hazeldine on alcoholic liver disease

ALCOHOL IN THE ICU:A HEPATOLOGISTS VIEW OF ALCOHOL-RELATED LIVER DISEASE (ARLD)

Dr Simon HazeldineGastroenterologist and HepatologistFiona Stanley HospitalDecember 2015

Why is this important?

The burden of alcohol• 3.8% global mortality• 4.6% disability-adjusted life-years (DALYS) lost due to

premature death.

• Australian alcohol consumption

The burden of alcohol

NCEPOD- National Confidential Enquiry into Patient Outcome and Death (UK, 2013)

2454 cases over 6 months identified385 reviewed

NCEPOD – ArLD report

• Average age of death 59 and falling.• 8500 alcohol-related deaths in the UK in 2011

NCEPOD

Main points from NCEPOD• 71% patients that died due to ArLD had an admission to

hospital within the 2 years prior to their death and 46% within 3-months!

• Patients outcomes were considerably better if cared for by a specialist.

• Simple things were missed.• Lack of escalation to higher levels of care and referral to

specialists.• Missed opportunities for the alcohol services to intervene.

NCEPOD recommendations• ALL patients presenting to hospital should be screened for

alcohol misuse.• ALL patients presenting to acute services with a hx of

harmful drinking should be referred to alcohol services• EACH hospital should have a 7-day alcohol specialist

nurse service, psych liaison and brief interventions / access to services within 24 hours.

• Integrated Alcohol Care Team • ALL patients with decompensated liver disease should be

seen by a specialist within 72 hours. • Close liaison between medical and critical care teams

FSH alcohol in the ICU audit• Over a 3-month period those patients ‘at risk’ of alcohol

excess including: liver related illnesses, pancreatitis, seizures, overdoses, GI bleed etc.

• 20% had an admission within the last 3 months and 41% within the last 2 years.

• Only 80% patients had an alcohol history at all during the entire admission.

• Of those patients that were documented to drink alcohol to excess only 12% were referred to the alcohol services.

ICU perspective: What do you want to know about a patient with ArLD?

• Name, age etc• Stage of liver disease and complications• Indication for admission to ICU• Comorbidities• Detailed alcohol history• Likelihood of abstinence• Prognosis• Are they on the liver transplant list?

• Threshold can be as low as 25g ethanol / day

• Binge drinking – M ≥5 SD in 2 hours

F ≥4 SD in 2 hours

• Consuming 60g alcohol / day

An approach to ArLD

•Bleeding

•Renal impairment and electrolyte abnormalities

•Ascites

•Infection

•Nutrition and Neoplasm

•Encephalopathy

•Social issues

Comorbidities• Cardiomyopathy• Mental illness and poly-drug use / addiction• Pancreatic insufficiency• Diabetes• Malnutrition• Ischaemic heart disease• Malignancy• Central and peripheral neuropathy• Myopathy

Detailed alcohol history: why is this important?

• Screening tools used are the AUDIT-C, CAGE or ASSIST screening tool.

• Identify those at risk of• Complications of liver disease• Alcohol withdrawal

• Referral to the liver service• Opportunity to intervene and change drinking behaviour through referral

to alcohol services

• Early identification and intervention in the setting of hazardous drinking is successful and cost effective in reducing consumption in primary care (1) and ED (2).

• Up to 65% of patients with early liver disease stopped drinking at harmful levels simply as a result of being informed of the diagnosis (1)1. Kaner et al. The Cochrane library. Apr 2007

2. Gornal J. Alcohol and Public health. Under the influence. BMJ 2014

A common first presentation - Alcoholic hepatitis

• Clinical syndrome • Recent onset of jaundice +/- decompensation in patients with

recent alcohol misuse +/- tender liver +/- systemic inflammatory response syndrome

• Lab results• AST & ALT 1-6 ULN, high Bil & INR, low Alb, moderate CRP (20-

40)

Alcohol-related liver disease management

• Abstinence• Management of alcohol withdrawal• Nutritional• Screen and treat (and repeat)

• Extrahepatic complications (varices)• Infection• Renal failure (creatinine increase by 50%)

Alcoholic Hepatitis - Treatment

• Corticosteroids • Meta-anaylsis in 2011 showed that in severe ASH, corticosteroids

improve survival when compared to placebo (28 day mortality 20% vs 34%) (1). Can be used in patients with infection if controlled beforehand.

• Pentoxifylline • evidence is dwindling

• N-acetylcysteine – • only improves 1m survival in combination with steroids. Rarely used

(2). • 1. Mathurin et al Gut 2011• 2 E Nguyen-Khac et al. NEJM 2011

Steroids Or Pentoxifylline for Alcoholic Hepatitis (STOPAH) trial

• Group A : placebo / placeboGroup B : placebo / prednisoloneGroup C : pentoxifylline / placeboGroup D : pentoxifylline / prednisolone

• Primary end-point = death at day 28 • Secondary end-point = death or liver transplant at day 90

and 1 year• Prednisolone 40mg od and or pentoxifylline 400mg tds for

1 month

Stopah trial. NEJM. 2015

STOPAH trial- Results

• Over 3 years, 5234 patients were screened and 1103 patients underwent randomisation.

• 1053 were available for the primary end-point.• All patients were followed for 12 months or until death. • The 4 groups were well matched in regards to their

baseline characteristics and lab results.

STOPAH - Results

Died % Lost to f/u % Withdrawn %

28 days 16 1 2

90 days 29 5 3

1 year 56 (died / liver transplant)

8 4

STOPAH - Results

P = 0.06

STOPAH - Results

P = 0.69

STOPAH - Results

STOPAH – Factors associated with 28 day mortality

STOPAH – Main points• The use of steroids did not significantly reduce mortality at

28 days (although there was a trend) and made no difference at 90 days and 1 year

• In secondary analysis – adjustments made for baseline determinants of prognosis did reveal a significant improvement in prognosis with steroids but only short term (28 days).

• Pentoxifylline added no benefit• Abstinence (self-reported) rates at 1 year were …………

STOPAH – Main points• The use of steroids did not significantly reduce mortality at

28 days (although there was a trend) and made no difference at 90 days and 1 year

• In secondary analysis – adjustments made for baseline determinants of prognosis did reveal a significant improvement in prognosis with steroids but only short term (28 days).

• Pentoxifylline added no benefit• Abstinence (self-reported) rates at 1 year were

37%!

Alcohol-related liver disease management

• Abstinence• Management of alcohol withdrawal• Nutritional• Screen and treat (and repeat)

• Extrahepatic complications (varices)• Infection• Renal failure (creatinine increase by 50%)• Encephalopathy!!

Prognostic indicators of ArLD in the ICU• MELD score: creatinine, bilirubin, INR• Designed initially to improve organ allocation but is more widely

used.• Studies have failed to demonstrate that other clinical

manifestations of liver decompensation, such as variceal haemorrhage, HE, new onset ascites or SBP were independent predictors of survival over and above the MELD score.

• Predicts 3 month mortality Score Mortality40 71.3%

30-39 52.6%

20-29 19.6%

10-19 6.0%

<9 1.9% Kamath PS et al. Hepatology. 2001Kim WR. N Engl J Med. 2008

Prognostic indicators of ArLD in the ICU

• SOFA score: BP/Pressors, plts, bilirubin, GCS, creatinine, PaO2/FiO2 ratio, mechanical ventilation

• Objective score to organ dysfunction over time, used in clinical trials

• Not useful in deciding need for admission or predicting outcome.

Moreno R. Intensive Care Med. 1999

Prognostic factors of ArLD

030

60

% survival at 48 months

% survival at 48 months

• Alc. fatty liver disease – patients died of other causes not liver related• Alc. r. hepatitis – ascites, ALT, gms of alcohol consumed, continued intake,

clinical disease severity.• Alc. r. cirrhosis – INR, histology severity score. ?MELD• Alc. r. hepatitis + cirrhosis – age, gms of alcohol consumed, AST:ALT ratio, histology,

clinical disease severity

Chedid A. Am J Gastro. 1991

Prognostic factors in ArLD – cirrhotic patients

No com

plica

tions

(11%

)

Ascite

s alon

e (55

%)

Varice

al ble

eding

(6%)

Ascite

s + va

ricea

l blee

ding (

4%)

Hepati

c enc

epha

lopath

y (11

%)0

20

40

60

80

% survival at 1 year% survival at 5 years

Jepsen P. Hepatology. 2010

Alcoholic Hepatitis – Prognostic indicators

Altamirano et al. J. Clin. Gastro 2012

Outcomes of decompensated liver disease

• 165 consecutive patients were followed after there 1st episode of decompensation alcohol related cirrhosis (without HCC) and followed up until death.

• Median survival was 61 months.

Long-term Clinical Course of Decompensated Alcoholic Cirrhosis: A Prospective Study of 165 Patients.Alvarez, Marco et al. Journal of Clinical Gastroenterology. 45(10):906-911, 2011.

© 2011 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc. 2Long-term Clinical Course of Decompensated Alcoholic Cirrhosis: A Prospective Study of 165 Patients.Alvarez, Marco et al. Journal of Clinical Gastroenterology. 45(10):906-911, 2011.

TABLE 1. Significant Factors Correlating With Survival

Prognostic indicators

NCEPOD

• Lack of escalation of care

Outcomes of patients with cirrhosis in the ICU

• Admission to ICU is associated with improved survival during the first 3 days of deterioration compared to ward care (1).

1. Truog R et al. Crit Care Med 2006.

ICU mortality % Hospital mortality %

Patients without cirrhosis

Patients with cirrhosis (2-4)






20







20 30







20 30

Patients with cirrhosis

37(2-4)



1. Truog R et al. Crit Care Med 2006.2. Aggarwal A et al. Chest 2001.3. Olson J et al Hepatology 2011.4. Harrison et al. Crit Care. 2004.



20 30

Patients with cirrhosis

37 49(2-4)


• Mortality is closely related to the number of organs requiring support.

• MELD and SOFA are strongly associated to 28 day and 1 year mortality in a retrospective cohort study (1). This study also showed that, as in other studies, improvement in MELD and SOFA scores at 48 hrs after admission to ICU predicts improved 28 day and 1 year mortality.

• MELD appears to be more accurate in predicting survival confirming that liver dysfunction is the main factor in predicting survival (1).

1. Boone M et al. J Critical Care. 2014

Fig. 2. Hospital mortality in the 246 patients with cirrhosis admitted to the ICU and who required mechanical ventilation according to the degree of Acute on Chronic Liver Failure (ACLF) at admission as defined by the CLIF-SOFA score.

Eric Levesque et al. J of Hepatol 2014

Fig. 3. Cumulative one-year survival of the 246 patients with liver cirrhosis admitted to the ICU and who required mechanical ventilation.

Cirrhotic patients requiring ventilation


• In a study from Kings Hospital, London• 660 cirrhotic patients admitted to ICU from 2000-2007• Alcohol 47%, and variceal bleed 37% were the most

common causes for admission• Invasive ventilation was required in 74% of cases,

vasopressors in 49% and 50% required RRT.• 50% survived their ICU admission and 34% survived

hospital.• Patients admitted with variceal bleeding and organ

dysfunction to ICU have a significantly better outcome than other groups.

Shawcross D. J Hepatol 2012


• This study showed that patients with alcohol-related liver disease do not have poorer outcomes or higher hospital costs than those with cirrhosis from other etiologies (1).

• Just as Wildman and colleagues have shown for patients with chronic obstructive pulmonary disease and asthma admitted to ICU in the UK (2).

1. Shawcross D. J Hepatol 20122. Wildman M. BMJ. 2007

Outcomes of ‘alcoholics’ in the ICU• Some studies show that alcohol dependence is

associated with increased rates of sepsis, organ failure and hospital mortality amongst ICU patients (1).

• Christensen et al. studied 16,848 patients of whom 1229 (7.3%) were deemed to be alcoholic as determined by ICD 10 codes, past discharge summaries and drug history (2).

• They divided this group up into those with and without complications of their alcoholism!

• Compared the 30 mortality of ‘non-alcoholics’ to ‘alcoholics’

Obrien JM. Crit Care Med 2007Christensen S. Crit Care. 2012

30-d mortality %

Adjusted MRR

3-yr mortality %

Adjusted MMR

Non alcoholic patients

19.7 1.0 40.9 1.0

Alc with complications

33.6 1.64 64.5 1.67

Alc. Without complications

15.9 1.04 36.2 1.16

Christensen S. Crit Care. 2012

The effects of abstinence• The most important intervention is abstinence as it is an

important risk factor for disease progression (1). • Outcomes improve with abstinence

• Histological improvement• Decreased rates of progression to cirrhosis• Reduction in portal pressure• Decreased rates of variceal rebleeding• Reduction in hospital admissions• Improved survival

• Abstinence is more likely in those patients that receive treatment for dependence or alcohol abuse both pharmacological and psychosocial.

1. Chedid A. Am J Gastro. 1991

The effect of abstinence on mortality

Long-term Clinical Course of Decompensated Alcoholic Cirrhosis: A Prospective Study of 165 Patients.Alvarez, Marco et al. Journal of Clinical Gastroenterology. 45(10):906-911, 2011.

FIGURE 1 . Actuarial probability of survival in relation o abstinence.

Rates of abstinence relapse• After an episode of severe alcoholic hepatitis 37% are abstinent at 1 year (1).

• After first diagnosis of decompensated liver disease 60% remained abstinent at 10 years (2)

• Post liver transplantation reports vary from 10-50% of “any use” (3,4). 10% of patients resume heavy drinking after 1 year (5)

1. STOPAH Trial2. Alverez. Journal Clinical Gastro. 2011 3. Mackie J et al. Liver transpl. 20014. Tome S. et al. J Hepatol. 2002 5. Tang et al Gut 1998

A common question from ICU• Is this patient on the transplant list?

Liver Transplantation for ArLD• Benefit is restricted to patients with advanced

decompensation (Child’s Pugh score 11-15)(1,2)• 6-month ‘rule’

• Allow some patients to recover obviating the need• Helps identify subset of patients likely to maintain abstinence after

liver transplant.

1. Poynard, T. et al. J Hepatol 19992. Vanlemmens C. et al. Ann Intern Med 2009

Liver transplantation for severe alcohol related hepatitis

• Early liver transplantation• Steroid non-responders• First liver disease event

• Non response by Lille score ≥0.45 or worsening of liver function by day 7.

• Patients selected on the basis of: • absolute consensus of paramedical and medical staff• no co-morbidities• social integration• supportive family members • psychiatric evaluation and addictive profile

Mathurin NEJM 2011

Liver transplant for alcohol related hepatitis

• By definition the patient is still consuming alcohol• In the setting of Alc. Hep, if the patient has shown no

improvement by 3 months of medical management, including abstinence the chance of spontaneous recovery in patients with ASH and cirrhosis are poor.

• A study has shown an unequivicol improvement of survival in patients who received early transplant.

Mathurin NEJM 2011

0

25 %

50 %

75 %

100 %

0 50 100 150 180

74.7±9.8%

35±10.7%

p=0.005

Liver Transplantation for Severe Alcoholic Hepatitis

Transplanted

Non-transplanted

Days Mathurin, NEJM 2011

Liver transplantation for severe alcohol-related hepatitis

Alcohol in the ICU - Conclusion• The stage of liver disease and likelihood of abstinence are

strong prognostic factors in predicting outcomes.• Our main role, in patients with alcohol related liver

disease, is to give their liver the chance to recover by treating the reversible problems and making sure they are supported to maximise rates of long-term abstinence.

• Prevention is better than cure. Identification of patients drinking hazardous amounts of alcohol will make the biggest impact in the mortality figures.

hazeldine on alcoholic liver disease

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