Acute&and&Chronic&Liver&Failure&

Jesse&Hall&MD&

&

Professor&of&Medicine,&Anesthesia&&&Cri<cal&Care&

&

Sec<on&Chief,&Pulmonary&and&Cri<cal&Care&

Medicine&

University&of&Chicago&

Faculty&Disclosures&

Dr.$Hall$•  $ receives$honoraria$from$the$ACCP$for$this$course$$$$$$$$$$

$and$SEEK$•  $ receives$honoraria$from$the$ATS$for$SOTA$•  $ receives$honoraria$from$McGraw@Hill$and$Taylor@ $

$ $Francis$publishing$

Learning&Objec<ves&•  Acute&liver&failure&

–  Define&e<ologies&of&FHF&–  Differen<ate&between&encephalopathy&and&cerebral&edema&

–  Conduct&a&preItransplanta<on&evalua<on&–  Describe&transplant&complica<ons&in&the&ICU&

•  Chronic&liver&failure&–  Define&pathophysiology&of&portal&hypertension&–  Adhere&to&general&suppor<ve&measures&–  Describe&complica<ons&of&cirrhosis&

•  SBP&and&secondary&peritoni<s&•  Hepa<c&encephalopathy&•  Hepatorenal&syndrome&•  Variceal&hemorrhage&

Acute&Liver&Failure!

Defini<ons!•  Acute&Hepa<<s:&&&&

–  Acute&liver&parenchymal&injury&from&exposure&to&hepatotoxins&or&infec<ous&agents,&such&as&viral&hepa<<s,&toxins,&alcohol,&or&medica<ons.&

&

•  Acute&Liver&Failure:&&&&

–  Development&of&liver&dysfunc<on&in&the&sePng&of&severe&acute&hepa<<s.&&&&

–  Features:&&&•  Jaundice&&•  Coagulopathy&•  Encephalopathy&

•  Timing:&

–  Fulminant&(Trey&and&Davidson,&1970):&within&8&weeks&of&the&onset&of&jaundice&

•  hyperacute:&&jaundice&to&encephalopathy&in&0&I&7&d&•  &acute&7&I&28&d&&•  &subacute&(5&I&26&weeks).&

QuesGon$1:$Which$of$the$following$is$the$most$common$cause$of$acute$liver$failure?$

A. Wilson�s$disease$B. HepaGGs$B$C. HepaGGs$C$D. Acetaminophen$overdose$E. Autoimmune$hepaGGs$

E<ology&of&ALF&

NIH$Study$Group;$Hepatology,$April$2008$

Acetaminophen&Toxicity&

•  Most&common&cause&of&acute&liver&failure&

•  Low&therapeu<c&index&

–  As&li^le&as&5&grams&can&be&toxic&

–  Body&size&is&important&

•  Treatment&

–  Ac<vated&charcoal&if&<&4&hours&since&<me&of&inges<on&

–  Acetylcysteine&(PO&or&IV)&•  If&above&the&line&on&the&RumackIMa^hew&nomogram&line&

•  If&unknown&<me&of&inges<on&and&level&>&10mcg/ml&

•  If&>&7.5&gm&inges<on&and&level&not&available&for&>&8&hours&

–  Suppor<ve&care&–  Intuba<on&with&stage&III&or&IV&encephalopathy&to&prevent&pneumonia&

–  ICP&monitoring&if&intubated&and&awai<ng&transplant&

–  Liver&transplant&

NAC:&PO&or&IV?&

•  No&convincing&evidence&of&improved&outcome&with&IV&prepara<on&

•  Anaphylactoid&reac<ons&likely&more&common&with&IV&administra<on&(reported&incidence&with&IV&drug&5&to&15%,&predominance&of&skin&reac<ons)&

•  Deaths&have&been&reported&from&these&reac<ons&

•  Accordingly,&PO&route&preferred,&IV&used&only&when&gut&administra<on&is&precluded&

Selec<ng&Pa<ents&for&Transplanta<on&

•  Major&challenge&in&ALF&is&to&determine&those&who&

will&recover&with&medical&treatment,&those&for&whom&

surgery&is&fu<le,&and&those&in&whom&the&risks&of&

surgery&and&lifelong&immunosuppression&are&jus<fied&

•  Perform&the&above&with&the&best&alloca<on&of&organ&

to&pa<ent&(in&the&US,&17&K&pts&on&wai<ng&list,&5&K&

xplants/yr)&

QuesGon$2:$Which$of$the$following$set$of$parameters$is$used$to$calculate$the$MELD$score?$

A.  Lactate,$bilirubin,$and$albumin$B.  Lactate,$creaGnine,$bilirubin$C.  Platelet$count,$INR,$FVII$D.  CreaGnine,$bilirubin,$INR$E.  Bilirubin,$level$of$encephalopathy,$INR$$

Model&for&Endstage&Liver&Disease&

•  MELD&Score&=&10&(.957&*&Cr&+&1.12&*&Tbili&+&1.12&(INR&

+&.643))&

•  What&you&should&know&

–  Cr,&Bili,&INR&–  Designed&to&allow&UNOS&to&be&more&efficient&and&did&so&

–  Based&predominantly&on&CLD&but&now&more&widely&applied&

ICU&Management&of&ALF&

•  Prophylaxis&against&UGI&Bleed:&&&Acid&suppression&with&H2&blocker,&protonI

pump&inhibitor&or&mucosal&protec<on&with&sucralfate.&

•  Coagulopathy:&&&Prophylac<c&use&of&coagula<on&factors&to&prevent&bleeding&

events&is&ineffec<ve&and&discouraged.&&Their&use&can&obscure&early&signs&

(improving&PT)&of&hepa<c&recovery.&

•  Sepsis:&&&Sepsis&is&one&of&the&leading&causes&of&death&in&these&pa<ents.&&

Febrile&pa<ents&should&be&panIcultured&and&an<bio<c&therapy&ins<tuted&

early.&

•  Hypoglycemia:&&&Severe&liver&injury&markedly&disrupts&glucose&homeostasis&

as&the&liver&is&one&of&the&main&stores&of&glycogen.&&Intravenous&glucose&

infusions&are&a&mainstay&of&treatment.&

•  Encephalopathy:&&The&cause&of&encephalopathy&in&the&sePng&of&acute&liver&

failure&is&cerebral&edema.&&Any&pa<ent&with&grade&II&or&higher&

encephalopathy&should&be&evaluated&for&cerebral&edema&(imaging&studies&of&

the&brain&and/or&intracranial&pressure&monitoring)&

Mechanisms&of&Encephalopathy&

•  Chronic&Liver&Disease&–  Ammonia,&GABA,&Glutamate&–&Glutamine,&Benzodiazepine&Receptors&

–  Treatment&with&lactulose,&neomycin,&lowIprotein&diet&

•  Acute&Liver&Failure&&–  Cerebral&Edema&&(possible&role&for&NH3)&

–  Treatment&with&ICP&monitor,&mannitol,&dialysis,&HOB&eleva<on,&pressure&

control,&induced&coma.&

•  Development&of&Grade&III&encephalopathy&is&an&ominous&sign,&

predic<ve&of&poor&outcome&

Grades&of&Encephalopathy&

•  Grade&0: &No&altera<on&of&mental&status&

•  Grade&I: &Awake&and&responsive&

& & & &Mild&confusion&and&disorienta<on&

& & & &Altered&personality&

& & & &Asterixis&may&or&may&not&be&present&

&

•  Grade&II: &Awake,&but&agitated&

& & & &Increasingly&confused&and&disoriented&

& & & &Hallucina<ons&

&

•  Grade&III: &Increasing&suppression&of&mental&status&

& & & &Stuporous&but&arousable&to&vocal&or&tac<le&s<muli&

& & & &May&require&endotracheal&tube&for&airway&protec<on&

&

•  Grade&IV: &Unresponsive&to&vocal&or&tac<le&s<mula<on&

& & & &Essen<ally&comatose&but&with&intact&pupillary&reflexes&

& & & &Usually&s<ll&withdraw&to&painful&s<muli&

QuesGon$3:$$What$is$true$about$intracranial$pressure$and$ICP$monitors$in$fulminant$hepaGc$failure?$

A.  Parenchymal$intracranial$pressure$transducers$are$$preferred$over$subdural$or$epidural$monitors$

B.  ICP$monitors$should$be$placed$regardless$of$ability$to$$correct$coagulopathy$$

C.  The$increase$in$ICP$is$reversible$by$treatment$with$$lactulose$

D.  Cerebral$perfusion$pressure$(MAP$–$ICP)$<$40$mmHg$for$$more$than$4$hours$results$in$irreversible$brain$injury$

E.  The$ICP$should$be$measured$twice$daily$

ICP&Monitoring&

•  Place&the&Intracranial&Pressure&(ICP)&Monitor&in&the&Epidural&Space&

•  ICP&Monitoring&

–  Should&be&strongly&considered&when&pa<ents&evolve&from&stage&II&(agitated&confusion)&to&stage&III&(stuporous)&encephalopathy.&

–  Maintain&adequate&platelet&count&(>&60,000)&with&platelet&transfusions&and&INR&<&1.5&with&fresh&frozen&plasma,&if&necessary.&

•  Treatment&Guidelines&

–  Mannitol&is&used&to&control&ICP&in&pa<ents&with&intact&renal&func<on&or&in&those&on&dialysis.&

–  Mannitol&is&given&in&0.5&to&1.0&g/kg&doses.&&Serum&electrolytes,&glucose,&and&osmolarity&should&be&checked&every&4&to&6&hours.&&If&ICP&elevated,&osmolarity&<&310,&and&Na&<145,&then&give&mannitol.&&Mannitol&should&be&held&if&the&pa<ent&has&excessive&serum&osmolarity&or&significant&hypernatremia.&

Hall,$Schmidt$&$Wood$Principles$of$CriGcal$Care,$2005$

Acute&alcoholic&hepa<<s&

•  May$not$exhibit$all$the$features$of$ALF$•  Rapid$onset$of$jaundice,$fever,$ascites,$and$proximal$muscle$loss$

•  Liver$typically$large$and$tender$•  Aspartate$aminotransferases$levels$>$2x$normal$but$rarely$above$300$IU/ml,$and$AST/ALT$typically$>$2$

NEJM$2009$

NEJM$2011$

174$pts$randomized$Prednisolone$x$4$weeks$NAC$x$5$days$or$not$$Primary$endpt$6$mos$survival$not$diff$Short$term$mortality$improved$$Less$hepatorenal$syndrome$and$$$$$$infecGon$in$NAC$group$

NEJM$2011$

Relapse$to$drinking$in$3$pts$over$two$year$period$

Causes&of&hyperammonemia&in&the&

absence&of&hepatocellular&injury&

Clay$and$Hailine;$Chest$2007$132:1368$

Causes&of&hyperammonemia&in&the&

absence&of&hepatocellular&injury&

Clay$and$Hailine;$Chest$2007$132:1368$

Causes&of&hyperammonemia&in&the&

absence&of&hepatocellular&injury&

Liver&Transplanta<on!

Criteria&for&Liver&Transplanta<on&

in&FHF:&&King�s&College&UK&

Criteria&for&Liver&Transplanta<on&

in&FHF:&&King�s&College&UK&

MELD&Score&for&predic<ng&need&for&liver&

transplant&

Liver&Transplanta<on&in&FHF!

551 Cases Referred

129 Met Tx Criteria 422 Did Not Meet Criteria

39 Tx 90 No Tx

72% 11% 93% Survival

Williams'R,'ILTS'Barcelona'Mee5ng,'June'2003'

Survival&of&ALF&vs&CLD&aser&transplant&

NIH$Study$Group;$Hepatology,$April$2008$

Complica<ons&of&Transplanta<on&

&

&Are&closely&related&to:&

I&PreImorbid&disease&and&condi<on&

I&Transplant&&procedure&

I&Rejec<on&of&the&gras&or&host&

I&Consequences&of&&immunosupression&

May$be$divided$into:$@$NoninfecGous$complicaGons$@$InfecGous$complicaGons$

&

Early&nonIinfec<ous&complica<ons&

•  Hemorrhage$•  Primary$grak$failure@$1$to$5%$(change$with$DCD?)$•  HepaGc$artery$thrombosis$

•  Massive$liver$necrosis$•  Bile$leak$•  HepaGc$abscesses$•  U/S$dx$

•  Bile$leaks$or$strictures$•  Acute$rejecGon$

•  4$@14$days$post$transplant$•  Fever,$mild$elevaGon$transaminases$

Chronic&Liver&Failure&(Management&of&

the&Pa<ent&with&Cirrhosis)!

Management&of&the&Pa<ent&with&Cirrhosis!

•  Stable&(unlisted)&pa<ent&with&major&new&problem&

(variceal&hemorrhage,&SBP&and&sepsis)&

•  Listed&pa<ent&with&deteriora<on&•  In&either&case,&cri<cal&care&at&nexus&of&hepatology,&IR,&transplant&surgery,&GI&endoscopy,&etc&

Pathophysiology&of&Portal&Hypertension!

•  Normally&2/3&of&hepa<c&flow&is&portal&at&low&

resistance&(portocaval&gradient&2I6&mm&Hg)&

•  With&fibrosis,&bridging,&gradient&rises,&portal&flow&

reduced&with&collateral&circula<on&

•  Massive&splenic&dila<on,&sequestra<on&

•  Ascites&•  Hyperdynamic&systemic&circula<on&

Management&of&the&Pa<ent&with&Cirrhosis!

•  High&risk&of&infec<on&–  Immune&compromise&

– Wider&range&of&organisms&and&prior&healthcare&contact&

–  Adjusted&RR&for&hospitaliza<on&related&to&sepsis&2.6&for&cirrhosis,&ARR&for&death&2.0&

– Most&common&site&is&urine,&followed&by&ascites,&blood,&

and&respiratory&tract&

Management&of&the&Pa<ent&with&Cirrhosis!

•  Bacterial&peritoni<s&–  Any&pa<ent&with&fever&or&abdominal&pain&should&be&

considered&for&paracentesis&&

–  Dis<nguishing&SBP&from&secondary&peritoni<s&may&be&

difficult&by&exam&

U/S&Guidance&for&paracentesis&

U/S&Guidance&for&paracentesis&

Management&of&the&Pa<ent&with&Cirrhosis!

SBP& Culture&neg&

neutrocy<c&

ascites&

Bacterascites& Secondary&

peritoni<s&

PMN$Count$(cells/mm3)$

>250$ >250$ <250$ >>250$

Culture$ Single$organism$

NegaGve$ Single$organism$

MulGple$organisms$

Protein$ Usually$low$ Usually$low$ Usually$low$ Usually$>$1g/dl$

LDH$ Normal$ Normal$ Normal$ High$

Glucose$ Normal$ Normal$ Normal$ Low$

Repeat$para$can$be$of$use$to$determine$course$of$ambiguous$findings$

Management&of&SBP/CNNA/BA!

•  Most&cases&caused&by&gut&flora&but&Strep&or&

Staph&may&occur&

•  Cefotaxime&a&reasonable&empiric&choice&

•  If&outpa<ent&quinolone&prophylaxis&is&being&employed,&wider&spectrum&may&be&needed&

•  Renal&failure&common&complica<on&(30I40%)&

and&one&study&showed&drama<c&benefit&(ARF&

incidence&and&survival)&from&albumin&1.5&g/kg&at&

dx&and&1&gm/kg&on&d&3&(NEJM&1999;&341:403)&

&

Management&of&the&Pa<ent&with&Cirrhosis!

•  HE/PSE&–  Precipitants&

•  Drugs&•  GIH&•  Infec<on&•  Dehydra<on&•  Electrolyte&disturbances&•  Hepa<c&decompensa<on&

•  Inc&protein&intake&•  Uremia&&

•  Acidosis&•  Portosystemic&shunts&

Management&of&the&Pa<ent&with&Cirrhosis!

•  HS/PSE&–  A^en<on&to&airway&–  Lactulose&

•  Standard&rx&•  Said&to&dec&transit&<me,&bind&nitrogenous&toxins,&alter&

gut&pH&

–  Abx:&metronidazole,&neomycin,&rifaximin&&

–  Probio<cs&

Management&of&the&Pa<ent&with&Cirrhosis!

•  Hepatorenal&syndrome&

–  Implies&exclusion&of&nephrotoxic&drugs,&sepsis,&intrinsic&

renal&disease,&hypovolemia&

–  Occurs&in&up&to&39%&of&pts&with&cirrhosis&>&5&years&– Marker&for&poor&outcome&

–  Crea<nine&overes<mates&GFR&in&these&pts&

–  Should&prompt&considera<on&for&liver&xplant&if&other&

condi<ons&don�t&preclude&this&

Management&of&the&Pa<ent&with&Cirrhosis!

•  Hepatorenal&syndrome&

–  HRS&Type&IIrapid&progression&of&RF&over&2&weeks&or&less&with&a&2Ifold&increase&in&crea<nine&or&50%&reduc<on&in&

crea<nine&clearance&

–  HRS&Type&III&develops&streadily&over&months&with&a&

crea<nine&clearnace&less&than&40&ml/min&

– Median&survival&is&less&than&two&weeks&for&Type&I&and&less&

than&six&months&for&Type&II&

Management&of&the&Pa<ent&with&

Cirrhosis!•  Hepatorenal&syndrome&

–  Reversing&liver&damage&or&transplant&reverse&the&

condi<on&

–  No&role&for&dopamine,&octreo<de&as&single&agents&

–  Conflic<ng&data&for&terlipressin&as&single&agent&–  Perhaps&benefit&from&combined&therapy&with&

midodrine&and&octreo<de&

•  Hepatology&1999;&29:1690&•  Dig&Dis&Sci&2007;&52:742&

Management&of&the&Pa<ent&with&

Cirrhosis!•  Hepatorenal&syndrome&

–  Plasma&expansion&with&albumin&and&paracentesis&in&

cri<cally&ill&pts&with&tense&ascites&and&hepatorenal&

syndrome&(Crit&Care&2008&12:1I9&

–  200&ml&20%&albumin&followed&by&large&volume&

paracentesis&

Management&of&the&Pa<ent&with&

Cirrhosis!

Management&of&the&Pa<ent&with&

Cirrhosis!

J Hepatol 2012

SBP&Prophylaxis&for&the&asci<c&cirrho<c&in&

the&ICU&

Mortality&benefit&shown&in&pa<ents&

hospitalized&with&GIH&

May&begin&with&cesriaxone&1&g&IV&daily,&

switch&to&norfloxacin&400&mg&orally&when&

po&begun&

Balloon&Tamponade&

Balloon&Tamponade&

•  Pa<ent&will&need&spectacular&access&•  Three&devices&

–  SengstakenIBlakemore&

– Minnesota&

–  LintonINachlas&(large&volume&gastric&balloon&only)&

•  Airway,&airway,&airway&•  Immobilize,&immobilize,&immobilize&

•  Plan&b,&plan&b,&plan&b&

Octreo<de&

•  LongIac<ng&analog&of&somatosta<n&

•  IV&administra<on&causes&marked&and&rapid&

decrease&in&portal&venous&inflow,&portal&pressure,&

and&intravariceal&pressure&

•  While&these&effects&are&transient&bleeding&reduc<on&

and&reduced&risk&of&rebleeding&are&sustained&

Salma Akram

Transjugular&Intrahepa<c&

PortalISystemic&Shunt:&

(TIPS)&

•  Has&largely&replaced&earlier&surgical&shunts&•  Hemostasis&achieved&in&90%&of&pts&

•  Complica<ons&

– Misplacement&

–  PSE&(30%)&–  Hemoly<c&anemia&(10%)&

–  TIPS&stenosis&(less&with&coated&devices)&–  Vegeta<ve&infec<ons&(rare)&–  Acute&cerebral&edema&(very&rare)&

Indica<ons&for&TIPS:&

Nat�l&Dig&Dis&Advisory&Board&

Acute&bleeding&not&successfully&controlled&with&

medical&or&endoscopic&therapy&

Pa<ents&refractory&or&intolerant&to&medical&or&

endoscopic&therapy,&with&recurrent&bleeding&

Bleeding&from&gastric&varices?&

June$2010$

EARLY&USE&OF&TIPS&IN&PATIENTS&

PRESENTING&WITH&VARICEAL&

BLEEDING&

CP$class$C$or$class$B$with$conGnued$bleeding$at$endoscopy$known$to$have$high$failure$rate$63$such$paGents$randomly$assigned$at$24$h$to$either$TIPS$within$72$h$vs$TIPS$s$rescue$therapy$Followed$for$16$mos$for$rebleeding$or$failure$to$control$bleeding$

Management&of&the&Pa<ent&with&Cirrhosis!

One&point& Two&point& Three&point&

Bilirubin$ <2$ 2@3$ >3$

Albumin$ >$3.5$ 3.5@2.8$ <2.8$

INR$ <$1.7$ 1.7@2.3$ >2.3$

Ascites$ Absent$ Mild@Mod$ Severe/refractory$

Encephalopathy$ Absent$ I@II$ III@IV$

Class&A:&5I6&

Class&B:&7I9&

Class&C:&10I15&