Acute Liver Failure

From Alice Springs ICU 2009

Liver Failure Information and Management Guideline

 

Thanks to Royal Prince Alfred Hospital pharmacy department for supplying the drug information

 

Acute liver failure:

 

Characterised by the development of encephalopathy within the onset of symptoms, most commonly jaundice:

Hyperacute with encephalopathy developing within 7 days.

Acute encephalopathy within 7-28 days

Subacute encephalopathy after more than 4 weeks.

 

By definition acute liver failure is potentially reversible. The onset and severity of encephalopathy is variable. The rapidly worsening encephalopathy has a better prognosis than the slowly progressive form.

Cerebral oedema is frequent in severe encepholpathy and accounts for most deaths.

 

Acute liver failure is a rapidly progressive disease, is potentially reversible or may require a liver transplant. Therefore any patient with acute liver failure is best managed in a specialized centre and referral should be made early.

 

Clinical Features:

Encephalopathy is graded 0-4, admission to ICU is mandatory for the higher grades.

Grade 0- Normal mental state

Grade 1- Mild or episodic drowsiness, impaired intellect, concentration and psychomotor function but rousable and conversant.

Grade 2- Increased drowsiness with confusion and disorientation, rousable and conversant.

Grade 3- Very drowsy, disorientated, responds to simple verbal commands, often agitated and aggressive.

Grade 4- Responds to painful stimuli at best, but may be unresponsive. May be complicated by cerebral oedema.

 

Cerebral Oedema is present in 80% of patients with grade 4 encephalopathy. The pathogenesis is debated a combination of vasogenic and cytotoxic mechanisms are involved. Abnormalities in the blood brain barrier, plasma and cerebral accumulation of ammonia, false transmitters and GABA.

One of the earliest signs of progression is generalized increase in muscle tone which may progress to decerebrate posturing. There is an increase in deep tendon reflexes, extensor plantar response and clonus (clonus of the iris is called hippus and is a feature of hepatic encephalopathy.) Spontaneous hyperventilation is common often resulting in respiratory alkalosis.

 

Hourly neurological observations required. If grade 3- 4 encepholpathy treat as for raised intra cranial pressure. Mechanical ventilation usually necessary watch the CO2 level as patient may have been hyperventilating before.  Avoid large changes in CO2. Support MAP to >70 mmHg. Watch fluid balance carefully normovolaemia should be maintained avoid positive balance and salt loads. Nurse 20-30 degrees head up and venous return from the head unimpeded. Mannitol a dose of 0.5g/kg may be considered if renal function preserved and serum osmolality <320 mosmol/kg.

Lactulose less helpful in acute liver failure and if liver transplant an option discuss with transplant centre prior to giving as bowel gaseous distention may complicate transplant.

 

Coagulopathy results mainly from the loss of synthesis of clotting factors and the inhibitors however is made worse by DIC. The most common site for haemorrhage is the gastrointestinal tract, other common sites include the nasopharnyx (do not insert nasogastric tube, always an orogastric), respiratory tract, skin puncture sites and retoperitoneal. Spontaneous intracranial bleeding is rare.

 

Monitor coagulation stasis with 6-8 hourly coags and FBC. The INR gives a good indication of liver status and is major indicator for transplant. Only correct INR if overt bleeding or prior to invasive procedures. Give 10mg IVI Vitamin K daily.

Place on prophylactic H2 antagonist or omeprazole to decrease the risk of GIT haemorrhage.

 

Hypoglycaemia is common and results from impaired gluconeogensis, reduced glycogen stores and increased circulating insulin concerntrations.

 

Monitor BSL every 4 hours, and hourly if rapid changes, hypogylcaemia or change in mental state. Support with dextrose solutions if low. May need to use 10% or 50% dextrose solution if problems with fluid balance.

 

Cardiovascular disturbances are common typically they have a low systemic vascular resistance and a high cardiac index.

 

Careful volume loading with possible use of vasoconstrictors in order to maintain a cerebral perfusion pressure.

 

Respiratory problems include hyperventilation, ARDS and those associated with poor conscious state (atelectasis and aspiration.)

 

Renal failure occurs in 75% of patients with grade 4 encephalopathy. Hepatorenal syndrome is either type 1 with acute deterioration or type 2 with rising serum creatinine over weeks or months.

The criteria for diagnosis of hepatorenal syndrome are:

1)     Chronic or acute liver disease with advanced hepatic failure and portal hypertension.

2)     Low GFR defined by serum creatinine>130mmol/l or creatinine clearance <40ml/min

3)     Absence of shock, bacterial infection and recent treatment with nephrotoxic drugs

4)     No sustained improvement of renal function after volume expansion of 1.5L Normal Saline (this may be inappropriate if cerebral oedema is likely)

5)     Proteinuria<0.5g/day, and no ultrasonographic evidence of renal tract disease.

Additional criteria:

a)     Urine volume < 500ml/day

b)    Urine sodium <10mmol/L

c)     Urine osmolality >plasma osmolality

d)    Serum sodium < 130mmol/l

The additional factors are what normally happens not required for diagnosis.

 

Renal failure and fluid accumulation necessitates immediate continuous veno-venous haemofiltration. The use of lactate free solutions important as the liver is unable to metabolise lactate.

 

Infective complications are common, the early infections are usually from the urinary or respiratory tract and are usually gram positive or negative aerobes. Fungal infections may occur after the first week.

 

As these patients are immunosupressed strict asepsis and vigilant surveillance required. Appropriate antibiotic therapy instituted early often with the use of empiric broad spectrum antibiotics. Prophylactic fluconazole is recommended.

 

Impaired Drug Metabolism patients with acute liver failure are particularly sensitive to sedative and analgesic drugs. For a full list of drugs with altered metabolism see Appendix 1.

 

Nutrition should be established early preferably enteral. There is no evidence that protein restriction or use of branch chance amino acids have been shown to improve encephalopathy or decrease mortality.

 

N acetyl cysteine is used for paracetamol overdoses. In other forms of ALF it efficacy is controversial. In one trial was found to improve tissue perfusion, oxygen extraction ratio and mean arterial pressure, this has not able to be repeated.

 

Liver Failure and Drug Doses

Drugs requiring dosage alteration and/or monitoring in severe hepatic dysfunction:

ACE Inhibitors
Acitretin
Allopurinol
Aminophylline
Amlodipine
Amprenavir Amsacrine
Antidepressants, SSRIs
Azathioprine
Azithromycin
Benzodiazepines
Bicalutamide
Bisoprolol
Bupivacaine
Bupropion
Cabergoline
Carbamazepine
Caspofungin
Chloramphenicol
Clindamycin
Cyclophosphamide
Cyclosporin
Cytarabine
Dacarbazine
Danaparoid
Daunorubicin
Demeclocycline
Didanosine
Diltiazem
Disopyramide
Doxorubicin
Efavirenz
Epirubicin
Erythromycin
Felodipine

Flecainide
Fluorouracil
Fusidic acid
Gemcitabine
Heparin
Histamine H2 antagonists
Hydralazine
Idarubicin
Indinavir
Isotretinoin
Itraconazole
Lamotrigine
Levetiracetam
Lignocaine
LMW Heparins
Mercaptopurine
Methoxsalen
Metoclopramide
Metoprolol
Metronidazole
Mexiletine
Mirtazapine
Mivacurium
Moclobemide
Modafinil Nelfinavir Nifedipine Nimodipine Olanzapine Ondansetron
Opioid analgesics
Paracetamol
Phenobarbitone
Phenytoin
Procainamide
Propylthiouracil
Proton pump inhibitors

Praziquantel
Prazosin
Propranolol
Quetiapine
Quinidine
Reboxetine
Repaglinide
Rifabutin
Rifampicin
Risperidone
Rocuronium
Ropivacaine
Roxithromycin
Saquinavir
Sirolimus
Sodium nitroprusside
Sulfamethoxazole
Sulfonyurea hypoglycaemics
Tacrolimus
Tadalafil
TetracyclineTheophyline
Thiopentone
Tramadol
Tretinoin
Verapamil
Venlafaxine
Vinca alkaloids
Voriconazole
Zidovudine
Zoledronic acid
Zolmitriptan
Zolpidem
Zopiclone

 

 

Drugs that should be avoided in severe hepatic dysfunction:

Abacavir
Abciximab
Acamprosate
Amifostine
Anastrozole
Androgens
Angiotensin II receptor antagonists
Antidepressants, irreversible MAOIs
Antidepressants, tricyclic
Antihistamines (sedating)
Antipsychotics (typical)
Auranofin
Bosentan
Buspirone
Capecitabine
Carvedilol
Cetrorelix
Chlorpromazine
Clomifene
Clopidogrel
Clozapine
Cotrimoxazole
COX-2 inhibitors
Dantrolene
Docetaxel
Drotrecogin alfa (activated)
Entacapone
Ergot alkaloids
Etoposide

Ezetimibe
Fenofibrate
Flutamide
Gallantamine
Ganirelix
Gemfibrozil
Gestrinone
Griseofulvin
Ifosfamide
Interferons
Irinotecan
Iron (parenteral)
Isoniazid
Ketoconazole
Labetalol
Lercanidipine
Methotrexate
Methyldopa
Mianserin
Mitoxantrone
Nandrolone
Nevirapine
Nilutamide
NSAIDS
Oestrogens
Leflunomide
Lopinavir
Mefloquine
Methysergide
Moxifloxacin
Naratriptan

Paclitaxel
Pioglitazone
Procarbazine
Progestogens
Pyrazinamide
Quinupristin/dalfopristin
Raloxifene
Raltitrexed
Riluzole
Ritonavir
Rivastigmine
Rosiglitazone
Sibutramine
Sildenafil
Sodium aurothiomalate
Statins
Sumatriptan
Tamsulosin
Terbinafine
Tiagabine
Tibolone
Tirofiban
Topotecan
Toremifene
Valproic acid
Vardenafil
Verteporfin
Warfarin
Zafirlukast
Zalcitabine

References:
_ Sanford Guide to Antimicrobial Therapy 2002;
_ Drug Data Handbook, 3rd Edn, 1998
_ BNF Edn 46, Sept 2003
_ MIMS

Prepared by: Vanessa Simpson, Drug Information Pharmacist
Date: 3rd revision, January 2004

Appendix 2

DRUG NAME

TERLIPRESSIN ACETATE (GLYPRESSIN)

ACTION

  • Vasoconstriction
  • Reduction of portal venous pressure

INDICATIONS

  • For the treatment of acute oesophageal variceal haemorrhage
  • For the treatment of hepatorenal syndrome

PREPARATION & ADMINISTRATION

  • 1mg vial with 5ml diluent
  • Reconstitute by introducing the sterile diluents into the vial
  • Reconstituted solution should be used immediately
  • Given as a bolus injection

ROUTE

Strict intravenous to avoid local tissue necrosis.
Central venous administration is preferred.

PRECAUTIONS

Patients with hypertension and heart disease
Contraindicated in pregnancy

COMPATIBILITIES

n/a

DOSAGE

  • For the treatment of acute esophageal vertical hemorrhage: 1-2mg q4h iv
  • For the treatment of hepatorenal syndrome: 2-12 mg/day iv in 2-6 divided doses. Often administered concurrently with albumin.

ADVERSE REACTIONS

  • Hypertension
  • Abdominal pain, nausea & diarrhoea
  • Headache
  • Bradycardia
  • Local necrosis
  • Hyponatraemia due to antidiuretic effect

OBSERVATIONS

  • Heart Rate
  • Blood Pressure
  • Fluid Balance

REFERENCES

  • Product Information 2004
  • Ioannou G, Doust J, Rockey DC. Terlipressin for acute esophageal variceal hemorrhage (Cochrane Review). In: The Cochrane Library, Issue 2, 2004. Chichester, UK: John Wiley & Sons, Ltd.
  • Solanki P et al. J Gastroenterol Hepatol 2003; 18(2): 152-6.

 

 

 


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