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Unformatted text preview: Pediatric Resident Curriculum for the PICU UTHSCSA Fulminant Hepatic Failure &
Liver Transplantation Pediatric Resident Curriculum for the PICU UTHSCSA Fulminant Hepatic Failure
Definition Altered mental status with coagulopathy in setting of acute liver disease. Hepatic encephalopathy occurring within 8 weeks of onset of illness defines FHF. Pediatric Resident Curriculum for the PICU UTHSCSA Etiology
• Viral hepatitis
– Hepatitis A rarely
– Hepatitis B appx 1% of hep B
– Hep C probably not, but ??
– Hep D delta agent coinfects with Hep B
– Hep E
– CMV, HSV • Toxins – Carbon tetrachloride
– Amanita phalloides (antidote penicillin and silybin)
– Industrial cleaning solvents Pediatric Resident Curriculum for the PICU UTHSCSA Etiology
– Acetaminophen in Tx doses with alcohol
– Idiosyncratic reaction halothane, sulfonamides, phenytoin, and others. Vascular
— Heart failure centrolobular necrosis
— Sinusoidal obstruction secondary to metastatic dz
— Budd Chiari
— Venoocclusive disease Pediatric Resident Curriculum for the PICU UTHSCSA Pathology
• Viral, toxic hepatocellular necrosis, diffuse, extensive, resulting in caseating necrosis. • Cardiac similar, with particularly severe centrolobular necrosis from higher intravascular pressure and watershed effect. Blood flows from portal triad (hepatic artery and portal vein) to central veins to hepatic vein. With poor cardiac output, splanchnic flow markedly decreased, resulting in markedly decreased portal flow, which is a large proportion of flow to liver. Pediatric Resident Curriculum for the PICU UTHSCSA Pathology
• Fatty liver of pregnancy and Reye’s show microvesicular collections of fat in hepatocytes and much less necrosis.
• Special stains iron in hemochromatosis, copper in Wilson’s, etc. Pediatric Resident Curriculum for the PICU UTHSCSA Clinical Presentation
• Typically nonspecific symptoms, nausea, malaise, jaundice, altered mental status, coma all over a few days.
• The altered mental status occasionally precedes clinical jaundice.
• Mental status changes often start with agitation, delusions, irritability before progressing to lethargy, stupor, and coma. Pediatric Resident Curriculum for the PICU UTHSCSA Clinical Presentation
• Transaminases usually high (>1000)
• Bilirubin usually mixed hyperbilirubinemia
• Ammonia usually elevated
• Coagulopathy with prolonged PT, PTT, decreased factors
• Low level DIC
• Low level fibrinolysis
• Respiratory alkalosis
• Metabolic acidosis, increased lactate UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Etiology Etiology uncertain. Suggested mechanisms:
Depressed neural energy metabolism but autopsied animals show no changes of ischemia
Decreased hepatic clearance of neuro toxic substances Pediatric Resident Curriculum for the PICU UTHSCSA Hepatic Encephalopathy Neurotoxins Ammonia correlates poorly with encephalopathy
Amino acids aromatic and straight chain aa are increased in liver failure tryptophan may be preferentially transported into CNS • Methionine, mercaptans
• Gamma aminobutyric acid (GABA) this is an inhibitory neurotransmitter. GABA receptor is site of benzodiazepine action. GABA levels and endogenous benzodiazepines are elevated in hepatic failure. Enteric bacteria produce GABA and this may be absorbed across gut. Flumazenil anecdotally improves encephalopathy.
• UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Grading System
• Grade 0 Normal
Grade I Altered spatial orientation, sleep patterns, and affect • Grade II Drowsy but arousable, slurred speech, confusion, and asterixis
• Grade III Stuporous but responsive to painful stimuli
• Grade IV Unresponsive, with or without decorticate or decerebrate posturing UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Cerebral Edema • Etiology uncertain Correlated with degree of encephalopathy. Occurs in 50 85% of patients with late grade 3 to grade 4 encephalopathy.
• Evidence of altered blood brain barrier
• Impaired cellular Na+K+ ATP pump resulting in glial cell edema
• Inappropriate cerebral vasodilatation UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Cerebral Edema Signs of increased ICP (may not be present until late)
– Increased muscle tone
– Increased DTRs
– Dilated sluggish pupils
– Cushing reflex (very late) UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Treatment • Protect airway Most patients with grade III to IV should be intubated.
• Avoid precipitants:
– Excessive protein load particularly in form of GI bleed
– CNS depressants
– Electrolyte abnormalities – Respiratory alkalosis UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Treatment • Prevent hypotension • Lactulose although not shown to work well in FHF and felt to be less effective than in chronic liver disease.
• Branch chain amino acids theoretically appealing but studies are mixed results most authors feel they are not helpful. UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Treatment • Beware and intervene for cerebral edema
• ICP monitoring somewhat controversial because studies have not shown altered outcome and risk is significant because of coagulopathy. Reasons favoring monitoring: – Intracranial hypertension is erratic and can develop rapidly with few clinical signs
– Monitoring allows for early detection and minuteto
minute titration of therapy
– Cerebral perfusion pressure is prognostic sign and would spare poor risk patients a transplant (CPP < 50 for 2 hrs)
– Allows management of intraoperative events UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Treatment Consider ICP monitoring if
– Grade 3 4 with posturing
– PT corrected to < 20, platelets corrected
– Patient is listed for transplant and felt to be a candidate for transplant UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Treatment • Mannitol shown to be effective in improving outcome
• Hyperventilation probably useful for acute spikes in ICP. Has not been shown to be effective in hepatic failure. Concerns about effect on cerebral perfusion warrant consideration.
• Elevation of head ?? What is effect on CPP? Keep head midline, perhaps 20 30 degrees of elevation.
• Pentobarbital coma, hypothermia unproven, occasionally may be indicated.
• Steroids no good, may worsen outcome UTHSCSA Pediatric Resident Curriculum for the PICU Hepatic Encephalopathy Treatment Get better liver or Get liver better Pediatric Resident Curriculum for the PICU UTHSCSA Coagulopathy
• Decreased production of liver clotting factors (all but factor VIII), fibrinogen, ATIII, thrombocytopenia (splenic sequestration, low level DIC, other)
• PT/PTT prolonged
• Factors V and VII often followed as they are relatively labile
• Factor VIII normal or increased if just liver failure, decreased in DIC
• Euglobulin clot lysis time abnormal in primary fibrinolysis Pediatric Resident Curriculum for the PICU UTHSCSA Coagulopathy Management
Avoid nasal intubation
Beware with surgical procedures, line placement, etc.
FFP Not shown to be effective in changing bleeding risk (?). Most authors discourage routine attempts at normalizing PT. Use for active bleeding and procedures.
• Antifibrinolytics (Amicar) may be considered if bleeding and primary fibrinolysis is occurring. Caution with DIC.
• Maintain platelet count >50K, or 100K if bleeding
• Pediatric Resident Curriculum for the PICU UTHSCSA Metabolic Considerations
• Hypoglycemia decreased hepatic glycogen stores, impaired gluconeogenesis results in hyperinsulin state and insulin resistance. There is impaired glucose homeostasis and hypoglycemia.
∀ ↑↑glucagon, ↑insulin secondary to decreased hepatic clearance, leads to decreased insulin/glucagon ratio, which favors catabolism.
• Aromatic amino acids are increased, probably because of decreased hepatic clearance. Pediatric Resident Curriculum for the PICU UTHSCSA Metabolic Considerations
• Branch chain amino acids are cleared into skeletal muscle and are not elevated, so AAA > BCAA
• AAA and BCAA compete for entry to CNS. AAA, particularly tryptophan is converted to serotonin and other possible false neurotransmitters.
• Supplementing BCAA theoretically may improve encephalopathy, but studies give mixed results and most authorities feel the evidence does not favor their use for this indication.
• BCAA may also be more readily available for nutrition since the hyperinsulin state favors uptake by muscle, which is not true for other AA. Evidence indicates less catabolism and less muscle wasting with use of BCAA. Pediatric Resident Curriculum for the PICU UTHSCSA Hemodynamic Effects
Increased cardiac output
Decreased systemic vascular resistance
Decreased oxygen extraction ratio and decreased consumption despite increased delivery
• Oxygen consumption often becomes supply dependent.
• Lactic acidosis secondary to anaerobic metabolism ensues.
• Lactic acidosis has been shown to herald a poor prognosis.
• Pediatric Resident Curriculum for the PICU UTHSCSA Renal Effects
Renal failure common Prerenal azotemia Acute tubular necrosis Hepatorenal syndrome Pediatric Resident Curriculum for the PICU UTHSCSA Hepatorenal Syndrome Etiology uncertain prominent theory is that low SVR results in “arterial underfilling” and subsequent increase in renin, aldosterone, ADH, and norepinephrine resulting in renal arteriole vasoconstriction. Renal vasodilatory prostaglandins are important to attenuate this, so that when NSAIDS are given this compensation is lost. NSAIDS are known precipitants of hepatorenal syndrome.
Diagnosis in absence of hypovolemia see very low urine sodium, normal urine sediment. Exclude other causes.
Treatment recover hepatic function, otherwise the renal failure is very recalcitrant. Dialysis as needed and indicated. Pediatric Resident Curriculum for the PICU UTHSCSA Respiratory Effects
Respiratory failure can occur by several mechanisms:
• Neurogenic pulmonary edema
• Fluid overload because of hyperaldosterone and increased ADH with conservation of salt and water
• ARDS secondary to sepsis or MSOF
• Also,some have suggested capillary leak affecting pulmonary and CNS vasculature
• Hepatopulmonary syndrome Pediatric Resident Curriculum for the PICU UTHSCSA Hepatopulmonary syndrome
• Hypoxemia associated with chronic liver disease. • Thought to be secondary to intrapulmonary vascular dilatations with av shunting as well as diffusion block because of dilated capillaries.
• Sometimes, but not always resolves with transplant Pediatric Resident Curriculum for the PICU UTHSCSA Infectious Disease Issues
• Impaired host defenses
Defective opsonic activity
Impaired PMN function
Impaired cell and humoral immunity
Decrease clearance of enteric organisms by hepatic RES
• Ascites good culture medium
• Invasive lines, ETT, etc
• Pediatric Resident Curriculum for the PICU UTHSCSA Infectious Disease Issues
• Infection risk: 80% of patients had documented bacterial or fungal invasive infections, with a suspicion of infection in half the remaining patients. 25% had blood stream infection, with a respiratory source predominating in the remainder.
• Organisms: Predominantly gram positive (strep and staph), gram negatives also occur. 30% have fungal infection.
• Prophylactic antibiotics have not been shown to change outcome and most authors recommend meticulous surveillance and aggressive intervention with antibiotics when infection suspected. UTHSCSA Pediatric Resident Curriculum for the PICU Fulminant Hepatic Failure Therapy “Authors tend to publish isolated cases with a favorable outcome attributed to a given therapy, but not to publish cases in which therapy has failed. In fact it might be argued that the best future one can wish for a sufferer from SAHF (sudden acute hepatic failure) is to undergo a new treatment and have his case published ‘be published or perish!’ “
Benhanou, 1972 UTHSCSA Pediatric Resident Curriculum for the PICU Fulminant Hepatic Failure Therapy • Tried but failed
• Insulin and glucagon to stimulate regeneration
• Prostaglandin E
• Charcoal hemoperfusion
• Plasma exchange
• Liver transplantation best results. Greater than 60% one year survival in adult patients with acute liver failure. Only 10% of patients are deemed candidates and successfully supported until transplantation. UTHSCSA Pediatric Resident Curriculum for the PICU Fulminant Hepatic Failure Therapy • ELAD (extracorporeal liver assist device) most acute liver failure is thought to be recoverable if patient survives long enough. Most patients either die or have regeneration and normal liver function. Goal would be to:
• Support patient while awaiting recovery thus avoiding transplant and its risks short and long term
• Stabilize patient while awaiting transplant
• ELAD seems promising in animal studies and has been used on a few patients with encouraging results. Not yet a proven therapy. UTHSCSA Pediatric Resident Curriculum for the PICU Kings College, London Criteria for Predicting Death and Need for Liver Transplantation
• Depends on etiology
• For Acetaminophen poisoning – pH < 7.3 (irrespective grade of encephalopathy)
– or PT > 100 seconds and serum creatinine > 3.4 in patients with grade III or IV encephalopathy UTHSCSA Pediatric Resident Curriculum for the PICU Kings College, London Criteria for Predicting Death and Need for Liver Transplantation
• All other etiologies
– PT > 100 seconds (irrespective of grade of encephalopathy)
• OR any 3 of the following
– Age < 10 years or > 40
– Liver failure caused by nonA, nonB hepatitis, halothane, or idiosyncratic drug rxn
– Jaundice for > 10 days prior to encephalopathy
– PT > 50 seconds
– Serum bilirubin > 17.5 UTHSCSA Pediatric Resident Curriculum for the PICU United Network for Organ Sharing (UNOS) Status 1 most urgent level • Rapid development of grade 3 4 encephalopathy
• Prothrombin time > 25 sec
• On vasopressors or ventilatory support
• Have primary graft nonfunction
• Are expected to live less than 7 days without a transplant
• Inborn error of metabolism with metabolites that are toxic to the CNS UTHSCSA Pediatric Resident Curriculum for the PICU Transplantation in FHF Contraindications
• Uncontrolled sepsis
• Multiorgan system failure
• Irreversible brain damage
• By neurologic exam
• Imaging studies
• Sustained ICP > 50, or
• CPP < 40 for 1 2 hours UTHSCSA Pediatric Resident Curriculum for the PICU Fulminant Hepatic Failure Recommended Readings
• Lee WM. Acute Liver Failure. N Engl J Med 1993;329:1862 1872.
• Caraceni P, and Van Thiel DH. Acute Liver Failure. Lancet 1995;345:1639.
• Riordan SM, and Williams R. Treatment of Hepatic Encephalopathy. N Engl J Med 1997;337:4739.
• Whitington PF, et al. Pediatric Liver Transplantation. Seminars in Liver Disease 1994; 14:303317. ...
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- Fall '11