New Developments in the Management of Acute Liver Failure. Oren Fix, MD, MSc, FACP Assistant Professor of Medicine Division of Gastroenterology

Transcription

1 New Developments in the Management of Acute Liver Failure Oren Fix, MD, MSc, FACP Assistant Professor of Medicine Division of Gastroenterology

2 Learning Objectives Describe 3 new approaches to the management of acute liver failure at UCSF Describe how the diagnosis of acetaminophen toxicity can be facilitated by a point-of-care test Describe how the novel drug ornithine phenylacetate can improve the outcome of patients with acute liver failure Describe how a checklist can assist in the management of acute liver failure

3 Coagulopathy Encephalopathy No pre-existing liver disease

4 Etiology of ALF in the US Indeterminate 15% Autoimmune Acetaminophen 46% Viral Drug

5 Acetaminophen-Related ALF Patients unaware of the risks may not recall taking the medication Plasma acetaminophen concentrations are often undetectable by the time liver injury has occurred Unintentional cases present late when encephalopathy may already be present

6 Acetaminophen Metabolism Glucuronyl Transferase Glucuronide APAP Cytochrome P450 NAPQI Mercaptopuric Acid GSH Transferase Sulfotransferase Sulfate Covalent Binding NAPQI-protein adducts NECROSIS Adapted from Larson Clin Liver Dis 2007

7 Acetaminophen-Protein Adducts Known APAP overdose Indeterminate, protein adducts+ Non-APAP Indeterminate, protein adducts Davern et al Gastroenterology 2006;130:

8 Measuring Acetaminophen-Protein Adducts Using a Dipstick Proof-of-concept study Sample of blood from patient with ALF HPLC-EC Dipstick Visual interpretation (positive, negative, indeterminate) Dipstick reader Medical team blinded to assay results

9 Intracranial hypertension Infection Bleeding Renal failure COMPLICATIONS Shock Hypoglycemia Multi-Organ System Failure

10 ALFSG Outcomes Spontaneous survivors 28% 24% 48% Transplanted Died without transplant Overall survival 70%

11 Percent Transplant-free Survival Coma grade I-II patients had ~50% better survival than III-IV Coma I-II Coma III-IV

12 (ammonia) 3

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15 glutamate NH 3 (primarily from gut) glutamine synthetase Chronic Liver Failure export of organic osmolytes compensates astrocyte GLN glutamine Acute Liver Failure export of organic osmolytes overwhelmed Adapted from T. Stravitz Hepatic encephalopathy Tofteng, et al. J Cerebral Blood Flow Metab. 2006; 26: 21. Abnormal Neurotransmission cell swelling Hepatic encephalopathy + cerebral edema

16 Ammonia and Cerebral Herniation 230 μmol/l 118 μmol/l Clemmesen et al. Hepatology 1999;29:

17 Ammonia, ICH & Survival Intracranial hypertension Cumulative survival Bernal et al. Hepatology 2007;46:

18 Lactulose Rifaximin

19 ornithine OCR-002 phenylacetate Phenacetyl-CoA : Gln acyltransferase PAGN

20 Ammonia Capture OPA acts on 2 key enzymatic pathways favoring reduction in circulating ammonia Supplies substrate (glutamate) to maintain glutamine formation Shifts the glutamate pool to glutamine

21 Effect of OCR-002 on Ammonia & Intracranial Pressure (ALF Model) OP - but neither O, nor P alone - significantly reduces arterial ammonia

22 Effect of OCR-002 on Ammonia & Intracranial Pressure (ALF Model) The reduction in ammonia levels prevents a rise in ICP

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24 Primary Objective Evaluate the safety and tolerability of OCR-002 in patients with acute liver failure/severe acute liver injury due to acetaminophen overdose Secondary Objectives Evaluate the steady state pharmacokinetic and pharmacodynamic profile of OCR-002 in patients with intact and impaired renal function using urinary PAGN as a surrogate marker Evaluate the effect of OCR-002 on venous ammonia levels Evaluate the effect of OCR-002 on neurological function

25 Management of ALF multiple critical steps complex not standardized few controlled studies heterogeneous

26 Checklists Decrease human error Standardize a process Reduce variability Improve performance and teamwork Reminders of only the most critical steps, rather than steps that practitioners never fail to do Winters et al Crit Care 2009;13:

27 ENGINE FAILURE DURING FLIGHT Airspeed 68 KIAS FLY THE AIRPLANE! Fuel Shutoff Valve Fuel Selector Auxiliary Fuel Pump Mixture Ignition Switch ON (IN) BOTH ON RICH BOTH Gawande. The Checklist Manifesto. New York: Picador, 2009

28 CRBSI 11.3/1000 0/1000 catheter days Berenholtz et al Crit Care Med 2004;32:

29 Mortality: 1.5% 0.8% Complications: 11% 7% Haynes et al NEJM 2009; 360;

30 Checklist for ALF Management of ALF is an ideal process for a checklist Improve and standardize management of ALF Content sources: Published guidelines Expert opinion Consensus

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34 Checklist for ALF Pilot testing to begin at 10 ALFSG sites Survey users for usability and content Long-term outcomes: Process measures Proportion of indeterminate etiologies Spontaneous/overall survival

35 Point of care dipstick assay for acetaminophenprotein adducts can facilitate diagnosis of acetaminophen-related acute liver failure Summary

36 Summary Ornithine phenylacetate can lower circulating ammonia levels and may improve encephalopathy and intracranial pressure in ALF

37 Summary A checklist can improve and standardize the management of ALF

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