Liver failureLiver failure

Sub - acute liver failureLowest risk of cerebral oedema/ encephalopathyEasily confused with CLDAscitesLowest chance of spontaneous survival

Hyper - acute liver failureAcute liver failureGreatest risk of cerebral oedema, CVS failureGreatest chance of spontaneous survival

Cause Agent responsible

Viral Hepatitis A, B, D E, othersDrug related Idiosyncratic and dose related

Toxins Carbon tetrachloride, Phosphorous Amanita phalloidesVascular events Ischemic hepatitis, Budd-Chiari, VOD, heat

shock liver Other Pregnancy related, Wilson disease, lymphoma

Principle Causes of Acute Liver FailurePrinciple Causes of Acute Liver Failure

No previous liver diseaseVarious definitions Jaundice or symptoms to encephalopthy

• Decompensated chronic liver disease– Decompensation with sepsis

· Bacterial peritonitis : Rx as “peritonitis”· Bacteraemia, chest, urine

– Variceal bleed : frequently septic, endoscopic skills ± TIPS– Encephalopathy– Hepatorenal failure– Alcoholic hepatitis : steroids, pentoxifylline, feed, delta bilirubin

Differential with ALF :History Pattern of LFT’sImaging : ultrasound, CT scanBiopsy : vary rarely indicated

• Liver trauma

Multi system Multi system diseasedisease

Coagulopathy· INR important prognostic indicator in established ALF· Platelet dysfunction DIC - rare

Metabolic· Insulin resistance : Clarke et al Hepatology · Hyperlactataemia :Bernal et al Lancet 2002 : useful to track

· Liver net producer of lactate Murphy et al Crit Care Med 2001

· P04, Mg, Na, glucose, K, pH· High incidence of pancreatitis

Nutrition· Frequent poor recent oral intake ± vomiting · No evidence for protein restriction in either acute or CLD· Gastric prophylaxis· Increased metabolic requirements Walsh et al CCM 2000;28(3):649-

54

Renal Renal failurefailure

• Common 45% of all cases

• Multifactorial - frequently pre renal, ATN rather than HRS

• Role of intra-abdominal pressure

• Specific associations with viral disease, alcohol, auto-immune

• CRRT or slow haemodialysis is ideal

• Anticoagulation– epoprostenol, heparin, regional anticoagulation,

citrate

Infection : ALFInfection : ALF• Impaired innate and cellular immunity

• Bacterial infection 335 of 887 patients (550 episodes)• Severe sepsis 58% mortality

• Septic shock 98% mortality

• Fungal infection 99 of 887 : 11% : 64% mortality• Rolando et al Hepatology 2000 32:734, 31(4):872

• Components of SIRS associated with encephalopathy • Rolando et al Hepatology 2000;32:734-9, Vaquero et al Gastroenterology

2003;125:755-64, Shawcross D et al J Hepatol inpress

• Cultures +++

• Antibiotics : broad initially - 5/7 course Antifungals

• No benefit to routine prophylaxis or Selective gut decontamination• Rolando et al Semin Liver Dis 1996;16:389-402, Rolando et al Liver Trans

Surg 1996;2:8-13

Vasopressors in Vasopressors in ALFALF

• What mean arterial pressure ?– Clinical examination ….invasive– Determined by JV saturation and ICP : autoregulating or not ?

• Which drug?– Determine fluid responsiveness initially

· Whatever you can get your hands on

– In sepsis and MOF epinephrine may be detrimental· increases splannchnic V02 : glucose turnover Meier Hellman et al 1997

Crit care Med

– Phenylephrine : decreased flow with decrease in spl V02 Reinelt Crit Care Med 1999,27:325

– Norepinephrine as first choice– Vasopressin may be potentially detrimental : cerebral

complications and potential splanchnic ischaemia

Results stratified according to blood pressure on day of SSTResults stratified according to blood pressure on day of SST

00

500500

10001000

15001500

NS P<0.01 P <0.05

BaselineBaseline IncrementIncrement PeakPeak* P<0.001* P<0.001

Harry et al Hepatology 2002

mortality associated with lower baseline and increment (p<0.05)

–correlates with APACHE III and SAPS

–No correlate with other parameters other than cholesterol

–57% of patients have abnormal synacthen response

–hypotension associated with lower baseline and increment (p<0.05)

Marik 2005 CCM 53;1254Marik 2005 CCM 53;1254

• LDL cholesterol did separate groups

– 8.2±7.6 vs 28.4±14

• Mortality 39% vs 56%

• 75% of those on pressors had abnormal response

EncephalopathyEncephalopathy

HE of Acute Liver Failure

Hepatocellular failure

Rapid onset

Cerebral oedema

Myoinositol levels not reduced

Cytotoxic and vasogenic

Portal Systemic Encephalopathy

Portal systemic shunt– spontaneous collateral– Surgical– TIPPS

Not at risk of cerebral oedema

Precipitating factors

– Sepsis

· SBP Rx fluids ++

· Albumin

· Avoid renal failure

– CNS active drugs

– Electrolyte abnormalities

– Diuretics - over use

– Gastrointestinal bleeding

Hepatic encephalopathy in CLD

• Not a cause of death ……. Providing the airway is managed

• Treat precipitating cause : sepsis screen, fluids…….• Association of SIRS with encephalopathy • Feed - std protein, high calorie, fibre content ideally vegetable based• Lactulose and enemas - cleaning or acidification

– Als-Nielson BMJ 2004 ; 328: 1064• Non-absorbable antibiotics • Decreasing ammonia therapies

– (i) ornithine and (ii) benzoate

• Benzodiazepine antagonists - no efficacy Pomiers-Layrargues Hepatology 1989 10;969

• Sedation - real risk in ward environment – Yes, they are a menace : up all night, climbing into the wrong bed,

shouting

Progressive neuropsychiatric syndrome,

progressive neural inhibition

Occurs in both acute and chronic liver disease

Clinical state may change very rapidly

Incidence of cerebraloedema

Reviewed 229 patientsGrade III/IV coma1999-2002

Incidence Hyperacute : 24%Acute : 23%Subacute : 9%

NH4NeurosteroidsInflammatory response

Larsen Neurochem International 2004 (44)

Shawcross Lancet 365 2005

Increased ammonia in cerebral deaths :

splanchnic ammonia production Larsen et

al Hepatology 1998

NH4 cut off 124 .pH, cerebral oedema +

NH4 predict outcome Bhatia V Gut 2005

Partial pressure NH4 correlates with level

of encephalopathy Kramer Hepatology

2000:21

CBF variable : loss of autoregulation to

pressure

Terlipressin in ALF Shawcross et al;

Hepatology 2004;39(2):464-70

Jalan et al Gastroenterology2004;27:1338 Cooled to 32-33

o C PRE POST n=7 ICP 45 (25-49) 16 (13-17) * CBF 103 (25-134) 44 (24 -75) * CPP 45 (37-56) 70 (60-78) * CI 9.8 (7-13) 5.1 (4.3-6.1) *

•Arterial NH4 343 (109 - 490) to 259 (100-453)* •Uptake 2.6 ( 0.6-6.3) to -0.3 (-3.1 - 1.4)Jalan et al Lancet 354: 9185 :1164 1999

N=14

Reduction in ICP in treatment group (p<0.005)

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

Reduced risk of intracranial hypertension (p<0.05)

• Agitation and airway management

– Grade III : Intubate ventilate and sedate with opiate and propofol

– Control ventilation - avoid alkalosis

• Position - 10 to 20 degrees head up

• Insert reverse jugular line: JV sat 55 to 80%

• Tight control of glucose, K, pH, Na (145-150 mmol/L) Murphy et al Hepatology 2004;39(2):464-70

• Ammonia : early CRRT

• MAP >65 : frequently not autoregulating - need to measure ICP

• Treat “ICP” - pupillary abnormalities

– Mannitol 150 ml 20% (osmolarity < 320) or hypertonic NaCl (30%) : 20 ml Indomethacin 0.5 mg/kg

• Hyperventilation - only for ICP in association with high JV satn

• ICP trigger:-

– JV saturation, ammonia >150, pressors, fever, hyperacute and acute, pupilllary abnormalities

• Temperature - avoid fever : hypothermia should not be undertaken routinely

Currently available…

Phase III study with BAL Demetriou et al Ann Surg 2004;239 660-670

MARS Therapy Mitzner et al Liver Transpl 2000;6:277-286, Heemann et al Hepatology 2002;36:949-58

24 patients with CLD and ‘acute liver injury’

• MARS group: reduced bile acids, bilirubin, encephalopathy

• Controls: biochemistry static, worsening

encephalopathy– MARS 11/12 , SMT 6/12 (P<0.05)– 6 mnth survival 6/12 MARS vs 4/11

Coagulopathy and MARS treatment in CLDDoria et al Clinical transplantation 2004;18:365

Single Pass Albumin Dialysis (SPAD) Clearance of bilirubin, bile acids, NH4 : improvedSauer Hepatology 2004;39:1048

MARS Nathan et al Liver Transplant 2004;10:1109 Lai W et al Int Care Med

2005

• 18 patients with alcohol related AoCLD randomized to MARS or SMT over 7 days

• Significant improvement in encephalopathy

• No change in renal function or creatinine

• No change in ammonia or cytokine levels (TNF, IL-6, IL-10, IL-8), MDA, MELD fell in both groups

10 patients with ALF grade III/IV coma Treated 8 hours on 2 consecutive days

Increase SVRI on first Rx 1114±196 to 1432±245, changes not significant by end of second Rx

No change in ICP 14.5 (7-25) to 14 (3-25)

MARS+ SMT vs. SMT Acute on Chronic Liver Disease n=70 Significant improvements in encephalopathy grade

No differences in survival Hassanein et al AASLD 2004

Outcome of CLD in ITUOutcome of CLD in ITUWehler et al Hepatology 2001;34:255-261Wehler et al Hepatology 2001;34:255-261

143 patients :observational study,

Apache III>90, pressors, Clinical jaundice > 92% 1monthMortality vs 11% in those with < 3 criteria420 patients

Gildea Chest 2004;126:1598

30 patients with HRF8/30 30 day survival (median 21)Ventilated survival 0/15Non-ventilated survival 8/15

No difference INR/alb/pressorsJ Gastroenterology and Hepatology Witzke et al 2004 19;1369

Accuracy of ICU scoring systems

Child Pugh 0.72

MELD 0.72

APACHE II 0.78

SOFA 0.80

363 patients with CLD admitted to LITU

0102030405060708090

100

Mortality (Percent)

1 2 3 4 5 6

No. of organ failure

Graphical representation of LITU mortality and the Sequential Organ Failure Assessment System.

PSE+CVS+RENAL failure = 98% MortalitySOFA score cut off : 13

Guidelines for referral

Arterial pH < 7.30 or HC03 < 18 pH < 7.30 or or HC03 < 18

INR > 3.0 day 2 or > 4.0 thereafter INR >1.8

oliguria and/or elevated creatinine oliguria/renal failure

altered conscious level encephalopathy

hypoglycaemia hypoglycaemia

shrinking liver size

< 1000 ml need OLT

Na < 130 mmol/L

Bilirubin > 300 µmol/l

Paracetamol Non-Paracetamol

Children - coagulopathy

Budd Chiari

Pregnancy related

pH < 7.30 pH < 7.30 pH<7.3pH<7.3 all 3 of the followingall 3 of the following INR > 6.5INR > 6.5 within 24 hrswithin 24 hrs PT > 100 INR > 6.5PT > 100 INR > 6.5 any 3 of :any 3 of : Creatinine > 300 µmol/lCreatinine > 300 µmol/l seronegative hepatitis or seronegative hepatitis or grade 3 - 4 encephalopathygrade 3 - 4 encephalopathy drug related / halothanedrug related / halothane Bilirubin > 300 µmol/lBilirubin > 300 µmol/l INR > 3.5INR > 3.5 Age < 10 yrs or > 40 yrsAge < 10 yrs or > 40 yrs J - E > 7 daysJ - E > 7 days

Paracetamol Non-Paracetamol

Lactate : 4 hrs > 3.5 OR 43 p<0.001

Lactate : 12 hrs > 3.5 OR 63 p<0.001MELD > 30

Children - coagulopathy INR > 4.5 Encephalopathy + Factor V < 20% or

Budd Chiari : renal failure + HE < 30% if > 30 yrs of age

Low P04 : good prognosisAlpha feta protein

Liver volume

The future:Increasing liver disease alcohol, HCV, NAFLD HCC

Treatment changing Innovative treatment optionsliver support systems - furtherControlled trials required

Transplantation is a real optionEarly discussion

Assume fluid deplete: time is tissue Infection is commonAgitation=HE

Close observation

julia.wendon@kcl.ac.uk