57 (93%)

59 (98%)

HRS

20 (32%)

6 (10%)*

Hospital mortality

17 (27%)

6 (10%)*

* p<0.001

Sort et al., N Engl J Med 1999


EFFECTS OF HYDROXYETHYL STARCH (HES) AND

ALBUMIN (ALB) ON EFFECTIVE BLOOD VOLUME IN SBP

Baseline

At resolution

p

HES

80±15

81±8

NS

MAP (mmHg)

ALB

76±9

85±13

0.01

HES

8.5±7.3

16.8±24.6

NS

PRA (ng.mL/h)

ALB

5.7±4.7

3.1±3.4

0.04

Fernandez et al., Hepatology 2005


EFFECTS OF HYDROXYETHYL STARCH (HES)

AND ALBUMIN (ALB) ON PERIPHERAL ARTERIAL

CIRCULATION IN SBP

Baseline

At resolution

p

HES

777±239

778±290

NS

SVR (dyn/cm5)

ALB

668±134

803±197

0.03

HES

39±13

63±32

0.03

NO (nmol/mL)

ALB

61±30

78±55

NS

HES

297±44

278±47

NS

vWF:Ag (U/dL)*

ALB

331±35

257±65

0.01

* vWF:Ag Von Willebrand-related antigen factor

Fernandez et al., Hepatology 2005


EFFECT OF I.V. ALBUMIN ON

SYSTEMIC HEMODYNAMICS IN CIRRHOSIS

Albumin infusion

Intravascular

volume expansion

Inhibition of

endothelial activation

Increased

cardiac preload

Decreased

NO synthesis

Improvement in left

ventricular function

Increased systemic

vascular resistance

IMPROVEMENT

OF CIRCULATORY

DYSFUNCTION