Pediatric Liver Failure Kathleen P. Thompson, MPAS, PA-CAssistant ProfessorBaylor College of Medicine School of Health Professions – Physician Assistant ProgramDepartment of Pediatrics – Section of Critical Care Medicine

Disclosures:

• I am NOT a hepatologist

• No conflicts of interests• But you will see some industry slides

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Objectives:

1. Identify key clinical features for acute vs chronic pediatric liver failure.

2. Formulate appropriate treatment options based on severity of illness.

3. Recognize acute on chronic and acute fulminant liver failure need for liver transplantation and extracorporeal support.

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What is Liver Failure? • Loss of functional liver cell mass below a

critical level results in liver failure.• Production of and failure to clear endogenous

toxins • Bile Acids, Bilirubin, Prostacyclins, Nitric

Oxide, Toxic fatty acids• Further necrosis/apoptosis vicious cycle

• Detrimental to renal, brain and bone marrow function; results in vascular failure

• Most toxins thought to be protein-bound

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Pediatric Liver Failure

• Types:• Acute Liver Failure• Chronic Liver Failure• Acute on Chronic Liver Failure

• Biliary atresia and neonatal hepatitis • ~60% of all liver disease.

• Difficult to quantify incidence• Chronic more common than acute

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Case Study – Patient A22 month old previously healthy, full term, fully immunized male presented to his pediatrician after 10 days of intermittent episodes of fever, cough, congestion, diarrhea, and emesis. With a one day history of decreased PO intake and lethargy.

Vitals: HR 140 RR 55 BP 90/45, T102.1, SpO2 94%

Physical Exam reveals:

• General: visibly fatigued, laying in mother’s lap

• HEENT: Normocephalic atraumatic. slight scleral icterus bilaterally. PERRLA. EOMI bilaterally. No LAD

• Respiratory: tachypneic, mild intercostal retractions, no wheezing, rhonchi, or rales.

• Cardiac: tachycardiac, Normal S1 and S2. No M/R/G

• Abdomen: distended but soft. BS x 4 quadrants. No masses or ascites. No splenomegaly. +hepatomegaly with 7cm liver span at the Rt MCL.

• Extremities/skin: few less than 10 petechiae around lateral & medial malleolus bilaterally. 2+ pulses to radial, brachial, dorsalis pedis, and posterior tibialis bilaterally. +jaundice.

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Case Study – Patient A

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Case Study – Patient A Sent to the EC and then admitted to the PICU.Initial labs revealing:AST/ALT in the 1000’s. Total Bilirubin 12, INR 4; Ammonia 180.Subsequently: Pt was intubated for airway protection. Started on CRRT for hyperammonemia and TPE for coagulopathy. Patient was immediately listed as status 1A for liver transplantation while undergoing further work up.

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Definition of ALF in Adults1. Coagulation abnormality (INR ≧ 1.5)2. Any degree of encephalopathy3. Jaundice to encephalopathy in 8 weeks4. No pre-existing Liver Disease5. ≦ 26 weeks duration

Hyperacute(< 7 days)

Acute(7-21 days)

Subacute(3 – 26 weeks)

EXCEPTIONS TO : “ No pre-existing LD/cirrhosis”1)Wilsons Disease2)Vertically acquired HBV3)AI hepatitis

AASLD 2011 position paper

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Pediatric Acute Liver Failure (PALF)

• Elusive definition• PALF Study Group Specific Criteria:

• 1. Absence of Chronic Liver Disease• 2. Evidence of hepatic injury

• Coagulopathy not corrected by vitamin K administration• 3. PT > 15 sec/INR > 1.5 + Hepatic Encephalopathy (HE)• 4. PT > 20 sec/INR > 2 +/= HE

• Rapid life threatening MSOF

Desai MS, Lion R, Ackan-Arikan A. Critical liver failure: Pathophysiological Considerations and Current Management. Turner DA, Killinger JS. In: Current Concepts in Pediatric Critical Care. 2016 Ed. P15-34. Lutfi R, et al. Intensive Care Management of Pediatric Liver Failure. Journal of Pediatric Gastroenterology and Nutrition. 2017; 65(5):660-670. Squires RH. Acute Liver Failure. Murray KH, Horslen S. In: Diseases of the Liver in Children. 2014 Ed. P445-461.

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Pediatric Acute Liver Failure (PALF) – Clinical Features

• Non specific prodrome; variable duration• Exception with ingestion

• Common features at presentation• Jaundice• Hepatomegaly• +/- encephalopathy • +/- ascites

• Wide variation in presentation and progression

Desai MS, Lion R, Ackan-Arikan A. Critical liver failure: Pathophysiological Considerations and Current Management. Turner DA, Killinger JS. In: Current Concepts in Pediatric Critical Care. 2016 Ed. P15-34. Lutfi R, et al. Intensive Care Management of Pediatric Liver Failure. Journal of Pediatric Gastroenterology and Nutrition. 2017; 65(5):660-670. Squires RH. Acute Liver Failure. Murray KH, Horslen S. In: Diseases of the Liver in Children. 2014 Ed. P445-461.Horslen S. Phenotypes of Liver Disease. Diseases of the Liver in Children 2014 Ed.

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Pediatric Acute Liver Failure (PALF) – Etiologies

Bernal, Wendon. NEJM 2013; 369:2525-2534

D’Agata. Peds in Review, 1999.

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Pediatric Acute Liver Failure (PALF) – Initial Lab Work

AASLD position paper Hepatology 2011 and 2103

Case Study – Patient B

• 10 month Hispanic female with a late diagnosis of biliary atresia at 3 months of age, s/p kasai procedure at 4 months now failed awaiting liver transplantation that is admitted to the GI floor for increased abdominal distension.

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Case Study – Patient B

Hospital Course – 24 hours after admission: • Patient is now febrile, irritable, and tachypneic. • Rapid response team was called, patient was

transferred to the PICU and intubated upon arrival due to respiratory failure.

• Over the next 12hrs – anuric with worsening coagulopathy, and hyperammonemia.

• CRRT is initiated with TPE.

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What is Chronic Pediatric Liver Failure?

• Chronic Liver Failure • Usually in the context of cirrhosis or existing

liver disease unable to perform normal synthetic and metabolic function

• Wide spectrum of disorders• Infectious, metabolic, genetic, drug induced,

idiopathic, structural, and autoimmune.

Mew C et al. pediatrics in review, 1993.

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Pediatric Chronic Liver Failure (CLF) – Clinical Features

• Known or established liver dysfunction• Cirrhosis• Slower and insidious • 80%

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Pediatric Chronic Liver Failure –Etiology

Mew C et al. pediatrics in review, 1993.

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Acute vs Chronic vs Acute on Chronic Liver Failure

• Acute Liver Failure (ALF)• Chronic Liver Failure (CLF)• Acute on Chronic Liver Failure

• Distinct clinical syndrome in adults and pediatrics• No pediatric specific definition• Asia-Pacific Association for the Study of Liver Disease• European Association of the Study of the Liver (EASL) &

American Association for the Study of Liver Disease (AASLD)

• Acute hepatic insult manifesting as: jaundice and coagulopathy, complicated within 4 weeks by ascitesand/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease

Hepatol Int. 2009 Mar; 3(1): 269–282.

Acute vs Chronic vs Acute on Chronic Liver Failure

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Broken Dam Theory*

*Curiosity of Dan Thomas, MD Medical Director Hepatology & Liver Transplantation, Children’s Hospital of Los Angeles, Professor of Clinical Pediatrics, Keck/USC School of Medicine – Acute Liver Failure in Children Presentation

Why should we care?

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ALFStatus 1A

Transplant is urgent (stability will come only after LT)

Transplant free survival ~ 55%

Encephalopathy is dramatic

INR very high; platelets normal; risk of bleeding low

Death secondary to brain injury

Trigger is hepatic necrosis

Difficult to predict : wait vs LT

Post-op course usually unremarkable

ACLFPELD/Status 1B

Transplant is essential (must be stable for LT)

Transplant free survival ~ unlikely

Coagulopathy, shock, AKI is dramatic

INR elevated; platelets low; risk of bleeding high

Death secondary to MSOF

Trigger is infection

Difficult to stabilize for LT

Post-op course usually dramatic

Moreshwar Desai, MD 2019 PCCM lecture

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Where is the Patient & What is

going on?!?!

Objective #2 – Overview of Management in Critical Liver Failure

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Systemic Manifestation of Liver Failure

Knowing the pathophysiology will guide the management.*IE ICU MULTI-TASKING

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Principles of Critical Liver Failure Management

1. Only established treatment for LF is OLT.2. Primary goal: Transfer of patient to a

TRANSPLANT CENTER3. Consider PICU admission EARLY

1. Absolute if there is any degree of HE

4. Support of individual organ system function1. Maximize recovery2. Viability for transplantation

Squirres, R. Ch 23 Acute Liver Failure; Diseases of the Liver in Children 2014Arikan, A PCCM 2016

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Neurological System –Hepatic Encephalopathy

• Major catastrophic event• Brain herniation kills• Irreversible brain injury is an indication to delist• Ammonia plays a central role, but is NOT the only

culprit.

Arikan, A. PCCM Current Concepts 2016

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Neurologic System –Hepatic Encephalopathy

1) In ALF, NH4 is a critical mediator of HE, not the only mediator of HE2) < 75 µM NO HE3) >100 independently associated with high risk HE4) >200 associated with HE+ICH+Death………..Revised position paper AASLD 2011

5) NH4 of over 75, despite lactulose/Rifax and a rapid rise of NH4 by over 50 are indications for HET……. Ayse Arikan et al PCCM 2018

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Neurological System – Hepatic Encephalopathy Treatment

• Grade 1 & 2 HE Category:– Minimal stimulation, NVS, and AVOID sedatives

• LACTULOSE: oral or rectal in early stages. May interfere with surgical field (III).

• BOLTS: only in high grade HE, to be done in centers with expertise (III)

• Mannitol for sudden raised ICP. Do not profylax (II) • Hypertonic saline and induction of hyperNa in high risk

HE (I) • Barbiturates and induction of hypothermia (II) • Corticosteroids should NOT be used for ICP (I)

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Respiratory System• Airway protection

• Hepatic encephalopathy

• Respiratory dysfunction • Sepsis• Volume overload• Pulmonary hemorrhage• ARDS

• Depending on the etiology of respiratory will dictate how its managed:

• Increased ICP standard of care• Normocapnia & avoid hypoxemia

• Pediatric Acute Lung Injury Consensus • Low TV• Moderate elevated PEEP• Permissive hypercapnia & hypoxemia – ARDS management

Arikan et al. PCCM 2016Lutfi et al. Intensive care management of pediatric acute liver failure JPGN, 2017

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Respiratory: HepatopulmonarySyndrome (HPS)

• Caveat for AoCLF - Defined:• 1. Impaired oxygenation (PaO2 < 80mmHg or AA gradient >15mmHg) on RA

AND• 2. Intrapulmonary vasodilatations leading to R to L shunting within the lungs

• Pathognomonic – Arterial desaturations• The degree of hypoxemia determines the severity.

• Treatment:• Oxygen• Vent Mgt.

• Outcome: • Resolves after OLT, but

will take time.

Arikan et al. PCCM 2016Lutfi et al. Intensive care management of pediatric acute liver failure JPGN, 2017

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Cardiovascular System• Failure is common in both ALF and AoCLF• Hallmarks:

• Distributive physiology with low SVR & preserved or augmented CO leads to high output heart failure

• Vasoactives often required• If HRS – may require vasoconstrictive agents.

Brogan T et al. Ch 24 Intensive care management of children with liver failure, Diseases of the liver in children, 2014.

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Cardiovascular:Cirrhotic Cardiomyopathy

• Caveat for AoCLF

• Chronic cardiac dysfunction (in the absence of known heart disease) characterized by

• Hypertrophic and hyperdynamic left ventricle

• Diastolic dysfunction• Systolic incompetence

during exercise, catecholamine or hemodynamic stress

• Electromechanical abnormalities (QT prolongation)

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Metabolic System

• Hypoglycemia• High GIR, (~10-15mg/kg/min)

• Nutritional Considerations• Goal minimize muscle catabolism

• Hyponatremia• Very common• Can be complicated in the setting of hepatic

encephalopathy & acute renal failure requiring CRRT.

• Fluid requirements• Minimize fluid overload as much as possible!

Squirres, R. Ch 23 Acute Liver Failure; Diseases of the Liver in Children 2014Arikan, A PCCM 2016

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Gastrointestinal & Adrenal Systems

• Hepatoadrenal syndrome • Adrenal insufficiency

• Worsen hypotension & Low SVR• +/- stress dose hydrocortisone

• Life threatening GI bleed• Mainly with AoCLF• Variceal in origin due to portal hypertension • Treatment Options:

• Octreotide gtt• PPI• Banding vs ligation• TIPS procedure

Arikan, A PCCM 2016Brogan T et al. Ch 24 Intensive care management of children with liver failure, Diseases of the liver in children, 2014. Shepard, R. Ch 25 Chronic liver disease part 1. Diseases of the liver in children, 2014.

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Gastrointestinal System: Portal Hypertension & Spontaneous

Bacterial Peritonitis • Complications of Chronic Liver Failure

• Treatment Options: • Directed at preventing

complications associated with PH• Variceal bleed• Ascites• HRS• HE

Brogan T et al. Ch 24 Intensive care management of children with liver failure, Diseases of the liver in children, 2014. Shepard, R. Ch 25 Chronic liver disease part 1. Diseases of the liver in children, 2014.

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Hematological System • Coagulopathy

• pro-coagulant (Factors V, VII, X, fibrinogen) & anticoagulant (AT, III, protein C & S) proteins

• Monitor PT/INR/PTT, fibrinogen• Treatment:

• Transfusion Medicine Service are AMAZING• Therapeutic plasma exchange (TPE)

• Hemorrhage• Actually rare

• Needs an inciting event – infection or increased portal hypertension

• AASLD recommendations 2011 position paper:• INR > 7, abnormal TEG then FFP may be transfused to keep

INR 5-7• Correct thrombocytopenia• Correct coagulopathy aggressively for invasive procedures or

hemorrhage. AASLD 2011 position paper

Arikan et al. PCCM Current Concepts 2016.

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Hematologic System –Therapeutic Plasma Exchange

(TPE) Modality

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Immunological System

• Bone marrow suppression & Immune dysregulation

• Lymphopenia & neutropenia

• Infection risk is HIGH• Very complicated pathophysiology

• On going research needed

Arikan, A PCCM 2016

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Renal System• AKI is common with PALF

• ~10% required hemofiltration

• A wide variety of etiologies leading to AKI• ATN• Hypovolemia• Sepsis• APAP induced kidney injury• Nephrotoxic medications• Functional renal failure

• Renal Replacement Therapy • Degree of renal dysfunction• Overall fluid balance• Electrolyte disturbances• Metabolic derangements

1. Brogan, T. Ch24 Intensive care management of children with liver failure. Diseases of the liver in children, 2014. 2. Lutfi et al. JPGN 2017

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Renal System: Hepatorenal Syndrome (HRS)

• Caveat of AoCLF

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Objective #3

Recognize acute on chronic and acute fulminant liver failure need for liver transplantation and

extracorporeal support.

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Liver Transplantation Scoring Systems –Pediatric End-Stage Liver Disease (PELD) vs Model for End Stage Liver Disease (MELD)

Score

• Designated Status:• 1A - PALF• 1B – very sick chronically ill

• PELD score• ≦ 11 years• Model for waist list mortality

• Bilirubin, INR, albumin, growth failure, & age < 1 yr.

• MELD score• Ages 12 to 18 • Score includes:

• INR, bilirubin, & creatinine

Rana et al. Pediatric liver transplant center volume & the likelihood of transplantation. Pediatrics 2015

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Extracorporeal Liver Support (ELS) Modalities

• TPE – discussed previously• CRRT – discussed previously• MARS

• Albumin bound dialysis• Its one of many different brands

• Prometheus• Single Pass Albumin Dialysis (SPAD)

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Rationale for ELS

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Molecular Adsorbent Recirculating system (MARS)

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Postoperative OLT – Challenges• Fluid overload vs Intra-vascular depletion

• Post-operative bleeding vs Thrombosis

• Post-op infections vs Adequate immunosuppression

• Prolonged need for mechanical ventilation

• Prolonged need for hemodynamic support

• Prolonged need for dialysis

• Multi-disciplinary communications

Goss, J. MDDesai, M. MD

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Postoperative OLT -Basic Management Strategies

• Avoid hypotension

• Avoid hypovolemia

• “Bleeder” preferred over “clotter”

• Tight sugar control

• Infections kill

• Things are better if child tolerates feeds and fluid removal

• Less is more

…........John Goss MD

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Future Considerations:

• Hepatocyte transplantation• Auxiliary liver transplantation• Granulocyte colony-stimulating factor (G-

CSF)

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Questions?

Thank you!

Special Thanks to: • Moresh Desai, MD• Fong Lam, MD• Amy Arrington, MD• TCH/BCM Pediatric Liver ICU team

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Supplemental Information

Extra slides for your information and reference later or to refer to during the lecture.

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Clinical Features - Physical Exam

Acute• Jaundice• Hepatomegaly alone OR• Hepatosplenomegaly• Peripheral edema• Bruising • Petechiae• Easy bleeding• Alerted mental status• Fetor hepaticus associated with

HE (but rare)

Chronic• Jaundice• Ascites• Digital clubbing• Palmar erythema• Cutaneous xanthoma• Spider angiomata• Failure to thrive• Caput medusa• Hepatomegaly or non-palplable

liver• Splenomegaly

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Specific PALF Etiologies with Treatment:Slides courtesy of M. Desai, MDTHANK YOU!

Evidence based etiology specific treatment of ALF:

Tylenol toxicity:

1)10g/day (150mg/kg/day) = toxic dose2)NAC is GOLD STANDARD (CAT I recommendation)3)IV better than PO (we learned a lesson)4)Normograms are good but may not help in co-ingestion/comorbidity 5)Initial ph (<7.3), INR (>6), creatinine (>3) can predict need for LT (Kings criteria) 6)If child continues to worsen despite appropriate therapy with NAC, then think of OTHER ETIOLOGY (we learned a lesson )

DILI:

1)Discontinue non-essential medications (Cat III)2)NAC should be given (Cat I)

NAC:

1)Given to any adult with ALF (whether or not Tylenol poisoning is confirmed)2)In children, NAC given to non-Tylenol ALF caused decreased transplant free 1 year- survival. (……………..Squires et al PALF group. Hepatology 2012.)

Evidence based etiology specific treatment of ALF:

Wilson’s Disease:

1)2 to 3% of cases2)Presents as FLF (hence bestowed Status 1A)3)Teenager with:

4)Treatment: Lower Cu [ HET= Albumin dialysis; TPE] +CRRT+ LTIn FLF do not try chelators (penicillamine)

Roberts et al Hepatology 2003 (AASLD guidelines)

Coombs negative hemolytic anemiaHigh Bili (Total, Direct and Indirect)Low AlkPO4Total bili : Alk PO4 ratio >2. KF ring in 50%Low ceruloplasminHigh Cu in sera and urine

Evidence based etiology specific treatment of ALF:

Autoimmune hepatitis

1)Liver biopsy recommended2)+/- Bone marrow3) Start steroids4) IVIG (trial will start)5) Consider for LT (status 1A) in FLF

Budd-Chiari Syndrome

1)Abdominal pain, ascites, hepatomegaly, cholestasis2)CT, Doppler, venography, MRV3)Hypercoagulable conditions (polycythemias, malignancies)4)Poor prognosis5)Defibrotide; LT (only after excluding Ca)

Acute Ischemic Liver Injury:

1) Often referred to as “Shock Liver”2) Hypotensive episode may not always be present3) Portal flow is low pressure and gets compromised in early shock4) Worse when there is a pre-existing liver damage5) Usually resolves with resolution of shock6) AST >> ALT; LDH is high (from muscle and cell necrosis rather than hemolysis)

Just to be complete….

Neonatal hemochromatosis

1) Now called Gestational Alloimmune Liver Disease (GALD)2) Maternal-fetal allo-immune disorder mediated by IgG3) Fe overload occurs secondary to liver injury (inability to make hepcidin)4) Double volume exchange transfusion and IVIG

Mushroom poisoning:

1) Treat with antidotes: Pen G and silbillin