1. Arterial pH <7.25 despite adequate \202 uid resuscitation or 2. Co-existing PT >100s o r INR >6.5, creatinine >300mol/l or Adrenal insuf \201 ciency Adrenal insuf \201 ciency is common in acute liver failure. IV hydrocortisone should be given to patients who do not have a satisfactory response to a sho rt synacthen test. anuria, grade III \200\223IV encephalopathy or 3. Serum lactate >3.5mmol/l on admission or >3.0mmol/l >24 h after overdose and after \202 uid resuscitation or Renal support Acute renal failure is common and associated with poor prognosis. Acetaminoph en has a direct nephrotoxic effect that peaks later than hepatotoxicity. Care should be tak en to avoid dehydration, hypotension and potentially nephro- toxic agents. Continuous haemo \201 ltration is associated with improved cardiovascular and intracranial parameters when compared with intermittent haemodialysis once renal fail- ure is established. 4. Two of 3 criteria from category 2 with clinical evidence of deterioration (e.g. increasing ICP, FiO2 >0.5, increasing inotrope requirements) in the abs ence of clinical sepsis Non-acetaminophen-induced acute liver failure: 1. Any grade of ence phalopathy and any 3 of: unfavorable etiology (idiosyncratic drug reaction, seronegative hepatitis), age >40yrs, jaundice to enc ephalopathy time <7 days, serum bilirubin >300 mol/l, PT >50s or INR >3.5 2. Hepatitis A or B, idiosyncratic drug reaction, seronegative hepatitis: PT >100s or INR >6.5 and any grade of encephalopathy Ventilation Once grade III encephalopathy develops, endotracheal intubation should be perfo rmed. Ventilatory support should be provided according to standard protocols. 3. Acute presentation of Wilson disease or acute Budd \200\223Chiari syndrome: coagulopathy and any degree of encephalopathy Speci \201 c therapies If paracetamol overdose is suspected NAC should be insti- tuted wit hout delay. There may be some bene \201 t from treatment even if 48h have elapsed since th e time of inges- tion. There is no evidence to suggest that the routine administration of N AC improves haemodynamic parame- ters, but it is common practice to start therapy with NAC in signi \201 cant acute liver failure of any etiology. Speci \201 c therapies for causes of acute liver failure are infre- quent and rarely subject to clinical trials. Lamivudine is given to patients with acute liver failure secondary to HBV infection, but there are no randomized trial data to sup- port this. Aciclovir is given for acute liver failure seconda ry to acute herpes simplex hepatitis. Acute autoimmune hep- atitis is an indication for ste roids. There are case reports of improvement in acute liver failure secondary to lymphoma t reated with chemotherapy. None of these therapies should delay listing for liver transplant ation if poor prog- nostic criteria are met. predictive value. Current UK criteria for super-urgent list- ing for liver transplantation in acute liver failure are sum- marized in Table 21.2.2. The most common procedure in acute liver failure is whole organ cadaveric orthotopic liver transplantation. Auxiliary transpl antation, in which a donor organ is implanted with- out recipient hepatectomy, has the adva ntage that immu- nosuppression can be withdrawn once liver function has recovered in the na tive organ. Living-related transplanta- tion is limited because of the short window of oppo rtunity to transplant. Liver support systems A number of systems utilizing hepatocytes or adsorption and dialysis techniques have been trialed in acute liver fail- ure. Although minor improvements in encep halopathy score have been seen, no improvement in survival has been demonstrated. Further reading Hawton K, Simkin S, Deeks J, et al. UK legislation on analgesic packs: befo re and after study of long term effect on poisonings. BMJ 2004; 329: 1076. Liver transplantation Liver transplantation is the only treatment proven to be of bene \201 t in acute liver failure. Survival at 12 months after liver transplantation for acute liver failure is 65%, signi \201 - cantly less than following transplantation for chronic liver disease. The majority of the excess risk is in the \201 rst month. There is a risk that patients with acute liver failure may deteriorate to a point that transplantation is not possible. Mortality rates whilst waiting for a suitable organ are up to 40%. Prognostic criteria for poor prognosis have been derived from historical cohorts of patients with acu te liver failure and validated in large numbers of patients awaiting liver transplant. Thes e criteria have high speci \201 city for detecting those likely to die without liver trans plantation, but are criticized for low sensitivity and low negative Rahman T, Hodgson H. Clinical management of acute hepatic fail- ure. Intensive Care Med 2001; 27: 467 \200\22376. Bernal W, Donaldson N, Wyncoll D, et al. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002;359: 558 \200\22363. Liu JP, Gluud LL, Als-Nielsen B, et al. Arti \201 cial and bioarti \201 cial sup- port sy stems for liver failure. Cochrane Database Syst Rev 2004; (1): CD003628. Transplant UK. Guidelines for completing the super-urgent liver recip- ient registration fo rm. 2005. https://www.uktransplant. org.uk/ukt/newsroom/bulletin/archive_bulle- tins/bullet in50/bulletin50-spring2004.pdf 352 M COWAN, S THOMSON, & T RAHMAN Hepatic encephalopathy Hepatic encephalopathy may occur in acute liver failure, acute on chronic liver failure or pose a long-term problem in cirrhosis. The etiology of hepatic encephalopathy is poorly und erstood. Encephalopathy in acute and chronic liver disease has been considered to have sepa rate causes, but this is now challenged. Clinical features are indistin- guishable, but man agement is different. Hepatic encepha- lopathy is graded according to the West Haven criter ia (Table 21.3.1). Once grade III encephalopathy is diagnosed, patients are at risk of airw ay compromise and should be electively intubated and mechanically ventilated. liver failure. Acute renal failure and oliguria reduce ef \201 cacy without haemo \201 lt ration to prevent \202 uid overload. Mannitol is contraindicated if plasma osmolarity >32 0mmol/l. Hypertonic saline The administration of 30% hypertonic saline to raise serum sodium levels to 145 \200\223155mmol/l was associated with a reduced incidence of intracranial hypertensi on in a single small study. Indomethacin Indomethacin causes cerebral vasoconstriction and reduces ICP after head traum a, and may be useful in patients with acute liver failure. Side effects including neph- rot oxicity limit its use in this setting. Management of hepatic encephalopathy in acute liver failure Acute liver failure is complica ted by the development of intracranial hypertension. This arises as a consequence of cerebr al oedema secondary to astrocyte accumulation of glutamine contingent upon hyperammonaemia, and cere- bral vasodilatation with increased CBF. Cerebral oedema occurs in 35% of patient s with grade III encephalopathy and acute liver failure, and in 65 \200\22375% of those in grade IV coma. Patients with acute liver failure and encephalopathy should be discussed wit h the local liver transplant center as a mat- ter of urgency. Thiopentone The barbiturate thiopentone causes cerebral vasoconstric- tion and may reduce I CP, but is associated with systemic hypotension and recurrence of intracranial hypertension on withdrawal. Hyperventilation Hyperventilation to reduce PaCO2 is known to cause cer- ebral vasoconstric tion and hence decreased CBF; however, this effect is transient. Prophylactic hyperventilat ion in acute liver failure does not reduce the incidence of intrac- ranial hypertension or improve survival. Short periods of hyperventilation may be useful in controlling surges of ICP that do not respond to other therapies. Monitoring Clinical signs correlate poorly with ICP. Direct ICP monitoring provides useful clinical information and may lengthen survival, but has not been subject to randomized tria ls. Epidural catheters predispose to infection and a 1% chance of fatal hemorrhage, but are safer than subdural or intraparenchymal devices. Jugular bulb satura- tion <65% or <80% ma y predict an elevated ICP. Trans- cranial Doppler ultrasonography and other non-invasive me thods of measuring cerebral blood \202 ow are not reliable at monitoring ICP. Corticosteroids Although useful in treating some causes of intracranial hypertension, corti costeroids do not reduce ICP in acute liver failure. Corticosteroids may be indicated in a sub- group of patients with adrenal insuf \201 ciency secondary to acute liver failure. Liver transplantation Liver transplantation is the only therapy proven to improve survival significantly in acute liver failure complicated by hepatic encephalopathy. Liver support s ystems and iso- lated hepatocyte transplantation are not of proven survival bene \201 t. Treatment ICP should be maintained <20 \200\22325mm Hg, and CPP (MAP \200\223 ICP) >50 \200\22360mm Hg. Airway suctioning and patient repositioning may cause surges in ICP and sh ould be preceded by sedation bolus. Cooling to 32 \200\22333 C resulted in a mean reductio n in ICP of 20mm Hg in 14 patients with acute liver failure and intracranial hypertension r efractory to standard therapy. A multi-center trial on the usefulness of moderate hypotherm ia in acute liver failure is underway. Lactulose, gut decontamination and enemata are not e ffec- tive in treating encephalopathy secondary to acute liver failure. Management of hepatic encephalopathy in chronic liver failure Chronic liver disease may be complicated by hepatic encephalopathy in a way that is clinically indistinguishable from th at seen in acute liver failure. Although hyperam- monaemia, abnormalities of GABAergic neur otransmis- sion, elevated cytokine levels and even disturbances in CBF may be similar to th ose seen in acute liver failure, intracra- nial hypertension is not a feature of hepatic en cephalopa- thy in chronic liver disease. Hepatic encephalopathy may complicate any acute ex acerbation of chronic liver disease, whether secondary to infection, GI bleeding, electroly te disturbance, constipa- tion or drug side effects. Chronic encephalopathy may develop in end-stage disease as a consequence of hepat- oportal venous shunting, and is a complication of TIPS insertion. Mannitol IV mannitol (0.5 \200\2231g/kg bolus over 30min) reduces ICP by increasing serum o smolarity and improves survival in acute Table 21.3.1 West Haven staging of hepatic encephalopathy I Lack of awareness, euphoria or agitation, reduced attention span II Intermittent disorien tation, drowsiness, inappropriate behavior III Marked confusion, incoherent speech, reduced conscious level but rousable to voice IV Comatose with or without response to painful stim uli Diagnosis Hepatic encephalopathy is usually diagnosed clinically. Subtle encephalopathy may only be apparent on psychometric 353 CHAPTER 21.3 Hepatic encephalopathy testing. Arterial ammonia levels lack both sensitivity and speci \201 city. Slow waves (1. 5 \200\2233Hz) on the EEG are a non- speci \201 c sign of metabolic encephalopathy. Visual provoked potentials may be prolonged in subclinical encephalopathy. Patients with chronic liver disease who develop encepha- lopathy should be examined for evidence of constipation of GI bleeding. Bloods should be taken to exclude electro- lyte abnormality, hypoglycaemia or signs of infection. A full septic screen including ascites cell count and culture is man datory. Cerebral imaging (e.g. CT brain scan) may help to rule out focal intracerebral caus es of altered sensorium. L-Ornithine L-aspartate (LOLA) converts L-ornithine to glutamate in muscle and utilizes amm onia to produce glutamine. LOLA reduces ammonia and may reduce encephalopathy; however, it is not licensed for use in the UK. Benzoate Benzoate is used in urea cycle disorders to reduce ammo- nia but has no effect on ammonia levels or degree of hepatic encephalopathy in liver disease. Liver transplantation Once encephalopathy has developed in a patient with chronic liver dis ease, referral for consideration of elective liver transplantation should be considered, on ce the acute illness has passed. Treatment Management of encephalopathy is supportive, with attempts to correct the underlyi ng cause of the acute deterioration. Infections should be treated aggressively. Further reading Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomized trials. BMJ 2004; 328: 1046. Constipation Non-absorbable disaccharides such as lactulose reduce colonic pH, alter gut \202 ora in favor of Lactobacillus spp and sequester ammonia. A meta-analysis showed no sig ni \201 cant effect on mortality or the development of encephalopathy with the use of lact ulose over placebo. In patients with encephalopathy, constipation should be prevented with regular purgatives (e.g. lactulose) to achieve 2 soft stools per day. Encephalopathy second ary to consti- pation may require enemata. Blei AT, Olafsson S, Webster S, et al. Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet 1993; 341: 157 \200\2238. Jalan R, Damink SW, Deutz NE, et al. Moderate hypothermia for uncontrolled intracranial hyp ertension in acute liver failure. Lancet 1999; 354: 1164 \200\2238. Kircheis G, Nilius R, Held C, et al. Therapeutic ef \201 cacy of L-orni- thine-l-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-cont rolled, double-blind study. Hepatology 1997; 25: 1351 \200\22360. Gut decontamination Neomycin does not reduce encephalopathy. Newer antibi- otics such as ri faximin or vancomycin may be more effec- tive, but predispose to bacterial overgrowth. A fe w small studies have suggested bene \201 t from probiotics or synbiot- ics in patients wit h chronic low-grade encephalopathy. Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut \202 ora: effect on minimal hep atic encephalopathy in patients with cir- rhosis. Hepatology 2004; 39: 1441 \200\2239. Murphy N, Auzinger G, Bernel W, et al. The effect of hypertonic sodium chloride on intracra nial pressure in patients with acute liver failure. Hepatology 2004; 39: 464 \200\22370. Diet Patients with chronic liver disease are usually malnourished and do not need to be pro tein restricted. There is no con- sensus on the role of branched chain amino acid supple- m ents in the management of encephalopathy in chronic liver disease. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41: 1179 \200\22397. Tofteng F, Larsen FS. The effect of indomethacin on intracranial pressure, cerebral perfusi on and extracellular lactate and gluta- mate concentrations in patients with fulminant hepa tic failure. J Cereb Blood Flow Metab 2004; 24: 798 \200\223804. 354 M COWAN, S THOMSON, & T RAHMAN Chronic liver failure Cirrhosis is the end-stage of all chronic liver insults. Decompensation of cirrhosis leads to liver synthetic failure, hepatic encephalopathy and symptomatic portal hyperten- sion. W ith modern standards of supportive care, the out- come of critically ill patients with chro nic liver disease is signi \201 cantly better than historical data, but long-term survival can often only be improved by liver transplantation. Patients with chronic liver disease c ommonly present with an acute on chronic illness. Acute deterioration can be precipitated b y bacterial or, less commonly, viral infection. Patients with hepatitis B may decompensate fol- lowing acquisition of hepatitis D. Other causes of decom- pensation include GI bleedin g, constipation, metabolic derangement, iatrogenic drug side effects, hepatocellular carcin oma and ongoing toxic liver insult including alcohol excess. and dose titrated to effect. Non-steroidal drugs should be avoided because of the risk of n ephrotoxicity. Constipation should be avoided, with regular lactulose (nasogastrically if n ecessary) titrated to achieve 2 soft stools per day. Regular enemata may be needed in acute encephalopathy. Hyponatraemia is common despite total body sodium overload. Diuretic thera py should be curtailed, especially if there is evidence of renal failure. The management of severe hyponatraemia (serum sodium <120mmol/l) is dif \201 - cult and controversial. In t he presence of hypovolaemia, cautious plasma expansion with colloids may prevent dete- rior ation of renal function. Nutrition Hypoglycaemia is common and responds to IV dextrose. Patients with chronic liver disease are almost universally malnourished and are hypercatabolic as a consequence of acut e illness. Early provision of nutrition, preferably via the enteral route, is a priority. L ow sodium feeds are standard. It is normally neither necessary nor desirable to restrict pr otein intake. Oesopahageal varices are not a contraindica- tion to the passage of a \201 ne bore feeding NG tube, although this should be avoided in the days immediately following acute variceal bleeding. Patients with alcoholic liver disease may present with Wernicke \200\231s encephalopathy (nystagmus, ophthalmoplegia, ataxia and confusion) secondary to th iamine de \201 ciency. Acute, irreversible polyneuropathy may be precipitated by a carbohy drate load and is prevented with IV thiamine (usually as a multi-vitamin infusion). History and examination Clinical history and examination should aim to determine both the u nderlying cause of liver disease (summarized in Table 21.4,1) and the reason for deteriorat ion. A collateral history may be necessary if the patient is encephalopathic. A careful alc ohol history including the remote past and recent binges is important. Alcohol dependence s yndrome is not necessary to develop alcoholic liver disease. Risks for viral hepatitis (IV drug use, unsterilized tattooing equip- ment, receipt of blood products prior to the introd uction of universal screening, occupational exposure, unsafe sex- ual practices, vertical t ransmission in patients from endemic areas) should be explored. A family history of autoimm une disease, diabetes or movement disorders may be helpful. A full drug history including o ver-the-counter and herbal remedies is necessary. Symptoms of encephalopathy, infec- tion i ncluding spontaneous bacterial peritonitis, upper GI bleeding and constipation should be so ught. Examination may be salient for the features of chronic liver disease. Asterixis and o ther evidence of hepatic encepha- lopathy are important signs. Intravascular and extravascu - lar \202 uid status including the presence of ascites and oedema should be carefully as sessed. Synthetic support IV vitamin K will correct coagulopathy secondary to de \201 - ciency of vitamin K, which is common in chronic cholesta- sis. FFP and platelets may be necessary in acute hemorrhage. Cryoprecipitate and activated factor VII may be useful in severe blood lo ss and coagulopathy not responsive to standard measures. There are no data to support the r outine use of IV albumin in patients with chronic liver disease and hypoalbu- minaemia. Management of decompensated cirrhosis on the ITU General features The drug chart of all pat ients should be carefully reviewed for potentially toxic medication. Opiates and benzodi- a zepines accumulate and should be prescribed with care Sepsis and spontaneous bacterial peritonitis Sepsis is a common cause of decompensation in patients with chronic liver disease who are functionally immuno- suppressed. Physicians sho uld have a low threshold for empiric broad-spectrum antibiotics active against Gram- negati ves and skin commensals antifungals. Antibiotics reduce rebleeding in variceal bleeding. All patients with ascites and clinical deterioration should undergo diagnostic ascitic tap with samples sent for micro- scopy and inoculated in blood culture bottles. Bacterial peri tonitis is diagnosed if the ascites neutrophil count is >250 cells/mm3. Spontaneous bacteri al peritonitis is usu- ally monomicrobial. Coliforms, streptococci and entero- cocci are th e most common organisms. Multiple organisms on culture are suggestive of intestinal perfora tion. There is no evidence to support total paracentesis in spontaneous bacterial peritonit is. Adrenal dysfunction is common in cirrhotic patients with severe sepsis and may contribu te to circulatory dysfunction. Table 21.4.1 Causes of chronic liver disease in the UK Alcohol excess Hepatitis B and C infection Autoimmune liver disease (autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis) Non-alcoholic steatohepatitis He reditary haemochromatosis Wilson \200\231s disease 1-Antitrypin de \201 ciency Budd \200 \223Chiari syndrome Cystic \201 brosis 355 CHAPTER 21.4 Chronic liver failure IV hydrocortisone (100mg tds) improves haemodynamics, reduces vasopressor requirements and improves survival in cirrhotics with severe sepsis and a \202 at short synacthen test (se e Chapter 27.9). acterized by a rapid decline in renal function frequently precipitated by severe sepsis or GI hemorrhage. It is his- torically associated with extremely poor prognosis. Type 2 HRS ca uses a milder and more slowly progressive decline in renal function, with severe ascites po orly responsive to diuretics. Survival of patients with type 2 HRS is less than that of non -azotaemic cirrhotics. The administration of IV albumin (1g/kg then 20 \200\22340g/day) and terlipressin (0.5mg 4 hourly increasing to max 12mg daily) may reverse type 1 HRS in up to 58%. Long-term survival bene \201 ts are dif \201 cult to interpret because of a high ra te of liver transplantation. Small studies suggest bene \201 t of TIPS and extracorporeal albumin dialysis (MARS) in selected groups of patients. These therapies are not widely avai lable. Type 2 HRS responds less well to albumin and vasopressors and is more prone to recur rence. Bleeding Upper GI bleeding is a common cause and consequence of decompensation in chronic l iver disease because of coagu- lopathy, thrombocytopaenia, portal hypertension and criti- c al illness-associated peptic ulceration. 50% is non-variceal. Early endoscopy, following ha emodynamic stabilization, is diagnostic and potentially therapeutic. Propranolol should be given to all patients with varices as prophylaxis against bleeding if tolerated. The manage ment of upper GI bleed- ing is discussed elsewhere (see Chapter 20.5). The manage- ment of non-variceal bleeding is as that of patients without liver disease. Alcoholic hepatitis Acute alcoholic hepatitis occurs on the background of chronic alcohol e xcess. Liver biopsy invariably shows underlying hepatic \201 brosis. Alcohol withdrawal s hould be avoided by reducing doses of chlordiazepoxide or benzodi- azepines. Corticosteroid s reduce mortality in patients with severe alcoholic hepatitis (discriminant function >32) in patients without acute bleeding or sepsis. Pentoxy \201 lline reduces the incidence of HRS and in-hospital mortality in alcoholic hepatitis. Hepatic encephalopathy Hepatic encephalopathy is discussed in the previous chapter. Ascites Ascites secondary to portal hypertension is suggested by a serum \200\223ascites al bumin gradient >11g/dl. Alternative diag- noses should be sought in high protein ascites, a nd treat- ment directed to the cause. Patients with chronic liver disease and ascites shoul d be sodium restricted. Diuretic therapy with spironolactone (100mg/day increasing to maxim um 400mg/day) frusemide (40mg/day to max 160mg/day) should be undertaken, with careful m onitoring of electrolytes and renal function. Diuretics are stopped if serum sodium falls o r creatinine rises. Patients who do not tolerate diuretics, or develop tense ascites (intra -abdomi- nal pressure >20cm H2O, signs of respiratory or ventila- tory compromise, discomfo rt) may be treated with large volume paracentesis. Paracentesis <5l does not require albumi n but should be followed by volume expansion with a synthetic colloid. Paracentesis >5l sho uld receive 8g albu- min per liter of ascites removed (e.g. 100ml 20% albumin per 3l ascite s). The canula used to drain ascites should be removed after 6h. Scoring systems for outcome The mortality of cirrhotic patients with critical illness remai ns high, with in-hospital mortality rates of 44 \200\22374% in those requiring admission to ITU. Mortality is dependent not only on the severity of liver disease but also on the pres ence of cardiovascular or renal failure. Prognosis in the critically ill patient with chron ic liver disease is more accu- rately predicted by ITU-speci \201 c scoring systems such a s APACHE II or SOFA than the Child \200\223Pugh score. Liver transplantation For patients with decompensated chronic liver disease and no reversib le cause, liver transplantation is the only treat- ment proven to improve long-term surviva l. There is no provision for emergency liver transplantation for chronic liver failure in t he UK. Patients should be discussed with the local transplant unit with a view to considera tion of transplantation once the acute episode is passed. There is potential for signi \201 cant improvement in liver function if patients with alcoholic liver disease achieve ab stinence after recovery from their initial illness. Cardiovascular system Patients with chronic liver disease have increased splanch- nic blood \202 ow and high cardiac output with low SVR, resulting in hyperaldosteronism and second ary sodium retention. Such patients are prone to hypotension, treata- ble initially with \202 uid challenges. There is debate about the ideal fluid resuscitation since sodium-conta ining fluids exacerbate ascites and peripheral oedema whilst dextrose worsens hyponatraemia . The opinion of the authors is that maintenance of renal and cerebral perfusion with collo ids is the initial priority in resuscitation of the cirrhotic patient. Hypotension unrespon sive to volume resuscitation is an indication for vasopressor inotropes such as norepine- p hrine. Further reading Cowan M, Tilliard A, Cook M, et al. Morbidity and mortality associ- ated wi th alcoholic liver disease following admission to St George \200\231s Hospital HDU/ICU. Gut 2006; 55 (Suppl 2): A46. Fernandez J, Escorsell A, Zabalza M, et al. Adrenal insuf \201 ciency in patients with cir rhosis and septic shock: effect of treatment with hydrocortisone on survival. Hepatology 20 06; 44: 1288 \200\22395. Renal Renal dysfunction is common in patients with chronic liver disease. Since hepatic pro tein turnover is reduced and muscle mass low, serum levels of urea and creatinine may remai n within the normal ranges despite signi \201 cant reduc- tions in GFR. Renal failure may develop as a consequence of volume depletion, drug nephrotoxicity, sepsis, intrinsic renal disease or out \202 ow obstruction. Renal failure in the absence of these factors, and per sisting despite diuretic withdrawal, \202 uid challenge and treatment of sepsis, is terme d hepatorenal syndrome (HRS). Type 1 HRS is char- McCullough AJ, O \200\231Connor JF. Alcoholic liver disease: proposed rec- ommendations for the American College of Gastroenterology. Am J Gastroenterol 1998; 93: 2022 \200\22336. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006;55 (Suppl 6): vi1 \200\22312. 356 M COWAN, S THOMSON, & T RAHMAN Abnormal liver function tests Enzymes The liver contains a number of different enzymes that are released from damaged hep atocytes and can be detected in serum. The levels of such enzymes are fre- quently normal i n patients with chronic liver disease, especially if there is little ongoing in \202 ammat ion. Elevated liver enzymes may be considered hepatitic (i.e. a conse- quence of hepatocell ular damage; raised AST and ALT), cholestatic (i.e. a consequence of biliary obstruction; r aised alkaline phosphatase and -glutamyltransferase ( GT)) or mixed. Table 21.5.2 Causes of elevated AST/ALT Hepatitis (any cause) Drug-induced liver injury Impaired hepatic perfusion Biliary obstruct ion Hepatic congestion Myocardial infarction Myocarditis Trauma (including post-surgery) Rh abdomyolysis Myositis Muscular dystrophy Renal infarct Trauma Hepatocellular (ALT and AST) Myocardial damage (AST>ALT) Skeletal muscle injury (AST>>ALT) Aspartate aminotransferase/alanine aminotransferase These are cytoplasmic hepatic enzymes t hat may be detected in excess in serum in liver disease with ongoing activity of any etiolo gy, but are most raised in hepatocel- lular injury. AST and, to a lesser extent, ALT are pr esent in skeletal muscle and myocardium, thus myocardial necrosis and skeletal muscle damag e should be excluded in cases of elevated aminotransferase levels (especially AST). AST may also be elevated in renal or intestinal infarction, pancreati- tis or hypothyroidism. ALT is more speci \201 c for liver injury than AST. Causes of raised transaminases are summari zed in Table 21.5.2. The ratio AST/ALT may be used to differentiate the aetiol- ogy of live r disease. In acute viral hepatitis, the ratio is com- monly <1, whereas in alcoholic liver disease the ratio is typically >2. An AST/ALT ratio >1 has been proposed as a marker of ci rrhosis in chronic liver disease, but lacks sensi- tivity. Renal necrosis (AST) alcohol abuse, and is sometimes used as a screening test for ongoing alcohol intake. This a pproach lacks sensitivity and is non-speci \201 c. Carbohydrate-de \201 cient transferrin is not more accurate than GT as a screening test for chronic alcohol abuse. GT is also present in prostate tissue and may be elevated in prostate cancer. Excretory liver function Bilirubin is a byproduct of haem breakdown that is taken up by hep atocytes, conjugated and excreted into bile. Elevated bilirubin may occur as a result of ha emolysis, hepatic disease or biliary obstruction. Alkaline phosphatase Alkaline phosphatase is found in a number of tissues includ- ing liver , bone, intestine, kidney and placenta. Elevations in alkaline phosphatase occur in disease s affecting any of these organs and in normal pregnancy (Table 21.5.3). Although the tissue of origin can be determined by deter- mining the predominant isoform of the enzyme, this i s rarely necessary in clinical practice. In the liver, alkaline phosphatase is localized to the sinusoidal membrane, hence it is the primary enzyme raised in cholestatic liver diseas e, of intra- or extrahepatic etiology. It is elevated to a lesser degree in hepatocellular injury. -Glutamyltransferase ( GT) GT is located in the hepatocyte membrane and is a sensi- tive but non-speci \201 c marker of liver disease. It may be ele- vated in cholest atic, hepatocellular or in \201 ltrative liver disorders. GT may be elevated in patient s with chronic Synthetic liver function Albumin Albumin, the most abundant serum protein, is synthesized e xclusively in the liver, with a half-life of 15 days in health. Hypoalbuminaemia is a marke r of poor synthetic liver function and is predictive of morbidity and mortality in chronic liver disease. Albumin is a negative acute phase marker, falling in acute illness as well a s a consequence of renal or GI loss. Serum albumin below the normal level is almost univers al in the critically ill, present in 98% of patients on admission to the general ITU. Table 21.5.3 Causes of elevated alkaline phosphatase Extrahepatic biliary obstruction Intrahepatic cholestasis Primary biliary cirrhosis Hepatoc ellular damage Healing fracture Metastatic tumor Paget \200\231s disease of bone Osteomalac ia Physiological bone growth Intestinal infarction Normal pregnancy Sepsis Renal failure Hepatobiliary Table 21.5.1 Normal values for liver function tests (values may differ slightly between lab oratories) Bone Alanine aminotransferase Aspartate aminotransferase Alkaline phosphatase -Glutamyltransf erase Bilirubin Albumin Prothrombin time Ammonia Lactate 3 \200\22335 IU/l 3 \200\22335IU/l 30 \200\223300IU/l 10 \200\22350IU/l 3 \200\22317 mol/l 35 \200\22348g/dl 12 \200\22316s 15 \200\22345mcg/dl <1.5mmol/l Intestine Placenta Other 357 CHAPTER 21.5 Abnormal liver function tests Table 21.5.4 Causes of hyperlactataemia Table 21.5.5 Suggested initial investigations for patients with acute liver injury Hypotension/cardiac arrest Regional infarction Septic shock Poisoning (e.g. ethylene glycol , methanol) Liver failure Diabetes mellitus Renal failure Drugs, e.g. metformin Hematologic al malignancy Pancreatitis Thiamine de \201 ciency Glucose-6-dehydrogenase de \201 ciency Short bowel syndrome (D-lactate) Type A Urea and electrolytes Glucose Liver function tests (bilirubin, ALT/AST, alkaline phosphatas e, GT, albumin) Creatine kinase Full blood count Prothrombin time/INR Arterial blood gas Arterial lactate Paracetamol levels Blood group Toxicology screen Viral hepatitis markers (anti-HAV IgM, HBsAg, anti-HBc IgM, anti-HEV IgM, anti-HCV Ab, anti-EBV IgM, anti-CMV IgM) Autoimmune markers (immunoglobulin, antinuclear antibody, anti-smooth muscle antibody) Caer uloplasmin Pregnancy test Type B Clotting factors Almost all the proteins that make up the coagulation cas- cade are produce d by the liver. The PT is sensitive to low levels of factor VII, which, with a short half-l ife of 4 \200\2236h, is a sensitive test of liver synthetic function in the absence of vita min K de \201 ciency. Prolongation of the PT is predictive of mortality in both acute and chronic liver failure. Reduced factor V level is a poor prognostic marker in non-paraceta- mol acute liver failure. critically ill patients with septic shock or following liver transplantation, but is not wi dely available. Indocyanine green clearance Indocyanine green (ICG) is an infrared-absorbing, iodine- conta ining dye that is excreted unchanged in bile. Plasma levels can be measured non-invasively by transcutaneous infrared spectrophotometry. The rate of ICG clearance can be expressed as blood clearance or plasma disappear- ance rate. Normal values are >700ml/min/m2 and >18%/ min. ICG clearance is dependent upon liver perfusion, hepatocellular function and biliary e xcretion. Low ICG clearance predicts poor survival in cirrhotic patients listed for liver t ransplantation, dysfunction in the graft and worse outcome after liver resection. Reduced I CG clearance is an independent risk factor for mortality in critically ill patients without pre-existing liver disease with septic shock or acute respiratory distress. Ammonia Ammonia is produced throughout the body as the nitrog- enous waste product of amino acid catabolism. The liver detoxi \201 es ammonia to urea via the urea cycle prior to ren al excretion. Ammonia levels rise as a consequence of hepatoportal shunting and may contrib ute to hepatic encephalopathy. Ammonia levels also rise in acute liver fail- ure, Reye synd rome and rare inborn errors of metabolism. Lactate Lactic acid is produced by peripheral tissues, particularly skeletal muscle, brain and red cells as a byproduct of glu- cose metabolism, and metabolized by the liver and kidn ey. Blood lactate levels rise as a consequence of mitochondrial dysfunction secondary to ti ssue hypoxia or sepsis, or due to reduced hepatic perfusion or function. Lactic acidosis in the presence of tissue hypoxia is termed type A, whilst lac- tic acidosis secondary to red uced hepatic clearance is termed type B. Common causes of hyperlactataemia are summarized i n Table 21.5.4. Hyperlactataemia is a poor prognostic sign in acute paracetamol-induced liv er failure. Lactic acidosis is a common feature of critical illness in acute on chronic liv er failure. Monoethylglycinxylidide (MEG-X) test Lidocaine is metabolized to MEG-X via the cytochrome P 450 system. MEG-X is assayed immediately before and 15min after an IV dose of lidocaine (1m g/kg). The MEG-X test therefore measures liver blood \202 ow and hepatocellu- lar functio n. Low rates of conversion of lidocaine to MEG-X are predictive of poor outcome in stable p atients with cirrhosis, cirrhotic patients undergoing liver resection and critically ill pa tients with cirrhosis on the ITU. Measurement of MEG-X requires complex laboratory analysis , so it is not suitable as a bedside test. Accuracy is reduced by concurrent medication tha t induces or sup- presses cytochrome P450. Dynamic tests of liver function Dynamic LFTs assess the ability of the liver to metabolize or eliminate substrates over a short period of time. Dynamic liver function testing is supe rior to static tests (e.g. bilirubin, PT) in the assessment of liver function in This page intentionally left blank 359 Chapter 22 Neurological disorders Chapter Contents Agitation and confusion 360 Status epilepticus 362 Meningitis 364 Intracer ebral hemorrhage 366 Subarachnoid hemorrhage 368 Ischaemic stroke 370 Guillain \200\223Barr e syndrome 372 Myasthenia gravis 374 ICU neuromuscular disorders 376 Tetanus 378 Botulism 3 80 Neurorehabilitation 382 Hyperthermias 384 360 R BOURNE & M BORTHWICK Agitation and confusion Agitation and confusion are common features in critical ill- ness. Agitation is a symptom o r sign of numerous acute and chronic disease states that include pain, anxiety and delir- i um. Agitation is present in around half of ICU patients, with 15% experiencing severe agita tion. Confusion may also be chronic or acute and arise from an overlapping set of path- olo gical processes that includes hypoxia, hypotension, hypoglycaemia and dementia. It is possi ble to be agitated and not confused, and vise versa. Recognition and treat- ment of the und erlying condition is of utmost importance, rather than treating the symptoms alone. Acute c onfusional states are frequently the result of delirium. Delirium is de \201 ned as an acu te change in mental status with a \202 uctuating course, characterized by inattention and disorganized thinking. It is acute cerebral insuf \201 ciency and should be considered as an organ failure (i.e. brain failure). Three subtypes of delirium exist. 1 Hyperactive (ag itated, paranoid) 2 Hypoactive (inattentive, stuporous, withdrawn) 3 Mixed ( \202 uctuates , hyperactive \200\223hypoactive) The incidence of delirium is reported to be between 15 an d 80% in critical care patients. The pure hyperactive form only accounts for 10% of deliri um cases, with the mixed form accounting for a further 45% of cases. The hypoactive form ca n be missed completely or misdiagnosed as depression. The presence of delirium and/or agita tion increases the duration of mechanical ventilation and intensive care LOS. It is also as sociated with higher rates of adverse events, including a 3-fold increase in mortality. The degree of sedative exposure, in particular to benzodi- azepines, is predictive of delirium occurrence Analgesia evaluation Often non-speci \201 c physiological parameters are utilized to guide analgesia, although behavioral aspects are more reliable. Systematic evaluation of pain an d agitation using a behavioral pain score decreases the incidence of pain and agitation. Sleep monitoring Direct nurse assessment of nocturnal sleep time over- estimates sleep quan tity but provides a useful trend marker. Patient report allows sleep quality to be compared with the patient \200\231s own baseline, but a degree of caution is req uired as memory re call can be adversely affected by sedatives, delirium and sleep disturbance itself.