Acute Liver Failure

1. Acute Liver Failure Dr. Eduardo Martinez

3. Foie Gras • Foie gras (pronounced /fwɑːˈɡrɑː/ in English; French for "fat liver") is a food product made of the liver of a duck or goose that has been specially fattened.

4. Functions of the Liver • Metabolic • Carb metabolism • Protein and lipoprotein metabolism • Fatty acid metabolism • Biotransformation of drugs • Storage • Glycogen • Vitamins A, D, E, and K • Iron and copper

5. Functions of the Liver • Immunological function s • Synthesis of immunoglobulins • Phagocytosis by Kupffer cells • Filtration of bacteria • Degradation of endotoxins • Excretion of bilirubin and urea formation • Haematological functions • Blood reservoir • Haematopoiesis in the foetus

6. ALF Syndrome that leads to MOF and death Previously normal liver may fail within days High grade encephalopathy, survival is <20% Early death: cerebral oedema, CVS collapse Late death: Sepsis , MOF

7. Definition and Classifications ALF: Sd. defined by Encephalopathy Coagulopathy Jaundice Individual with previously normal liver

8. Definition and Classifications Fulminant Hepatic Failure Potentially reversible condition Consequence of severe liver injury Encephalopathy appears within 8 wks. of initial Sx. Absence of pre-existing liver ds.

9. Definition and Classifications King’s classification: Hyperacute: encephalopathy within <7 days Paracetamol, ischaemic, viral, toxins Acute: 8-28 days Subacute: 5-26 weeks Seronegative, idiopathic, drug-related Different etiology Poorer prognosis

10. Cause Agent Responsible Viral Hepatitis Hep. A, B, D, E, CMV, HSV, seronegative hepatitis (14-25% in UK) Drug-related Dose-related, e.g.paracetamol; idiosyncratic reactions, e.g. anti-TB, statins, recreational drugs, anticonvulsants, NSAIDs, many others Toxins Carbon tetrachloride, amanita phalloides Vascular events Iscahemic hepatitis, veno-occlusive disease, Budd-Chiari, heatstroke Other Pregnancy-related liver disease, Wilson’s disease, lymphoma, carcinoma, trauma Etiology

11. Etiology Most common causes: Worldwide: Hepatotrophic viruses A-E UK Paracetamol overdose Seronegative or non-A-E hepatitis Idiosynchratic drug rxs. or Wilson’s ds.

12. Workup Identify the etiology Hx., examination, viral and autoimmune profiles Bloods FBC, EUC, CMP, coags, LFTs, drug levels Abdo USG and CT Vascular pattern, ascitis, splenomegaly

13. Workup Liver Bx. Done by transjugular route Mays suggest specific Dx. Watch for sample from healthy liver >50% necrosis assoc. with poor prognosis Need to reverse coagulopathy before doing it

14. Pathophysiology Hepatic encephalopathy alteration in mental status and cognitive function occurring in the presence of liver failure Liver failure leads to: portal HTN splachnic vasodilation Hypoalbuminaemia Reduced plasma oncotic pressure Leads to ascitis and organ oedema

15. Pathophysiology Decreased intravascular volume Kidneys try to “compensate” and retain Na+ and water making oedema worse Also, Gut-derived toxins reach the liver Ammonia levels are often high Correlation between ammonia and symptoms is poor

16. Clinical Features Depend on the severity, which depends on: Etiology Speed of onset of symptoms Non-specific N&V, abdo pain Neurological Confusion, agitation, coma

17. Scale Of Hepatic Encephalopathy Grade Level of Consciousness Personality and Intellect Neurologic Signs Electroencephalogram (EEG) Abnormalities 0 Normal Normal None None Subclinical Normal Normal Abnormalities only on psychometric testing None 1 Day/night sleep reversal, restlessness Forgetfulness, mild confusion, agitation, irritability Tremor, apraxia, incoordination, impaired handwriting Triphasic waves (5 Hz) 2 Lethargy, slowed responses Disorientation to time, loss of inhibition, inappropriate behavior Asterixis, dysarthria, ataxia, hypoactive reflexes Triphasic waves (5 Hz) 3 Somnolence, confusion Disorientation to place, aggressive behavior Asterixis, muscular rigidity, Babinski signs, hyperactive reflexes Triphasic waves (5 Hz) 4 Coma None Decerebration Delta/slow wave activity

18. Clinical Features Mortality is higher for Grade III/IV Mostly due to cerebral oedema Occurs in 80% of pts. w/ALF Due to lack of equilibration of osmotic gradient 30% of those have cerebellar tonsil and/or temporal lobe herniation causing death We’re now better at treating cerebral oedema

19. Clinical Features Elevated ICP HTN, bradycardia, blown pupils: occur late CTB won’t tell you ICP monitor is best way of knowing CVS changes Similar to sepsis Might be due to infection

20. Clinical Features Renal failure Oliguric Poor prognosis Except with paracetamol overdose where it has a good prognosis Impaired immunity Decreased complement synthesis, Kupffer cell dysfunction, poor neutrophil adhesion and superoxide production

21. Clinical Features Increased susceptibility to infection 80% of pts. have bacteriologically proven infections Major sepsis is contributor to death in 20% of cases Staph. aureus 70% of gram (+) E. Coli most common gram (-) C. albicans in 30% of pts.

22. Monitoring Pts. need HDU/ICU Need CVC and continuous IBP monitoring and IDC Baseline ABG and lactate Lactate >3mmo/L after adequate resus has same sensi. and speci. for death as The King’s College Hospital criteria

23. Prognosis Early indicators of prognosis in fulminant hepatic failure. O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Gastroenterology. 1989 Aug;97(2):439-45. King’s Collage Hospital Criteria Originally devised as prognostic criteria to predict patient survival without liver transplant Now used as selection criteria for potential liver transplant recipients

25. KCH Criteria • Other patients • Prothrombin time >100 seconds orThree of the following variables: • Age <10 yr or >40 yr • Jaundice >7 days before encephalopathy • PT > 50s • Bilirubin > 300mmol/L Patients with paracetamol toxicity pH <7.3 (7.25 if given NAC) Or all three of the following: Prothrombin time >100s Serum creatinine level >300 μmol/l Grade III or IVencephalopathy

26. KCH Criteria • Positive predictive value for ICU death without transplantation of 0.98 • Negative predictive value of 0.82

27. Treatment Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH et al. Critical Care Medicine 2007; 35: 2498-508

28. Treatment Adult U.S. Acute Liver Failure Study Group Data from 23 liver transplant centers >1,110 pts. In 2005 convened to review literature on management Care of pts. w/high ICPs Compare practices of different centers

29. General Management Admit to hospital and HDU/ICU When evidence of ALF E.g.: INR>1.5 D/W: Physician Intensivist Nearest transplant center Regarding best time to refer

30. General Management Etiology-specific treatment Studies only for paracetamol overdose NAC regardless of time of overdose IV if Grade I encephalopathy Hypotension Any other reason PO NAC is not tolerated HELLP or acute fatty liver of pregnancy Tx. Is immediate delivery

31. General Management NAC 150mg/kg IV in 200ml NS over 15-60mins 50mg/kg IV over 4hrs 100mg/kg IV over 16hrs Total dose: 300mg/kg over 20hrs Infusion recommended until there is evidence of improved hepatic function rather than time or paracetamol levels

32. Management of Complications Hepatic encephalopathy and hyperammonaemia Infections Sedation and analgesia Bleeding diathesis Nutrition Seizures Circulatory dysfunction

33. Encephalopathy Standard treatment: Lactulose Watch for: Abdo distension Oesophageal varices will need a scope Avoid intravascular depletion Non-absorbable ATBs Neomycin not recommended by ALFSG because of nephrotoxicity

34. Infection prophylaxis and surveillance Infection is one of main causes of death in ALF Most common sites: Lung Urinary tract Blood Most common M.O. Gram (+) cocci: Staph aureus Gram (-) rods: E. coli Fungi: candida

35. Infection prophylaxis and surveillance Empirical ATBs are recommended by ALFSG when: Surveillance cultures reveal significant isolates Advanced stage (III/IV) encephalopathy Refractory hypotension SIRS 3rd gen. Cephalosporin or Timentin, Vancomycin, Fluconazole

36. Sedation and analgesia Agitation contributes to raised ICP Propofol vs. Benzos Both increase GABA neurotransmission, therefore may exacerbate encephalopathy Propofol decreases ICP and wears off quickly Opioids Shorter acting are preferable When there is concommitant ARF, avoid morphine or pethidine due to metabolite accumulation

37. Correction of bleeding diathesis Pts. with ALF are by definition coagulopathic Low plts. and fibrinogen, Vit. K deficient Spontaneous bleeding is rare Very difficult to obtain complete correction ALFSG recommends aiming for: INR 1.5 Plts. 50,000

38. Correction of bleeding diathesis Prophylactic FFP not recommended Obscures the trend of PT as prognostic marker Cryo recommended when fibrinogen low When FFP fails to correct PT/INR, then recombinant factor VIIa can be given Should be given before planned procedures Avoid in patients with risk of thrombotic complication MI, DVTs, etc.

39. Correction of bleeding diathesis UGI bleeding reduced by H2 antagonists or PPIs TEDS and Scuds

40. Nutrition ALF is a catabolic state Negative nitrogen balance Immunodeficiency Enteral nutrition when possible Hi-cal Avoid free water and hypo-osmolarity TPN when: Specific contraindication for enteral feeds

41. Seizure Prophylaxis and Surveillance Nonconvulsive seizure activity is common Prophylactic antiepileptics not recommended EEG when: Grade II/IV encephalopathy Sudden neuro deterioration Myoclonus To titrate use of barbiturates Tx. Phenytoin Propofol, midaz, barbiturates

42. CVS Dysfunction Correct hypovolaemia before starting vasopressors Pressors needed for hypotension and low CPP Norad is first line, can give high dose dopamine Adrenaline may compromise HBF Vasopressin not recommended because directly causes cerebral vasodilation and high ICPs Medium doses of steroid may improve pressor response

43. Mx. of Cerebral Oedema and Intracranial Hypertension Raised ICP due to cerebral oedema is one of major causes of M&M CTB for Grade III/IV To rule out anything else, i.e. bleed ICP monitor Grade III/IV encephalopathy To optimize CPP Not routine

44. Raised ICP Aim for ICP<25mmHg CPP 50-80 General recommendations Keep it quiet , minimize chest physio and ETT suctioning, head at 30o Don’t treat spontaneous hyperventilation, keep PaCO2 35-40mmHg, treat fever aggressively with physical measures

45. Raised ICP Specific management Manitol: first line therapy Hypertonic Saline Induced hypothermia Barbiturate coma Indomethacin: 25mg IV over 1min.

46. Mechanical Ventilation When to intubate: Respiratory failure Airway protection in advanced encephalopathy Agitation Imminent ICP monitor placement

47. Mechanical Ventilation Pts. w/ALF often develop ALI/ARDS Follow ARDSNet protocol Avoid high PEEP Use the minimum needed

48. CRRT Indicated for: Renal failure Fluid overload Metabolic derangements Need to create space for IV colloids, i.e. FFP CRRT preferred over IRRT HD instability common

49. CRRT Use citrate over heparin Monitor ionized calcium Use bicarb buffer over lactate or citrate buffer Liver won’t be able to convert them to HCO3- Avoid hyponatraemia May exacerbate cerebral oedema

50. Liver Transplant • Orthotopic liver transplant is the definitive treatment for patients who meet the criteria • or·tho·top·ic (ôrth-tpk)adj.In the normal or usual position • 1 yr. and 5 yr . survival of patients undergoing OLT for ALF is about 20% lower than elective cases for cirrhotic patients • Auxiliary liver transplantation is and alternative