Acute Liver Failure the quick and the dead. The Apostles Creed

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 Wilson�s Transplant contraindicated infiltrating cancer (breast, melanoma, lymphoma)

23. Severity AssessmentOstapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)

24. Severity AssessmentKing�s 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, pRBC�s 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 Antibiotics�no data for prophylaxis. Don�t 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 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

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, Wilson�s, 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 aceto�ophen and 8 non-aceto�phen 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 aceto�phen 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