Acute Liver Failure. Critical Care Medicine and Trauma Course May 30, 2000

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1 Acute Liver Failure Critical Care Medicine and Trauma Course May 30, 2000 Tim Davern, MD Director - Acute Liver Failure Program CPMC Liver Transplant Program davernt@sutterhealth.org

2 Acute Liver Failure - Outline - Incidence Definition Etiology Diagnosis Prognosis Complications Treatment Current Future Prevention

5 Chronic Liver Disease Acute Liver Disease ~ 2-2 4,000 cases in USA per year ALF

6 Acute Liver Failure -Definition- a a potentially reversible condition, the consequence of severe liver injury with an onset of encephalopathy within 8 weeks of appearance of the first symptoms of the disease and in the absence of pre-existing existing liver disease Trey and Davidson, 1973 Critical Points: A liver-related related illness of short duration ---> no chronic liver disease Coagulopathy (INR > 1.5) Any alteration in mental status (presumed not due to sedation alone) May be subtle Asterixis = stage II

Etiology of ALF in the USA Adult Registry (n = 1,321) n 700 600 500 605 46% More than half of all US ALF is drug-related related 400 300 12% 15% 200

7 Etiology of ALF in the USA Adult Registry (n = 1,321) n % More than half of all US ALF is drug-related related % 15% APAP Drug Hep B Hep A Autoimm Ischemic Wilson's Budd-Chiari Pregnancy Other Indeterminate Data courtesy W. Lee

9 Increasing Incidence of APAP-related ALF in US Total ALF cases: Percent of ALF Cases 60% 50% 44% 47% 51% 40% 38% 38% 30% 28% 20% 10% 0% YEAR

10 Suicidal vs. Accidental APAP cases Female (%) Suicidal (n = 101) 75 Unintentional (n = 109) 76 p Value NS APAP (g) NS APAP/day (g) Coma (% > 3) ALT (IU/L) 6,118 3, Spont Surv (%) NS Antidepressant (%) NS APAP/opiate (%)

Adduct+ Indeterminate ALF 3.0 APAP ALF nmol APAP-CYS / mg protein 2.5 2.0 1.5 1.0 0.

12 Adduct+ Indeterminate ALF 3.0 APAP ALF nmol APAP-CYS / mg protein Non-APAP ALF controls APAP OD (no ALF) Adduct- Indeterminate ALF 0.0 A B C D E Patient Group Davern TJ,, et al. Gastroenterology 2006;130:687-94

13 Pt B, Admission APAP = 105 mg/dl ALT (IU/L) Pt A, Admisssion APAP = 90 mg/dl Acetaminophen-CYS (umol/l)/mg protein ALT (IU/L) Hospital Day Pt D (Admission APAP = 0 mg/dl) Pt C, Admission APAP = 0 mg/dl ALT (IU/L) Acetaminophen-CYS (umol/l)/mg protein ALT (IU/L) 0 Hospital Day Hospital Day Hospital Day Davern TJ,, et al. Gastroenterology 2006;130: Acetaminophen-CYS (umol/l)/mg protein Acetaminophen-CYS (umol/l)/mg protein

14 Other 30% APAP 30% Occult APAP toxicity Drug 10% Viral Hepatitis 10% Other 30% Indeterminate 20% APAP 30% Approximately 20% of indeterminate ALF cases appear to be related to occult APAP toxicity Approximately 4% of all ALF cases appear to be related to occult APAP toxicity Drug 10% Viral Hepatitis 10% Indeterminate 16% Occult APAP 4%

16 Acute Liver Failure - Prognosis - King s s College Criteria APAP-induced ALF ph < 7.3 (s/p hydration and irrespective of grade of HE) Or Grade III+ HE and: INR > 6.5 and Creat > 3.4 Survival if: If ph < > > 5% If INR > > > 28% If creat > > > 44% Non-APAP APAP-induced ALF INR > 6.5 (irrespective of HE grade) Or any three of following: Cryptogenic or drug-related related Age <10 and > 40 > 7 days of jaundice prior to HE Bilirubin > 17.5 INR. 3.5 Survival if: One adverse predictor > > 20 % Two -----> > 6%

17 ALF: Prognostic scores King s s College Hosptial (KCH) criteria are reasonably specific for predicting poor outcome but identify only 50-60% of patients who will ultimately die or need tx KCH in US ALFSG ALFSG - unpublished data

18 Key Points in Caring for the ALF Patient Requires multidisciplinary team Transplant hepatologist,, surgeon, social workers, coordinators ICU physicians and nurses Nephrologists Neurosurgeons Rapidly assess for contraindications (medical, psych/social) to liver transplant List ALF patient for transplant as soon as eligible (barring contraindications) Anticipate/prevent/manage complications of ALF Support patients to allow/facilitate hepatic repair/regeneration

19 Etiology-based Medical Therapy for ALF NAC for APAP poisoning Given early (<8 hours) ----> > completely prevents liver injury Given later (?how late) -----> > still helps Charcoal, PCN, silimarin,, NAC for Amanita Delivery for pregnancy-related related ALF Steroids for autoimmune hepatitis Chelation for Wilson Disease * Entecavir for HBV; Acyclovir for HSV; Gancyclovir for CMV Correct hemodynamics for shock Decompressive vascular shunting for BCS * Probably marginal benefit

20 NAC is TPA for the Liver NAC should be given ASAP to patients with suspected APAP overdose We always be suspicious APAP levels are unreliable IV NAC is safe and more reliable than oral NAC in patients with ALF Treat patients with cryptogenic ALF and high aminotransferases with NAC Late administration of NAC appears to be ameliorate APAP toxicity Role for non-apap APAP-related ALF may help

21 Liver Transplant for ALF

22 TRANSPLANT LISTING = LIVER TRANSPLANT Listing is necessary but not sufficient Current UNOS criteria for Status 1 listing: Onset of hepatic encephalopathy (any grade) within 8 weeks of the first symptoms of liver disease» Absence of preexisting (clinically overt?) liver disease is critical Life expectancy of < 7 days In ICU requiring mechanical ventilation, renal support, or with INR > 2.0

23 TRANSPLANT LISTING = LIVER TRANSPLANT Hours (even minutes) can be the difference between life and death If the ALF patient is exhaustively evaluated for LTx prior to listing, he/she is likely to die Listing patients in the field may occasionally be appropriate The decision to proceed with LTx should be made at the time an acceptable organ is identified and represents one of the most difficult decisions that transplant physicians and surgeons must make. Prognostic models are imperfect

24 1033 Patients enrolled 455 (44%) listed Spontaneous survivors n= 465 (45%) Transplanted n= 262 (25%) Died (Not Transplanted) n= 306 (30%) Alive n= 134 (86%) Died n= 38 (14%) Overall survival: n = 695 (67%)

25 Liver Transplant for ALF Right Lobe Graft Left Lobe Graft Photographs courtesy of Bob Brown, Columbia P&S

26 ALF Complications Elevated Intracranial Pressure (ICP)/cerebral edema/cerebral herniation/brain death Multi-organ failure -> > ICU care Renal failure-- --> > continuous dialysis (CVVH) Infection-- --> > culture, empiric abx Hypoglycemia-- --> > glucose Electrolyte problems-- --> > replacement Misc - pancreatitis, aplastic anemia

27 Cerebral edema Poorly understood pathogenesis Arterial NH3 appears to be predictive of complications Role of lactulose and enteric abx undefined Difficult to diagnose accurately on clinical grounds CT insensitive and impractical ICP monitoring is controversial

28 Brain Edema in ALF 8 HOURS LATER

29 Is ICP monitoring worth the risks? Data regarding utility are thin Major complication: bleeding

30 First Do No Harm

31 Acute Liver Failure - Treatment - Treatment of elevated ICP Goals: : ICP < 20 mm Hg, CPP > 50 mm Hg* Maintain MAP > 60 mm Hg Avoid volume overload (----( ----> > early renal support) Avoid/treat factors that may increase ICP» Fever, seizures, hypertension, vasodilating drugs (e.g., nitroprusside), agitation, jugular venous compression, neck flexion, unnecessary stimulation/suctioning Elevate head of bed to 20 degrees * CPP = MAP - ICP

32 Acute Liver Failure - Treatment - Treatment of elevated ICP Mannitol (20%)» 0.5 to 1 g/kg over 5 min; repeat q hours as necessary until serum osmolarity > mosm/l» Not effective with renal failure (----( ----> > consider renal support early) Barbituate coma > > brain metabolism > > CBF, CBV» Pentobarbital load (3-5 5 mg/kg; maximum 500 mg) over 15 min then continuous infusion ( mg/kg/hr)» Use limited by cardiac depression, hypotension (----( ----> consider PA line early)» Can no longer follow neuro exam, EEG

33 Acute Liver Failure - Treatment - Treatment of elevated ICP Moderate Hypothermia» degrees Celsius» Decreases ICP in uncontrolled studies» Decreases liver injury in mouse models» Side effects - shivering, infection, PLT dysfunction, impaired hepatic regeneration?» ALFSG study planned Intracranial Pressure (mmhg) C Lancet 1999 Gastroenterology Time (hours)

34 IV NAC for non-acetaminophen ALF Synopsis 173 patients enrolled IV NAC (72 hours) vs. placebo No improvement in overall 3 week survival Significant improvement in transplnat-free survival (p=0.04) especially in patients with grade I/II HE (p=0.01) NAC was well tolerated Cox proportional hazards model by treatment and coma grade

35 Novel medical therapies are desperately needed We need better medical therapies aimed at limiting liver injury and enhancing liver repair/regeneration We need better therapies to prevent and treat cerebral edema a a potentially reversible condition,, the consequence of severe liver injury with an onset of encephalopathy within 8 weeks of appearance of the first symptoms of the disease and in the absence of pre-existing existing liver disease Trey and Davidson, 1973

37 Is ALF Preventable? Mass vaccination for viral hepatitis A and B Appropriate food handling and preparation Education for mushroom pickers Safer drugs Drug Induced Liver Injury Network (DILIN) Limitation of package size for acetaminophen Uncoupling acetaminophen/opiate combinations Who came up with the idea of mixing a dose-dependant dependant toxin with a highly addictive drug?

38 APAP-Opiate Combinations An ill-conceived idea Like mixing candy and poison No good medical reason the drugs can not be prescribed separately Regulatory action to uncouple APAP-opiates is needed FDA meeting 6/24/09 APAP-opiate combinations (e.g., Vicodin R ) should be removed from the market

39 ALF: Evaluation and Management - Summary - ALF is a rare but important syndrome Multiple etiologies may cause ALF but APAP toxicity is the most common cause of ALF in the US Some cases of ALF from APAP may be occult If etiology is at all in doubt, treat with NAC (quickly) Prognostic models for ALF are imperfect Early listing of the ALF patient is potentially life saving ALF patients appear to benefit from a multidisciplinary approach to care > refer to transplant center early! We need better medical therapies aimed at limiting liver injury and enhancing liver repair/regeneration Uncoupling APAP-opiates may decrease the incidence of ALF by over 10% in the US

40 ALF Resources Questions regarding ALF patients: Urgent: Non-urgent: sutterhealth.org Resources for physicians: Stravitz Stravitz RT, Kramer AH, Davern T. et al. Intensive care of patients with acute liver failure: recommendations of the US Acute Liver Failure Study Group. Crit Care Med. 2007;35(11): Resources for patients and their families: Google: : Acute liver failure knol Google: : Drug-induced hepatitis knol Google: : Hepatic encephalopathy knol

Acute Liver Failure UCSF Critical Care Medicine and Trauma Meeting June 6, 2008 Tim Davern, MD UCSF Liver Transplant Program

Acute Liver Failure UCSF Critical Care Medicine and Trauma Meeting June 6, 2008 Tim Davern, MD UCSF Liver Transplant Program timothy.davern@ucsf.edu Acute Liver Failure - Outline - Incidence Definition