Acute Liver Failure

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UtIS alter INet transplantauon J Med Vitol, 1989. la Gmson AE$. WhIle )IS, EddJesron ALWF& WAams R (1983) CJirocaJand prognostJc differences In /uJmlnant ...
THE SOUTHERN AFRICAN JOURNAL OF CRITICAL CARE

Acute Liver Failure review

M. D. VOIGT MBChB MMEO FCP MRC Uver Centre, University of Cape TCNVn, Groote Schuur Hospital, Observatory 7925.

SUMMARY This

paper reviews the definition, aetiology, elln;'

ca! presenlalion and management of patients with acute liver failure (ALF). Current management of the main complications, namely cerebnlI oedema, Infection, coagulopathy, metabolic disturbance, renal and cardiorespiraloly failure and the role of liver Ira... plantation in patients with ALF in South Africa, are discussed.

Definition Acute liver failure is broadly defined as the presence 01 severe liver dysfunction, complicated by hepatic encephalopathy occuring within 6 months of the onset of the first manifestations of liver disease and where no liver disease pre-existed 1• lINO major subgroups have been defined according to the rapidity of onset of encephalopathy and with variations in the natural history of the disease (vide infra). The compli· cations and prognosis differ between these subgroups. Fulminant hepatic failure (FHF) has been defined by different authors as: The onset 01 hepatIC encephalopethy within four', six', or eight weeks', of the appearence 01 the first symptoms of acute liver disease or within 2 weeks of the onset of jaundice'. A greater than 50% reduction in factor V has been used by some to define FHP. A subgroup with a more protracted course and delayed onset of hepatic encephalopathy (HE) have been Identified: The late onset hepatic failure (LOHF) HE occurs between 8 and 24 weeks after the onset of the first symptoms. Subfulminant Hepatic Failure, an alternative name given to this late onset group, has been defined as the onset of HE between 2 and 12 weeks after the onset of jaundices . .. This subgroup have a poorer prognosis11 .

Aetiology and Diagnosis The ep 250 ml. The dose is repeated as frequently as half to one hourly until ICP is reduced to below 20 mm Hg and signs of intracranial hypertension disappear. If the patient does not have a diuresis, and measured plasma osmolality is below 310, the dose should be repeated. Concomitant use of loop diuretics is often effective and has the added benefit of increasing free water clearance. If there is co-existent renal failure, a volume of fluid equal to 3-4 times the volume of mannitol given, should be removed 15·30 minutes after the mannitol infusion, by haemofiltration of continuous arteriovenous haemotiltration (CAVHF). Rebound increases in ICp49 caused by mechanical ultrafiltration may be circumvented with the use of CAVHFso. Patients with renal failure and intracranial hypertension unresponsive to mannitol and ultrafiltration have a very poor prognosis ( < 10%). HCMleVer, in a recent uncontrolled trial of barbiturate anaesthesia, 38% of 13 patients with oliguric renal failure and unresponsive intracranial hypertension survived43 compared to survival of 5-100/0 in historical controls. A bolus infusion of 250 mg of thiopentone at a rate sufficient to cause a reduction in intracranial hypertension. The thiopentone was temperarily stopped if systemic hypotension or hypothermia occurred, then restarted at a reduced dose. Confirmation of these promising results in a controlled trial, is awaited. Corticosteroids are of no benefit and may be detrimental in the treatment of brain swelling due to fulminant hepatic failurel48. 51. Reccwery of cerebral function in survivors, even in those with severe intracranial hypertension, is usually excellenr-'.

The exceecingly high prevalence (up to 90% of all patients) of secondary bacterial or fungal infection in ALp'S6.57 is due to both host and environmental factors. Deficiency of complement, fibronedin, and abnormalities of chemotaxis, neutrophil adherence and locomotion, blockade of leukocyte binding by fibronectin or fibrinogen fragments, abnormal mononuclear phagocyte function impaired mucosal barriersand portal systemic shunting may all contribute to thissusceptibility to infection. Most infections occur within the first 3 days of FHF,56 but fatal infections may also occur late in the course of the disease after recovery of consciousness and improvement of hepatic function. Gram positive cocci account for approximately half to two thirds of infectionsS6 , the most important of these being caused by staphylococci56 . Fungal infections especially with candida, occur in up to one third of patients surviving 5 days. These patients typically have concomitant bacterial infection, asablished renal failure, a markedly elevated white cell count, a pyrexia unresponsive to antibiotics and show a deterioration in coma grade after initial improvements7 • Management There should be an extremely low threshold for starting antibiotics. Features such as opacification on chest X·ray, temperature exceeding 38CC, white cell count >11x1eJ9/f, evidence of inflammation at wound or catheter sites or laboratory evidence of infection in urine, wound or sputum samples, should be aggressively treated with antibiotics. Peripheral catheters should be replaced at 3 days and urinarycatl)eters should be removed from anuric patients. The role of selective bowel decontamination has not been investigated in these patients. It is our practice to use topical oral and vaginal antifungal therapy to reduce the incidence of late candida infection. Treatment of established infection is based on the sensitivities of the cultured organism. If therapy is initiated without a bacteriological diagnosis, it should include anti-staphylococcal and gram negative cover. Specific choice of antibiotics depends on antibiotic sensitivities at the centre in question. Anti-fungal therapy with amphotericin Band f1ucytosineis relatively non-toxic in these patients, and should be used where fungal infection is suspected or proven.

Metabolic Abnormalities Hypoglycaemia

Haemorrhagic Complications The liver is the major site of synthesis of coagulation factors and coagulalion inhibitors. Coagulopathy is almost universal in patients with fulminant liver failure, due to reduced synthesis and increased consumption trom diffuse intravascular coagulation (DIG). FactorVIII·von Willebrand tactor which has pro-coagulant activity, is released by endothelial damage. CoagUlation inhibitors including protein C and S, anti-thrombin 3 and a1pha·2 macroglobulin are markedly reduced in fulminant hepatic failure49 . The platelet count drops in approximately 75% of patients to less than 100x109 due to impaired release and abnormalities of aggregation and adhesionS2 53.

Dilutional hyponatraemia is common 60 but sodium depletion may occur due to inadequate replacement of losses caused by mannitol and other diuretics. Dilutional hyponatraemia is treated by fluid restriction and avoiding the use 01 hypotonic IV fluids. Normal saline should be used for replacement in sodium depleted patients, as hypertonic saline may cause osmotic shifts and aggravate brain swelling.

Treatment

Hypematraemia

The following should be monItored twice daily: prothrombin time. partial thromboplastin time, fibringogen levels, fibrin(ogen) degradation products (FOPs) and platelet count Clotting tactors and platelets are replaced according to need. Fresh frozen plasma is used to correct the INR while cryoprecipitate IS required to replace fibrinogen. Random platelet concentrates are infused if bleeding continues desptte the adequate replacement of other clotting factors. Platelet counts> SOx109

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Hypoglycaemia occurs in up to 600/0 of patients with fulminant hepatic failure 58 and may be diffICult to control even with large doses of intravenous glucose. This is partly due to hypersecretion of insulinS9. Electrolyte and acid based imbalance

Hypernatraemia usually results from the inappropriate use of isotonic

or hypertonic fluid replacement in patients with osmotic diarrhoea (e.g. lactulose) or following diuretic use. It is avoided by careful monitoring of electrolytes. Correction should be slow (1-2 mmol/hr) using hypotonic fluid. Rapid correction may aggravate cerebral oedema by creating disequilibrium in osmolality between intra and extracellular brain tIssue.

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DIE SUIDER-AFRIKAANSE TYDSKRIF VIR KRITIEKE SORG

Other electrolytes Hyperkalaemia'" and hypophosphataemia are particularty prevalent in paracetamol induced FHF. Hypokalaemia may aggravate metabolic alkalosisAcid-based homeostasis MetabofIC acidosis is usually associaled with renal failure or paracetamol intoxication and is a iX>Of prognostic feature.

TABLE 1 PARACETAMOL INDUCED ALF

1. pH < 7.30 2. Prdhrombintime >100 sand serum creatinine >300umollt and grade 3 or 4 encephalopathy.

Respiratory Complications Bacterial and aspiration pneumonia, non-cardiogenic pulmonary oedema, ata/ectasis and ventilation perfusion defectscausing hypoxaemia are the most frequent respiratory abnormalities found in patients with FHF. 50-00% of patients may develop pneumonia'"_ Non-cardiogenic pulmonary oedema is commonly seen in patients with paracetamol overdose, particularly in the presence of metabolic acidosis- PertpheraJ oxygen utilisation at tissue level may be impaired leading to a relative tissue hypoxia.

Most patients with grade 3 and 4 encephalopathy require ventilation. PEEP should not exceed 5cm of water ta avoid impairing venous return and aggravating cerebral oedema. N-acetyl cysteine may improve the microcirculation and tissue oxygen exchange, but has nat been shown to be ot any clinical beneli~ except possibly in patients with paracetamol induced hepatotoxicity"'"'. The use of N-acetyI cysteine awaits validation in controlled clinical trials.

Renal Failure Renal impairment develops in up to 80% patients with ALF. Pre-renal uraemia, ATN, functional renal failure (hepatorenal failure)60 accou"nt for the majority of cases. Renal failure may also resutt directy from paracetamol toxicity, acute fatty liver of pregnancy, and the use of nephrotoxic drugs. Pre-renal uraemia may be indistinguishable from the hepatorenal ayndrome. Management consists of optimising fluid and haemodynamic status, ideally with the aid of pulmonary capillary wedge pressure monitoring. Colloid and crystalloids are infused until the plasma space is replete as sholf,," by a sustained rise in the pulmcr nary capillary wedge pressure after fluid challenge. In the presence of established renal failure, haemodialysis is performed for srtandard indications- In FHF this is usually done tor lKliumeOllel1oad and haemofiftration is required in the management of cerebral oedema Chronic artertOllenOUs haemofiltration (CAVHF) may be preferable in view of the rebound intracranial hypertension that occurs after mechanical haemofiltration_

ALF NOT DUE TO PARACETAMOL

1. Prothrombin time >100 s or 2. Any three 01 the lollowing: a) Age 40 b) NANB hepatitis or idioayncratic drug reaction. c} Prothrombin time> 50s d) Serum bilirubin> 300 umoll/ (Modified trom reI 64: O'Grady JG and Williams R: Uver transplantation vor Viral Hepatitis. Br Med Bull 1990; 46(2):481-491.)

encephalopathy has progressed to a severe grade, to ensure that the patient is in an optimal condition for tansplantation and to allow time for finding a donor. Orthotopic liver tansplantation remains the procedure of chcice, although heterotopic liver transplantation may be considered. While transplantation is technically less difficutt in ALF than in patients with chronic liver disease. major problems relate to intraoperative haemodynamic instability and surges in intracranial hypertension. Results in fulminant hepatic failure are considerably poorer than in chronic liver disease.

Acknowledgements I wish to acknowledge the research and input of my colleagues,

R. E. Kirsch, J Terblanche, D. Khan, S. C. Robson, R. J. Hilt, R. Hlckman who helped prepare a previous review on Acute Liver Failure, (Acute Liver Failure: tn Wright A (ed): Wrights Textbook of Liver and Biliary Disease. Bailliere Tindal!. London 1991), and Dr. f' A. Kirby for constructve criticism. This work was supported by MAC.

R-.nces 7 O'Graay JG & WiJiams R (1989) /lcule LJver failure. Ba:1Iieres CbmcaJ Gastroenterology

General Non-specific Measures: Prostaglandins Prostaglandin El has been evaluated in the management of fulminant hepatic failure in an uncontrolled trial of 17 patients with fulminant or subfulminant hepatic failure. Survival in this trial was 71%~. These promising preliminary results require validation In controlled trials. N-acetyl cysteine N-acetyl cysteine was shown to have a non-specific effect on tissue oxygenation, but has not been shown to improve survival. Until a survival benefit is proven, routine use of this agent is not justified. There is no place for the use eX charcoal hemoperlusion, exchange transfusion 62 or plasmapheresis&_ Liver transplantation Uver transplantation is the only current effective therapy for certain groups of patients with a poor prognosis. Prognostic indicators used by the Kings College group are given in table 1. The most important feature is the presence of an ongoing insult, eg with NANB-FHF and idiosyncratic drug reactions that progress after withdrawal of the drug. Livef transplantalion should be conSIdered early, even before hepaliic

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