From Alice Springs ICU 2009

Chronic liver disease:

The clinical signs of decompensation include jaundice, ascites and encephalopathy. These are often precipitated by insults such as gastrointestinal bleeding, sepsis, dehydration, alcohol binge, new or reactivation of viral hepatitis.
The patient requires supportive care of the liver dysfunction until the cause of acute deterioration is reversed.

Management of the complications of liver failure:

Ascites is almost invariable in patients with advanced chronic liver disease. The pathogenesis is a combination of portal hypertension, hypoalbuminaemia, excessive hepatic lymph formation and abnormalities in sodium and water balance.

If patient is hypotensive with low albumin consider fluid resuscitation with albumin based solutions rather crystalloid solutions.
If the patient has raised intrabdominal pressures consider paracentesis. Usually remove 3-5 litres of ascites and cover with albumin. Use 20% Albumin 100mls/2l ascites (if patient is hypovolaemic use 500mls 4% Albumin instead.) In patients who are not haemodynamically compromised control of ascites with salt and water restriction and use of diuretics is appropriate.

Complications of diuretic Rx include
-hypoNa (definitely stop when <120),
-hypo or hyper -kalaemia
-renal impairment (usually reversible),
-hepatic encephalopathy, and
-muscle cramps (can try quinine).


Bleeding from the gastrointestinal tract due to oesophageal varices or gastric mucosal erosions.

If active bleeding correct coagulopathy often have low platelets, low factors 2, 7, 9 and 10 and low fibrinogen levels. All patients should be place on omeprazole. Consider the use of octreotide to reduce portal pressures. Endoscopy should be done early if persistent bleeding despite pharmacological control.

Encephalopathy is very rarely associated with raised intra cranial pressure in chronic liver disease.

Prevent with the use of lactulose usual dose is 30 mls QID. Avoid sedative drugs particularly the benzodiazepines. Diazepam or lorazepam has to be used for alcohol withdrawal.
Intubate and ventilate the patient if requires airway protection.

Nutrition: These patients are often under nourished so feeds should be established early. Avoid high protein load as this may precipitate encephalopathy. Hepatamine may be added to feeds. This has little efficacy.
Hypoglycaemia is common and results from impaired gluconeogensis, reduced glycogen stores and increased circulating insulin concentrations.

Monitor BSL every 4 hours, and hourly if rapid changes, hypoglycemia or change in mental state. Support with dextrose solutions if low.

Sepsis is the common cause of decompensation so consider the risk of spontaneous bacterial peritonitis and fungal infections.
Subacute bacterial peritonitis
Diagnosed by a ascitic polymorphonuclear count of >250/mm3 
Albumin rehydration prevents renal failure and improves survival
Albumin given at 1.5g/kg within 6 hours of diagnosis of SBP followed by 1g/kg on day 3 day reduces incidence of hepatorenal syndrome and mortality (one limited study)

Consider prophylactic third generation cephalosporin.
If becomes septic once on antibiotics or sick for more than one week consider fluconazole for candida infection.

Renal failure is usually due to hypo perfusion or hepatorenal syndrome.
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 occurs but not required for diagnosis.

Treatment of hepatorenal syndrome is with Terlipressin 0.5-2mg q4h i.v.(appendix 2) and albumin 1g/kg the first day then 20-40g/kg thereafter.
Hepatorenal syndrome carries a poor prognosis and reversibility of the acute precipitant must be considered.

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

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


Alcohol withdrawal:
Patients with a heavy alcohol history must have thiamine 100mg daily and an alcohol withdrawal scale written up.

Portal Hypertension Explanation:
Portal hypertension is the main consequence of cirrhosis of the liver, and is responsible for its most common complications, the development of which mark the transition from compensated to decompensated liver disease.
The most common complication is the development of ascites.
The 2nd most common is hepatic encephalopathy.
The 3rd most common is variceal bleeding, however variceal bleeding is the major cause of death in patients with chronic liver disease.
Preventable complications include variceal bleeding, Spontaneous Bacterial Peritonitis (SBP), and Hepatorenal Syndrome (HRS).

The severity of cirrhosis correlates strongly with overall patient survival.

Child-Pugh classification of severity of liver disease (3)

Variable
Score 1
Score 2
Score 3
Ascites
Absent
Mild
Mod/severe
Encephalopathy
Absent
Stage I/II
Stage III/IV
Albumin (g/L)
>35
28-35
<28
Br (mcmol/L)
<34
34-51
>51
INR
<1.7
1.7-2.3
>2.3
Child-Pugh A: 5-6 points, B: 7-9 points, C:10-15 points


PATHOPHYSIOLOGY
The portal v: is formed by the union of the superior mesenteric and splenic veins. It drains blood from the abdominal GIT, spleen, and pancreatic bed.
A key consequence of increased portal pressure is the development of portosystemic collateral circulation that allows blood from the hypertensive portal system to return to the systemic circulation. These are varices.
Portal pressure initially increases as a result of increased intrahepatic resistance, but once collaterals have formed, high portal pressure is maintained by an increased splanchnic blood inflow secondary to vasodilation from locally produced factors such as nitric oxide. In advanced cirrhosis, this vasodilation is so pronounced, that effective arterial blood volume decreases markedly, and arterial BP falls. As a consequence, arterial BP is maintained by by homeostatic activation of vasoconstrictive and natriuretic factors, resulting in Na and fluid retention.
The combination of portal hypertension and splanchnic vasodilation alters intestinal capillary pressure and permeability, facilitating the accumulation of ascites.
As the disease progresses, there is marked impairment of renal excretion of free water and renal vasoconstriction, which leads to dilutional hypoNa and the hepatorenal syndrome.
Although it is the increased portal pressures that initially cause the formation of varices, it is the increased flow through them from hyperdynamic splanchnic circulation that causes their enlargement and then rupture.

Normal pressures in the human portal venous system range from 3-6 mmHg. Portal hypertension is defined by an increase to >10 -12 mm Hg.



Appendix 1

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.