Acute Liver FailureAcute Liver Failure“…the quick and the dead.”“…the quick and the dead.”

The Apostles CreedThe Apostles Creed

17 Feb 200917 Feb 2009

Paul H. Hayashi, MDPaul H. Hayashi, MDMedical Director, Liver TransplantationMedical Director, Liver Transplantation

University of North Carolina Liver ProgramUniversity of North Carolina Liver Program

Reference/ReviewReference/Review

• Polson J, Lee WM. AASLD Position Paper: The Management of Acute Liver Failure. Hepatology 41:1179-97; 2005

• www.UpToDate.com – Search “AASLD Guidelines”

ALF ManagementALF ManagementLearning objectivesLearning objectives

• Be able to make the diagnosis of ALF

• Etiology and severity assessment– Acetominophen & drugs (DILI) most common

• Understand when and how to transfer the ALF patient

• Initial support

• Role of transplant

Patient KC

46 yo AA woman, RN, healthy Day -40:

Abdominal pain, nausea; 2 weeks after starting simvistatin.

Day -14: self-d/c’ed simvistatin.

Day -1: Sent to local ER by supervisor for icteru ALT >2000; INR 7; bilirubin 24. Local ER to UNC MICU direct transfer.

Patient KC

Day 1 (Dec 21, 2008; UNC) Oriented x 3, deep jaundiceALT 2418; AST 2918; AP 307;

bilirubin 24.1; INR 9.8N-acetylcysteine IV continued.Viral serologies negativeANA (+), ASMA (-)

Patient KC

Day 1-2: Diagnostic work-up HBV, HAV serologies, HCV RNA negative ANA 1:640, ASMA negative; IgG 1618

(600-1700) ceruloplasmin 19 (15-52). Acetaminophen level below <10 ug/ml Patent hepatic veins on MRI.

Patient KC

Day 2-3: INR >14.4 Bilirubin 23.5 Progressively confused Listed Status 1 for liver transplant on

Day 2 (22 Dec 08). Entubated for airway protection

Patient MP

Day 4: 0730:T 38.6 Cultured and broad spectrum

antibiotics ordered. ~09:00: liver offer in Memphis, TN

UNC surgical team dispatched. 13:00: progressive hypotension, sepsis

picture. 15:00: Surgical team recalled. Liver

diverted.

Patient KC

Day 5 (25 Dec 2008): Progressive hypotension despite 2-3

pressors and antibiotics. FIO2 requirement climbing. Patient made DNR Dies 06:15.

DefinitionsDefinitions

• Absence of underlying liver disease

• INR >/= 1.5, mental status changes

• Illness < 26 weeks in duration

• ALT & AST >2000 to 5000; rising bilirubin

• Categories:– Hyperacute Liver Failure– Acute Liver Failure– Subacute Liver Failure (worst prognosis)

Incidence and DemographicsIncidence and Demographics

• 2000 cases/year– 200-300 transplants

• Duration of symptoms– Median 6 days (0-74)

• Jaundice to encephalopathy– Median 2 days (0-61)

• Dispostion:– 93% in 3 weeks.

Women 73%

Median age (yr)

38 (15-78)

White

Hispanic

AA

Other

74%

10%

9%

7%

Acute Liver Failure Group: Ostapowicz et al, Ann Int Med 2002Acute Liver Failure Group: Ostapowicz et al, Ann Int Med 2002

Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)

Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)

Drug IschemiaHep A Budd-Chiari Other

Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)

Unintentional

Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)

Etiology of ALF in the USA:Etiology of ALF in the USA:Adult RegistryAdult Registry (n = 610)(n = 610)

Drug IschemiaHep A Budd-Chiari Other

Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)

Drug induced liver injury and ALFDrug induced liver injury and ALF

ALF Etiology by DILI versus Non-DILI(DILI = Drug induced liver injury including

acetominophen)

0

50

100

150

200

250

300

350

400

450

Drug Other

Adapted from Ostapowicz et al, Ann Int Adapted from Ostapowicz et al, Ann Int Med 2002; Lee W. Hep 2004 Med 2002; Lee W. Hep 2004 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)

8 Center NIH Study8 Center NIH Study

• Children ≥ 2 years and adults

• Pre-defined biochemical criteria

- AST or ALT > 5 ULN twice consecutively

- Alk Phos > 2 ULN twice consecutively

- Bilirubin ≥ 2.5 mg/dl

Chalasani N, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006Chalasani N, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006

Percent ALFPercent ALF

Death

(within 6 months)

12.7%

Liver Transplant

(event related up to 6 months)

2%

Oral Presenation, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006Oral Presenation, American College of Gastroenterology, Las Vegas, NV, October 20-25, 2006

Complications of ALFComplications of ALF

• Multi-organ failure

• Encephalopathy – cerebral edema– CNS ammonia

• Infection

• Coagulapathy

• Hypoglycemia

Grades of EncephalopathyGrades of Encephalopathy

Grade 0 No change in mental status

Grade I Awake/responsive; mild confusion & disorientation; altered personality

Grade II Awake/agitated; more confused & disoriented; Hallucinations

Grade III Stuporous but arousable; more somnelent; ?ability to protect airway

Grade IV Unresponsive; comatose.

Recognition & TransferRecognition & Transfer

• INR is key: >/=1.5 must be admitted– ICU or step-down if mental status changes

• Call and transfer early.– ALF is rare so often takes us by surprise– Grade I-II encephalopathy--transfer– Grade III encephalopathy--intubate

• Consider distance

• Consider local expertise

N-Acetylcysteine N-Acetylcysteine in in NonNon-acetominphen ALF-acetominphen ALF

• Multi-center, placebo controlled.– Outcomes: overall and transplant free survival

• 81 NAC vs. 92 placebo– No difference in primary outcomes

• Secondary analysis– Transplant free survival odds = 11.3 (p<0.01)

for Grade 1-2 coma at randomization.

• Lee WM, et al. Hepatology 46:268A (2007) abs.

Look for etiologyLook for etiology• Treatable

– Acetominophen NAC– Amanita phalloides PCN; silymarin– Acute fatty liver of pregnancy delivery– Herpes Acyclovir– Autoimmune Steroids– Budd-Chiarri Heparin/TIPS

• Transplant only hope – Wilson’s

• Transplant contraindicated– infiltrating cancer (breast, melanoma, lymphoma)

Severity AssessmentSeverity AssessmentOstapowicz et al, Ann Int Med 2002 Ostapowicz et al, Ann Int Med 2002

(US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)

Severity AssessmentSeverity AssessmentKing’s College Criteria, N=585King’s College Criteria, N=585

• Acetominophen– pH < 7.3 after

resuscitation

– OR

– All of the following• INR>7

• Cr >3.4mg/dL

• Grade III or IV encephalopathy

• All other causes– INR > 7

– OR

– 3 of the following:• INR >3.5

• Age <10 or >40

• Jaundice to enceph >7 days

• Bilirubin > 17.5 mg/dL

• Indeterminate ALF

• Drug reaction

PPV: 70-100%

NPV: 25-94%

Support: General ManagementSupport: General Management

• Central venous access, arterial line– ?Pulmonary artery catheterization

• Avoid fluid overload

• Glucose monitoring (FS q 2-4 hours)

• CVVHD as necessary

• Enteral feeding (avoid TPN)

General ManagementGeneral Management

• Intubate for Grade III or IV encephalopathy

• Elevate head of bed

• Sedate PRN (propofol preferred)

• Limit rolling

• Limit suctioning; use endotracheal lidocaine

• Frequent neurologic checks (q 1-2 hrs)

HyperventilationHyperventilation

• Apply acutely for rise in ICP and/or deterioration of neurologic exam.

• Prophylactic use not recommended.

Blood pressure supportBlood pressure support

• Use colloid (albumin, pRBC’s if indicated)

• Aim = MAP 50-60 mm Hg

• Epinephrine, Norepinephrine, Dopamine preferred

• Vasopressin generally avoided– Terlipressin found to elevate ICP*

*Shawcross DL, et al. Hepatology 2004

MedicationsMedications • H2 blocker, ppi, or carafate

• Antibiotics—no data for prophylaxis.

• Don’t correct INR unless overt bleed.

• Mannitol (acute use)

• Lactulose—?

• N-acetylcysteine use for non-Tylenol cases

Severity Assessment and Severity Assessment and TransplantationTransplantation

All ALF patients

No benefit from or need for transplant

Benefit from Transplant

Transplant

Cadaveric Liver TransplantationCadaveric Liver TransplantationSurvivalSurvival

“Short term” (21 days)

1 year 5 year

ALF 15% w/o Tx NA NA

ALF 65%^ 59%* 51%*

Non-ALF 90% 85%* 69%*

* European Transplant Registry

^ US Acute Liver Failure Group; Ann Internal Med 2002

Cadaveric TransplantationCadaveric TransplantationOstapowicz et al, Ann Int Med 2002 Ostapowicz et al, Ann Int Med 2002

(US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)

308 ALF patients

136 (44%)Listed for Transplant

30 Died on list

17Removed from list

89 (65%)Transplanted

14Dead

75Alive

10Alive

7Dead

63% survival on intention-to-transplant analysis

Cadaveric TransplantationCadaveric TransplantationOstapowicz et al, Ann Int Med 2002 Ostapowicz et al, Ann Int Med 2002

(US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)

308 ALF patients

207 (67%) alive 101 (33%) dead

132 No Tx 75 Tx’d 14 Tx’d 87 No Tx

30 died waiting

47 died unlisted63% survival on intention-to-transplant analysis

Live Donor Liver TransplantationLive Donor Liver Transplantation

• Reported cases of good outcome.

• ALF patients are often young previously healthy.

• Heroism ethic valued.

• Minimal time to evaluate patient, donors and family

• Pressure for accurate donor evaluation is high.

• Outcomes for UNOS status 2a patients is poor.

PROS CONS

LDLT for ALF: a rare occurenceLDLT for ALF: a rare occurence

• 11079 potential LDLT cases– 11 (1%) cases ALF

• Mean time for donor evaluation = 2 days

• Outcome– 8 received LDLT and 7 alive at 5 year.– 2 received DDLT– 1 improved w/o transplant

Trotter JF, et al. (abs) Hepatology 362A (2006)

Molecular Adsorbents Recirculating System (MARS)

Heemann et al. Hepatology 2002

Liver Support Systems:Meta-analysis Liver Support Systems:Meta-analysis (Kjaergard et al., JAMA 2002)(Kjaergard et al., JAMA 2002)

System Mortaility Rx Mortality Control RR

Biologic DT 4/10 4/10 1.00 (0.34-2.93)

Biologic DT 3/5 3/3 0.60 (0.39-1.23)

Biologic DT 5/5 5/5 NA

MARS 6/8 5/5 0.75 (0.50-1.12)

Hemoperfusion 10/27 17/27 0.59 (0.33-1.04)

MARS* 1/12 6/12 0.17 (0.02-1.18)

Total 29/67 40/62 0.67 (0.51-0.90)

Acute-on-chronic liver failure

*Heemann et al. Hepatology 2002

ALF Goals of TreatmentALF Goals of Treatment

All ALF patients

No benefit from or need for transplant

Benefit from Transplant

All ALF patients

No need for transplant

Transplant

Benefit from Transplant

ALF ManagementALF ManagementLearning objectivesLearning objectives

• Be able to make the diagnosis of ALF

• Etiology and severity assessment– Acetominophen & drugs (DILI) most common

• Understand when and how to transfer the ALF patient

• Initial support

• Role of transplant

Extra SlidesExtra Slides

From here onward.From here onward.

Etiology of ALF: USAEtiology of ALF: USAEtiology of ALF: USAEtiology of ALF: USA

1998-20001998-2000

2001-20032001-2003

www.fda.gov/cder/livertox/presentations2004

Acetominophen DebateAcetominophen DebateKaplowitz, N Hepatol 2004Kaplowitz, N Hepatol 2004

Acetominophen Bad:• More stern warnings• Should be removed

from combinations.• Blister packs.• Limit amount sold at

one time.

– Lee W. Hepatol 2004

Acetominophen okay:• Present insert enough• “Unintentional” cases

are not so.• Benefit of blister

packs and limiting amounts short lived.

– Rumack B. Hepatol 2004

Cadaveric TransplantationCadaveric TransplantationOstapowicz et al, Ann Int Med 2002 Ostapowicz et al, Ann Int Med 2002 (US Acute Liver Failure Study Group)(US Acute Liver Failure Study Group)

308 ALF patients

136 Listed for Transplant

30 Died on list

17Removed

172 Not listed

47 died89

Transplanted

14Died

75Lived

10Lived

7Died

63% survival on intention-to-transplant analysis

Transplantation for Substance Transplantation for Substance and Drug Reactions/Toxicityand Drug Reactions/Toxicity

(Non-Acetominophen)(Non-Acetominophen)

24

13

10

10977

66

4

41

Isoniazid

PTU

Phenytoin

Valproate

Amanita

Nitrofuratoin

Herbal

Ketoconazole

Disulfiram

Troglitazone

Misc 1-3 cases

42%

(3 cases of statins)

Russo RW, et al. Liver Transpl 2004

Ammonia and Cerebral Edema:Ammonia and Cerebral Edema:Pros & Cons of lactulosePros & Cons of lactulose

(6) (10) (6) (10)

Strauss et al, Gastro 2001

Cons

1. Abdominal distention

2. No proven efficacy

Pros

1. Relatively benign

2. NH4 implicated linked to mortality

Rationale for N-acetylcysteine in Rationale for N-acetylcysteine in non-paracetamol induced ALF non-paracetamol induced ALF

• Anti-oxidant properties– Animal studies with ARDS– Human trials equivocal

• Cardiovascular effects– Animal studies in sepsis and liver failure– Human studies equivocal

• Immune modulation– Reduced inflammatory cytokines in sepsis

Increased BMI and ALFIncreased BMI and ALF

• High BMI not a risk factor for ALF

• High BMI increases risk of death or transplant in ALF– BMI >30: OR = 1.63 (1.04-2.55)– BMI >35: OR = 1.93 (1.02-3.62)

• Rutherford A, et al. Clin Gastro Hep 2006

Other interventions Other interventions for cerebral edemafor cerebral edema

• Hypertonic saline– Serum Na 145-155 may help lower ICP

• Barbiturates– Helps, but hypotension problematic

• Hypothermia (32-34 C)– Animal studies show benefit– Human studies limited but encouraging

Etiology of ALF in the USA:Adult Registry (n = 489)

ICP MonitoringICP Monitoring

• ICP Goals:– ICP <20 mm Hg

• >20 mm Hg x >5 min requires intervention (e.g. mannitol)

• >40 mm Hg x >2 hrs may contraindicate transplant

– MAP – ICP >50 mm Hg• <50 mm Hg x >2 hrs may contraindicate transplant

Complications of ICP monitoringComplications of ICP monitoringBlei et al. Lancet 1993Blei et al. Lancet 1993

• US Survey• 75% response• 60% of responders

used ICP’s• 262 ICP’s reported

• Epidural type (n=160)– 3.8% complication

• Subdural (n=79)– 20% complication

• Parenchymal (n=23)– 22% complication

• Bleeding : Infection– 7 : 1

rFVIIa and INR change in ALFrFVIIa and INR change in ALFShami et al. Liver Transpl 2003Shami et al. Liver Transpl 2003

rFVIIa and ALFrFVIIa and ALF Shami et al. Liver Transpl 2003Shami et al. Liver Transpl 2003

Plasma alone (n=8)

VIIa (n=7)

p value

PT correction

0/8 (0) 7/7 (100) 0.0002

Ability to place ICP

3/8 (0) 7/7 (100) 0.03

Mean FFP 19 13 0.35

Anasarca 7/8 (88) 2/7 (29) 0.04

ICP Monitoring and VIIa ICP Monitoring and VIIa Cons Cons ProsPros

• Cost!!– 8000 ug = $11,200– 12 units FFP=$1500

• No evidence that aVII decreases ICP complications.

• No evidence that ICP monitor improves outcomes.

• Small volume• ICP monitoring makes

sense.• ICP does dictate

change in care.

Bad Prognostic SignsBad Prognostic Signs

• APACHE score >15 on admission

• Etiology– Indeterminate, drug, Autoimmune, HBV,

Wilson’s, Budd-Chiari, Mushroom poisoning

• Coma grade III or IV on admission

MARS in Hyperacute Liver Failure:MARS in Hyperacute Liver Failure:Change in SVR Change in SVR (Schmidt et al. Liver Transpl 2003)(Schmidt et al. Liver Transpl 2003)

-100

0

100

200

300

400

500

600

700

0 1 2 3 4 5 6

MARS

Hypothermia

Hours on MARS

p=0.006

Molecular Adsorbents Recirculating System (MARS) Heemann et al. Hepatology 2002

N = 12

N = 12

Liver Support Systems:Meta-analysis Liver Support Systems:Meta-analysis (Kjaergard et al., JAMA 2002)(Kjaergard et al., JAMA 2002)

System Mortaility Rx Mortality Control RR Whole blood exchange

14/15 9/13 1.35 (0.92-1.98)

Charcoal hemoperfusion

19/29 20/33 1.08 (0.74-1.58)

Biologic DT 4/5 2/5 2.00 (0.63-6.38) Biologic DT 4/12 5/12 0.80 (0.28-2.27) Biologic DT 1/5 1/5 1.00 (0.08-11.93) Biologic DT 0/1 1 /2 0.50 (0.04-7.10)

Hemoperfusion 10/37 15/33 0.59 (0.31-1.14)

HepatAssist 20/73 30/74 0.68 (0.42-1.08)

Total 72/177 83/177 0.95 (0.71-1.29)

Acute liver failure

VIIa and Clotting CascadeVIIa and Clotting Cascade

VIIa

X Xa Prothrombin

Thrombin

Va

Effect of rF-VIIa on prostatectomy Effect of rF-VIIa on prostatectomy perioperative blood lossperioperative blood loss

0

200

400

600

800

1000

1200

1400

1600

1800

2000

Gauzes Suction Additional

Placebo

20ug/kg

40ug/kg

mL

Friederich et al, Lancet 2003

Artificial & Bioartificial Support Artificial & Bioartificial Support Systems in ALF: Meta-analysis Systems in ALF: Meta-analysis

Mortality Mortality

Number randomized trials

With support Standard care Risk Ratio

(95% CI)

8 72/177 83/177 0.95

(0.71-1.29)

Kjaergard LL, et al. JAMA 2003

“It’s worth every penny.”

March 13, 2003

Eric Gibney, MD, Nephrology fellow, commenting on aVII

after placing quinton catheter in ALF patient given factor aVII

HyperventilationHyperventilation• Head Trauma:

– Increased vasculature sensitivity to low PCO2 from days 2 to 5 post-injury.

– Correlated with decreases in brain tissue oxygen pressure.

– Carmona et al, Crit Care Med 2000.

• Cerebral blood flow does fall with hyperventilation in ALF– 43 ml/100g/min to 32 ml/100g/min (p<0.01)

– Strauss et al, Liver Transpl 2001

Bioartificial Liver Support in ALFBioartificial Liver Support in ALFMulticenter Randomized Controlled TrialMulticenter Randomized Controlled Trial

• N = 147 (73 BAL; 74 Controls)

• Overall 30 day survivals– BAL: 44/79– Controls: 53/73

• Cox proportional Hazard analysis to account for transplantation intervention– RR for BAL patients: 0.56, p = 0.05

p = 0.12

Demetriou AA, et al. Ann Surg 2004

Rationale for N-acetylcysteine in Rationale for N-acetylcysteine in non-paracetamol induced ALFnon-paracetamol induced ALF

O2 delivery & consumption <1hr IV NAC

– 12 aceto’ophen and 8 non-aceto’phen – Harrison et.al. NEJM 1991

– 15 pts with liver dysfunction of misc. causes– Devlin et al, Crit Care Med 1997

• No improvement seen at 5 hours infusion– Randomized, placebo controlled (11 vs 7 pts)– Most pts aceto’phen related.

– Walsh et al, Hepatology 1998

Hepatocyte TransplantationHepatocyte Transplantation

• Lack of cell source• Invasive delivery• Need for

immunosuppression• Likely need for large

hepatocyte mass

• hTERT immortalized human hepatocytes

• Xenotransplanted hepatocytes

• Bone marrow, embryonic stem cell, placental derived cells.

– Strom et al (ed.), Gastro 2003

Problems Promises

Hyperventilation in Head TraumaHyperventilation in Head Trauma

• Hyperventilation: the controversy– lower ICP vs. increase cerebral ischemia risk.

• Guidelines in Severe Head Trauma – Moderate hyperventilation (pCO2 30-35) =

first line measure if ICP elevated.– Heavy hyperventilation (pCO2 25-30)

considered second line.– Procaccio F et al, J Neurosurg Sci 2000

Effect of VIIa on prostatectomy Effect of VIIa on prostatectomy perioperative blood lossperioperative blood loss

Placebo (n=12)

20ug/kg (n=8)

40ug/kg (n=16)

pRBC 1.5 (0-4) 0.6 (0-3) 0.047 0 (0) 0.0003

% pts transfused

7(58%) 3(38%) 0.651 0 (0) 0.001

Perioperative blood loss (L) median & range

2.69

(1.71-3.57)

1.24 (1.02-1.41)

0.001 1.09 (0.93-1.32)

0.001

Friederich et al, Lancet 2003

Factor VIIa in Liver TranplantationFactor VIIa in Liver Tranplantation(de Wolf et al, Transfusion 39:87s, 1999)(de Wolf et al, Transfusion 39:87s, 1999)

• 5 patients given 80ug/kg VIIa at time of transplant

• pRBC given in first 24 hrs compared to 104 historical controls.

• Median pRBC given: 3 (range 0-5)– “…far below the lower limit of the 95%

confidence intervals for the mean in the control group.”

– One patient had hepatic artery thrombosis.

Liver Support SystemsLiver Support Systems

• Artificial– Whole blood exchange– Charcoal

hemoperfusion– BioLogic DT– Hemoperfusion– MARS (Molecular

Adsorbent Recirculating System)

• Bioartificial– ELAD (Extracorporeal

Liver Assist Device)• Human hepatocyte cell

line

– HepatAssist• Porcine hepatocytes

Cadaveric Liver TransplantationCadaveric Liver TransplantationEuropean Liver Tranpslant RegistryEuropean Liver Tranpslant Registry

1 year survival 5 year survival

ALF 59% 51%

Non-ALF 78% 69%

TransplantationTransplantation

• Cadaveric

• Live donor

• Hepatocyte

Seizure ProphylaxisSeizure Prophylaxis(Ellis et al. Hepatology 2000)(Ellis et al. Hepatology 2000)

Phenytoin (n = 20) Controls (n = 22) p value

Pupillary abnormalities

5 (25%) 11 (50%) NS

Seizure activity 3 (15%) 10 (32%) NS

Increased ICP 3 (15%)  7 (32%) NS

Cerebral edema (autopsy)

2†(22%)  7†(70%) < .05

†Number of autopsies performed in prophylactic phenytoin and control group (9 and 10, respectively).

Seizures and Cerebral EdemaSeizures and Cerebral Edema

NH3

Glutamine

Glutamine

Glutamine

Glutamine

ICP

Stimulation for seizures

Astrocyte

Clichy CritieriaClichy Critieria

• Factor V <20% and age <30 yr– Gr III-IV coma

• Factor V <30% and age >30 yr

– Bernuau et al, Hepatology 1986

• Not as good as KCC in acetominophen cases– PPV: 92% KCC &

73% Clichy

• Equal to KCC in non-acetominophen cases– PPV 89% for both

Clichy and KCC– NPV: 47% KCC & 36%

Clichy

Factor aVII and clottingFactor aVII and clotting

VII

aVII

aVII

aVII

aVII

aVII

aVII

aVII

aVII

aVII

Tissue factor

Phosphate Levels Phosphate Levels Acetaminophen ALFAcetaminophen ALF (Schmidt et al, Hepatology 2002)(Schmidt et al, Hepatology 2002)

Indicator Sensitivity Specificity PPV NPV Accuracy

Phosphate

 >1.2 mmol/L day 2 90 100 100 99 99

KCH criteria 67 97 80 93 92

Glutamine and Cerebral Edema:Glutamine and Cerebral Edema:Argument for hyperventilationArgument for hyperventilation

Strauss et al, Gastro 2001

Hyperventilation

Normoventilation

MARS in Hyperacute Liver Failure:MARS in Hyperacute Liver Failure:Change in MAP Change in MAP (Schmidt et al. Liver Transpl 2003)(Schmidt et al. Liver Transpl 2003)

-2

0

2

4

6

8

10

12

14

16

0 1 2 3 4 5 6

MARS

Hypothermia

Hours on MARS

p<0.0001

(Mean Cr: 2.9 to 1.7)

(Mean Cr: 3.82 to 4.05)

DILIN Centers and DILIN Centers and SatellitesSatellites

>12.8 million>12.8 million liveslives>12.8 million>12.8 million liveslives

http://dilin.dcri.duke.edu/