FULMINENT HEPATIC FAILURE

PICU Perspective
 HISTORICALEVENTS
HISTORICAL EVENTS

Giovanni Battista Morgagni in 1765

Lucké and Mallory 1946
The pathologic basis of the massive hepatic necrosis was described in
detail
Trey & Davidson, 1970
“ Potentially reversible condition as a consequence of liver disease with
onset of encephalopathy within 8 weeks in the absence of pre existing
liver disease”
Hyperacute, acute & subacute
Kings college group definition

Not always applicable to children

 DEFINITION
DEFINITION
Pediatric Angle ?
Pediatric Angle ?

O’Grady et al, ALF, Redifined Lancet 1993

Not always applicable to children

KINGSCOLLEGE
KINGS COLLEGECRITERIA
CRITERIA

Emphasis: Biochemical

Again NO Pediatric Perspectives

 CHILDRENARE
CHILDREN ARE DIFFERENT
DIFFERENT
Druand, J Pediatr 2001
Druand, J Pediatr 2001

ENC is difficult to assess.

ENC may not develop until terminal stages.

“Poor outcome can occur without ENC” (Squires, J Pediatr 2006)

 PALFSGCriteria
PALFSG Criteria

PALF Study Group Began in 2000; Independently funded

Multi-center, Multi-national study
• United States
• Canada (Toronto)
• United Kingdom
Data
• Clinical and Laboratory data, plus serum, daily for 7 days
• Treatment trial
NAC for non-acetaminophen ALF
 PALFSGCriteria
PALFSG Criteria

The currently accepted definition in children

1. Biochemical evidence of acute liver injury (usually <8 wk
duration)
2. No evidence of chronic liver disease.
3. Hepatic-based coagulopathy

PT >15 sec or international normalized ratio (INR) >1.5 “not

corrected by vitamin K” in the presence of clinical hepatic
encephalopathy
oR
PT >20 sec or INR >2 regardless of the presence of
clinical hepatic encephalopathy.
Recommends PALFSG definition
ETIOLOGY
ETIOLOGY
CAUSES OF
CAUSES OFFHF
FHF
Indianscenario
Indian scenario
Metabolic Conditions Associated With ALF in Children
Metabolic Conditions Associated With ALF in Children

Wilson’s disease
Neonatal haemochromatosis
Tyrosinemia Type 1
Mitochondrial disorders
Hereditary fructose intolerance
Alpha-1 anti-trypsin deficiency
Niemann - Pick disease
Indian childhood cirrhosis
Glycogen storage disease Type IV.
 Drugs Associated
Drugs AssociatedWith
WithFHF
FHFin
inChildren
Children

Acetaminophen
Isoniazid
Halothane
Sodium Valproate
Phenytoin
Nimuselide

Precipitating Factors

Infection/ Persistent fever

Persistent vomiting / hypovolemia
Hepatotoxic drugs
Mixed viral infections / Super-infection
Zinc deficiency
PATHOBIOLOGY
PATHOBIOLOGY
 SYMPTOMATOLOGY
SYMPTOMATOLOGY

History: No major illness, Medical problems

Initail nonspecific prodromal symptomps
Signs of liver failure
Hepatic encephalopathy
EARLYCLINICAL
EARLY CLINICALINDICATORS
INDICATORSOF
OFHE
HE
CLINICALINDICATORS
CLINICAL INDICATORSOF
OFCEREBRAL
CEREBRALEDEMA
EDEMA
HE:Classification
HE: Classification

Rodgers textbook of Ped Intensive Care

 EEGin
EEG inHepatic
HepaticEnceph
Enceph

• Type 1 slow polyrhythmic activity.

5-6 Hz, 3-4 Hz, 1-2 Hz with reactive/
inconsistent EEG pattern
• Type 2 slow theta- delta 3-4 Hz
inconsistent/absent reactivity
• Type 3 1-3 Hz , no reactivity
• Type 4 < 1 Hz, no reactivity
• Type 5 progressive disappearance of activity
DIAGNOSTICPRIORITIZATION
DIAGNOSTIC PRIORITIZATION

Age appropriate
Potentially treatable
Would exclude patient from transplant
 LAB:Basic
LAB: BasicEvaluation
Evaluation

- Cbc - Urea, creatinine

- SGPT/SGOT/bilirubin - Serum protein
- PT/ INR - Ammonia
- Glucose - ABG
- Electrolytes
- Ionized calcium
 LAB:Diagnostic
LAB: DiagnosticEvaluation
Evaluation

• Infection
Hep A,B,C serology, Herpes, enterovirus, adenovirus, CMV; if concerned,
Maternal Serologies for Hep A,B,C
• Metabolic disease
Urine: succinylacetone, reducing substances, organic acids
Blood: ammonia glucose lact Blood: ammonia, glucose, lactate ate pyruvate
carnitine , pyruvate, carnitine, ferritin, RBC Gal-1-phosphate uridyl transferase
Skin for fibroblasts: fatty acid oxidation, Niemann-Pick type C
Newborn screen results may be helpful, but specific tests needed
• Iron Storage Disease
Ferritin
Buccal Mucosal biopsy
MRI to identify iron stores
. Autoimmune Workup
 SMARTINTERPRETAION
SMART INTERPRETAION

• Serum aminotransferase levels reaching 5000 to

10,000 IU/L,

• Aminotransferase levels decrease rapidly in

response to stabilization of the circulation.

• The rapid decrease in aminotransferase levels in

the absence of increasing serum bilirubin or
worsening coagulopathy.
 INTERPRETINGPT
INTERPRETING PT

“Inexpensive, readily available” >> Lets Transfuse

• Asseses Pro-coagulant factors synthesized by the liver

• Anti-coagulant factors (anti-thrombine , protein C, protein S)
not measured by PT are also low in FHF
• Pro- and anti-coagulant factors may be balanced in a disease
Process

Tripodi A, et al Aliment Pharm Thera 2007;26:141

 PT AS A MEASURE OF BLEEDING RISK
PT AS A MEASURE OF BLEEDING RISK

Little or no evidence that PT/INR predicts bleeding risk

In the PALF study 50/671(7.5%) reported any bleeding

Bleeding diathesis in liver disease is complex

Balanced reduction of pro- and anti-coagulant factors
Neutralize bleeding risk
Renal failure, portal hypertension, sepsis may precipitate
bleeding despite maintained PT

Unnecessary prophylactic plasma may produce unforeseen problems

Fluid overload; exacerbate portal hypertension
Transfusion related acute lung injury

Tripodi A, et al Aliment Pharm Thera 2007;26:141

 SHOULDWE
SHOULD WECORRECT
CORRECTINR
INR??

“In the absence of bleeding, No need to correct the INR,

since significant blood loss is rare (<1%) and
correction obscures trends in the INR, an important
marker of prognosis”.
PCMLEVELS
PCM LEVELSand
andNOMOGRAMS
NOMOGRAMS
 SERUMAMMONIA
SERUM AMMONIAIN
INFHF
FHF

• Arterial ammonia levels of < 75 mmol rarely develop

intracranial hypertension
• Levels of >100 mmol risk factor for raised ICP and
high-grade HE
• Level of >200 mmol predicts raised ICP.

“The risk of developing ICH is decreased by raising the

serum sodium to 145-155 mEq/L with hypertonic
saline”

31
 LAB:Histology
LAB: Histology

Controll slide
 LAB:Histology
LAB: Histology
Roleof
Role ofliver
liverhistology
histologyin
inthe
themanagement
managementof
ofALF
ALF

“Severity of necrosis may not predict potential liver recovery”

Chenard-Neu MP, et al Hepatology 1996;23:111
 COMPLICATIONS
COMPLICATIONS

CNS
cerebral edema
raised ICP
encephalopathy
seizures
 COMPLICATIONS
COMPLICATIONS

INFECTIOUS
sepsis
septic shock
gram positive
gram negative
fungal
 COMPLICATIONS
COMPLICATIONS

Bleeding
Impaired coagulation
Decreased/ dysfunctional platelets
Decreased fibrinogen
DIC
 COMPLICATIONS
COMPLICATIONS

RENAL
Hepatorenal syndrome
Prerenal AKI
ATN
 FHFAND
FHF ANDPICU
PICUTEAMWORK
TEAMWORK

CEREBR
“ICU care have reduced mortality by 33% - USALF Study”
AL
EDEMA

SEPSIS

MODS

UNDER UMBRELLA OF INVASIVE

& NONINVASIVE MONITORING
ETIOLOGYTARGETED
ETIOLOGY TARGETEDTHERAPY
THERAPY
 CAREIN
CARE INPICU
PICU

The Objective:
Maximize chances of liver regeneration
- meticulous monitoring
- supportive care
- prevent & treat complications
The Goal

Native liver regeneration liver transplantation

 MONITORING
MONITORING

• Vitals continuous
• CNS
Hourly pupils
GCS
Muscle tone
DTR
Grading of HE
 ICPMONITORING
ICP MONITORING
WHY?
WHY?

GOLD
STANDARD
 ICP MONITORING
ICP MONITORING

Ideal location???
Intraventricular- highest risk of bleed
( added therapeutic potential)
Epidural- lowest risk, low accuracy
Subdural- common
Local expertise/ comfort level
 RAISED ICP
RAISED ICP

Quiet room
Minimal stimulus
Infrequent ET suction ( lidocaine)
300 head elevation
Avoid neck rotation/ flexion
Control of fever- cooling/ cold saline
Avoid rigors/ shivering
 RAISED ICP
RAISED ICP

• ICP < 20 mm Hg if monitoring available

• MAP adequate to maintain CPP 50-80
• Avoid higher CPP – may cause cerebral hyperemia
• Avoid hypo/hyperglycemia, hyponatremia,
hypercapnia, hyperlactatemia
 MANNITOLVs
MANNITOL VsHYPERTONIC
HYPERTONICSALINE
SALINE

Increases brain capillary osmolality, drawing water from brain tissue

into capillaries shown to significantly reduce extent of CE & improve
survival

Trials using dexamethasone in advanced ALF have shown little effect

on the frequency of cerebral oedema or survival

‘Controlled trial of dexamethasone and mannitol for the cerebral oedema of

fulminant hepatic failure. Canalese J et al. Gut. 1982 Jul;23(7)’
 MANNITOLVs
MANNITOL VsHYPERTONIC
HYPERTONICSALINE
SALINE

• Mannitol – serum osmolality < 320 mOsm/l

• Limited use once AKI sets in
• Hypertonic saline
Target S.Na 145- 155 mEq/L

Prophylactic use: high serum ammonia, high grade hepatic

encephalopathy, acute renal failure, and/or requirement for vasopressors.

Murphy N et al. Hepatology. 2004 Feb;39(2):464-70.

 ICH-THERAPEUTIC
ICH- THERAPEUTICHYPOTHERMIA
HYPOTHERMIA

Moderate hypothermia 32- 34 C

Reduces brain metabolism
Suppression of subclinical seizures
Normalization of CBF & autoregulation
Reduced delivery of NH3 to brain
Reduced anaerobic glycolysis & oxidative stress in
astrocytes
Reduced glutamate
Reversal of SIRS
 ICH-THERAPEUTIC
ICH- THERAPEUTICHYPOTHERMIA
HYPOTHERMIA

• Using cooling blankets to induce moderate hypothermia (target

core temp. 32–33◦C) can lead to a reduction in ICP, even in patients
unresponsive to mannitol and/or ultrafiltration

Lancet. 1999 Oct 2;354(9185):1164-8.Moderate hypothermia for uncontrolled intracranial hypertension

in acute liver failure.Jalan R, et al
• Improves cardiovascular haemodynamics with reduced
noradrenaline requirements likely related to reduction in arterial
ammonia & brain ammonia extraction & flux

“Used for the treatment of refractory ICH and as a bridge for LT”
 VENTILATIONSUPPORT
VENTILATION SUPPORT

When grade 3 HE develops or when patients with grade 1 or 2 HE

who require sedation and prior to transport
Early elective intubation Vs emergent .
For RSI: Suxamethonium and fentanyl are safe.
Sedation: Morphine or fentanyl.
In suspected brainstem herniation, acute hyperventilation
Lowest level of PEEP that can maintain adequate oxygenation

51
 WHYVENTILATE?
WHY VENTILATE?

Complications of liver disease, such as intra-

abdominal hypertension (IAH) secondary to bowel
oedema or ascites
Pleural effusions
Acute lung injury and acute respiratory distress
syndrome
Depressed level of consciousness.

52
VENTILATION
VENTILATION
Reduce Rx Errors
Reduce Rx Errors
 VENT STRATEGIES
VENT STRATEGIES

Avoid hypoxemia, hypercarbia

Aim for - Normocarbia
Hyperventilation only for sudden ICP surge
Adequate analgesia & sedation
Fentanyl infusion
Propofol intermittent
Avoid high PEEP
 SEIZURE
SEIZURE
Aggravate CE & ICH
Prophylactic phenytoin?
Benefit in gr. 3/ 4 encephalopathy
Hepatology 2000;32:536–41.

Trial from India noted no benefit

Prophylactic phenytoin does not improve cerebral edema or survival
in acute liver failure, a controlled clinical trial. J Hepatol 2004, Bhatia
V. et al
 CIRCULATORY CHANGES
CIRCULATORY CHANGES

Hyperdynamic circulation

High cardiac output, low SVR, systemic vasodilatation

Pulmonary arteriovenous shunting resulting in hypoxemia

Elevated portal pressure

Sodium and fluid retention

Marked renal vasoconstriction, ATN

 FLUID PRESCRIPTION
FLUID PRESCRIPTION

*Strict fluid balance is essential

 NAC
NAC

• Usually used in acetaminophen toxicity

• MOA: replenishment of depleted glutathione stores in liver

• Oral/ i.v.: Efficacy and adverse effects not significantly different

• Oral: 140 mg/kg followed by 17 doses of 70 mg/kg every 4 hours

• I.v. (for child >20 kg): 150 mg/kg in 200 ml of 5%Dx over 15 mins, 50

mg/kg in 500 ml of 5% Dx over 4 hours and then 100mg/kg in 1000 ml of

5% Dx over 15 hours
 NAC In Non PCM FHF
NAC In Non PCM FHF

7 patients, 17 – 57 yrs
5 qualified for OLT
3 complete recovery without OLT
Dynamic variables (PT and Factor V) improved in 4 cases

Hepato Gastroenterology 2000

 NAC In Non PCM FHF
NAC In Non PCM FHF
Retrospective review of 170 children with FHF over
15 years (1989-2004)
NAC introduced in management in 1995
Median duration of NAC administration 5 days

Shorter length of hospital stay

Higher incidence of native liver recovery with out LT
Better survival after transplantation
Liver Transplantation 2007
 NAC In Non PCM FHF
NAC In Non PCM FHF
Intravenous N-acetylcysteine in pediatric patients with
nonacetaminophen acute liver failure: A placebo-controlled
clinical trial. Hepatology. 2013 Apr;57(4) PALFSG
- 1-year LTx-free survival was significantly lower (P = 0.03)
in those who received NAC (35%) than those who
received placebo (53%), particularly, but not significantly
so, among those less than 2 years old with HE grade 0-1
(NAC 25%; placebo 60%; P = 0.0493)
-  NAC did not improve 1-year survival in non-APAP PALF.
One-year LTx-free survival was significantly lower with
NAC, particularly among those <2 years old.
 HEPAMERZ
HEPAMERZ

Amino acids L-Ornithine and L-Aspartate

Used for hyperammonemia conditions  &

       hepatic coma and encephalopathy
 COAGULATION ABNORMALITIES
COAGULATION ABNORMALITIES

Platelet dysfunction ( qualitative and quantitative)

Clotting factor production decreases
Consumption increases ( DIC)
Factor VII: 1st to be depleted in ALF

(To be considered in pediatric patients with hemorrhagic shock

or before invasive procedures)
 MANAGEMENT OF COAGULOPATHY
MANAGEMENT OF COAGULOPATHY

• Vitamin K
• Give FFP if bleeding or intervention is required (INR > 2)
• 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
• Factor VII concentrate for earliest correction
HEPATORENAL SYNDROME
HEPATORENAL SYNDROME
 MANAGEMENT OF
MANAGEMENT OFRENAL
RENALISSUES
ISSUES

• Avoid hypovolemia
• Early RRT
• CVVH preferred over Intermittent HD
• Can be contd. intraoperatively
 INFECTIOUSDISEASE
INFECTIOUS DISEASECONSIDERATION
CONSIDERATION

MC cause of death & morbidity

MC site- lung> urinary tract> blood
Gram positive- staph. aureus, streptococcus
Enteric gram negative
Fungal, candida
CRBSI- avoidance of unnecessary lines, proper
hygiene essential
 INFECTIOUSDISEASE
INFECTIOUS DISEASECONSIDERATION
CONSIDERATION

Prophylactic ATx do not alter survival.

Empiric use
- surveillance cultures positive
- rapidly progressive encephalopathy
- hemodynamic instability
- SIRS
Antifungal in pts with prior ATx use
 INFECTIOUSDISEASE
INFECTIOUS DISEASECONSIDERATION
CONSIDERATION

• Broad spectrum
• Gm positive & Gm negative coverage
• 3rd gen. cephalosporins
• Antibiotic stewardship
• Dose adjustment in renal insufficiency
 NUTRITION
NUTRITION

• Prone to hypoglycemia
loss of glycogen, impaired gluconeogenesis, increased insulin
• Dextrose infusion
• Hyperglycemia avoided– ICP concern

• Oral feeding wherever possible

Calorie directed as per requirement
0.5-1 gm/kg/day protein
Avoid glutamine
 LACTULOSE
LACTULOSE

One of the important part of PICU prescription

Lactulose 0.5 ml/kg/dose (max. 30 ml/dose) PO/NG q.i.d. for 3-4 loose

stools (contraindicated in intestinal ileus)

Enemas are almost as effective and circumvent the problem of gastric

stasis.

“Risk of gaseous abdominal distention due to fermentation, particularly

with aggressive oral regimes and also simultaneous GI stasis associated

with ventilation and sedation”

 LACTULOSE:MOA
LACTULOSE: MOA

• Trapping of NH4+ in the lumen and prevention of

absorption.

• In the colon, lactulose is metabolized by bacteria to release

lactic, acetic, and other organic acids and decreases stool pH
to approximately 5.5
 ORALNONABSORBABLE
ORAL NONABSORBABLEANTIBITICS
ANTIBITICS

MOA -modulation of bacterial flora

Reduce small intestinal bacterial overgrowth, reducing ammonia
levels, and reducing inflammation
In patients with HE who were already receiving lactulose, rifaximin
was found to significantly reduce the risk of HE recurrences and
HE-related hospitalizations over a 6-month period

Bass NM et al. Rifaximin treatment in hepatic encephalopathy.N

Engl J Med. 2010;362:1071-1081.
 FHF: EXTRACARPOREAL LIVER
FHF: EXTRACARPOREAL LIVER

Non biologic systems:

- CVVH, charcoal hemoperfusion, plasmapheresis
- Molecular adsorbents recirculation systems (MARS)
- Fractionated plasma separation , adsorption and dialysis system (FPAD)
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
MRS
MRS
 PredictiveFactors
Predictive Factors&&Outcomes
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

– MODS
 O’Grady etetalal1993
OUTCOMESO’Grady
OUTCOMES 1993

• Hyperacute liver failure

– Onset < 8 days; survival - 36%

• Acute liver failure

– Onset 8 - 28 days; survival - 7%

• Subacute liver failure

– Onset 4 - 26 weeks; survival - 14%
A variety of other calculations have been done based
on similar parameters to determine the risk of
mortality in acute liver failure.

The Acute Physiology and Chronic Health Evaluation II (

APACHE II) score has a comparable sensitivity to the
King's College Criteria in determining prognosis.
 FHF in Children: Disease Specific
FHF in Children: Disease Specific
PredictiveFactors
Predictive Factorsand
andOutcomes
Outcomes

• Overall survival for patients with FHF and stage 3 or 4 HE has

increased from 20% to 50% over past 2 decades.
• The best independent predictor of outcome is the etiology of
the FHF.
Survival Acetaminophen 40 - 64%
Non-ABC hepatitis < 20% Wilson’s disease
< 5%

• Without OLTx - survival ~30%

 PATIENTEDUCATION
PATIENT EDUCATION

I STRICTLY FOLLOWED THE PRESCRIPTION, 8 ML 4 TIMES…….

1000 MG/DOSE
X 4 TIMES
APPROXIMATELY
600
MG/KG/DAY

82
King’s College Hospital Criteria for LTx in FHF

• Acetaminophen
– pH < 7.30 ( irrespective of grade of HE ) or
– PT > 100 sec and serum Cr > 300 umol/L ( 3 or 4 HE)
• Non - acetaminophen
– PT > 100 sec ( irrespective of grade of HE ) or
– Any 3 of the following ( irrespective of grade of HE )
• Age < 10 yr.
• Etiology - nonAB hepatitis, idiosyncratic drug reactions
• Jaundice to HE duration > 7 days
• PT > 50 sec.
• Serum bilirubin > 300 umol/L