Critical illness in patients

with chronic liver diseases

Aleksander KragProfessor of Hepatology

Odense University Hospital

Ever had disagreement regarding patients with cirrhosis?….

– referral to ICU?– potential benefit?– when to stop?

Complications to cirrhosis

� CO ��� ?� MAP ��� ?� PVR ��� ?� CBV ��� ?� GFR ��� ?� RBF ��� ?� Splanchnic perfusion ��� ?� Plasma volume ��� ?� Norepinephrine (SNS) ��� ?� Renin, aldosteron (RAAS)��� ?� Vasopressin ��� ?

A challenge !! – are yopu ready

Cirrhosis

Portal hypertension

Portosystemic shunting

Hepatocellular failure

Splanchnic and arteriolar vasodilatation (NO, CGRP, etc

Systemic vascular resistance

Effective arterial blood volume

Arterial blood pressureSNS

RAAS

Vasopressin

ET-1

Cardiac output

Splanchnic blood flow

Arterial blood pressure

Sodium-water retention

Plasma volume

Gastroenheden, medicinsk sektion

Big bang

Progressive vasodilatory syndrome

Big Bang Theory in cirrhosis

There is one organ to There is one organ to There is one organ to There is one organ to

ru le them all?ru le them all?ru le them all?ru le them all?

Lord of organsHepatic encephalopathy

Hepatopulmonary syndrome

Cirrhotic cardiomyopathy, hyperkinetic syndrome

Ascites, Hepatorenal syndrome,

Infections, Immune system, metabolism

Gut function, bacterial translocation

Sarcopenia, HCC

Overall challenges

Medical need- burden on healthcare systems

Alcoholic liver cirrhosis:

� 493,000 deaths/year

� 50% of global deaths

from cirrhosis

� 1.8% of all deaths in

Europe

� US: Cirrhosis, 8 leading

cause of death

JAMA 2013;591-608, J Hep 2013;59:160-8.

Hidden burden of disease

� 75% have their initial diagnosis of cirrhosis during hospitalisation with a decompensating event

� 5-year mortality up to 88% in late cirrhosis compared to 1.5% in earliest stage of cirrhosis

The 3-Month Readmission Rate Remains Unacceptably High in a Large

North American Cohort of PatientsWith Cirrhosis

Akut Gastro-Hepatologi

Case story 1827

• Past medical history: � Icterus, haemoptysis, hepato-splenomegali, � Ascites, prior paracentesis� Alcohol overuse, chronic abdominal pain (Crohns disease??)

• Hospitalised January 1827� Tense ascites � Paracentesis� Alcohol against pain and delirium tremens

• Hospitalised March 1827� Dyspnoea, haemoptysis� Becomes jaundiced, tense ascites, leg oedema� Paracentesis twice 11 and 22 liters

• Infection at the paracentesis point� Abdominal pain� Decreased urine production� Anuria and hepatic coma

• Mors March 26. 1827

Ludwig van Beethoven 1770-1827

does it work?

YES

Several evidence based interventions –

grade 1 evidence

� Acute variceal bleeding:� Terlipressin� Antibiotics� Banding � TIPS

� Hepatorenal syndrome� Terlipressin and albumin

� Hepatic encephalopathy� Lactulose� Rifaximin

� Albumin: AKI, SBP, paracentesis

Prevalence and types of acute renal failure /acute

kidney injury in hospitalized patients with cirrhosis

Garcia-Taso G et al. HEPATOLOGY 2008;48:2064-2077

Hecker and Sherlock, Lancet 1956

Epstein M et al. Am J med 1970;49:175-185

Diagnostic criteria of hepatorenal

syndrome criteria

1. Cirrhosis with ascites.

2. Serum creatinine >133 µmol/l (1.5 mg/dl).

3. No improvement of serum creatinine (decrease to a level of 133 µmol/l) after at least 2 days with diuretic withdrawal and volume expansion with albumin. The recommended dose of albumin is 1 g/kg of body weight per day up to a maximum of 100 g/day.

4. Absence of shock.

5. No current or recent treatment with nephrotoxic drugs.

6. Absence of parenchymal kidney disease as indicated by proteinuria >500mg/day, microhaematuria (>50 red blood cells per high power field) and/or abnormal renal ultrasonography.

Salerno F. et al. GUT 2007

The syndrome is classified into two types:

• Type 1 is characterized by a doubling of the serum creatinine level to more than 2.5 mg/dl (221 µmol/liter) in less than 2 weeks.

• Type 2 is characterized by a stable or less rapidly progressive course than in type 1.

Terlipressin alone or with albumin versus no intervention or

albumin,

Outcome: Mortality

Terlipressin alone or with albumin versus no intervention or

albumin,

Outcome: Reversal of hepatorenal syndrome

Terlipressin as continuous infusion in HRS

Cavallin et al. Hepatology 2016

Treatment of HRS-1: Terlipressin combined with albumin

�Terlipressin:

�0.5–1 mg every 4–6 hr intravenously,

�increase up to 2 mg every 4–6 hr until serum creatinine

decreases to 1–1.2 mg/dl (88–106 μmol/liter); usual duration

of therapy 5 to 15 days.

�Continuous infusion ( in 5% dextrose) if AE’s

�Albumin

�Intravenous administration of albumin together with

vasoconstrictor drugs (1 g of albumin/kg of body weight on

day 1, followed by 20–40 g/day).

�

Survival after acute variceal bleeding

Chalasani N et al. Am J Gastroenterol 2003;98:653-659

Comparison of survival curves of acute variceal bleeding reported over 6 decades.

Today 6 week mortality must be below 20%!

N Engl J Med 2013;368:11-21

Transfusion when Hgb below 4,3 vs 5,6 mmol/L

Antibiotic prophylaxis for cirrhotic patients

with gastrointestinal bleeding

� 8 randomised trials, 864 patients

� Decreased mortality RR 0.73 (CI 0.55-0.95)

� Decreased bacterial infections RR 0.40 (CI 0.32-0.51)

� Quinolones were tested in most trials, median 7 days treatment

Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal

bleeding. The Cochrane Database of Systematic Reviews 2002, Issue 2. Art. No.: CD002907. DOI:

10.1002/14651858.CD002907.

Terlipressin for acute esophageal variceal hemorrhageG Ioannou, J Doust, DC Rockey

The Cochrane Database of Systematic Reviews 2005 Issue 3

Terlipressin for acute esophageal variceal hemorrhage

G Ioannou, J Doust, DC Rockey

The Cochrane Database of Systematic Reviews 2005 Issue 3

Terlipressin for acute esophageal variceal hemorrhage G Ioannou, J Doust, DC Rockey

The Cochrane Database of Systematic Reviews 2005 Issue 3

TIPS

Overall survival in random effect model

Sengstaken tube

AK 2016

Ella Danis stent

Liver assist devices

MARS, PROMETEUS

70 patients randomised. 3 year recruitment from 7 tertiary centres.

The endpoint of the study was improvement in HE of 2 grades from baseline.

The median time to the first 2 grade

improvement in HE was 72 hours in the ECAD

group versus 108 hours in the SMT group.

HEPATOLOGY 2013;57:1153-1162

10 centres, 3 years, 145 with ACLF.

The primary end points were survival probabilities

on days 28 and 90 irrespective of liver transplant

The Bottom Line

� Save lives� Acute bleeding

� Cautious blood volume restitution� Terlipressin 2 mg/4 hour� Antibiotics (quinolones) 7 days� Banding with-in 12 hours - always terlipressin

before (consider erythromycin 250mg iv)� TIPS in persistent bleeding

� Hepatorenal syndrome� Terlipressin combined with albumin

To ITU or not to ITU?

What criteria are relevant to select and TIME

patients with cirrhosis for intensive care ?

� Alcohol?� Quality of life?� Patients own wishes?� Worth fighting for?� Severity of disease?

� What about this patient?

� Would these information's change your view?� 30 day mortality of 10%, 50%

or 85%� One year of 10%, 50%, 90%

ACLF 1

ACLF 3

ACLF ??

Acute-on-chronic liver failure

ACLFgrad

28 dages

mortalitet

90 dages

mortalitet

Antal organsvigt

0n=1040

4.7% 15% 0 eller 1 ikke nyre

1 n=148 22,1 40,7% 1+ nyre påvirkning

2 n=108 32% 52,3% 2

3 n=47 76,7% 79,1% 3 eller flere

Mortality of cirrhotic patients in ICU

37%37% 56%56% 89%89%

How high should mortality

be?

Is there a stage when intensive care is futile or un-ethical in end stage liver disease – palliative

care?

All ignore premorbid

performance and liver

function

Intensive care

candidate

1) Premorbid Child-Pugh A/B

OR Premorbid MELD score < 20

2) Premorbid Child-Pugh C

OR Premorbid MELD score >=20

AND ACLF grade <=2

Unlikely to benefit

from intensive care

therapy

Special cases can be

discussed, eg. patients

listed for

transplantation.

Premorbid Child-Pugh C

OR Premorbid MELD score >=20

AND ACLF grade ≥3

To be, or not to be, that is the question—

Whether 'tis Nobler in the mind to suffer

The Slings and Arrows of outrageous Fortune,

Or to take Arms against a Sea of troubles,

And by opposing end them? To die, to sleep—

No more; and by a sleep, to say we end

Scoring systems to predict mortality

Child-Pugh Score

SOFA-Clif Score

WHO performance status score