Acute Liver Failure Acute Liver Failure “…the quick and the “…the quick and the dead.” dead.” The Apostles Creed The Apostles Creed 17 Feb 2009 17 Feb 2009 Paul H. Hayashi, MD Paul H. Hayashi, MD Medical Director, Liver Transplantation Medical Director, Liver Transplantation University of North Carolina Liver Program University of North Carolina Liver Program
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Acute Liver FailureAcute Liver Failure“…the quick and the dead.”“…the quick and the dead.”
The Apostles CreedThe Apostles Creed
17 Feb 200917 Feb 2009
Paul H. Hayashi, MDPaul H. Hayashi, MDMedical Director, Liver TransplantationMedical Director, Liver Transplantation
University of North Carolina Liver ProgramUniversity of North Carolina Liver Program
Reference/ReviewReference/Review
• Polson J, Lee WM. AASLD Position Paper: The Management of Acute Liver Failure. Hepatology 41:1179-97; 2005
Incidence and DemographicsIncidence and Demographics
• 2000 cases/year– 200-300 transplants
• Duration of symptoms– Median 6 days (0-74)
• Jaundice to encephalopathy– Median 2 days (0-61)
• Dispostion:– 93% in 3 weeks.
Women 73%
Median age (yr)
38 (15-78)
White
Hispanic
AA
Other
74%
10%
9%
7%
Acute Liver Failure Group: Ostapowicz et al, Ann Int Med 2002Acute Liver Failure Group: Ostapowicz et al, Ann Int Med 2002
Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)
Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)
Drug IschemiaHep A Budd-Chiari Other
Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)
Unintentional
Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)
Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)
Drug IschemiaHep A Budd-Chiari Other
Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)
Drug induced liver injury and ALFDrug induced liver injury and ALF
ALF Etiology by DILI versus Non-DILI(DILI = Drug induced liver injury including
acetominophen)
0
50
100
150
200
250
300
350
400
450
Drug Other
Adapted from Ostapowicz et al, Ann Int Adapted from Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)
8 Center NIH Study8 Center NIH Study
• Children ≥ 2 years and adults
• Pre-defined biochemical criteria
- AST or ALT > 5 ULN twice consecutively
- Alk Phos > 2 ULN twice consecutively
- Bilirubin ≥ 2.5 mg/dl
Chalasani N, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006Chalasani N, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006
Percent ALFPercent ALF
Death
(within 6 months)
12.7%
Liver Transplant
(event related up to 6 months)
2%
Oral Presenation, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006Oral Presenation, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006
Complications of ALFComplications of ALF
• Multi-organ failure
• Encephalopathy – cerebral edema– CNS ammonia
• Infection
• Coagulapathy
• Hypoglycemia
Grades of EncephalopathyGrades of Encephalopathy
Grade 0 No change in mental status
Grade I Awake/responsive; mild confusion & disorientation; altered personality
Grade II Awake/agitated; more confused & disoriented; Hallucinations
Grade III Stuporous but arousable; more somnelent; ?ability to protect airway
Grade IV Unresponsive; comatose.
Recognition & TransferRecognition & Transfer
• INR is key: >/=1.5 must be admitted– ICU or step-down if mental status changes
• Call and transfer early.– ALF is rare so often takes us by surprise– Grade I-II encephalopathy--transfer– Grade III encephalopathy--intubate
• Consider distance
• Consider local expertise
N-Acetylcysteine N-Acetylcysteine in in NonNon-acetominphen ALF-acetominphen ALF
• Multi-center, placebo controlled.– Outcomes: overall and transplant free survival
• 81 NAC vs. 92 placebo– No difference in primary outcomes
Cadaveric TransplantationCadaveric TransplantationOstapowicz et al, Ann Int Med 2002 Ostapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)
308 ALF patients
136 Listed for Transplant
30 Died on list
17Removed
172 Not listed
47 died89
Transplanted
14Died
75Lived
10Lived
7Died
63% survival on intention-to-transplant analysis
Transplantation for Substance Transplantation for Substance and Drug Reactions/Toxicityand Drug Reactions/Toxicity
(Non-Acetominophen)(Non-Acetominophen)
24
13
10
10977
66
4
41
Isoniazid
PTU
Phenytoin
Valproate
Amanita
Nitrofuratoin
Herbal
Ketoconazole
Disulfiram
Troglitazone
Misc 1-3 cases
42%
(3 cases of statins)
Russo RW, et al. Liver Transpl 2004
Ammonia and Cerebral Edema:Ammonia and Cerebral Edema:Pros & Cons of lactulosePros & Cons of lactulose
(6) (10) (6) (10)
Strauss et al, Gastro 2001
Cons
1. Abdominal distention
2. No proven efficacy
Pros
1. Relatively benign
2. NH4 implicated linked to mortality
Rationale for N-acetylcysteine in Rationale for N-acetylcysteine in non-paracetamol induced ALF non-paracetamol induced ALF
• Anti-oxidant properties– Animal studies with ARDS– Human trials equivocal
• Cardiovascular effects– Animal studies in sepsis and liver failure– Human studies equivocal
• Immune modulation– Reduced inflammatory cytokines in sepsis
Increased BMI and ALFIncreased BMI and ALF
• High BMI not a risk factor for ALF
• High BMI increases risk of death or transplant in ALF– BMI >30: OR = 1.63 (1.04-2.55)– BMI >35: OR = 1.93 (1.02-3.62)
• Rutherford A, et al. Clin Gastro Hep 2006
Other interventions Other interventions for cerebral edemafor cerebral edema
• Hypertonic saline– Serum Na 145-155 may help lower ICP
• Barbiturates– Helps, but hypotension problematic
• Hypothermia (32-34 C)– Animal studies show benefit– Human studies limited but encouraging
Etiology of ALF in the USA:Adult Registry (n = 489)
ICP MonitoringICP Monitoring
• ICP Goals:– ICP <20 mm Hg
• >20 mm Hg x >5 min requires intervention (e.g. mannitol)
• >40 mm Hg x >2 hrs may contraindicate transplant
– MAP – ICP >50 mm Hg• <50 mm Hg x >2 hrs may contraindicate transplant
Complications of ICP monitoringComplications of ICP monitoringBlei et al. Lancet 1993Blei et al. Lancet 1993
• US Survey• 75% response• 60% of responders
used ICP’s• 262 ICP’s reported
• Epidural type (n=160)– 3.8% complication
• Subdural (n=79)– 20% complication
• Parenchymal (n=23)– 22% complication
• Bleeding : Infection– 7 : 1
rFVIIa and INR change in ALFrFVIIa and INR change in ALFShami et al. Liver Transpl 2003Shami et al. Liver Transpl 2003
rFVIIa and ALFrFVIIa and ALF Shami et al. Liver Transpl 2003Shami et al. Liver Transpl 2003
Plasma alone (n=8)
VIIa (n=7)
p value
PT correction
0/8 (0) 7/7 (100) 0.0002
Ability to place ICP
3/8 (0) 7/7 (100) 0.03
Mean FFP 19 13 0.35
Anasarca 7/8 (88) 2/7 (29) 0.04
ICP Monitoring and VIIa ICP Monitoring and VIIa Cons Cons ProsPros
• Cost!!– 8000 ug = $11,200– 12 units FFP=$1500
• No evidence that aVII decreases ICP complications.
• No evidence that ICP monitor improves outcomes.
• Small volume• ICP monitoring makes
sense.• ICP does dictate
change in care.
Bad Prognostic SignsBad Prognostic Signs
• APACHE score >15 on admission
• Etiology– Indeterminate, drug, Autoimmune, HBV,
Wilson’s, Budd-Chiari, Mushroom poisoning
• Coma grade III or IV on admission
MARS in Hyperacute Liver Failure:MARS in Hyperacute Liver Failure:Change in SVR Change in SVR (Schmidt et al. Liver Transpl 2003)(Schmidt et al. Liver Transpl 2003)
-100
0
100
200
300
400
500
600
700
0 1 2 3 4 5 6
MARS
Hypothermia
Hours on MARS
p=0.006
Molecular Adsorbents Recirculating System (MARS) Heemann et al. Hepatology 2002
N = 12
N = 12
Liver Support Systems:Meta-analysis Liver Support Systems:Meta-analysis (Kjaergard et al., JAMA 2002)(Kjaergard et al., JAMA 2002)
System Mortaility Rx Mortality Control RR Whole blood exchange
• Lack of cell source• Invasive delivery• Need for
immunosuppression• Likely need for large
hepatocyte mass
• hTERT immortalized human hepatocytes
• Xenotransplanted hepatocytes
• Bone marrow, embryonic stem cell, placental derived cells.
– Strom et al (ed.), Gastro 2003
Problems Promises
Hyperventilation in Head TraumaHyperventilation in Head Trauma
• Hyperventilation: the controversy– lower ICP vs. increase cerebral ischemia risk.
• Guidelines in Severe Head Trauma – Moderate hyperventilation (pCO2 30-35) =
first line measure if ICP elevated.– Heavy hyperventilation (pCO2 25-30)
considered second line.– Procaccio F et al, J Neurosurg Sci 2000
Effect of VIIa on prostatectomy Effect of VIIa on prostatectomy perioperative blood lossperioperative blood loss
Placebo (n=12)
20ug/kg (n=8)
40ug/kg (n=16)
pRBC 1.5 (0-4) 0.6 (0-3) 0.047 0 (0) 0.0003
% pts transfused
7(58%) 3(38%) 0.651 0 (0) 0.001
Perioperative blood loss (L) median & range
2.69
(1.71-3.57)
1.24 (1.02-1.41)
0.001 1.09 (0.93-1.32)
0.001
Friederich et al, Lancet 2003
Factor VIIa in Liver TranplantationFactor VIIa in Liver Tranplantation(de Wolf et al, Transfusion 39:87s, 1999)(de Wolf et al, Transfusion 39:87s, 1999)
• 5 patients given 80ug/kg VIIa at time of transplant
• pRBC given in first 24 hrs compared to 104 historical controls.
• Median pRBC given: 3 (range 0-5)– “…far below the lower limit of the 95%
confidence intervals for the mean in the control group.”
– One patient had hepatic artery thrombosis.
Liver Support SystemsLiver Support Systems
• Artificial– Whole blood exchange– Charcoal
hemoperfusion– BioLogic DT– Hemoperfusion– MARS (Molecular
Glutamine and Cerebral Edema:Glutamine and Cerebral Edema:Argument for hyperventilationArgument for hyperventilation
Strauss et al, Gastro 2001
Hyperventilation
Normoventilation
MARS in Hyperacute Liver Failure:MARS in Hyperacute Liver Failure:Change in MAP Change in MAP (Schmidt et al. Liver Transpl 2003)(Schmidt et al. Liver Transpl 2003)
-2
0
2
4
6
8
10
12
14
16
0 1 2 3 4 5 6
MARS
Hypothermia
Hours on MARS
p<0.0001
(Mean Cr: 2.9 to 1.7)
(Mean Cr: 3.82 to 4.05)
DILIN Centers and DILIN Centers and SatellitesSatellites
>12.8 million>12.8 million liveslives>12.8 million>12.8 million liveslives