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, 3^rd Edn, 1998
_ BNF Edn 46, Sept 2003
_ MIMS

Prepared by: Vanessa Simpson, Drug Information Pharmacist
Date: 3^rd 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.