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Home , Acute liver failure, Hepatology, Hyperdynamic circulation, Liver, Liver failure, Resuscitation

Acute Failure

A. W. HOLT Department of Critical Care , Flinders Medical Centre, Adelaide, SOUTH AUSTRALIA

ABSTRACT Objective: To consider the classification and to present an approach to the diagnosis and management of complications associated with . Data sources: A review of studies reported from 1966 to 1998 and identified through a MEDLINE search on treatment of . Summary of review: Acute liver failure can be subdivided into hyperacute, ( within 7 days of onset of ) acute (8-28 days from jaundice to encephalopathy) and subacute (29 to 72 days from jaundice to encephalopathy) forms. Management of all forms involves largely supportive care until and recovery occurs (predominantly in the hyperacute group), or bridging supportive until orthotopic can be performed. New such as bioartificial liver support devices and ex-vivo liver offer exciting possibilities for this bridging therapy. While orthotopic liver transplantation remains the definitive treatment for many patients with acute liver failure, N- acetyl-cystine (150 mg/kg over 15 minutes followed by 12.5 mg/kg/hour) and PGE1 (10 – 40 µg/hour) are reported to have an additional role and are being used increasingly in the management of all forms of acute liver failure. Conclusions: Acute liver failure is the end stage of many acute viral and drug induced hepatic . Management is largely supportive until hepatic repair or transplantation can be performed. Recently, additional hepatic protective, regenerative and supportive therapies have been successfully used. (Critical Care and 1999; 1: 25-38)

Key words: Acute liver failure, hepato-renal syndrome, , cerebral oedema, liver assist device, orthotropic liver transplantation

Classification King’s group, the French do not recognise the Two different classifications of acute liver failure ‘hyperacute’group. The reason for this is probably due (ALF) have been proposed by two prominent groups to their casemix, with ALF due to who work in this field1,2 (Table 1). Both seek to describe being much less common in France. the clinical spectrum of ALF within subgroups to Using the King’s classification,1 the difference highlight the association of aetiology and prognostic between the forms of ALF is reflected in the aetiology, features, to facilitate the delineation of management incidence of life-threatening cerebral oedema and (particularly with respect to the need for and timing of prognosis without orthotopic liver transplant (Table 2). orthotopic liver transplant). Given the substantial contribution to the literature of The French (Hopital Beaujon classification) ALF made by the King’s unit, and the lack of need from advocate that ALF occurs at the pre-encephalopathy a critical care point of view to include less severe forms stage and that the most sensitive marker is synthetic of ALF, I would advocate the use of the King’s function.2 This approach means that ALF is not a definition of ALF. clinical diagnosis, and as most patients with ALF have The clinical syndrome of hyperacute liver failure levels well below 50% by the time reflects largely the features of paracetamol with a encephalopathy ensues, this results in more patients with significant proportion surviving without orthotopic liver acute being diagnosed with ALF. Unlike the transplant (this is likely to be greater than the 36%

Correspondence to: Dr. A. W. Holt, Department of Critical Care Medicine, Flinders Medical Centre, Bedford Park, South Australia 5042

25 A. W. HOLT Critical Care and Resuscitation 1999; 1: 25-38 quoted from the King’s unit, with recent advances in made difficult by differing definitions. In Australia the critical care). best data available are from patients who have received an hepatic transplant. Cryptogenic/non-ABC group is by Table 1. Classifications of Acute liver failure far the most common cause of ALF in Australia, Classification Features whereas drug-induced ALF (particularly paracetamol- 4 induced) appears to be less common in Australia 3 King’s compared with of America (Table 3). a) Hyperacute liver failure encephalopathy within 7 days of onset of Table 3. Causes of acute liver failure and incidence jaundice. in Australia and USA b) Acute liver failure 8-28 days from jaundice Australia USA to encephalopathy c) Subacute liver failure 29-72 days from jaundice Drug-Induced (Total) 21% 32% to encephalopathy Paracetamol 20% Hopital Beaujon Idiosyncratic 12% Acute liver failure prothrombin or factor V below Cryptogenic/NonABC 43% 15% 50% of normal B 16% 10% a) early encephalopathy (<28days Hepatitis A 0% 7% from onset of jaundice) Wilson’s 6% 12% b) Subfulminant late encephalopathy (>28 days from onset of jaundice) Treatment Treatment of patients with ALF generally involves Recent data from a large cohort of ALF patients supportive care until hepatocyte regeneration and drawn from 12 transplant centres, 295 patients over 2 recovery occurs (predominantly in the hyperacute years (1994-96) demonstrated a spontaneous survival group) or bridging therapy until OLT can be performed rate in paracetamol induced-ALF of 57%.3 However, (Table 4). The major reasons why patients fail to survive cerebral oedema with life-threatening intra-cranial to OLT (or are precluded from OLT) are brain injury hypertension is a major determinant of poor prognosis. from intra-cranial hypertension, acute injury, Acute and subacute liver failure syndromes define pulmonary oedema and overwhelming . patients in whom orthotopic liver transplant (OLT), if possible, is the treatment of choice due to their poor Table 4. Treatment of Acute Liver Failure prognosis. With patients who have a clear subacute syndrome, less emphasis is required to detect and treat System Support cerebral oedema due to a much lower incidence and CNS - Hepatic encephalopathy severity of the disorder. - Cerebral oedema Respiratory Table 2. Acute liver failure data from King’s unit Circulatory Classification Hyperacute Acute Subacute Renal Haematological Aetiology Paracetamol Hepatitis C Gastrointestinal NANBNC* NANBNC Metabolic Hepatitis B Prevention of Sepsis Cerebral Common Common Infrequent Hepatic Rescue oedema (69%) (59%) (14%) Hepatic Support Survival without 36% 7% 7% Liver Transplant orthotopic liver Orthotopic transplant Auxiliary

* NANBNC = presumed viral non A non B non C A. SYSTEM SUPPORT Aetiology The spectrum of causes of ALF varies between 1. Central countries and centres, although direct comparisons are The main issues in treatment are:

26 Critical Care and Resuscitation 1999; 1: 25-38 A. W. HOLT a) Protection of airway OLT. The pathophysiology of cerebral oedema of ALF The rapid progression to high-grade encephalopathy is being increasingly defined using animal models. Both with airway obstruction, hypoventilation and aspiration cytotoxic and vasogenic mechanisms have been is a common preventable sequence leading to death or described8 and include the following, 1) inhibition of unsuitability for OLT. Na-K ATPase with the resulting accumulation of intracellular sodium and consequent cerebral swelling, b) Treatment of hepatic encephalopathy 2) toxic disturbance of the -brain barrier, and 3) Naso-gastric . Gentamicin (80mg via a increase in osmotically active molecules, particularly nasogastric tube 8-hourly) has replaced neomycin as the glutamine and other amino acids. aminoglycoside of choice for hepatic encephalopathy as Glutamine accumulation (which is the result of it is cheaper and plasma levels are measurable compared in ) has been with neomycin. emphasized.9 The accumulation of this Lactulose. While lactulose is the mainstay of therapy correlates with the increase in brain water in animal for chronic hepatic encephlopathy, gastrointestinal stasis models. However, a major shortcoming of the glutamine associated with ventilation and sedation results in a high hypothesis is the lack of brain oedema in patients with risk of gaseous due to chronic who have similar elevations of fermentation, particularly with aggressive oral regimes brain glutamine levels. It is possible that rapidity of (the addition of cisapride in this regard may be helpful onset and elevation of organic osmolar particles, in emptying the bowel). Lactulose enemas (100 ml in particularly glutamine and myo-inositol, overwhelm the 100 ml of water) appear to be at least as effective as oral compensatory mechanisms that regulate cerebral cell lactulose and circumvents the problem of gastric stasis. volume. The appropriateness of combining gastrointestinal antibiotics and lactulose is argued. The problem of CEREBRAL HAEMODYNAMIC AND METABOLIC rapidly gaining control with lactulose makes the addition PROFILE IN ALF of nasogastric gentamicin initially advisable.5 While Despite this understanding of the mechanisms of plasma ammonia levels do not correlate well with the cerebral oedema in ALF, considerable uncertainty severity of encephalopathy (or indeed with severity of surrounds much of the clinical data dealing with cerebral ALF) within the individual patient, the trend is a haemodynamics, and the implications for treatment of reasonable guide to the adequacy of intestinal raised ICP resulting from this cerebral oedema. decontamination and worsening or resolution of the The pressure dependency and loss of autoregulation ALF. of cerebral blood flow (CBF) in severe ALF has been Flumazenil. Flumazenil has been used in ALF, based well demonstrated, and has been found in all patients on the hypothesis that excessive gamma-aminobutyric studied with grade IV encephalopathy.10 The CBF acid (GABA) receptor stimulation by endogenous autoregulation is restored rapidly (usually within 24 agonists is a major cause of hepatic encephalopathy. In hours) following OLT. In ALF patients who have patients dying from paracetamol induced ALF with recovered without OLT, CBF autoregulation is usually grade IV encephalopathy, substances which inhibit the restored prior to complete recovery of the binding of labeled flumazenil are found in cerebral encephalopathy. Clinical data from the King’s group , which are absent in controls.6 In chronic liver appears to imply that inadequate CBF is the most disease with portal systemic encephalopathy, the doses common finding in high grade encephalopathy whereas of flumazenil quoted vary from 0.3-5 mg.7 However, the Pittsburgh group appear to regularly find normal or there appears to be a decreased response in ALF high CBF, and that low CBF is a pre-terminal event.11 compared with chronic hepatic encephalopathy, The most recent data from the King’s group shows although the non-responders in high grade that 73% of patients with grade IV encephalopathy have encephalopathy are likely to have raised intra-cranial a low CBF and that all patients who were studied had a pressure (ICP). Nevertheless, in patients with ALF any low cerebral metabolic rate for .12 This reduced resolution of encephalopathy with flumazenil is rarely of oxygen consumption was associated with evidence of great benefit in reducing the need for airway protection. anaerobic with increased cerebral lactate production. In these patients hyperventilation resulted in c) Detection and treatment of cerebral oedema further fall in CBF and oxygen consumption, although The prevention of neurological injury and death due lactate production was not increased. I2 to intra-cranial hypertension with subsequent cerebral did not alter CBF but increased oxygen consumption. ischaemia and transtentorial herniation, is crucial to and NAC significantly increased CBF and recovery from severe ALF or to a successful bridge to oxygen consumption.

27 A. W. HOLT Critical Care and Resuscitation 1999; 1: 25-38

In contrast, the Pittsburgh group found that only through each phase at variable rates, with the aim of 52% of patients studied had reduced CBF.11 therapy of course to prevent this progression. The Importantly, 24% had an elevated CBF and these increase in CBF with the progression from phase 1-3 patients were more likely to show cerebral oedema on was associated with a rise in ICP and it is tempting to CT scan, and have a worse prognosis. In patients with an conclude that the hyperaemia contributes to the cerebral ICP greater than 24 mmHg, all were found to have high oedema. CBF. The CBF was also significantly higher in patients The possibility that hyperaemia contributes to in grade IV encephalopathy. This work strongly cerebral oedema has a number of important implications suggests that cerebral swelling, intra-cranial for treatment. For example, hypertension and poor prognosis is associated with high 1. As cerebral autoregulation is lost in ALF, CBF or cerebral hyperaemia. The obvious difference unnecessary augmentation of mean arterial between these findings and the data from the King’s unit pressure (MAP) may be detrimental as it may is difficult to reconcile, although it must be noted that exacerbate the hyperaemia. only 21% of the Pittsburgh’s patients were in grade IV 2. Therapies that are associated with cerebral encephalopathy compared to all of the patients studied vasoconstriction may be of benefit in the early by the King’s unit. phases in the setting of increased ICP and luxury The Pittsburgh group has characterised five cerebral perfusion or hyperaemia. haemodynamic phases (Table 5) by measuring epidural 3. of cerebral blood flow (using Xe133 ICP, CBF (Xe133 technique) and arterio-jugular venous washout or transcranial doppler) or jugular bulb oxygen content difference (AVDO2). The mean CBF in venous oxygen saturation (as an index of patients with ALF was lower (28.7ml/min/100g) than adequacy of global oxygenation), becomes healthy controls (53ml/min/100g).13 However, from the important along side MAP and ICP. Measuring Pittsburgh data the reduced flow was initially associated actual flow is largely confined to research with reduced cerebral metabolic rate as the O2 extraction protocols, whereas the insertion of a jugular bulb was normal. With increasing severity, CBF initially is simple and safe even in coagulopathic increased, although not to ‘healthy’ levels, and the patients. reduced cerebral O2 consumption produced a low AVDO2 and effective luxury flow or hyperaemia. Diagnosis of cerebral oedema While the Pittsburgh group conclude from their data Patients with hyperacute and acute ALF can be that patients with ALF progress through the five phases, assumed to have cerebral oedema as it can occur in up to it is perhaps more correct to conclude: 80% of ALF patients with grade IV encephalopathy. 1. Patients who survive with medical therapy were Clinical signs of cerebral oedema (e.g. pupillary changes never observed to be beyond phase 2 and motor posturing) are usually late features, and as 2. Patients observed beyond phase 2 and survived most patients when they reach grade III encephalopathy underwent OLT are being sedated (to facilitate intubation and ventilation 3. Patients who died without OLT, all achieved for airway protection), clinical assessment of phase 4 or 5. neurological status is usually unhelpful. Cerebral CT The data in patients who died without OLT did not scanning is also of little help as it has a low sensitivity in show a sequential deterioration through each phase. the detection of elevated ICP (although it will exclude However these measurements were taken intracranial haemorrhage). intermittently and it is reasonable to infer a progression In a small series, 15 ALF patients in either stage III

Table 5. Five cerebral haemodynamic and metabolic phases of ALF

Phase 1 Phase 2 Phase 3 Phase 4 Phase 5

ICP <25 <25 >25 >25 >25 mmHg CBF <29 >29 >29 10-29 <10 /min/100g AVDO2 high narrow narrow high high- normal eventually low, with no oxygen extraction Cerebral Normal Hyperaemic Hyperaemic Impending Ischaemia perfusion perfusion low compliance ischaemia herniation

28 Critical Care and Resuscitation 1999; 1: 25-38 A. W. HOLT or IV encephalopathy, 80% had an elevated ICP of 32 + The King’s unit have proposed that aggressive 22 mmHg (mean + SD) and range of 18 - 100 mmHg.14 treatment of raised ICP increases survival in ALF when Four patients had CT scan evidence of an elevated ICP compared with their historical controls.18 However, (these patients had pressures of 100, 40, 27, and 23 there are no controlled data to suggest that monitoring mmHg). The 8 patients who had normal CT scans had ICP improves outcome in ALF. Moreover, in reviewing ICP’s of 24 + 4 mmHg (mean + SD), with a range of 18 data presented by Bernuau J et al,2 on their ALF patients - 29 mmHg. For this reason many centres routinely over a 4 year period without monitoring ICP, their measure ICP (at extradural, subarachnoid or results (without measurement of ICP or aggressive intracerebral sites) in patients with ALF with high-grade therapy for an elevated ICP) compare very favorably encephalopathy who require . with other units (the 1 year survival for OLT for ALF in Benefits of an ICP monitor. The advantages of an Australia is 60%). The results of 132 patients with factor ICP monitor include, V < 50% were instructive. Of the 69 who had no 1. measurement and maintenance of cerebral indication for OLT only 2 (2.8%) died of septic , perfusion pressure, and of the 63 who had an indication for OLT, 8 (13%) 2. an ability to target treatment for cerebral oedema, recovered without OLT, and 11 (17%) died with to reduce ICP and prevent transtentorial decerebration prior to OLT. Forty four patients (70%) herniation, received OLT with an 82% 3 month survival and 2 OLT 3. selection of salvageable patients for OLT (in one patients died of neurological complications. Overall, series all patients with sustained cerebral only 13 (10%) died of cerebral oedema. perfusion pressure of < 40 mmHg over 2 hours The excellent results of this unit need to be died. Even those that went on to OLT died post- interpreted in the light of the more inclusive definition operative from brain injury), of ALF, greater availability of liver donors and fewer 4. management of peri-operative surges in ICP patients in the ‘hyperacute’ group. My own opinion is associated with OLT (e.g. reperfusion of graft that in Australia with the low availability of donor can be associated with brain threatening surges in organs and the resulting need to support patients with ICP).15 ALF for longer (e.g. 24 hours or less in Europe compared with 4 days or more in Australia following However, ICP monitoring in ALF is not without it’s urgent listing) makes brain salvage a greater problem. risks. In a survey of centres performing OLT for ALF in Experienced personnel (using a cover of clotting factors) United States of America, a population of 262 patients can safely insert parenchymal monitors and they are with ICP monitoring was examined for complications indicated in patients with hyperacute and acute ALF (Table 6).16 requiring airway protection and ventilation (i.e. grade III While the fibreoptic catheter tipped parenchymal and IV encephalopathy). are more reliable, this data would suggest that they have a higher haemorrhagic rate Treatment of cerebral oedema compared with epidural monitors. However, experience While it is reasonable to assume patients with high- from the Scottish Liver Transplant Unit, Edinburgh, grade encephalopathy with hyperacute or acute ALF suggests that, with experience, a lower complication rate have cerebral oedema, a rational approach to its can be achieved with the parenchymal monitoring treatment requires consideration of the actual ICP, MAP technique. For example, in a review of 53 parenchymal and jugular bulb venous oxygen saturation (SJvO2). monitors, total haemorrhages were 4 (7.5%), two of Important therapeutic strategies and issues include: which were haemorrhages in patients with neurological 1. Augmentation of mean arterial pressure (MAP). death and importantly there were no haemorrhagic With intact cerebral autoregulation, the range of normal complication in the last 37 monitors.17

Table 6. Incidence of ICP complications in patients with ALF

Complication No. (%) Monitor type Number Total H’ges Fatal H’ges Total

Epidural 160 1 (0.6) 5 (3.1) 2 (1.3) 6 (3.8) Subdural 79 2 (3) 14 (18) 4 (5) 16 (20) Parenchymal 23 1 (4) 3 (13) 1 (4) 5 (22)

29 A. W. HOLT Critical Care and Resuscitation 1999; 1: 25-38 autoregulatory threshold is higher than commonly uptake) was increased. These changes were 12 appreciated (i.e. 75 - 85 mmHg). MAP in patients with interpreted as resolving a covert O2 debit. ALF being ventilated will often be significantly lower, 6. Cerebral vasoconstrictors. The association and cerebral perfusion pressure (CPP) may be between cerebral hyperaemia, intracranial hypertension borderline or inadequate even without significant and poor prognosis suggests the possible benefit of elevation of the ICP. Furthermore, as cerebral vasocontrictors. Indomethacin has been shown to be autoregulation is lost with high grade encephalopathy, effective at normalizing severe intracranial hypertension unnecessary empirical augmentation of MAP may well in a single case report.23 exacerbate the hyperaemia (and perhaps ICP) if present 7. Hepatic Support. Bridging to liver regeneration or in the early stages. Therefore the appropriate MAP will OLT with some method of hepatic support will clearly not only be dependent on the ICP (i.e. CPP) but also on be the way of the future. This is particularly true for the SJvO2. In ALF, data relating to adequacy of CPP is Australia where waiting times for donor organs is lacking. In the setting of neurotrauma a CPP of 70 variable and can be many days. While the aim of these mmHg has been found to be an important goal of therapies is to replace the entire liver function, pre- therapy. In ALF maintenance of CPP above 50 mmHg vention of cerebral oedema and brain injury will be was associated with full neurological recovery in all crucial. Early clinical data using high volume patients.19 Extrapolating from these data, patients with plasmapheresis and bioartificial suggests that they ALF, by stage III and IV encephalopathy have are effective in reducing ICP. intracranial hypertension (mean ICP 32 mmHg), and therefore augmentation of MAP to levels of 80 - 85 Neurological Prognosis mmHg may be required. The vasodilatation associated Up to 10% of patients undergoing OLT for ALF with ALF together with avoidance of excessive volume become brain dead during or immediately after loading due to propensity to pulmonary oedema results transplantation. To select which patients are not in the near universal requirement of a catecholamine neurologically salvageable and avoid proceeding to infusion to augment MAP. However to augment MAP in OLT is important. The target CPP of 50 mmHg arose the setting of SJvO2 > 70% (indicating hyperaemia), is from the fact that any patient who had a CPP < 40 not only unnecessary but potentially deleterious. mmHg for 2 hours died a neurological death, with or 2. Hyperventilation. Reducing ICP with the cerebral without OLT.19 However, in a report of 4 cases of ALF vasoconstriction produced by hyperventilation is a time- due to with an ICP > 35 mmHg honored strategy. However, the potential to cause for 24 hours or longer (with the peak ICP ranging ischaemia in the setting of neurotrauma has seen it fall between 44 - 101 mmHg) and CPP < 50 mmHg for over from favour.20 It may well be safe to hyperventilate 2 hours (with a minimum CPP ranging between 15 - 39 patients in association with hyperaemia (high SJvO2), mmHg), all survived neurologically intact without however as with neurotrauma, the data from King’s OLT.24 There are also cases described where pupillary unit12 argues that hyperventilation should be avoided response to light has been lost with subsequent full and normocapnia targeted. recovery. The only brainstem reflex, which has been 3. Mannitol. Mannitol has been shown to be of shown to 100% specific for predicting neurological consistent benefit in lowering ICP without eroding CPP. death with or without OLT, is the oculovestibular It’s use appeared to increase survival in ALF with reflex.25 increased ICP (using historical controls).21 The benefit in lowering ICP in this study was reduced in the setting 2. Respiratory of acute renal failure (although these data are recorded Patients with ALF readily develop pulmonary before continuous renal replacement techniques were oedema and the combination of high oxygen used). requirement and the circulatory consequences of 4. Thiopentone. In one study, thiopentone was of ventilating stiff often precludes OLT. The additional benefit in the setting of raised ICP refractory aetiology of the pulmonary oedema is frequently to mannitol. Once again survival in this group was multifactorial (Table 7). greater than expected on historical grounds.18 While acute lung injury often occurs in ALF, 5. N- (NAC). N-Acetylcysteine is pulmonary oedema in these patients is often very associated with a reduction in the incidence of cerebral responsive to redressing fluid balance, suggesting a oedema in ALF due to paracetamol.22 NAC was also significant hydrostatic component. Even though ALF is shown to increase CBF (effect on MAP was not considered a cause of acute lung injury, significant mentioned) and cerebral metabolic rate (i.e. O2 and ARDS is usually a result of aspiration or sepsis.

30 Critical Care and Resuscitation 1999; 1: 25-38 A. W. HOLT

Table 7. Causes of pulmonary oedema in ALF variable with most demonstrating no deleterious effects on splanchnic blood flow.27,28 However, others have Hydrostatic failed to show noradrenaline restoring splanchnic flow Myocardial depression despite restoration of .29 Fluid overload due to, In ALF, both and noradrenaline restore treatment of MAP while maintaining cardiac index by increasing renal failure systemic . Adrenaline results in a blood product requirement significant rise in rate unlike noradrenaline. Both Acute lung injury/ARDS agents cause a fall in O2 consumption despite 30 Aspiration maintaining global O2 delivery. Sepsis : Dopamine has no redeeming features as Acute liver failure an inotropic or vasopressor agent in ALF. In particular, dopamine’s indirect activity reduces its efficacy over time, and the demonstrated elevation in pulmonary Important issues in the management of these patients wedge pressure is clearly undesirable in this 31 are; setting. Low dose dopamine does not confer any renal 32 Early airway protection protective effects and the hastening in onset of bowel Judicious volume loading. Hypotension is often ischaemia in an animal model of haemorrhagic shock 33 poorly responsive to volume loading and early raises the issue of detrimental gastrointestinal effects. catecholamine support is required. Adjunctive Agents Early haemofiltration. Early haemofiltration is PGI2/PGE1: results in an increased delivery and 34 important not only for metabolic control but the consumption of O2 in patients with ALF. There is emphasis on its early introduction highlights the also reversal of the reduction in O2 consumption and importance of fluid balance control from a lung point of increased extraction ratio associated with the use of view. adrenaline and noradrenaline to increase the MAP. In one study this was associated with an increase in 3. Circulation cardiac index and O2 delivery without significant 30 The haemodynamic disturbance associated with ALF erosion of MAP. PGI2 at 5µg/kg/minute without a is characterised by: catecholamine infusion, achieves the same 1. hypotension, improvement in O2 flux at the expense of a 35 2. high -low systemic vascular significant rise in and fall in MAP. resistance, N-Acetylcysteine (NAC): N-acetylcysteine has 3. impaired oxygen extraction, and had an interesting and evolving role in the 4. depressed myocardial contractility management of acute liver disease. Following it’s role in preventing hepatic due to The pattern of disturbance is similar to that of the paracetamol poisoning, by replenishing depleted systemic inflammatory response syndrome (SIRS), stores of glutathione, NAC has been shown to although increased pulmonary vascular resistance is improve survival in patients with established liver 36 usually not a feature. The pathogenesis is also likely to injury. The mechanism of this beneficial effect is be multifactorial with pathological induction of not well delineated. However observational studies inducible nitric oxide synthetase causing vasodilatation have demonstrated circulatory benefits. NAC results by increasing guanylyl cyclase activation,26 and in a significant elevation of plasma levels of cyclic impairment of mitochondrial energy generating 3’,5’-guanosine monophosphate (cGMP) in acute systems playing a central role. ALF. Levels of cGMP already elevated in ALF, Resuscitation, following judicious volume loading, increase by a further 200% after a NAC infusion. will include a catecholamine infusion. The issues Interestingly, NAC has no significant effect on levels 36 relevant to the choice of catecholamines are: of cGMP in patients recovered from ALF. It is Adrenaline: Increases splanchnic blood flow in likely that NAC improves nutrient flow by healthy volunteers and in animal models of SIRS. microcirculatory as a consequence of However, the utility of adrenaline is reduced by the enhanced activity of the nitric oxide-soluble guanylate cyclase enzyme system. propensity of β2 stimulation to produce type B lactic . NAC at a dose of 150mg/kg over 15 minutes Noradrenaline: Reduces splanchnic blood flow in followed by 12.5 mg/kg/hour, results in an even healthy volunteers. The data in animal models is greater improvement in O2 consumption and similar

31 A. W. HOLT Critical Care and Resuscitation 1999; 1: 25-38

increase in O2 delivery compared with PGE1, but without the rise in heart rate or decrease in MAP.35 More recent work in patients in circulatory failure, Pathogenesis post OLT (due to poor graft function or sepsis), 1. Vasoconstriction of interlobular and arcuate sepsis, and decompensation of , and afferent arterioles. confirms the beneficial circulatory effects of NAC 2. Reduced glomerular capillary ultrafiltration above those of vasodilatory . In these coefficient.

patients PGI2 (5ηg/kg/minute) increased O2 delivery While it is likely that the cause of the hepatorenal at the expense of MAP but this time without increase syndrome is multifactorial, circulating levels of in O2 consumption. In contrast, NAC maintained endothelin correlate with the development and 39 MAP while increasing both O2 delivery and oxygen severity of hepatorenal syndrome. The hepatorenal consumption. Importantly, only NAC increased liver syndrome can be considered conceptually as pre- blood flow as measured by indocyanine green renal renal failure in the setting of severe liver clearance.37 While these benefits appear to be disease. Treatment, particularly with respect to consistently demonstrated by the King’s group, not avoidance of is a more common problem in all units have been able to reproduce this benefit decompensated rather than ALF. The using the same dose.38 in hepatorenal syndrome is primed for ischaemic injury. The progression to renal injury and In summary, NAC and (less reliably) PGE1/PGI2 appear requiring dialysis is associated to resolve the covert O2 debit frequently found in ALF with any additional ischaemic injury. With (although the clinical significance of this is unclear). paracetamol induced ALF a significant component However, unlike PGE1/PGI2, NAC maintains the MAP may be direct paracetamol nephrotoxicity. and increases liver blood flow. From a total patient care consideration the haemodynamic therapeutic goals are, Treatment catecholamines and adjunctive agents titrated to The treatment of the hepatorenal syndrome includes: optimise oxygen delivery and consumption, although 1) Augmentation of the MAP adequate perfusion pressure is crucial and often 2) Reduction in the intra-abdominal pressure hardest to achieve. For example, to improve or maintain From first principles, reducing intra-abdominal specific organ function from a cerebral, cardiac and pressure by draining a tense must improve renal point of view, maintenance or augmentation of not only renal but also hepatic blood flow. In MAP is the major circulatory goal. From a splanchnic animal models of elevated intra-abdominal point of view, vasopressors require caution because of pressure, the reduction of liver blood flow is of a the absence of a reliable and practical measure of greater magnitude than renal blood flow. If intra- adequacy of splanchnic blood flow. Gastric tonometry abdominal pressure is greater than 30 cmH2O has not been embraced in ALF patients. then the ascites should be drained. The results In conclusion, noradrenaline plus NAC are the from studies are variable and drainage of ascites agents of choice in ALF, although in the setting of ALF has been a common precipitating event for the due to noradrenaline plus PGE1 may be hepatorenal syndrome. Obviously hypovolaemia better. needs to avoided, although in one study a large volume was associated with a fall in 4. Renal clearance even though cardiac index, Renal impairment is almost universal in ALF and MAP, central venous pressure and pulmonary renal failure requiring dialysis is very common. The capillary wedge pressure were apparently issues of metabolic and uraemia control often have a maintained.40 In a more recent study, Luca et al lower priority than fluid balance control. In severe liver found that ascitic drainage was associated with a disease, the kidney is ‘prostaglandin driven’ or very significant improvement in liver blood flow and dependent on intrarenal vasodilatory reserve, renal function.41 particularly with respect to medullary blood flow. This 3) Renal vasodilators is due to relative hypotension, hypovolaemia and in the Dopamine is often considered a renal vasodilator. case of chronic liver disease, ascitic fluid induced However, in clinical practice where medullary increase in intra-abdominal pressure. The kidney in this vasodilator reserve is already exhausted, setting has no reserve for any minor insult and if it dopamine has no specific renal vasodilator occurs, progression of liver disease and development of properties and is no better at increasing renal hepatorenal syndrome ensues.

32 Critical Care and Resuscitation 1999; 1: 25-38 A. W. HOLT

blood flow than any other or mortality and may complicate or preclude progression to vasopressor. OLT. PGE1 seems an ideal agent if the MAP is not reduced. In one study, intra-arterial PGE1 over 60 7. Metabolic minutes was of no benefit (although MAP was Fastidious monitoring of blood glucose is required not controlled).42 In contrast, misoprostal (i.e. an and intravenous dextrose infusions should be provided. 43 oral analogue of PGE1) was of benefit. Endothelin antagonists: are likely to be of benefit B. PREVENTION OF SEPSIS and studies are awaited. Many patients with ALF present with, or develop 4) Dialysis severe circulatory failure and exclusion of supervening Continuous renal replacement techniques not sepsis is impossible. Furthermore, animal models readily only have the benefit of haemodynamic stability demonstrate intestinal bacterial translocation in acute in the setting of ALF but also have been shown liver .47 not to exacerbate intra-cranial hypertension Following a thorough culture screen, empiric broad compared with intermittent dialysis.44 spectrum antibiotics are indicated until culture results are known. The King’s unit has advocated the 5. Haematology combination of ceftazidine and ,48 although There is much debate about the appropriateness of this regimen seems to lack adequate anaerobic cover. In correction of any with these patients there is little room for error and as they (FFP). Many prominent workers in the field strenuously are often hospitalised with intravenous catheters prior to advocate the avoidance of FFP, so that the critical care episode, I would advocate the parameters can be used as a sensitive marker of hepatic combination of vancomycin (monitoring blood levels in recovery. It is my belief that procedures such as the presence of renal failure) and meropenem (500 mg insertion of intra-cranial pressure monitors require i.v. 8-hourly) until cultures are known. Continued broad aggressive coagulopathy correction, thereafter the INR cover in a prophylactic sense is indicated until recovery should be maintained below 2.5. of liver function or transplantation. During this phase, prevention of and frequent surveillance for nosocomial 6. Gastrointestinal infection is crucial. Selective decontamination of the Prevention of upper gastrointestinal due to digestive tract appears to offer no benefit to prophylactic stress ulceration and portal gastropathy, in the presence parenteral antibiotics.48 of coagulopathy, is important. While In patients receiving broad spectrum antibiotics, is normally considered a feature of chronic liver disease, fungal prophylaxis is important. Regimes proposed vary significantly elevated portal pressures are often present from fluconazole, to treatment with liposomal in ALF. The portal hypertension correlates with a degree . Given that many of these patients will of hepatic architecture collapse and systemic proceed to OLT and subsequent , vasodilation. In one study, the mean hepatic venous the risk of selecting non-candida fungi with fluconazole pressure gradients were significantly elevated in patients is a concern. I would advocate a low intravenous daily with ascites (15 mmHg) and renal failure (14 mmHg), dose (e.g. 10mg) or alternate daily (e.g. 20mg) above a mean hepatic venous pressure of 13 mmHg.45 amphotericin B as the strategy of choice. Significant While ALF patients will not have the mucosal and colonisation demands the full dose of amphotericin B vessel changes of chronic liver disease, the potentiation treatment. Nebulised amphotericin (30 mg in 5 ml of of the incidence and severity of bleeding due to elevated 0.9% saline) should be added for fungal colonisation of portal pressures requires aggressive prophylaxis. the respiratory tract. Intravenous (40 mg twice daily appears to be necessary for rapid acid suppression) and C. HEPATIC RESCUE is indicated for the prevention of erosive gastro- The administration of both PGE1 and NAC has been oesophagitis. Nasogastric tranexamic acid should be shown to improve liver function and survival in some added to the regime if there is evidence of bleeding. cases of ALF. Acute is an important complication of ALF. While the association between PGE1: Prostaglandin E1 has been shown to have an and acutely decompensating chronic liver disease is hepatic cytoprotective effect.49 In animal models of 50 51 better appreciated, a recent study found evidence of hepatic ischaemic injury, and viral injury, PGE1 has pancreatitis in one third of patients with ALF.46 The been shown to reduce the hepatic injury. In patients with presence of pancreatitis is associated with higher acute or subacute ALF due to viral , B or C;

33 A. W. HOLT Critical Care and Resuscitation 1999; 1: 25-38

PGE1 was associated with improved liver function and High volume plasmapheresis an improved survival rate. This study was a small and Preliminary data from Clemmesen et al, suggests uncontrolled study (e.g. 17 patients) where 71% that a 10 - 16 liter plasmapheresis with FFP may be survived without OLT. In the group with grade IV associated with improved indices of cerebral encephalopathy, 45% survived without OLT (normally oxygenation.56 However, this effect may be just a the survival in this group in this setting is less than function of increased CPP (which increase from 62 to 92 10%). The results suggested it is important to start PGE1 mmHg). In this study, the ICP fell from 19 to 11 mmHg early as the responders had lower grade encephalopathy in 8 patients (although this did not reach statistical and the non-responders had grade IV encephalopathy. significance). The benefits appear to be sustained for There was also a convincing temporal relationship about 12 hours. Until other liver assist devices are between improved liver function with commencement, widely available, short term gains may be of benefit in relapse with withdrawal and improvement again with critical cases in the lead up to an OLT. 52 recommencement of PGE1. In a subsequent small randomised, double-blind Bioartificial liver support devices. -controlled trial, PGE1 (10 – 40 µg/hour) was There are currently two systems that have been not associated with clinical or biochemical introduced into clinical trials. improvement. However there were only 18 patients 1. Bioartificial liver (Demetrious, LA, USA).57 This included, all excluded from OLT for various reasons and system involves a plasma filter which separates the the overall survival was surprisingly high at 55%. cellular and plasma components (to remove Duration of ALF was the major predictor of survival, biocompatability problems with and white and PGE1 appeared to be ineffective if started more than cells). The plasma is then passed over a charcoal 10 days after the onset of ALF.53 column, followed by a column containing suspended pig . Thereafter, the plasma is remixed with the NAC: The King’s group have shown that in cellular component and returned to the patient. Using paracetamol induced ALF, continuation of NAC beyond this technique for 6 hours per day in 7 patients with 20 hours until there is recovery (or OLT), is associated ALF, the ICP normalised and ammonia fell in all with improved survival compared with historical patients and they all survived to OLT. Further results controls,54 this has been confirmed subsequently in a from phase 1 clinical trials have yielded encouraging randomised controlled study.22 Whether NAC mediates results and a prospective randomised controlled trial has it’s beneficial effect via improved hepatic function or been initiated.58 reduced end , is not clear. 2. Extracorporeal liver assist device (Sussman, Houston, USA). This device utilises a column of D. HEPATIC SUPPORT suspended cultured human cells which The use of an extracorporeal system for blood are unique in retaining full synthetic function. This purification is not a new idea and charcoal system functions similarly to a continuous renal haemoperfusion has a long history in the treatment of replacement circuit. However, the mass of hepatocytes ALF. While this technique has not been shown to be of per cartridge in this system is significantly less than the any benefit, it highlights the problem of the adverse bioartificial liver, and continuous application is crucial. effects of maintaining these circuits over a prolonged Successful bridging to recovery in an animal model of period of time, which readily erodes any benefit of paracetamol induced ALF has been reported.59 In a purification. Recently, a new system which separates human pilot-controlled trial the biocompatability of the blood cellular components from a sorbent suspension device was satisfactory and no adverse effects on the using a membrane dialyser system was developed to count or haemodynamic stability was detected.60 overcome the adverse effects of charcoal haemoperfusion. However, early data from an Ex-vivo liver perfusion evaluation of this BioLogic-DT sorbent-suspension The use of animal livers for ex-vivo perfusion is not dialyser was disappointing with no significant effect on a new idea and has been performed. The utility of this ammonia levels and adverse effects on the coagulation procedure is poor due to the rapid destruction of the system.55 liver and adverse systemic effects of the hyperacute The development of a successful hepatic support rejection. The development of the ‘transgenic’ pig which strategy will offer a tremendous potential to bridge has hidden the immunogenic galactose haptens of the patients in ALF to hepatic recovery or OLT. endothelial molecules, thereby minimising hyperacute rejection, offers hope for a successful ex-

34 Critical Care and Resuscitation 1999; 1: 25-38 A. W. HOLT vivo pig liver perfusion over a more effective period. In a report of outcome of 548 patients with E. LIVER TRANSPLANT paracetamol induced liver injury referred to the King’s unit over a 6-year period, the utility of using these Orthotopic liver transplantation criteria for progression to OLT was evaluated.62 The This remains the treatment of choice for many OLT criteria were fulfilled by 124 patients. Of these, 56 patients with ALF. The decision to proceed to OLT is patients were not actually listed and received medical made on the basis of likely aetiology, clinical treatment because of rapid progression to multiple organ presentation and progression of biochemical markers of dysfunction precluding OLT (37 patients), advanced age hepatic injury, synthetic function and degree of end and comorbidities (4 patients) and psychiatric organ dysfunction. For this reason it is important that contraindications (15 patients). Only 5 (9%) of these patients with ALF be transferred to a transplant centre as patients survived. In the 68 patients who were listed for soon as possible to enable early assessment of this OLT, 24 patients did not receive a transplant due to their progression. deteriorating condition (24 patients), 4 of these patients Survival in Australia following OLT for ALF is 60 - survived. The total number of patients who met the 70% at 1 year, with very little ‘drop-off’ after the early criteria, but who received medical treatment only were post-operative period, and remaining above 60% at 5 80. Only 9 (11%) of these patients survived. years.4 Therefore, the challenge is to be able to pick There are other proposed prognostic indicators for those patients with ALF who have a survival of less than patients with ALF.63 Factor V levels, long advocated by 60% with supportive care only. Bernuau et al, has not been found to be as useful as the In patients presenting with acute and subacute King’s criteria for paracetamol induced ALF.64 hepatic failure syndromes, once progression of the However these are guidelines only and need to be injury is established, and in cases of presumed viral taken in context with other features. For example, aetiology following a trial of PGE1, the decision to clinical information (ICP, circulatory support) and proceed to OLT is often straight forward given the poor perceived course of disease at the time a donor liver prognosis in these patients with medical management. In becomes available. patients presenting with hyperacute hepatic failure Auxillary liver grafts syndromes, the prognosis with OLT needs to be The implantation of an auxiliary allograft liver in balanced against the possibility of survival without patients in whom the recovery of their native liver is OLT, and free of a lifetime of immunosuppression. The expected, provides time for the recovery to occur. The King’s unit has published criteria for predicting death (< technique currently used involves a left and 20% survival) and need for OLT (Table 8).61 implantation of a cut down liver graft. Currently, this orthotopic positioning is preferred despite the morbidity Table 8. Predictors of mortality in hyperacute liver of partial hepatectomy, because the venous outflow failure obstruction and the need for prosthetic closures of the heterotopic technique precludes its use. Paracetamol pH < 7.3 When the native liver recovery occurs, or immunosuppression is tapered and the graft atrophies.65 > 100sec, In a report of 30 cases of auxiliary liver transplant from creatinine > 300 µmol/l and 12 European centers, where the aetiology of ALF was grade III or IV encephalopathy hepatitis A, hepatitis B, paracetamol, , preeclampsia, ecstasy and other hepatoxic 66 All other causes prothrombin time >100seconds drugs, 19 (63%) patients survived and 13 (43%) had or resumed normal native liver function. Patients who had any 3 of the following: complete hepatic regeneration had mainly paracetamol 1. age < 10 or > 40 induced hepatic injury or were affected by hepatitis A or 2. Hepatitis C, NANBNC, B. or drug reaction 3. duration of jaundice > 7 days before encephalopathy Received: 8 January 1999 Accepted: 22 January 1999 (i.e. acute or subacute syndromes) 4. prothrombin time > 50 seconds REFERENCES 5. >300 µmol/l 1. O’Grady JG, Schalm SW,. Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273-

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66. Chenard-Neu MP, Boudjema K, Bernuau J, et al. hepatic failure--a multicenter European study. Auxiliary liver transplantation: regeneration of the Hepatology 1996;23:1119-1127. native liver and outcome in 30 patients with fulminant

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