Acute Liver Failure

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  • Hyperacutes more likely to be due to acetominophen Subacutes more likely to get transplanted and transplant free survival lowest compared to to other two.
  • 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)
  • Acute Liver Failure

    1. 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
    2. 2. Reference/Review <ul><li>Polson J, Lee WM. AASLD Position Paper: The Management of Acute Liver Failure. Hepatology 41:1179-97; 2005 </li></ul><ul><li>www.UpToDate.com </li></ul><ul><ul><li>Search “AASLD Guidelines” </li></ul></ul>
    3. 3. ALF Management Learning objectives <ul><li>Be able to make the diagnosis of ALF </li></ul><ul><li>Etiology and severity assessment </li></ul><ul><ul><li>Acetominophen & drugs (DILI) most common </li></ul></ul><ul><li>Understand when and how to transfer the ALF patient </li></ul><ul><li>Initial support </li></ul><ul><li>Role of transplant </li></ul>
    4. 4. Patient KC <ul><li>46 yo AA woman, RN, healthy </li></ul><ul><ul><li>Day -40: </li></ul></ul><ul><ul><ul><li>Abdominal pain, nausea; 2 weeks after starting simvistatin. </li></ul></ul></ul><ul><ul><li>Day -14: </li></ul></ul><ul><ul><ul><li>self-d/c’ed simvistatin. </li></ul></ul></ul><ul><ul><li>Day -1: </li></ul></ul><ul><ul><ul><li>Sent to local ER by supervisor for icteru </li></ul></ul></ul><ul><ul><ul><li>ALT >2000; INR 7; bilirubin 24. </li></ul></ul></ul><ul><ul><ul><li>Local ER to UNC MICU direct transfer. </li></ul></ul></ul>
    5. 5. Patient KC <ul><li>Day 1 (Dec 21, 2008; UNC) </li></ul><ul><ul><ul><li>Oriented x 3, deep jaundice </li></ul></ul></ul><ul><ul><ul><li>ALT 2418; AST 2918; AP 307; bilirubin 24.1; INR 9.8 </li></ul></ul></ul><ul><ul><ul><li>N-acetylcysteine IV continued. </li></ul></ul></ul><ul><ul><ul><li>Viral serologies negative </li></ul></ul></ul><ul><ul><ul><li>ANA (+), ASMA (-) </li></ul></ul></ul>
    6. 6. Patient KC <ul><li>Day 1-2: Diagnostic work-up </li></ul><ul><ul><ul><li>HBV, HAV serologies, HCV RNA negative </li></ul></ul></ul><ul><ul><ul><li>ANA 1:640, ASMA negative; IgG 1618 (600-1700) </li></ul></ul></ul><ul><ul><ul><li>ceruloplasmin 19 (15-52). </li></ul></ul></ul><ul><ul><ul><li>Acetaminophen level below <10 ug/ml </li></ul></ul></ul><ul><ul><ul><li>Patent hepatic veins on MRI. </li></ul></ul></ul>
    7. 7. Patient KC <ul><li>Day 2-3: </li></ul><ul><ul><li>INR >14.4 </li></ul></ul><ul><ul><li>Bilirubin 23.5 </li></ul></ul><ul><ul><li>Progressively confused </li></ul></ul><ul><ul><li>Listed Status 1 for liver transplant on Day 2 (22 Dec 08). </li></ul></ul><ul><ul><li>Entubated for airway protection </li></ul></ul>
    8. 8. Patient MP <ul><li>Day 4: </li></ul><ul><ul><li>0730:T 38.6 </li></ul></ul><ul><ul><li>Cultured and broad spectrum antibiotics ordered. </li></ul></ul><ul><ul><li>~09:00: liver offer in Memphis, TN </li></ul></ul><ul><ul><ul><li>UNC surgical team dispatched. </li></ul></ul></ul><ul><ul><li>13:00: progressive hypotension, sepsis picture. </li></ul></ul><ul><ul><li>15:00: Surgical team recalled. Liver diverted. </li></ul></ul>
    9. 9. Patient KC <ul><li>Day 5 (25 Dec 2008): </li></ul><ul><ul><li>Progressive hypotension despite 2-3 pressors and antibiotics. </li></ul></ul><ul><ul><li>FIO2 requirement climbing. </li></ul></ul><ul><ul><li>Patient made DNR </li></ul></ul><ul><ul><li>Dies 06:15. </li></ul></ul>
    10. 10. Definitions <ul><li>Absence of underlying liver disease </li></ul><ul><li>INR >/= 1.5, mental status changes </li></ul><ul><li>Illness < 26 weeks in duration </li></ul><ul><li>ALT & AST >2000 to 5000; rising bilirubin </li></ul><ul><li>Categories: </li></ul><ul><ul><li>Hyperacute Liver Failure </li></ul></ul><ul><ul><li>Acute Liver Failure </li></ul></ul><ul><ul><li>Subacute Liver Failure (worst prognosis) </li></ul></ul>
    11. 11. Incidence and Demographics <ul><li>2000 cases/year </li></ul><ul><ul><li>200-300 transplants </li></ul></ul><ul><li>Duration of symptoms </li></ul><ul><ul><li>Median 6 days (0-74) </li></ul></ul><ul><li>Jaundice to encephalopathy </li></ul><ul><ul><li>Median 2 days (0-61) </li></ul></ul><ul><li>Dispostion: </li></ul><ul><ul><li>93% in 3 weeks . </li></ul></ul>Acute Liver Failure Group: Ostapowicz et al, Ann Int Med 2002 74% 10% 9% 7% White Hispanic AA Other 38 (15-78) Median age (yr) 73% Women
    12. 12. Etiology of ALF in the USA: Adult Registry (n = 610) Drug Ischemia Hep A Budd-Chiari Other Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group) Unintentional
    13. 13. Etiology of ALF in the USA: Adult Registry (n = 610) Drug Ischemia Hep A Budd-Chiari Other Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)
    14. 14. Drug induced liver injury and ALF Adapted from Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)
    15. 15. 8 Center NIH Study <ul><li>Children ≥ 2 years and adults </li></ul><ul><li>Pre-defined biochemical criteria </li></ul><ul><li>- AST or ALT > 5 ULN twice consecutively </li></ul><ul><li>- Alk Phos > 2 ULN twice consecutively </li></ul><ul><li>- Bilirubin ≥ 2.5 mg/dl </li></ul>Chalasani N, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006
    16. 16. Percent ALF Oral Presenation, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006 2% Liver Transplant (event related up to 6 months) 12.7% Death (within 6 months)
    17. 17. Complications of ALF <ul><li>Multi-organ failure </li></ul><ul><li>Encephalopathy </li></ul><ul><ul><li>cerebral edema </li></ul></ul><ul><ul><li>CNS ammonia </li></ul></ul><ul><li>Infection </li></ul><ul><li>Coagulapathy </li></ul><ul><li>Hypoglycemia </li></ul>
    18. 18. Grades of Encephalopathy Unresponsive; comatose. Grade IV Stuporous but arousable; more somnelent; ?ability to protect airway Grade III Awake/agitated ; more confused & disoriented; Hallucinations Grade II Awake/responsive; mild confusion & disorientation; altered personality Grade I No change in mental status Grade 0
    19. 19. Recognition & Transfer <ul><li>INR is key: >/=1.5 must be admitted </li></ul><ul><ul><li>ICU or step-down if mental status changes </li></ul></ul><ul><li>Call and transfer early. </li></ul><ul><ul><li>ALF is rare so often takes us by surprise </li></ul></ul><ul><ul><li>Grade I-II encephalopathy--transfer </li></ul></ul><ul><ul><li>Grade III encephalopathy--intubate </li></ul></ul><ul><li>Consider distance </li></ul><ul><li>Consider local expertise </li></ul>
    20. 20. N-Acetylcysteine in Non -acetominphen ALF <ul><li>Multi-center, placebo controlled. </li></ul><ul><ul><li>Outcomes: overall and transplant free survival </li></ul></ul><ul><li>81 NAC vs. 92 placebo </li></ul><ul><ul><li>No difference in primary outcomes </li></ul></ul><ul><li>Secondary analysis </li></ul><ul><ul><li>Transplant free survival odds = 11.3 (p<0.01) for Grade 1-2 coma at randomization. </li></ul></ul><ul><ul><ul><ul><ul><li>Lee WM, et al. Hepatology 46:268A (2007) abs. </li></ul></ul></ul></ul></ul>
    21. 21. Look for etiology <ul><li>Treatable </li></ul><ul><ul><li>Acetominophen NAC </li></ul></ul><ul><ul><li>Amanita phalloides PCN; silymarin </li></ul></ul><ul><ul><li>Acute fatty liver of pregnancy delivery </li></ul></ul><ul><ul><li>Herpes Acyclovir </li></ul></ul><ul><ul><li>Autoimmune Steroids </li></ul></ul><ul><ul><li>Budd-Chiarri Heparin/TIPS </li></ul></ul><ul><li>Transplant only hope </li></ul><ul><ul><li>Wilson’s </li></ul></ul><ul><li>Transplant contraindicated </li></ul><ul><ul><li>infiltrating cancer (breast, melanoma, lymphoma) </li></ul></ul>
    22. 23. Severity Assessment Ostapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)
    23. 24. Severity Assessment King’s College Criteria, N=585 <ul><li>Acetominophen </li></ul><ul><ul><li>pH < 7.3 after resuscitation </li></ul></ul><ul><ul><li>OR </li></ul></ul><ul><ul><li>All of the following </li></ul></ul><ul><ul><ul><li>INR>7 </li></ul></ul></ul><ul><ul><ul><li>Cr >3.4mg/dL </li></ul></ul></ul><ul><ul><ul><li>Grade III or IV encephalopathy </li></ul></ul></ul><ul><li>All other causes </li></ul><ul><ul><li>INR > 7 </li></ul></ul><ul><ul><li>OR </li></ul></ul><ul><ul><li>3 of the following: </li></ul></ul><ul><ul><ul><li>INR >3.5 </li></ul></ul></ul><ul><ul><ul><li>Age <10 or >40 </li></ul></ul></ul><ul><ul><ul><li>Jaundice to enceph >7 days </li></ul></ul></ul><ul><ul><ul><li>Bilirubin > 17.5 mg/dL </li></ul></ul></ul><ul><ul><ul><li>Indeterminate ALF </li></ul></ul></ul><ul><ul><ul><li>Drug reaction </li></ul></ul></ul>PPV: 70-100% NPV: 25-94%
    24. 25. Support: General Management <ul><li>Central venous access, arterial line </li></ul><ul><ul><li>?Pulmonary artery catheterization </li></ul></ul><ul><li>Avoid fluid overload </li></ul><ul><li>Glucose monitoring (FS q 2-4 hours) </li></ul><ul><li>CVVHD as necessary </li></ul><ul><li>Enteral feeding (avoid TPN) </li></ul>
    25. 26. General Management <ul><li>Intubate for Grade III or IV encephalopathy </li></ul><ul><li>Elevate head of bed </li></ul><ul><li>Sedate PRN (propofol preferred) </li></ul><ul><li>Limit rolling </li></ul><ul><li>Limit suctioning; use endotracheal lidocaine </li></ul><ul><li>Frequent neurologic checks (q 1-2 hrs) </li></ul>
    26. 27. Hyperventilation <ul><li>Apply acutely for rise in ICP and/or deterioration of neurologic exam. </li></ul><ul><li>Prophylactic use not recommended. </li></ul>
    27. 28. Blood pressure support <ul><li>Use colloid (albumin, pRBC’s if indicated) </li></ul><ul><li>Aim = MAP 50-60 mm Hg </li></ul><ul><li>Epinephrine, Norepinephrine, Dopamine preferred </li></ul><ul><li>Vasopressin generally avoided </li></ul><ul><ul><li>Terlipressin found to elevate ICP* </li></ul></ul>*Shawcross DL, et al. Hepatology 2004
    28. 29. Medications <ul><li>H2 blocker, ppi, or carafate </li></ul><ul><li>Antibiotics—no data for prophylaxis. </li></ul><ul><li>Don’t correct INR unless overt bleed. </li></ul><ul><li>Mannitol (acute use) </li></ul><ul><li>Lactulose —? </li></ul><ul><li>N-acetylcysteine use for non-Tylenol cases </li></ul>
    29. 30. Severity Assessment and Transplantation All ALF patients No benefit from or need for transplant Benefit from Transplant Transplant
    30. 31. Cadaveric Liver Transplantation Survival * European Transplant Registry ^ US Acute Liver Failure Group; Ann Internal Med 2002 NA NA 15% w/o Tx ALF 85%* 59%* 1 year 69%* 90% Non-ALF 51%* 65%^ ALF 5 year “ Short term” (21 days)
    31. 32. Cadaveric Transplantation Ostapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group) 63% survival on intention-to-transplant analysis 308 ALF patients 136 (44%) Listed for Transplant 30 Died on list 17 Removed from list 89 (65%) Transplanted 14 Dead 75 Alive 10 Alive 7 Dead
    32. 33. Cadaveric Transplantation Ostapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group) 63% survival on intention-to-transplant analysis 308 ALF patients 207 (67%) alive 101 (33%) dead 132 No Tx 75 Tx’d 14 Tx’d 87 No Tx 30 died waiting 47 died unlisted
    33. 34. Live Donor Liver Transplantation <ul><li>Reported cases of good outcome. </li></ul><ul><li>ALF patients are often young previously healthy. </li></ul><ul><li>Heroism ethic valued. </li></ul><ul><li>Minimal time to evaluate patient, donors and family </li></ul><ul><li>Pressure for accurate donor evaluation is high. </li></ul><ul><li>Outcomes for UNOS status 2a patients is poor. </li></ul>PROS CONS
    34. 35. LDLT for ALF: a rare occurence <ul><li>11079 potential LDLT cases </li></ul><ul><ul><li>11 (1%) cases ALF </li></ul></ul><ul><li>Mean time for donor evaluation = 2 days </li></ul><ul><li>Outcome </li></ul><ul><ul><li>8 received LDLT and 7 alive at 5 year. </li></ul></ul><ul><ul><li>2 received DDLT </li></ul></ul><ul><ul><li>1 improved w/o transplant </li></ul></ul>Trotter JF, et al. (abs) Hepatology 362A (2006)
    35. 36. Molecular Adsorbents Recirculating System (MARS) Heemann et al. Hepatology 2002
    36. 37. Liver Support Systems:Meta-analysis (Kjaergard et al., JAMA 2002) Acute-on-chronic liver failure *Heemann et al. Hepatology 2002
    37. 38. ALF Goals of Treatment All ALF patients No benefit from or need for transplant Benefit from Transplant All ALF patients No need for transplant Transplant Benefit from Transplant
    38. 39. ALF Management Learning objectives <ul><li>Be able to make the diagnosis of ALF </li></ul><ul><li>Etiology and severity assessment </li></ul><ul><ul><li>Acetominophen & drugs (DILI) most common </li></ul></ul><ul><li>Understand when and how to transfer the ALF patient </li></ul><ul><li>Initial support </li></ul><ul><li>Role of transplant </li></ul>
    39. 40. Extra Slides From here onward.
    40. 41. Etiology of ALF: USA 1998-2000 2001-2003 www.fda.gov/cder/livertox/presentations2004
    41. 42. Acetominophen Debate Kaplowitz, N Hepatol 2004 <ul><li>Acetominophen Bad : </li></ul><ul><li>More stern warnings </li></ul><ul><li>Should be removed from combinations. </li></ul><ul><li>Blister packs. </li></ul><ul><li>Limit amount sold at one time. </li></ul><ul><ul><li>Lee W. Hepatol 2004 </li></ul></ul><ul><li>Acetominophen okay : </li></ul><ul><li>Present insert enough </li></ul><ul><li>“ Unintentional” cases are not so. </li></ul><ul><li>Benefit of blister packs and limiting amounts short lived. </li></ul><ul><ul><li>Rumack B. Hepatol 2004 </li></ul></ul>
    42. 43. Cadaveric Transplantation Ostapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group) 63% survival on intention-to-transplant analysis 308 ALF patients 136 Listed for Transplant 30 Died on list 17 Removed 172 Not listed 47 died 89 Transplanted 14 Died 75 Lived 10 Lived 7 Died
    43. 44. Transplantation for Substance and Drug Reactions/Toxicity (Non-Acetominophen) 42% (3 cases of statins) Russo RW, et al. Liver Transpl 2004
    44. 45. Ammonia and Cerebral Edema: Pros & Cons of lactulose (6) (10) (6) (10) Strauss et al, Gastro 2001 <ul><li>Cons </li></ul><ul><li>Abdominal distention </li></ul><ul><li>No proven efficacy </li></ul><ul><li>Pros </li></ul><ul><li>Relatively benign </li></ul><ul><li>NH4 implicated linked to mortality </li></ul>
    45. 46. Rationale for N-acetylcysteine in non-paracetamol induced ALF <ul><li>Anti-oxidant properties </li></ul><ul><ul><li>Animal studies with ARDS </li></ul></ul><ul><ul><li>Human trials equivocal </li></ul></ul><ul><li>Cardiovascular effects </li></ul><ul><ul><li>Animal studies in sepsis and liver failure </li></ul></ul><ul><ul><li>Human studies equivocal </li></ul></ul><ul><li>Immune modulation </li></ul><ul><ul><li>Reduced inflammatory cytokines in sepsis </li></ul></ul>
    46. 47. Increased BMI and ALF <ul><li>High BMI not a risk factor for ALF </li></ul><ul><li>High BMI increases risk of death or transplant in ALF </li></ul><ul><ul><li>BMI >30: OR = 1.63 (1.04-2.55) </li></ul></ul><ul><ul><li>BMI >35: OR = 1.93 (1.02-3.62) </li></ul></ul><ul><ul><ul><li>Rutherford A, et al. Clin Gastro Hep 2006 </li></ul></ul></ul>
    47. 48. Other interventions for cerebral edema <ul><li>Hypertonic saline </li></ul><ul><ul><li>Serum Na 145-155 may help lower ICP </li></ul></ul><ul><li>Barbiturates </li></ul><ul><ul><li>Helps, but hypotension problematic </li></ul></ul><ul><li>Hypothermia (32-34 C) </li></ul><ul><ul><li>Animal studies show benefit </li></ul></ul><ul><ul><li>Human studies limited but encouraging </li></ul></ul>
    48. 49. Etiology of ALF in the USA: Adult Registry (n = 489)
    49. 50. ICP Monitoring <ul><li>ICP Goals: </li></ul><ul><ul><li>ICP <20 mm Hg </li></ul></ul><ul><ul><ul><li>>20 mm Hg x >5 min requires intervention (e.g. mannitol) </li></ul></ul></ul><ul><ul><ul><li>>40 mm Hg x >2 hrs may contraindicate transplant </li></ul></ul></ul><ul><ul><li>MAP – ICP >50 mm Hg </li></ul></ul><ul><ul><ul><li><50 mm Hg x >2 hrs may contraindicate transplant </li></ul></ul></ul>
    50. 51. Complications of ICP monitoring Blei et al. Lancet 1993 <ul><li>US Survey </li></ul><ul><li>75% response </li></ul><ul><li>60% of responders used ICP’s </li></ul><ul><li>262 ICP’s reported </li></ul><ul><li>Epidural type (n=160) </li></ul><ul><ul><li>3.8% complication </li></ul></ul><ul><li>Subdural (n=79) </li></ul><ul><ul><li>20% complication </li></ul></ul><ul><li>Parenchymal (n=23) </li></ul><ul><ul><li>22% complication </li></ul></ul><ul><li>Bleeding : Infection </li></ul><ul><ul><li>7 : 1 </li></ul></ul>
    51. 52. rFVIIa and INR change in ALF Shami et al. Liver Transpl 2003
    52. 53. rFVIIa and ALF Shami et al. Liver Transpl 2003 0.04 2/7 (29) 7/8 (88) Anasarca 0.35 13 19 Mean FFP 0.03 7/7 (100) 3/8 (0) Ability to place ICP 0.0002 7/7 (100) 0/8 (0) PT correction p value VIIa (n=7) Plasma alone (n=8)
    53. 54. ICP Monitoring and VIIa Cons Pros <ul><li>Cost !! </li></ul><ul><ul><li>8000 ug = $11,200 </li></ul></ul><ul><ul><li>12 units FFP=$1500 </li></ul></ul><ul><li>No evidence that aVII decreases ICP complications. </li></ul><ul><li>No evidence that ICP monitor improves outcomes. </li></ul><ul><li>Small volume </li></ul><ul><li>ICP monitoring makes sense. </li></ul><ul><li>ICP does dictate change in care. </li></ul>
    54. 55. Bad Prognostic Signs <ul><li>APACHE score >15 on admission </li></ul><ul><li>Etiology </li></ul><ul><ul><li>Indeterminate, drug, Autoimmune, HBV, Wilson’s, Budd-Chiari, Mushroom poisoning </li></ul></ul><ul><li>Coma grade III or IV on admission </li></ul>
    55. 56. MARS in Hyperacute Liver Failure: Change in SVR (Schmidt et al. Liver Transpl 2003) Hours on MARS p=0.006
    56. 57. Molecular Adsorbents Recirculating System (MARS) Heemann et al. Hepatology 2002 N = 12 N = 12
    57. 58. Liver Support Systems:Meta-analysis (Kjaergard et al., JAMA 2002) Acute liver failure
    58. 59. VIIa and Clotting Cascade VIIa X Xa Prothrombin Thrombin Va
    59. 60. Effect of rF-VIIa on prostatectomy perioperative blood loss mL Friederich et al, Lancet 2003
    60. 61. Artificial & Bioartificial Support Systems in ALF: Meta-analysis Kjaergard LL, et al. JAMA 2003 Mortality Mortality 0.95 (0.71-1.29) 83/177 72/177 8 Risk Ratio (95% CI) Standard care With support Number randomized trials
    61. 62. “ It’s worth every penny.” March 13, 2003 Eric Gibney, MD, Nephrology fellow, commenting on aVII after placing quinton catheter in ALF patient given factor aVII
    62. 63. Hyperventilation <ul><li>Head Trauma: </li></ul><ul><ul><li>Increased vasculature sensitivity to low PCO2 from days 2 to 5 post-injury. </li></ul></ul><ul><ul><li>Correlated with decreases in brain tissue oxygen pressure. </li></ul></ul><ul><ul><ul><ul><li>Carmona et al, Crit Care Med 2000. </li></ul></ul></ul></ul><ul><li>Cerebral blood flow does fall with hyperventilation in ALF </li></ul><ul><ul><li>43 ml/100g/min to 32 ml/100g/min (p<0.01) </li></ul></ul><ul><ul><ul><ul><li>Strauss et al, Liver Transpl 2001 </li></ul></ul></ul></ul>
    63. 64. Bioartificial Liver Support in ALF Multicenter Randomized Controlled Trial <ul><li>N = 147 (73 BAL; 74 Controls) </li></ul><ul><li>Overall 30 day survivals </li></ul><ul><ul><li>BAL: 44/79 </li></ul></ul><ul><ul><li>Controls: 53/73 </li></ul></ul><ul><li>Cox proportional Hazard analysis to account for transplantation intervention </li></ul><ul><ul><li>RR for BAL patients: 0.56, p = 0.05 </li></ul></ul>p = 0.12 Demetriou AA, et al. Ann Surg 2004
    64. 65. Rationale for N-acetylcysteine in non-paracetamol induced ALF <ul><li> O 2 delivery & consumption <1hr IV NAC </li></ul><ul><ul><li>12 aceto’ophen and 8 non-aceto’phen </li></ul></ul><ul><ul><ul><ul><li>Harrison et.al. NEJM 1991 </li></ul></ul></ul></ul><ul><ul><li>15 pts with liver dysfunction of misc. causes </li></ul></ul><ul><ul><ul><ul><li>Devlin et al, Crit Care Med 1997 </li></ul></ul></ul></ul><ul><li>No improvement seen at 5 hours infusion </li></ul><ul><ul><li>Randomized, placebo controlled (11 vs 7 pts) </li></ul></ul><ul><ul><li>Most pts aceto’phen related. </li></ul></ul><ul><ul><ul><ul><li>Walsh et al, Hepatology 1998 </li></ul></ul></ul></ul>
    65. 66. Hepatocyte Transplantation <ul><li>Lack of cell source </li></ul><ul><li>Invasive delivery </li></ul><ul><li>Need for immunosuppression </li></ul><ul><li>Likely need for large hepatocyte mass </li></ul><ul><li>hTERT immortalized human hepatocytes </li></ul><ul><li>Xenotransplanted hepatocytes </li></ul><ul><li>Bone marrow, embryonic stem cell, placental derived cells. </li></ul><ul><ul><li>Strom et al (ed.), Gastro 2003 </li></ul></ul>Problems Promises
    66. 67. Hyperventilation in Head Trauma <ul><li>Hyperventilation: the controversy </li></ul><ul><ul><li>lower ICP vs. increase cerebral ischemia risk. </li></ul></ul><ul><li>Guidelines in Severe Head Trauma </li></ul><ul><ul><li>Moderate hyperventilation (pCO2 30-35) = first line measure if ICP elevated. </li></ul></ul><ul><ul><li>Heavy hyperventilation (pCO2 25-30) considered second line. </li></ul></ul><ul><ul><ul><ul><li>Procaccio F et al, J Neurosurg Sci 2000 </li></ul></ul></ul></ul>
    67. 68. Effect of VIIa on prostatectomy perioperative blood loss Friederich et al, Lancet 2003 0.001 1.09 (0.93-1.32) 0.001 1.24 (1.02-1.41) 2.69 (1.71-3.57) Perioperative blood loss (L) median & range 0.001 0 (0) 0.651 3(38%) 7(58%) % pts transfused 0.0003 0 (0) 0.047 0.6 (0-3) 1.5 (0-4) pRBC 40ug/kg (n=16) 20ug/kg (n=8) Placebo (n=12)
    68. 69. Factor VIIa in Liver Tranplantation (de Wolf et al, Transfusion 39:87s, 1999) <ul><li>5 patients given 80ug/kg VIIa at time of transplant </li></ul><ul><li>pRBC given in first 24 hrs compared to 104 historical controls. </li></ul><ul><li>Median pRBC given: 3 (range 0-5) </li></ul><ul><ul><li>“… far below the lower limit of the 95% confidence intervals for the mean in the control group.” </li></ul></ul><ul><ul><li>One patient had hepatic artery thrombosis. </li></ul></ul>
    69. 70. Liver Support Systems <ul><li>Artificial </li></ul><ul><ul><li>Whole blood exchange </li></ul></ul><ul><ul><li>Charcoal hemoperfusion </li></ul></ul><ul><ul><li>BioLogic DT </li></ul></ul><ul><ul><li>Hemoperfusion </li></ul></ul><ul><ul><li>MARS (Molecular Adsorbent Recirculating System) </li></ul></ul><ul><li>Bioartificial </li></ul><ul><ul><li>ELAD (Extracorporeal Liver Assist Device) </li></ul></ul><ul><ul><ul><li>Human hepatocyte cell line </li></ul></ul></ul><ul><ul><li>HepatAssist </li></ul></ul><ul><ul><ul><li>Porcine hepatocytes </li></ul></ul></ul>
    70. 71. Cadaveric Liver Transplantation European Liver Tranpslant Registry 69% 78% Non-ALF 51% 59% ALF 5 year survival 1 year survival
    71. 72. Transplantation <ul><li>Cadaveric </li></ul><ul><li>Live donor </li></ul><ul><li>Hepatocyte </li></ul>
    72. 73. Seizure Prophylaxis (Ellis et al. Hepatology 2000) † Number of autopsies performed in prophylactic phenytoin and control group (9 and 10, respectively). < .05   7 † (70%) 2 † (22%) Cerebral edema (autopsy) NS   7 (32%) 3 (15%) Increased ICP NS 10 (32%) 3 (15%) Seizure activity NS 11 (50%) 5 (25%) Pupillary abnormalities p value Controls (n = 22) Phenytoin (n = 20)
    73. 74. Seizures and Cerebral Edema NH3 Glutamine Glutamine Glutamine Glutamine ICP Stimulation for seizures Astrocyte
    74. 75. Clichy Critieria <ul><li>Factor V <20% and age <30 yr </li></ul><ul><ul><li>Gr III-IV coma </li></ul></ul><ul><li>Factor V <30% and age >30 yr </li></ul><ul><ul><li>Bernuau et al, Hepatology 1986 </li></ul></ul><ul><li>Not as good as KCC in acetominophen cases </li></ul><ul><ul><li>PPV : 92% KCC & 73% Clichy </li></ul></ul><ul><li>Equal to KCC in non-acetominophen cases </li></ul><ul><ul><li>PPV 89% for both Clichy and KCC </li></ul></ul><ul><ul><li>NPV : 47% KCC & 36% Clichy </li></ul></ul>
    75. 76. Factor aVII and clotting VII aVII aVII aVII aVII aVII aVII aVII aVII aVII Tissue factor
    76. 77. Phosphate Levels Acetaminophen ALF (Schmidt et al, Hepatology 2002) 92 93 80 97 67 KCH criteria 99 99 100 100 90   >1.2 mmol/L day 2 Phosphate Accuracy NPV PPV Specificity Sensitivity Indicator
    77. 78. Glutamine and Cerebral Edema: Argument for hyperventilation Strauss et al, Gastro 2001 Hyperventilation Normoventilation
    78. 79. MARS in Hyperacute Liver Failure: Change in MAP (Schmidt et al. Liver Transpl 2003) Hours on MARS p<0.0001 (Mean Cr: 2.9 to 1.7) (Mean Cr: 3.82 to 4.05)
    79. 80. DILIN Centers and Satellites >12.8 million lives http://dilin.dcri.duke.edu/

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