Fulminant Liver Failure

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Fulminant Liver Failure

• Stevos AHD
• April 3rd, 2008

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Introduction

• Sue, a 28 year old previously healthy 80 kg
  woman, is brought to the emerg department with
  progressive obtundation. Her ALT is 7,200 U/L,
  AST is 11,300 U/L, INR is 3.6 and a total
  bilirubin of 5.3 mg/dL. As the ICU fellow on, you
  are consulted to figure out what is going on and
  how to manage her.

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Take it away Dave.

1. What are some of the overarching themes of
   managing ALF?
2. How is acute liver failure defined? How is
   fulminant liver failure defined?
3. What is the differential for the etiologies of
   ALF?
4. How would you differentiate between these
   etiologies?
5. What is the most common cause of ALF in North
   America and what it is pathophysiology? What is
   the most common cause in the developing world?
   Why?
6. What are the specific therapies for each of these
   identified etiologies of ALF? Please give names,
   doses and frequency.
7. Describe the grades of hepatic encephalopathy.
   What is her grade?

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Presumed agents of idiosyncratic drug induced
hepatic failure
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Alcoholic hepatitis ----Pentoxifylline (400 mg PO
TID), looked at in one single centre randomized
study and showed a benefit where short-term
survival was significantly better with active
therapy (25 versus 46 percent, respectively).
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Norfloxacin in FHF

• A randomized trial reported significant benefits
  with the oral administration of norfloxacin at
  400 mg/day to 68 patients with
• cirrhosis with ascites with a total serum protein
  lt1.5 g/L
• And impaired renal function (serum creatinine
  gt106 micromol/L BUN gt25 mg/dL, serum sodium
  lt130 meq/L)
• Or severe liver disease (Child-Pugh score gt9
  points with serum bilirubin gt3 mg/dL).
• Benefits include a significantly decreased
  one-year probability of SBP (7 versus 61 percent)
  and hepatorenal syndrome (28 versus 41 percent),
  and improved survival at three months (94 versus
  62 percent) and one year (60 percent versus 48
  percent, p 0.05).

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Grades of hepatic encephalopathy
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Now onto NNNNNNaisan

• 8. Can we prognosticate at all for Sue right now
  (ie lactate values vs other values)? What is her
  MELD score? What is the MELD score anyway? What
  is the Child-Pugh score?

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MELD score

• It is calculated according to the following
  formula
• 3.8 x log (e) (bilirubin mg/dL) 11.2 x log
  (e) (INR) 9.6 log (e) (creatinine mg/dL)

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MELD score interpretation

• In interpeting the MELD Score in hospitalized
  patients, the 3 month mortality is
• 40 or more - 100 mortality
• 30-39 - 83 mortality
• 20-29 - 76 mortality
• 10-19 - 27 mortality
• lt10 - 4 mortality

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Child-Turcotte-Pugh score
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Gordo and interventions for FHF

• 9. What interventions would you like to start
  now? Specifically discuss the rationale and
  evidence for the following
• Lactulose
• Oral non-absorbable antibiotics
• Prophylactic systemic antibiotics
• Agents of sedation and analgesia
• Correction of coalopathy (FFP, Vitamin K,
  Platelets, cryoprecipitate, aminocaproic acid,
  factor VIIIa). Routine vs procedure specific
• Routine albumin administration
• Gastric acid suppression
• Nutrition
• Glycemic control

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Onto Yoan and infections and ascites

• 10. What is her risk for infection? How about
  from fungal pathogens?
• She has significant ascites. With a large right
  sided pleural effusion that is making it
  moderately difficult to ventilate her.
• 11. How do you manage her ascites?
• 12. What indicates SBP? How is it managed?

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Hepatic encephalopthy and crazy Yoan

• Her CNS status continues to deteriorate and now
  she is unresponsive to pain.
• 13. What etiologies should you consider at this
  point? What investigations/history do you want to
  get specifically?
• 14. What is the pathophysiology of cerebral
  edema in ALF? Whats the pathophysiology of
  multiple organ failure in ALF?
• 15. What is the evidence for ICP monitoring?
  What can be done in cases of high ICP?

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Take it away Scotto

• Things are not going so well for Sue. A GI keener
  says that we should just give up and send her to
  MARS.
• 16. What is MARS? Is there any evidence for it?
  How does it work?
• 17. What other similar technologies are out
  there for ALF?

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• Evidence for MARS
• Initial Phase I trials
• Subsequent randomized trial in acute on chronic
  hepatic failure, which was stopped early
• MARS registry paper and effects in encephalopathy
• Meta-analysis of 4 randomized and 2
  non-randomized trials
• Evidence in hepato-renal syndrome

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Scot redux

• She is now going into progressive renal failure.
• 18. What is the pathophysiology of hepato-renal
  syndrome?
• 19. How can you differentiate hepato-renal
  syndrome from other causes of renal failure
  commonly found in the ICU? What are the
  diagnostic criteria for hepatorenal failure?
• 20. What treatment options are there for
  hepato-renal syndrome? What are the prognostic
  implications of hepato-renal syndrome?

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Pathophysiology of HRS

• splanchnic vasodilation, possibly due to nitric
  oxide (pathogenesis of ascites), leads to reduced
  GFR, reduced Na excretion.
• increase in the ratio of vasoconstrictor
  thromboxanes to vasodilator prostaglandins may
  lead to renal ischemia.
• Other potential, although unproven, mediating
  factors in the renal vasoconstriction include
  endotoxemia (due, at least in part, to lack of
  hepatic removal), endothelin, the release of
  false neurotransmitters, and increased renal
  sympathetic tone (induced in part by an
  hepatorenal reflex that is activated by elevated
  hepatic sinusoidal pressure)

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Diagnostic criteria for HRS

1. Chronic or acute hepatic disease with advanced
   hepatic failure and portal hypertension
2. A plasma creatinine concentration above 133
   µmol/L that progresses over days to weeks. As
   noted above, the rise in plasma creatinine with
   reductions in glomerular filtration rate may be
   minimized by the marked reduction in creatinine
   production.
3. The absence of any other apparent cause for the
   renal disease, including shock, ongoing bacterial
   infection, current or recent treatment with
   nephrotoxic drugs, and the absence of
   ultrasonographic evidence of obstruction or
   parenchymal renal disease. It is particularly
   important to exclude spontaneous bacterial
   peritonitis, which is complicated by acute renal
   failure that may be reversible in 30 to 40
   percent of patients.
4. Urine red cell excretion of less than 50 cells
   per high power field (when no urinary catheter is
   in place) and protein excretion less than 500
   mg/day.
5. Lack of improvement in renal function after
   volume expansion with intravenous albumin (1 g/kg
   of body weight per day up to 100 g/day) for at
   least two days and withdrawal of diuretics.

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Treatment

• Prevention
• SBP dose of IV albumin (1.5 g/kg) at time of
  diagnosis, and another dose on third day of abx
  may reduce mortality.
• Alcoholic hepatitis pentoxifylline may improve
  survival.
• Severe liver disease with cirrhosis and impaired
  renal function norfloxacin.
• Active treatment
• Correct underlying hepatic disease eg.
  abstinence from EtOH in cirrhosis, or tx with
  lamivudine in Hep B.
• Liver transplant
• Midodrine and octreotide titrated to increase MAP
  by 15 mmHg reduces endogenous vasodilator
  release, and causes systemic vasoconstriction.
  Multiple studies show survival benefit.
• IV albumin at approximately 50 g/day for three or
  more days.

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Pentoxifylline

• is a tri-substituted xanthine unlike
  theophylline, is a hemorrheologic agent, i.e. an
  agent that affects blood viscosity.
• Its used commonly for claudication sympotoms.
• In one four-week study, 101 patients with severe
  alcoholic hepatitis were randomly assigned to
  pentoxifylline (400 mg orally three times daily)
  or placebo. Short-term survival was significantly
  better with active therapy (25 versus 46 percent,
  respectively).

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Naisans baaack..

• You successfully initiate CVVHD. Your annoying GI
  keener suggests talking to the transplant team?
• 21. What are the indications for liver
  transplant in ALF? What are the
  contra-indications?

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Transplant criteria

• The critical criteria include
• a) age gt18 yrs
• b) a life expectancy without a liver transplant
  of lt7 days
• c) onset of hepatic encephalopathy within 8 wks
  of the first symptoms of liver disease
• d) the absence of preexisting liver disease
• e) residence in an intensive care unit
• f) at least one of the following
• Ventilator dependence,
• Requiring renal replacement therapy,
• An INR gt2.0.

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Transplant contra-indications

• Active drug or alcohol abuse,
• Active suicidal ideation, or history of a
  previous suicide attempt
• Specific exclusion criteria for liver
  transplantation have not been formally
  established, although it is generally agreed that
  active sepsis and extrahepatic malignancy are
  absolute contraindications. Still controversial
  are conditions such as HIV infection in the
  absence of acquired immunodeficiency syndrome,
  large-size hepatocellular cancer (gt5 cm), or
  cholangiocarcinoma

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Liver transplant (cont)

• Sue goes onto transplantation and successfully
  undergoes orthotropic liver transplantation.
• 22. What are the complications that you can
  expect in the post op liver transplant patient?
• 23. What are some of the overarching themes of
  management of the fresh post-transplant liver?
• 24. Is there any evidence for using albumin as
  the resuscitation fluid post liver transplant?

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Post op liver transplant complications

• Primary Nonfunction
• Intra-abdominal Bleeding
• Vascular Thrombosis
• Biliary Leak
• Infections
• Acute Rejection