Care of the Liver Failure Patient

Critical Care Canada Forum 2016

Constantine J. Karvellas MD SM FRCPC

Associate Professor of Medicine

Divisions of Critical Care Medicine and Gastroenterology

Adjunct Professor, School of Public Health Sciences

University of Alberta

Liver Injury: Not all the same

Cirrhosis/Acute on Chronic Liver Failure

• Scaring/fibrosis

• Portal hypertension

• ACLF– Cirrhosis with acute deterioration in liver

function over 2-4 weeks• Hepatic encephalopathy (HE)• Hepatorenal syndrome (HRS)• Variceal bleeding

Acute Liver Injury/Failure

• Hepatocyte necrosis

• Pro-inflammatory cascade

• NO portal hypertension• No prior liver disease• Encephalopathy and jaundice• Complications

– Cerebral edema, lactic acidosis, MSOF

Acute (fulminant) Liver Failure

Definition ( O’Grady 1993 )

“Hepatic encephalopathy occurs within 24 weeks of

the onset of jaundice in an otherwise healthy individual

…”

Hyperacute liver failure < 7 days

Acute liver failure 7 - 28 days

Subacute liver failure > 4 weeks

ALF: Different phenotypes

Etiologies of ALF: US ALFSG (1998-2008)

William Lee et al, US ALFSG, 2009

NAC therapy: Non-acetaminophen ALF

• US ALFSG (2009)Grade 1 or 2

EncephalopathyAll grades of Hepatic

EncephalopathyOverall P-value

Placebo (n=56)

NAC (n=58) Placebo (n=92)

NAC(n=81)

Survival at 21 days (%) 75 79 66 70 0.28

Survival at 1 year (%) 61 72 57 63 0.19

Transplant-free survival at 1 year (%)

18 45 18 35 0.008

Proportion of patients transplanted at 1 year (%)

52 28 48 32 0.035

All ALF patients should probably receive NAC

Cerebral Edema and ALF

• 25% of deaths in ALF

• Astrocyte swelling

– Glutamine (amidation of glutamate)

• Cerebral vasodilatation

– Loss of autoregulation

• More common in the hyperacute liver failure

– Overwhelming accumulation of glutamine

– Expulsion of organic osmolytes from astrocytes

‘Protect the brain’• Head of bed at 30 degrees

• Minimize suctioning/cough

– Lidocaine, short-term paralytics for bronchoscopy

• Sedate agitated patients (propofol)

• Actively treat fever > 36.5

– Allow moderate passive hypothermia (34-35 C)*

• Maintain serum sodium at 145-150 mmol/L

• ICP monitoring in selected patients*

• Avoid fluid overload (low/normal CVP)

• Ammonia lowering modalities (CRRT/diffusion)

• Ammonia > 150 umol/L

• Hyperacute liver failure

– Acetaminophen

• Need for vasopressors

• Need for RRT

• Grade III/IV encephalopathy

• Presence of SIRS

• 629 patients with ALF, Grade III/IV Hepatic coma Observational study (03/2004-08/2011)

• ICP monitoring used in 143 patients (28% of cohort)

– 51% of pts had ICP > 25 mm Hg (ICH)

– ICPM strongly associated with listing for LTx (p< 0.001)

– ICPM patients received more ICP related therapies

– No mortality difference (33% ICP, 38% controls, p=ns)

• adjusted APAP (n=321) 0.95(0.44-2.03) p=0.89

• Adjusted non-APAP(n=308) 3.04 (1.26–7.34) 0.014

– Intracranial hemorrhage noted in 7% of patients

• 4/56 who reported complications (3 died)

Indications for ICP Monitoring (UAH)

• Grade 3 or 4 Hepatic encephalopathy

• Meet King’s College Criteria

• On CRRT

• Ammonia > 150

• Hyperacute liver failure (acetaminophen)

• Age < 50

• Retrospective cohort study of ALFSG

– 01/1998 and 09/2013

• N = 1135 patients (Grade III or IV HE)

– high risk of cerebral edema

• TH using an external cooling device

– 97 (8%) ALF patients treated with TH

cases

– 1135 (92%) controls

N=17

N=23

No difference in rates of transplant, adverse events or death (0.65 for all)

• Retrospective cohort study: 1551 ALF patients:

– Most common etiology: APAP (n=719 ~ 46%)

– N=600 (39%) received antimicrobial prophylaxis

– N=951 (61%) did not (controls)

– 226 (15%) developed bloodstream infection (BSI)

• Aims

– Effect of prophylaxis on 21-day mortality

– Effect of prophylaxis of development of subsequent BSI

– Independent predictors of 21-day mortality

Outcomes (unadjusted)

• Antimicrobial prophylaxis did not impact:

– Development of BSI (13% vs. 16%, p=0.12)

– 21-day survival (70% vs. 70%, p=0.88)

But… more patients listed/received LT were on prophylaxis (p <0.01)

Adjusted impact of BSI on 21-day Mortality (multivariable)

– Overall BSI associated with detrimental impact (p=0.004)

– Interaction effect of etiology

• Non-APAP: OR 2.034 (1.257-3.292)

• APAP: OR 1.136 (0.672-1.922)

Extracorporeal support in ALF

• AKI occurs in 50% of patients with ALF

– Pre-renal component,

– renal vascular auto-regulation disturbance

– Nephrotoxicity (acetaminophen, amanita)

• Renal replacement therapy

– oliguria, volume overload, lactic acidosis vs. azotemia

– CRRT preferred modality

• Minimize solute shifts, hemodynamic changes, ICP

Overall, a 22% reduction in median arterial ammonia concentration was observed over 24 h of HF from 156 (137–176) to 122 (85–133) umol/L, (P ≤ 0.0001).

Liver International, 2013

Total 102 patients (ITT)

• Main etiology Acetaminophen (38%)– SMT = 19, MARS=20

• 68/102 patients transplanted – 41% of acetaminophen group

• Median delay listing to transplant was 16.2 hrs.– Short delay from listing to LTx precludes conclusive

Saliba Ann Int Med Oct 2013

ExtracorporealLiver Support: MARS

P=0.28 (Log Rank)

Fig. 1. Intention-to-treat analysis survival data in the standard medical treated group (SMT) compared to the

high-volume plasma exchange (HVP) treated group (LogRank: p=0,0058).

Criteria in ALF for LTx (King’s College)

Acetaminophen

• pH 7.3 at 24 hrs – Adequate volume resuscitation

or

• Creatinine > 300 umol/L

• INR > 6.5

• Grade 3 or4 encephalopathy

Non-acetaminophen

• INR > 6.5

or

• INR > 3.5

• Bilirubin > 300 umol/L

• duration of jaundice before encephalopathy > 7 days

• age < 10 or > 40

• Unfavorable cause

O’Grady et al., Gastroenterology 1989.

ALFSG Index (n=1974)

• HE grade III/IV

• Favorable etiology

– APAP, Pregnancy, HAV, ischemia

• Vasopressors

• Bilirubin

• INR

(1998-2013)

ALFSG 0.843KCC (APAP) 0.56

KCC (non-APAP) 0. 65

Improve prognostications: Biomarkers?

P < 0.0001

P < 0.0001

Comparison of model performance of KCC, ALFSG Index

and FABP1 (Delong Method)Models EARLY (Day 1) LATE (Day 3-5)

Variable n AUROC (95% CI) N AUROC (95% CI)

KCC 174 0.552 (0.502,0.602) 110 0.604 (0.555,0.654)

KCC+FABP1 174 0.711 (0.635,0.787)1 110 0.797 (0.712,0.882)3,4

KCC+FABP1>350 ng/ml 174 0.651 (0.577,0.726)7 110 0.794 (0.719,0.869)9,10

ALFSG Index 192 0.686 (0.624,0.747) 124 0.711 (0.635,0.788)

ALFSG Index + FABP1 192 0.766 (0.699,0.833)2 124 0.815 (0.736,0.894)5,6

ALFSG + FABP1>350 ng/ml 192 0.720 (0.652,0.789)8 124 0.818 (0.746,0.890)11,12

FABP1 198 0.710 (0.639,0.782)* 186 0.820 (0.760,0.881)*

FABP1>350 ng/ml 198 0.626 (0.559,0.694)* 186 0.776 (0.715,0.836)*

1-12All Models (Delong method; Early and Late): p < 0.005 for all comparisons

*AUROC includes patients with FABP1 measurements including patients with missing KCC, ALFSG data

Liver transplant and ALF

Considerations of Liver Transplantation

• Medical need for transplant

– King’s College Criteria**

– Corroborating info:

• Clichy, lactate, phosphate (recovery)

• Are there any medical contra-indications for transplant

– Cerebral edema?

• Psychosocial contra-indications for liver transplant

– Expedited assessment (usually < 24 hours)

– Corroborating information from referring centre

ALF: When to Transfer to LTx Centre

• Any grade of hepatic encephalopathy

– Confusion, asterixis, GCS < 14

• INR > 2.0

• Deteriorating course

– Optimize stability for transport

• No obvious contra-indications to liver transplant

– Expedited liver transplant assessment

– 25% of ALF patients go on to LTx

• Young population

• Complicated psychosocial history

Conclusions

• The timely recognition of ALF is most important

– patient with liver dysfunction and altered mental state

• Management decisions critically influencing outcome

– Early and accurate diagnosis

– Transfer to a liver transplant centre

• Management of ALF

– Few randomized trials

– Basic neurocritical care and ICU supportive care

• Need for improved prognostic methods/biomarkers

Acknowledgements

William M Lee MD

Jaime Speiser MS

Holly Battenhouse MS

Christopher Rose PhD

UT Southwestern Medical CenterUniversity of Washington University of California-San FranciscoNorthwestern UniversityUniversity of California-Los AngelesUniversity of MichiganYale UniversityUniversity of Alabama Birmingham Massachusetts General HospitalMedical University of South CarolinaUniversity of PennsylvaniaVirginia Commonwealth UniversityUniversity of AlbertaEmory UniversityUniversity of KansasThe Ohio State University

US Acute Liver Failure Study GroupCollaborators

Funding

NIH: NIDDK U01-DK-58369

Transplant Fund Value Added

(University of Alberta)

University of Alberta Hospital Foundation