Acute on Chronic Liver Failure: Practical management ...

Acute on Chronic Liver Failure:

Practical management outside the tertiary centre.

William Bernal

Professor of Liver Critical Care

Liver Intensive Therapy Unit

Institute of Liver Studies

Kings College Hospital

United Kingdom

King’s College Hospital NHS Foundation Trust NHS

http://kweb/mediawiki/images/archive/5/50/20140307122819!Box_nhs_blue_hollow.jpg

ACLF & Practical Management



Admissions: Liver Critical Care Kings College Hospital 2016/17

n=1569

Hepatobiliary Surgery

Acute liver failure

Chronic liver disease

Transplants

Previous Transplants

Non Liver Patients


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Admissions Deaths

© ICNARC 2015

ACLF & Practical Management Intensive Care National Audit and Research Centre (ICNARC)

Extrapolated numbers of cirrhosis ICU admissions and ICU deaths

per 100,000 population (England, Wales & NI)

McPhail et al Manuscript Submitted 2017



Source: NHS Atlas of Variation in healthcare for people with liver disease 2017 (In press)

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Mortality from chronic liver disease, all ages, England, 1995-2014

Directly standardised mortality rate

Number of deaths (persons)


Acute on Chronic Liver Failure (ACLF):

Practical management outside the tertiary centre.

Overview:

• ACLF in the natural history of Chronic Liver Disease.

– Definitions

– Controversies

• ACLF: practical Issues in clinical care.

– Getting access to ICU: avoiding futility.

– Ward Interventions: preventing ACLF.

• ACLF: how can your Liver Unit help?

– Transfer

– Transplantation.


Compensated Cirrhosis No ascites or overt HE

Decompensated Cirrhosis Ascites, HE, Variceal bleeding

~ 5-10% patients / year

Recompensation

of hepatic function

Natural History Chronic Liver Disease.



D’Amico et al J Hepatology 2006;44:217-231


Natural History Chronic Liver Disease

Complication 1Year Mortality

Variceal Bleeding 20%

Ascites 29%

Ascites and Variceal Bleeding 49%

Hepatic Encephalopathy 64%

Jepsen et al Hepatology 2010;51:1675-82. n=466


Compensated Cirrhosis No ascites or overt HE

Decompensated Cirrhosis Ascites, HE, Variceal bleeding

Acute on Chronic Liver Failure (ACLF) Hepatic and Extra-hepatic organ failure

Death

~ 5-10% patients / year

~ 30% hospitalised patients

? Up to 50% hospitalised patients

Recompensation

of hepatic function

Resolution

of organ failures




Acute on Chronic Liver Failure (ACLF)

“Acute on chronic liver failure is a syndrome in patients

with chronic liver disease with or without cirrhosis which

is characterized by acute hepatic decompensation

resulting in liver failure (jaundice and prolongation of the

INR) and one or more extra-hepatic organ failures that is

associated with increased mortality within a period of 28

days from onset..’

World Congress of Gastroenterology

Gastroenterology 2014 ;147(1);4-10



• Who are we discussing?

– Cirrhotic

– Precipitating event • Bleeding / Sepsis / Drug effect

– Hepatic failure • Jaundiced, coagulopathic

– Extra-hepatic organ failure • Encephalopathy

• Hypotension

• Renal dysfunction



CANONIC:

Chronic liver failure Acute On-chronic liver failure In Cirrhosis

29 Liver Units, 8 European Countries

1343 Hospitalised patients with cirrhosis

Develop a definition and scoring system for ACLF.

Moreau et al Gastroenterology 2013 144: 1426-13



http://www.efclif.com/scientific-activity/score-calculators/clif-c-aclf



Organ System Criteria

Hepatic Bilirubin ≥ 200 mMol / L

Cerebral Encephalopathy ≥ Grade 3

Renal Creatinine ≥ 180 mMol/L and / or use of renal replacement therapy

Coagulation INR >2.5 and / or platelet count ≤ 20 x 109/L

Circulation Use of vasopressor agents and / or terlipressin

Respiratory Ratio of partial pressure of oxygen/ inspired oxygen ≤ 200 or

Ratio of Pulse oximetry saturation / inspired oxygen ≤214

Moreau et al Gastroenterology. 2013 Jun;144(7):1426-37.e9.

CLIF Organ Failures



ACLF Grades

ACLF-1

Renal or cerebral failure alone

or renal dysfunction with other organ failure.

ACLF-2

Two Organ Failures.

ACLF-3

Three or More Organ Failures.




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ACLF Grade and Mortality.



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ReactivationHBV

BacterialInfection

GI Bleed ActiveAlcohol

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More than 1

CANONIC Shi et al

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CLF

Cases

CANONIC n=303 Gastro. 2013 144: 1426-13

Shi et al n=405 Hepatology 2015 62:232-42

Reported Triggers to ACLF; Europe and China.



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ACLF: Systemic Inflammation & Severity of Illness

WB

C x

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9/l

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Leucocyte Count C-Reactive Protein

Inflammatory markers at enrolment in CANONIC Study. n=1343




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TNF-α Interleukin-6 Interleukin-8

pg/m

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Plasma Cytokine Concentrations according to Precipitating Event for ACLF

Claria et al Hepatology 2016 64(4) 1249-1264

n=237 Measurements at study enrolment

P<0.03 P<0.0001 P<0.0001



• ACLF: Definition – Precipitating event, hepatic and extra-hepatic OF.

– High short term mortality.

– Key to research and defining practice.

• ACLF: Controversies – Heterogeneous precipitants?

– Unified pathophysiology?

– No identifiable precipitants?

– Scores to instruct care?


ACLF & Practical Management. Critical Care: Inevitable Destination?


ACLF & Practical Management. Critical Care: Admission Impossible?



Escalation of care?

‘Both Advisors and clinicians identified patients in whom

escalation of care was not received despite it being

indicated..’

‘..Escalation of care should be actively pursued for patients

with Alcohol-related Liver disease who deteriorate acutely

and whose background functional status is good. There

should be close liaison between the medical and critical

care teams when making escalation decisions..’

NCEPOD 2013

Alcohol Related Liver Disease: Measuring the Units

www.ncepod.org.uk



Escalation of care?

Barriers to Critical Care: Aetiology.



Escalation of care?

Study Year n ICU Mortality

Cholongitas et al 2006 312 65%

Alim Pharm Ther 2006;23:883-893

Fang et al 2008 111 81%

Neph Dial Trans 2008;23(6):1961-9

Junea et al 2009 104 42% J Crit Care 2009;24(3):387-93

Thompson et al 2010 137 47% Aliment Pharmacol Ther 2010; 32: 233–243

Das et al 2010 138 41%

Crit Care Med 2010 38:2108-2116

Tu et al 2011 202 60% Shock 2011 36:445-450

Olemz et al 2012 201 42%

Ann Hepatol 2012 1;513-518

Levesque et al 2012 377 43% J Hep 2012 56:95-102

Frolich et al 2014 170 60% J Crit Care 2014 29;6: 1131

McPhail et al 2015 971 49% Clinical Gastro Hep 13(7) 1353-60

Barriers to Critical Care: Outcome



Escalation of care?

Barriers to Critical Care: Outcome Prognosis of cirrhotic patients admitted to intensive care unit: a meta-analysis.

Weil et al Annals of Intensive Care 2017 7:33

13 Studies 2532 patients 1995-2012

Mortality

ICU 43%

Hospital 54%

6-Month 75%



Escalation of care?

Liver ITU Kings College Hospital

ACLF admissions 2003-2007

• 534 Patients 226 (42%) ICU mortality

• 80% 2 or more organ failures

Average cost per Patient £28,409

Average cost per Survivor £23,206

Average cost per Non-survivor £37,329

Effective cost per Survivor £51,198

Shawcross et al J Hepatol 2012; 56(5):1054-62

Barriers to Care: Resource Use


High resistance to ICU admission

– Constrained resources.

– ‘Self inflicted’ aetiologies.

– High resource use and cost.

– ICU / Post-ITU Mortality high.

– Preconception of futility.


Escalation of care?



Escalation of care? Futile Critical Care? Mortality of cirrhotic patients admitted to LITU,

Kings College Hospital 2000-2010 n=971

p<0.001 Log-rank for comparison of Eras

McPhail et al Clin Gastro Hep 2015;13:1353–1360



Escalation of care?

Avoiding Futility: Admission and level of support?

– Standard ICU considerations

• Age

• Co morbidity

• Functional / nutritional state

• Severity of acute illness

– Liver-specific considerations

• Liver disease severity

• Indication for admission



Escalation of care?

Avoiding Futility: Age and Etiology?




Escalation of care?

Avoiding Futility: prognostic assessment ?

• Scoring Tools

– Child-Pugh Classification (CPC)

– Model for End-stage Liver Disease (MELD)

– Sequential Organ Failure Assessment (SOFA)

– Chronic Liver Failure Score (CLIF)



Escalation of care? Avoiding Futility: prognostic assessment ? Hospital Survival in ITU Admissions with Cirrhosis

KCH 2000-2010 n=933

Score AUROC (95% CI)

CLIF 0.813 (0.787-0.837)

SOFA 0.799 (0.772-0.823)

APA II 0.768 (0.724-0.806)

SAPS II 0.781 (0.753-0.806)

MELD 0.786 (0.758-0.811)




Escalation of care? Avoiding Futility: prognostic assessment ?

Time of Assessment AUROC

Score Admission 72 Hrs

MELD 0.79 0.78

SOFA 0.80 0.84

CLIF-SOFA 0.81 0.85




Withdrawal of Care? Avoiding Futility: prognostic assessment.

ACLF Scores to withdraw care?

Hernaez et al Gut 2017; 61:541-553


ACLF & Practical Management Avoiding Futility: Indications for Admission

Variceal Bleeding Encephalopathy Renal failure


P<0.001


ACLF & Practical Management.

Variceal Bleeding

Avoiding Futility: Indication for Admission?



Variceal Bleeding.





Variceal Bleeding

• Control the Airway

• Resuscitate

• Cultures and Antibiotics*

• Terlipressin*

• Endoscopic therapy*

– Band Ligation

• TIPS?

*Evidence Base Level A



Hepatic Encephalopathy

• Critical Care Environment

– Nursing levels

– Compliance with Rx

– Airway Protection

• Seek Precipitant

– Fluids

– Treat Infection

– Minimise Medication

– Treat Constipation

– Adjunctive agents?






Fichet et al J Crit Care 2009;24:364-370

• Outcomes in 71 patients with CLD and ICU

• 45 with isolated HE: Median GCS 8/15

• Median CPC 11

• 73% required intubation and ventilation

– Sole organ support

• ICU mortality 8.9%




Complication 1Year Mortality

Variceal Bleeding 20%

Ascites 29%

Ascites and Variceal Bleeding 49%

Hepatic Encephalopathy 64%

Jepsen et al Hepatology 2010;51:1675-82. n=466



Renal Failure.

Renal Failure: Futile care? Cholongitis et al Eur J Gastroenterol Hepatol 21:744–750

Royal Free Hospital London 1989-2004

ICU admissions with Cirrhosis (Mortality 62%)

RRT/ Creatinine >300 micMol/l / Urine <500ml/24 hrs (ARF)

ARF No ARF p

n 128 184

Mortality 91% 47% <0.0001

Odds Ratio 13.1 (95% CI 5.4-32)



Renal Failure.




Renal Failure.

Renal Failure and Chronic Liver Disease: Heterogeneity.

Martin-Llahi et al Gastro 2011:140:488-496

562 Patients with Cirrhosis and renal failure 2002-08

Serum Creatinine >1.5 mg/dl at 2 points within 48 hours

Cause % 3 Month Survival

Infection-related 46% 31%

Hypovolaemia 32% 46%

Hepato-renal 13% 15%

Parenchymal 9% 73%



Renal Failure.

Evolving Renal failure:

• Stop nephrotoxic therapies

• Volume expand

– Albumin (?)

• Antibiotics

• Vasopressors

– Terlipressin

• Decompress

– Paracentesis

• Critical Care review



Renal Failure.

Renal Failure Survival

Circulating Volume Expansion: Albumin? Thevenot et al Journal of Hepatology 2015(62);822-830

Multi-centre RCT. Hospitalised Cirrhotics with non-SBP sepsis (n=193)

Daily 20% Albumin + SMT vs. SMT



Renal Failure. Vasoconstrictors: Terlipressin

Systematic Review of Randomised Trials on Vasoconstrictor Drugs for

Hepato-renal syndrome

Gluud et al Hepatology 2010;51(2)


ACLF & Practical Management. Renal Failure: Early Intervention.

Responders Non-responders p

(n=12) (n=34)

Creatinine (μmol/l) 256 (±71) 369 (± 194) <0.001

Urine Vol. (ml/24hrs) 880 (± 440) 496 (± 420) 0.005

WBC 6.6 (± 3.5) 10.9 (± 8.1) 0.001

Martin-Llahi M et al Gastroenterology 2008:134

EARLY Intervention

Response to Terlipressin: Predictors


ACLF & Practical Management. Prevention: Early Ward Intervention

Cirrhosis and Outcome of Septic Shock

Arabi et al Hepatology 2012 ;56:2305-15

• n=638 Cirrhosis and Septic Shock

• ICU Mortality 62%

Adjusted OR p

Inappropriate Antimicrobials 9.5 (4.3-21) <0.001

Single vs. Combination Rx 1.8 (1.0-3.3) <0.05

Delay to Administration 1.1 (1.1-1.2) <0.001


ACLF & Practical Management. Prevention: Early Ward Intervention

Adjusted OR ; APACHE II, MELD, Immune compromise, Culture +ve

Cirrhosis and Outcome of Septic Shock: Antibiotic Delay

Arabi et al Hepatology 2012 ;56:2305-15


ACLF & Practical Management. Prevention: Early Ward Interventions.

• Timely and effective bedside review:

– Recognition of illness severity.

– Recognition of risk of deterioration.

• Escalation & Critical Care review.

• Antibiotic Therapy

– Prompt, appropriate.

• Intravenous Fluids

• Prescription Chart Review


ACLF & Practical Management. Critical Care Admission & Level of therapy ?

• Standard ICU criteria

– Age

– Nutritional state & Physiologic reserve

– Co-morbidity

– Severity of acute illness

• Severity of underlying liver disease

– How severity is measured may not be important

– Response to therapy key

• Indication for admission

– Variceal bleeding

– Isolated HE


ACLF & Practical Management. Critical Care Admission & Level of therapy ?

• Difficult decisions

– Is there a right answer ?

• Resource considerations

– Give the patient the benefit of the doubt ?

• Consider short and medium term prognosis.

• If in doubt, admit and treat

• Aggressive short term therapy

• Review after 48-72 hours

• Set ceilings for therapy

• Consider withdrawal if no response.



How can your Liver Unit Help?

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120%

Oct-16 Nov-16 Dec-16 Jan-17 Feb-17 Mar-17 Apr-17 May-17

Bed Occupancy: Liver Intensive Therapy Unit,

Kings College Hospital

October 2016-May 2017

Bed O

ccupancy



How can your Liver Unit help?

• Always happy to discuss (!)

– Getting early interventions right.

– ICU Admission / Escalation / withdrawal decisions.

• Consideration for Transfer

– Age

– Complexity

– Specialist Radiology / Endoscopy

– Transplant wait-listed patients

– Expedited Transplantation?



Schmidt et al Gastroenterology 2015;148:967–977

Futile Hospital Care ? Cirrhosis: Hospital Mortality in USA 2002-2010



How can your Liver Unit help?

Expedited Transplantation?




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Outpatient Inpatient; No Organ Failure Inpatient: Organ Failure

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Inferior Outcomes 90-Day Patient Survival for First Elective Liver Transplant for Cirrhosis

By Pre-LT status. United Kingdom 1994-2016 n=7479 p<0.0001

Bernal et al Clinical Liver Disease 2017 In Press.




Resource use and cost?

Markley Earl et al

Transplantation 2008;86:234-244

Cost analysis: Single Centre: 163 first transplants for CLD

Pre-transplant ICU stay Median Cost / LT (IQR)

No n=149 (91%) $81,134 (73,800-97,113)

Yes n=14 (9%) $149,890 (132,380-262,964)

p<0.0001




Practicalities? Finklestedt et al Liver Transplantation 2013 19:879-886

2002-1010 n=144

Fulfilling ACLF Criteria (n=144) Not Evaluated (n=50)

Evaluated for LT (n=94) Not Listed (n=23)

Listed for LT (n=71) Died on Waitlist (n=36)

Underwent LT (n=33)

Survived (n=28)

Died (n=5)

100%

23%

49%

67%

19%

Waitlist Mortality 54%




• An option only in a small minority

– Contraindications

– Waitlist deterioration

• Outcomes probably worse

• Highly selective use

– Previously assessed

– Young

– Seldom from ICU

– Minimal organ support


Acute on Chronic Liver Failure: Practical management ...

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