15 Hepatic Failure

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Fulminant Hepatic FailureFulminant Hepatic Failure

in Childrenin ChildrenJohn F. Sommerauer MD, FRCPC

Children¶s Mercy Hospital

University of Missouri-Kansas City

Sue Sreedhar MDMedical College of Virginia

Virginia Commonwealth University



Hepatic RegenerationHepatic Regeneration

Regenerating power of the liver is

well known

Perpetually regenerating liver in

Greek mythology - Prometheus



Liver FunctionsLiver Functions

Protein synthesis

Excretion of

metabolic wastesOxidative

phosphorylation

Breakdown of glycogen

Fatty acid oxidation

Synthesis of

cholesterol & bile

acidsEnzymes

NADPH

Cytochrome P-450 Cytochrome

reductase systems



Necessities for NormalL

iver FunctionNecessities for NormalL

iver Function

Adequate blood flow

20 ± 40% of cardiac output with only ~25% of

blood entering through the Hepatic Artery

Majority of blood flow comes from the portal

venous system

Oxygen Hepatocyte damage from hypoxia/hypotension

Low-pressure biliary system



Fulminant Hepatic Failure: BackgroundFulminant Hepatic Failure: Background

Fulminant hepatic failure in

children is a relatively rare clinical

syndrome - 2,000 patients/ yr. in theUSA (total ± adult and children)

Mortality rate is high- 60 to 80%

Challenge for the health care team



FHF: DefinitionsFHF: Definitions

FHFFHF - acute liver failure & encephalopathy within 8

weeks of signs and symptoms & without history or

physical evidence of chronic liver disease

Subfulminant HFSubfulminant HF- acute liver failure & encephalopathy

8 and 24 weeks after the onset of signs & symptoms

A Classification based on the time interval from the

onset of jaundice to the development of encephalopathy

Hyperacute LFHyperacute LF - within 7days

Acute LFAcute LF - within 8 to 28 days

Subacute LFSubacute LF - between 5 to 28 weeks



FHF: EtiologyFHF: Etiology -- InfectionsInfections

ViralViral

Hepatitis A, B,

C,, E, non-A,non-B, non-C

CMV

Herpes simplex Enterovirus

EBV

Parvovirus

HHV 6

Varicella ± zoster

Adenovirus

Leptospirosis



FHF: EtiologyFHF: Etiology ± ±Drugs and ToxinsDrugs and Toxins

ToxicityToxicity

Acetaminophen

Carbontetrachloride

Iron

Vitamin A

Mushrooms

Amanitaphalloides

Idiosyncratic reactionIdiosyncratic reaction

Phenytoin

Valproic acid INH

Halothane



FHF: EtiologyFHF: Etiology ± ± Metabolic DiseaseMetabolic Disease

Tyrosinemia

Galactosemia

Alpha-1 antitrypsindeficiency

Fatty acid oxidationdefects

Wilson¶s diseaseNeonatal iron storage

disease

Niemann-Pick disease

Hereditary fructose

intoleranceCF

Reye¶s syndrome

Mitochondrial electron

transport chain defectsFatty liver of pregnancy



FHF: Mechanisms of hepatic injuryFHF: Mechanisms of hepatic injury

Direct hepatocellular injury

Herpes virus family - HAV, HBV, HCV

Toxic or reactive metabolites - acetaminophen

Toxic metabolites of compounds - metabolic diseases

Immune mediated hepatocellular injury

Viral infections

Drug hepatotoxicity (dihydralazine, halothane)

Ischemic hepatocellular injury - shock states,

SIRS



FHF: Clinical FeaturesFHF: Clinical Features

FHF syndrome occurs from either acute

necrosis of a large mass of hepatocytes or the

sudden loss of hepatocellular function

Synthetic, excretory & metabolic functions are

impaired

Bacterial translocation, endotoxemia, activation

of macrophages, cytokine release, initiation of inflammatory cascade, circulatory compromise,

tissue hypoxia & end organ injury (SIRS)



Signs & SymptomsSigns & Symptoms

N/V, fatigue, anorexia, jaundice, ascites

Altered behavior (encephalopathy)

Euphoria, belligerence, foul language

Altered sleep, confusion, slurred speech,

disorientation, hyperventilation, lethargy,

hyperreflexia, unarousable, posturing

Increased bruisibility



Circulatory changesCirculatory changes

Hyperdynamic circulation

High cardiac output, low SVR

Pulmonary arteriovenous shunting

resulting in hypoxemia

Elevated portal pressure

Sodium and fluid retention

Marked renal vasoconstriction, ATN



FHF: Clinical FeaturesFHF: Clinical Features

Hepatic injury ± elevated transaminases (ALT,AST)

Hepatic dysfunction

hypoglycemia

low cholesterol

coagulopathy (PT> 20 sec.) not correctable with

parenteral vitamin K

progressively rising bilirubin

hyperammonemia and encephalopathy

Absence of chronic liver disease - malnutrition, portal

hypertension, rickets, spider angioma, clubbing



FHF: Common ComplicationsFHF: Common Complications

Encephalopathy

Cerebral edema

Increased intracranial

pressure*

Hemorrhage, DIC,

Coagulopathy*

Cardiac & circulatory

instability

Pulmonary failure

Renal failure, MOSF,

MODS*

Hypoglycemia

(profound)

Acid-base

derangements

Sepsis*

* Most common causes of death



FHF: Hepatic encephalopathyFHF: Hepatic encephalopathy

HE ± is a reversible neuropsychiatric

syndrome - depressed LOC, seizures &/or

multifocal muscle twitching prior to coma

Absence of other factors that suppress brain

80% patients have cerebral (cytotoxic)

edema30-50% of patients have raised ICP



Pathophysiology of Cerebral EdemaPathophysiology of Cerebral Edema

Glutamine hypothesis

Ammonia detoxified in the cerebral astrocytes to

Glutamine which in turn is synthesized to glutamate

Osmotic effect of Glutamine

HE a result of Glutamine/ Glutamate cycling

dysregulation

? Use of Glutamine/ Glutamate inhibitors

Short chain fatty acids & mercaptan

Cerebral vasodilatation hypothesis, increased CBF

Blei: J. Hepatology 1999; 31:771



FHF: Goals of CareFHF: Goals of Care

Perform a comprehensive evaluation -

diagnosis & specific treatment (if available)

To prolong life, allow time for either nativeliver recovery (regeneration) or for donor

organ procurement & liver transplantation

Intervene with supportive care measures toprevent & ameliorate the complications of

FHF, and treat catastrophic events



FHF: History and ManagementFHF: History and Management

History - risk factors for hepatitis, HIV, H/O anesthesia or

ingestion, depression/suicidal behavior, initiation of

galactose or fructose, neuropsychiatric symptoms

PMH - chronic liver disease Family history - liver disease, neurologic disease,

emphysema, hepatitis, deaths in infancy

Physical exam - chronic liver disease, complications

Evaluation multidisciplinary team, early referral to transplant

center

a broad diagnostic evaluation unless clear etiology



FHF: Etiology and treatmentFHF: Etiology and treatment

Specific treatment - directed at the cause

Herpes and CMV - acyclovir /ganciclovir

Tyrosinemia - NTBC (nitrotrifluoromethylbenzoyl

cyclohexanedione)

N-acetylcysteine - acetaminophen

Neonatal iron storage disease - antioxidant and

iron-chelating cocktail (Se, Vit. E, n-acetylcysteine,

PGE1 and deferoxamine) Prevent further toxic injury: Acetominophen,

fructosemia, galactosemia

Early decision for transplant: Wilson¶s disease



FHF:Management and TreatmentFHF:Management and Treatment

Laboratory evaluation: Tests for

cause of FHF

functional status of the liver and other organs

Liver Biopsy - percutaneous needle, open surgical,

percutaneous jugular transvenous hepatic biopsy

CNS - EEG, VEP, SEP, CT scan of brain, MRI &

MRS

Monitoring: for complications

Radiology: CXR, Doppler abdominal sonography,

ECHO (if appropriate), CT scan of brain



FHF: Supportive treatmentFHF: Supportive treatment

Maintain glucose (avoid hypoglycemia - D10W/D30W IV)

Maintain electrolytes (Na restricted, Hypophosphatemia -

KPhos infusions, Treat low K+, Ca++)

Maintain euvolemia with CVP monitoring - Diuresis withalbumin/blood products, fluid restriction

Maintain acid-base balance

Coagulation homeostasis

Hemodynamic & respiratory support to allow time for liver

regeneration or to bridge to liver transplantation

Prevent complications i.e. hemorrhage, cerebral edema, high

ICP



FHF:Management and TreatmentFHF:Management and Treatment

Nutrition:

NPO (initial stage)

Low Na+, low protein diet (stable - stage 1 or 2 HE)

TPN - use highest concentration of glucose tolerated

Amino acid (trophamine) 0.5 to 1.0 g/kg/day

Lipids (20% solution) 0.5 - 3 g/kg/day, ( triglycerides

< 250 mg/dl ) GI prophylaxis - H2 receptor antagonist - maintain

gastric pH > 4.0



FHF:Management of CoagulopathyFHF:Management of Coagulopathy

Vitamin K - 0.2 mg/kg/day (max. 10 mg) iv X 3

days, then every other day

Maintain PT at 20 - 25 sec (if no active bleeding)Maintain PT at < 20 sec ( if active bleeding )

Maintain Platelet count > 50,000 / ul

Maintain Hematocrit > 30%

FFP infusions for active bleeding

Plasmapheresis should be considered when

there is severe coagulopathy and/or bleeding



FHF:Management of EncephalopathyFHF:Management of Encephalopathy

Lactulose 0.5 ml/kg/dose (max. 30 ml/dose) PO/NG q.i.d.

for 3-4 loose stools (contraindicated in intestinal ileus )

Neomycin (vancomycin or metronidazole) not indicated -

not efficacious, significant GI absorption with toxicity

Sedation and Analgesia:

Avoid agents which may exacerbate HE

Agents initiated at low doses and intermittently

benzodiazepines - midazolam

opiates - fentanyl, remifentanyl

Continuous infusions are contraindicated



FHF: Intracranial HypertensionFHF: Intracranial Hypertension

ICP monitoring: controversial

signs and symptoms of raised ICP

stage 4 HE, rapidly progressing stage 3 HE

cerebral edema on CT scan (plasmapheresis prior to

catheter placement)

ICP therapy - ICP < 20 mmHg & CPP > 50 mmHg

Caution when using osmolar therapy

Barbiturate coma may be used if necessary

EEG monitoring

CVVH, plasmapheresis



FHF:FHF: PlasmapheresisPlasmapheresis

Double blood volumeDouble blood volume

exchangeexchange (1 -2 /day)

stage 3 or stage 4 HE active hemorrhage

severe coagulopathy

raised ICP

prior to procedures prior to OLTx with

ABO incompatible

graft

EffectEffect

reduces NH3

corrects PT controls

intravascular

volume

cerebral edemaor HE?

(inconsistent )



FHF: Bridge to transplantFHF: Bridge to transplant

Continuous veno-venous

hemofiltration

Bio-artificial liver support system

Liver cell transplantation

These techniques remain experimental



FHF: Extracorporeal liver support systemsFHF: Extracorporeal liver support systems

Non biologic systems:Non biologic systems:

- CVVH, charcoal hemoperfusion, plasmapheresis

Biologic systems:Biologic systems:

- Extracorporeal circuits utilizing a hollow fiber

cartridge loaded with biologically active hepatocytes:

- human hepatoma cell (ELAD)

- porcine hepatocytes (BAL)

- Whole liver perfusion systems:

- human livers

- porcine livers - unaltered or transgenic



BioBio--artificial liver support systemartificial liver support system

Extracorporeal liver perfusion via an

oxygenated heparinized circuit

Neurologic state & liver functionimprove within hours on the circuit

Decreased ICP, decreased pressor

support requirement, improved urine

output

Goss, Arch Surg 1998; 133:839



Liver cell transplantation: ExperimentalLiver cell transplantation: Experimental

Provides temporarymetabolic support

Transplanted intonative liver orspleen, acts as anectopic liver

Sustains life untildonor becomesavailable

Harvested liver cellsfrozen at -90o c,stored in liquidnitrogen

Percutaneoustranshepatic or

femoral arterialapproach to accessthe splenic artery



Hepatocyte transplantation: PrinciplesHepatocyte transplantation: Principles

Hepatocytes are isolated from cadaveric liver grafts

Hepatocytes are infused into the portal vein - seed

the native liver

Standard immunosuppression is required

Hepatocytes proliferate and express differentiated

function

Provide temporary liver function in models of liverfailure

Correct metabolic defects



Hepatocyte transplantation: AdvantagesHepatocyte transplantation: Advantages

Act as a bridge to native

liver recovery

If recovery occurs, the

immunosuppression maybe discontinued & graft

allowed to atrophy to

avoid long term

immunosuppression Reduced cost

Increase the donor pool

for other recipients

In metabolic diseases -

can provide the

necessary enzymes to

correct the deficiencyand yet allows the

patient to continue to

utilize their native liver

Hepatocytes could begenetically manipulated

Multiple infusions

possible if needed



FHF: Auxiliary liver transplantation (AOLT)FHF: Auxiliary liver transplantation (AOLT)

Potential Advantages:

AOLT acts as a bridge to native liver recovery

if recovery occurs, immunosuppression may bediscontinued and the graft removed or allowed to

atrophy to avoid long term immunosuppression

in metabolic diseases AOLT can provide the

necessary enzymes to correct the deficiency andyet allows the patient to continue to utilize their

native liver



Hepatic Transplantation: AuxiliaryHepatic Transplantation: Auxiliary



Fulminant Hepatic Failure in Children:Fulminant Hepatic Failure in Children:

Predictive Factors and OutcomesPredictive Factors and OutcomesOverall survival for patients with FHF and

stage 3 or 4 HE has increased from 20% to

50% over past 2 decades. (Without transplant)

The best independent predictor of outcome isthe etiology of the FHF.

Survival

acetaminophen 40 - 64%

Non-ABC hepatitis < 20%Wilson¶s disease < 5%

Without OLTx - survival ~30%



FHF: Predictive Factors & OutcomesFHF: Predictive Factors & Outcomes

Predictive factors of poor outcome:

Several studies combined

etiology stage 3 or 4 coma (HE)

marked coagulopathy (PT > 100 sec, INR > 4)

factor V or factor VII levels < 15%

cerebral edema and raised ICP GI hemorrhage

MOF



FHF: Indications for TransplantFHF: Indications for Transplant

3rd to 4th degree encephalopathy

Rising bilirubin (> 20mg/100ml)

Falling transaminases

Coagulopathy with prolonged PT >

100 seconds and Factor II, V, VII

decreased to < 20% of normal values

Acute renal decompensation



Status 1 - acute or chronic liver failure

(CLD), life expectancy < 7days without LTx

and 1 of the following:

FHF On ventilator

Upper GI bleed

Stage 3 or 4 HE

Refractory ascites Biliary sepsis

Hepatic artery thrombosis or Primary non-function

Hepatorenal syndrome

FHF:Hepatic TransplantationFHF:Hepatic Transplantation ± ± UNOSUNOS

Status designation in pediatricsStatus designation in pediatrics



Whole Organ Liver TransplantationWhole Organ Liver Transplantation



Reduced Sized Liver Transplantation: AnatomyReduced Sized Liver Transplantation: Anatomy



Indications for TransplantationIndications for Transplantation-- all patientsall patients

Biliary

hypoplasia

5%

Hepatitis

5%

Other

16%

Idiopathic

cirrhosis

6%Acute liver

necrosis

11%Metabolic

13%

Biliaryatresia

44%



Common causes leading to liver transplantCommon causes leading to liver transplant

Neonatal hepatitis in <4 month

Biliary atresia in < 3 years

Acetaminophen toxicity in teenagers

Metabolic disorders, acute liver necrosis,

idiopathic cirrhosis, biliary hypoplasia,

autoimmune hepatitis, tumors, CF



Status 1Status 1 -- FHF vs. Chronic liver disease patients: DiagnosisFHF vs. Chronic liver disease patients: Diagnosis

HF= 1

-CLD=

iral Hep. iliar tresia 1

o in C H

eta olic Dis. eonatal Hep.

cute e ection 1 C stic Fi rosis 1

n no n ther



Status 1Status 1 -- FHF vs. Chronic liver disease patients: Post LTxFHF vs. Chronic liver disease patients: Post LTx

15 Hepatic Failure

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