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Reference/Review. Polson J, Lee WM. AASLD Position Paper: The Management of Acute Liver Failure. Hepatology 41:1179-97; 2005www.UpToDate.com Search
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1. Acute Liver Failure
the quick and the dead.The Apostles Creed 17 Feb 2009
Paul H. Hayashi, MD
Medical Director, Liver Transplantation
University of North Carolina Liver Program
3. ALF ManagementLearning objectives Be able to make the diagnosis of ALF
Etiology and severity assessment
Acetominophen & drugs (DILI) most common
Understand when and how to transfer the ALF patient
Initial support
Role of transplant
5. Patient KC Day 1 (Dec 21, 2008; UNC)
Oriented x 3, deep jaundice
ALT 2418; AST 2918; AP 307; bilirubin 24.1; INR 9.8
N-acetylcysteine IV continued.
Viral serologies negative
ANA (+), ASMA (-)
6. Patient KC Day 1-2: Diagnostic work-up
HBV, HAV serologies, HCV RNA negative
ANA 1:640, ASMA negative; IgG 1618 (600-1700)
ceruloplasmin 19 (15-52).
Acetaminophen level below <10 ug/ml
Patent hepatic veins on MRI.
7. Patient KC Day 2-3:
INR >14.4
Bilirubin 23.5
Progressively confused
Listed Status 1 for liver transplant on Day 2 (22 Dec 08).
Entubated for airway protection
8. Patient MP Day 4:
0730:T 38.6
Cultured and broad spectrum antibiotics ordered.
~09:00: liver offer in Memphis, TN
UNC surgical team dispatched.
13:00: progressive hypotension, sepsis picture.
15:00: Surgical team recalled. Liver diverted.
9. Patient KC Day 5 (25 Dec 2008):
Progressive hypotension despite 2-3 pressors and antibiotics.
FIO2 requirement climbing.
Patient made DNR
Dies 06:15.
10. Hyperacutes more likely to be due to acetominophen
Subacutes more likely to get transplanted and transplant free survival lowest compared to to other two.Hyperacutes more likely to be due to acetominophen
Subacutes more likely to get transplanted and transplant free survival lowest compared to to other two.
11. Incidence 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.
14. Drug induced liver injury and ALF
15. 8 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
16. Percent ALF
17. Complications of ALF Multi-organ failure
Encephalopathy
cerebral edema
CNS ammonia
Infection
Coagulapathy
Hypoglycemia
18. Grades of Encephalopathy
19. Recognition & 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
20. N-Acetylcysteine in Non-acetominphen ALF Multi-center, placebo controlled.
Outcomes: overall and transplant free survival
81 NAC vs. 92 placebo
No difference in primary outcomes
Secondary analysis
Transplant free survival odds = 11.3 (p<0.01) for Grade 1-2 coma at randomization.
Lee WM, et al. Hepatology 46:268A (2007) abs.
21. Look for etiology Treatable
Acetominophen NAC
Amanita phalloides PCN; silymarin
Acute fatty liver of pregnancy delivery
Herpes Acyclovir
Autoimmune Steroids
Budd-Chiarri Heparin/TIPS
Transplant only hope
Wilsons
Transplant contraindicated
infiltrating cancer (breast, melanoma, lymphoma)
23. Severity AssessmentOstapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)
24. Severity AssessmentKings College Criteria, N=585 Acetominophen
pH < 7.3 after resuscitation
OR
All of the following
INR>7
Cr >3.4mg/dL
Grade III or IV encephalopathy All other causes
INR > 7
OR
3 of the following:
INR >3.5
Age <10 or >40
Jaundice to enceph >7 days
Bilirubin > 17.5 mg/dL
Indeterminate ALF
Drug reaction
25. Support: General Management Central venous access, arterial line
?Pulmonary artery catheterization
Avoid fluid overload
Glucose monitoring (FS q 2-4 hours)
CVVHD as necessary
Enteral feeding (avoid TPN)
26. General Management Intubate for Grade III or IV encephalopathy
Elevate head of bed
Sedate PRN (propofol preferred)
Limit rolling
Limit suctioning; use endotracheal lidocaine
Frequent neurologic checks (q 1-2 hrs)
27. Hyperventilation Apply acutely for rise in ICP and/or deterioration of neurologic exam.
Prophylactic use not recommended.
28. Blood pressure support Use colloid (albumin, pRBCs if indicated)
Aim = MAP 50-60 mm Hg
Epinephrine, Norepinephrine, Dopamine preferred
Vasopressin generally avoided
Terlipressin found to elevate ICP*
29. Medications H2 blocker, ppi, or carafate
Antibioticsno data for prophylaxis.
Dont correct INR unless overt bleed.
Mannitol (acute use)
Lactulose?
N-acetylcysteine use for non-Tylenol cases
30. Severity Assessment and Transplantation
31. Cadaveric Liver TransplantationSurvival
32. Cadaveric TransplantationOstapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)
33. Cadaveric TransplantationOstapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)
34. Live Donor Liver Transplantation Reported cases of good outcome.
ALF patients are often young previously healthy.
Heroism ethic valued.
Minimal time to evaluate patient, donors and family
Pressure for accurate donor evaluation is high.
Outcomes for UNOS status 2a patients is poor.
35. LDLT for ALF: a rare occurence 11079 potential LDLT cases
11 (1%) cases ALF
Mean time for donor evaluation = 2 days
Outcome
8 received LDLT and 7 alive at 5 year.
2 received DDLT
1 improved w/o transplant
37. Liver Support Systems:Meta-analysis (Kjaergard et al., JAMA 2002)
38. ALF Goals of Treatment
39. ALF ManagementLearning objectives Be able to make the diagnosis of ALF
Etiology and severity assessment
Acetominophen & drugs (DILI) most common
Understand when and how to transfer the ALF patient
Initial support
Role of transplant
42. Acetominophen DebateKaplowitz, N Hepatol 2004 Acetominophen Bad:
More stern warnings
Should be removed from combinations.
Blister packs.
Limit amount sold at one time.
Lee W. Hepatol 2004 Acetominophen okay:
Present insert enough
Unintentional cases are not so.
Benefit of blister packs and limiting amounts short lived.
Rumack B. Hepatol 2004
43. Cadaveric TransplantationOstapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)
44. Transplantation for Substance and Drug Reactions/Toxicity(Non-Acetominophen)
45. Ammonia and Cerebral Edema:Pros & Cons of lactulose
46. Rationale for N-acetylcysteine in 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
47. Increased 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
48. Other interventions for 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
50. ICP 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
51. Complications of ICP monitoringBlei et al. Lancet 1993 US Survey
75% response
60% of responders used ICPs
262 ICPs reported Epidural type (n=160)
3.8% complication
Subdural (n=79)
20% complication
Parenchymal (n=23)
22% complication
Bleeding : Infection
7 : 1
52. rFVIIa and INR change in ALFShami et al. Liver Transpl 2003
53. rFVIIa and ALF Shami et al. Liver Transpl 2003
54. ICP Monitoring and VIIa Cons Pros 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.
55. Bad Prognostic Signs APACHE score >15 on admission
Etiology
Indeterminate, drug, Autoimmune, HBV, Wilsons, Budd-Chiari, Mushroom poisoning
Coma grade III or IV on admission
56. MARS in Hyperacute Liver Failure:Change in SVR (Schmidt et al. Liver Transpl 2003)
58. Liver Support Systems:Meta-analysis (Kjaergard et al., JAMA 2002)
59. VIIa and Clotting Cascade
60. Effect of rF-VIIa on prostatectomy perioperative blood loss
61. Artificial & Bioartificial Support Systems in ALF: Meta-analysis
63. Hyperventilation Head Trauma:
Increased vasculature sensitivity to low PCO2 from days 2 to 5 post-injury.
Correlated with decreases in brain tissue oxygen pressure.
Carmona et al, Crit Care Med 2000.
Cerebral blood flow does fall with hyperventilation in ALF
43 ml/100g/min to 32 ml/100g/min (p<0.01)
Strauss et al, Liver Transpl 2001
64. Bioartificial Liver Support in ALFMulticenter Randomized Controlled Trial N = 147 (73 BAL; 74 Controls)
Overall 30 day survivals
BAL: 44/79
Controls: 53/73
Cox proportional Hazard analysis to account for transplantation intervention
RR for BAL patients: 0.56, p = 0.05
65. Rationale for N-acetylcysteine in non-paracetamol induced ALF ? O2 delivery & consumption <1hr IV NAC
12 acetoophen and 8 non-acetophen
Harrison et.al. NEJM 1991
15 pts with liver dysfunction of misc. causes
Devlin et al, Crit Care Med 1997
No improvement seen at 5 hours infusion
Randomized, placebo controlled (11 vs 7 pts)
Most pts acetophen related.
Walsh et al, Hepatology 1998 Keays et al, IV acetyl cysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 303:1026 (1991).
Harrison et al, Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. NEJM 324:1852 (1991)
Devlin et al, N-acetylcysteine improves indocyanine green extraction and oxygen transport during hepatic dysfunction. Crit Care Med 25:236 (1997)
Walsh et al, The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant heptaic failure. Hepatology 27:1332 (1998)
Walsh et al, N-acetylcysteine administration in the critically ill (ed) Int Care Med 25:432 (1999)
Ben-Ari et al, N-acetylcysteine in acute hepatic failure (non-paracetamol-induced) Hepatogastroenterol 47:786 (2000)
Ytrebo et al, N-acetylcysteine increases cerebral perfusion pressure in pigs with ALF. Crit Care Med 29:1989 (2001)
Keays et al, IV acetyl cysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 303:1026 (1991).
Harrison et al, Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. NEJM 324:1852 (1991)
Devlin et al, N-acetylcysteine improves indocyanine green extraction and oxygen transport during hepatic dysfunction. Crit Care Med 25:236 (1997)
Walsh et al, The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant heptaic failure. Hepatology 27:1332 (1998)
Walsh et al, N-acetylcysteine administration in the critically ill (ed) Int Care Med 25:432 (1999)
Ben-Ari et al, N-acetylcysteine in acute hepatic failure (non-paracetamol-induced) Hepatogastroenterol 47:786 (2000)
Ytrebo et al, N-acetylcysteine increases cerebral perfusion pressure in pigs with ALF. Crit Care Med 29:1989 (2001)
66. Hepatocyte Transplantation 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
67. Hyperventilation 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
68. Effect of VIIa on prostatectomy perioperative blood loss
69. Factor VIIa in Liver Tranplantation(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.
70. Liver Support Systems Artificial
Whole blood exchange
Charcoal hemoperfusion
BioLogic DT
Hemoperfusion
MARS (Molecular Adsorbent Recirculating System) Bioartificial
ELAD (Extracorporeal Liver Assist Device)
Human hepatocyte cell line
HepatAssist
Porcine hepatocytes
71. Cadaveric Liver TransplantationEuropean Liver Tranpslant Registry
72. Transplantation Cadaveric
Live donor
Hepatocyte
73. Seizure Prophylaxis(Ellis et al. Hepatology 2000)
74. Seizures and Cerebral Edema
75. Clichy Critieria Factor V <20% and age <30 yr
Gr III-IV coma
Factor V <30% and age >30 yr
Bernuau et al, Hepatology 1986 Not as good as KCC in acetominophen cases
PPV: 92% KCC & 73% Clichy
Equal to KCC in non-acetominophen cases
PPV 89% for both Clichy and KCC
NPV: 47% KCC & 36% Clichy
76. Factor aVII and clotting
77. Phosphate Levels Acetaminophen ALF (Schmidt et al, Hepatology 2002)
78. Glutamine and Cerebral Edema:Argument for hyperventilation
79. MARS in Hyperacute Liver Failure:Change in MAP (Schmidt et al. Liver Transpl 2003)
80. DILIN Centers and Satellites