Further reading Barie PS, Eachempati SR. Acute acalculous cholecystitis. Curr Gastroenterol Rep 2003; 5: 302 \200\2239. Kalliafas S, Ziegler DW, Flancbaum L, et al. Acute acalculous chole- cystitis: incidence, r isk factors, diagnosis, and outcome. Am Surg 1998; 64: 471 \200\2235. McChesney J, Northup P, Bickston S. Acute acalculous cholecystitis associated with systemic sepsis and visceral arterial hypoper- fusion: a case series and review of pathophysiology. Dig Dis Sci 2003; 48: 1960 \200\2237. Owen CC, Jain R. Acute acalculous cholecystitis. Curr Treat Options Gastroenterol 2005; 8: 99 \200\223104. Vogt DP. Gallbladder disease: an update on diagnosis and treatment. Cleveland Clin J Med 2002; 69: 977 \200\22384. 342 M JAVID & RB GALLAND Splanchnic ischaemia the dressings after formation of laparostomy, hence, con- tinued IAP monitoring may be nece ssary. Inadequate gut perfusion, due to imbalance of oxygen delivery compared with demand, leading to bowel damage and infarction if of suf \201 cient duration. Splanchnic hypoper- fusion is thought to have a signi \201 cant impact on the out- come of many critically ill patien ts. Diagnosis Rapid diagnosis and institution of treatment can signi \201 - cantly improve sur vival. Early clinical features include severe pain out of proportion to the physical \201 ndings. Peritonitis, fever, leucocytosis and lactic acidosis later develop. Abdominal comp artment syndrome may cause abdominal distension, shortness of breath, renal failure and syn cope Pathophysiology In shock, cardiac and CNS blood \202 ow are maintained at the expense of the mesenteric circulation. Current hypoth- eses suggest that GI tract barrier function is impaired dur- ing periods of insufficient gut perfusion, leading to translocation of enteri c bacterial endotoxin into the sys- temic circulation. A generalized in \202 ammatory resp onse is triggered, mediated by macrophage products, such as TNF- , which is released as a result of endotoxin stimulation. Ultimately this can lead to multiple organ failure. Gut r eperfusion may have similar deleterious effects as a result of oxidant-mediated damage. Investigations Gastric tonometry Measures intraluminal pCO2 as a measure of mucosal pCO2 (a nd, hence, pH) in the GI tract via a catheter in the stomach. It monitors splanchnic hypope rfusion and can guide resuscitative measures according to gastric pH levels. Maintenance of gastric mucosal pH of \211 7.32 can reduce morbidity and mortality; however, there are di f \201 culties in interpreting results, and some studies have shown no ben- e \201 t of s uch monitoring. When initially introduced it was thought that this form of monitoring would be popular; however its use has been con \201 ned to a few centers. Causes \200 \200 \200 \200 \200 \200 \200 All forms of shock Burns Trauma; multiple injuries Compromised MI Haemodialysis with ultra \201 ltration. Abdominal compartment syndrome Occlusive mesenteric ischaemia due to a thro mboem- bolic event. May be arterial, usually involving the supe- rior mesenteric artery, ve nous or combined. Obstructive sleep apnoea Weaning from mechanical ventilation Protein maln utrition Treatment Clinical \200 \200 Deal with underlying cause Volume resuscitation: crystalloids or colloids; blood in cases o f haemorrhagic shock. NB: those requiring >5l of \202 uid are at risk of abdominal compar tment syndrome. Assessment of volume status is, therefore, vital. End- diastolic volumetric or echocardiographic indexes will give more accurate estimates than CVP and PAoP meas- ure ments in these patients. Vasoactive drugs. Abdominal perfusion pressure (APP = MAP \200 \223 IAP) should be optimized. Inotropes may be nec- essary if APP <60mm Hg. Norepinephrine has no nega- tive effects on gut perfusion. Avoid epinephrine and dopamine as they have be en shown to reduce splanchnic perfusion. Early enteral nutrition, particularly containing i mmnu- nomodulating ingredients (e.g. glutamine and arginine), may improve clinical outcome in some clinical states. Surgery. Resection of ischaemic or gangrenous bowel; re-exploratio n at 24h may be advisable when demarcation of viable and non-viable bowel can be more obvio us. \200 \200 Prevention Prompt recognition/measurement of gut hypoperfusion and instigation of treatment . Monitoring of intra-abdominal pressures (IAPs) every 1 \200\2232h in those at high risk o f abdominal compartment syndrome and decompression prior to onset of end-organ failure can dramatically improve prognosis. Even mild elevations in IAP (>12mm Hg) worsen outcomes. Cri tical IAP values leading to higher incidences of complications are: \211 23mm Hg for delay in post-operative ventilatory weaning; \211 24mm Hg for renal dysfunction; and \211 25mm Hg for death. Non- surgical preventative measures may be used to reduce IAP prior to end-s tage complications: sedation and pain con- trol; gut emptying by NG tube placement, laxativ es and enemas; neuromuscular blockade to relax the abdominal wall and improve organ perfusi on; paracentesis in those with ascites or retroperitoneal collections; continuous haemofilt ration in those with interstitial oedema. Continuous negative abdominal pressure devices ha ve been designed, but require further research into their effects. Emergency surgery, i.e. formation of laparostomy, is required to prevent bowel ischaemia if IAP continues to rise a nd abdominal compartment syndrome develops. There are no established guidelines as to a cut -off pressure when surgery is necessary, and the pressure at which abdominal compartment sy ndrome occurs is dependent on host factors. The whole clinical picture should be taken into account, but early decompression may lead to improved outcomes. NB: \202 uid can re-accu mulate beneath Experimental \200 Small intestinal mucosal tissue oxygenation is improved after resuscitation with blood or g elatine infusions when compared with lactated Ringer \200\231s solution in pig models. Dobu tamine and enoxamone (PDE inhibitor) and fenoldopam (dopamine D1 receptor agonist) have bee n shown to maintain splanchnic blood \202 ow during hypop- erfusion in animal models. Dop examine may be an option; no clinical study has shown a bene \201 cial effect to date, and remains contro- versial. IL-1 . IV administration improves mesenteric blood \202 ow in pig models. 343 CHAPTER 20.13 Splanchnic ischaemia Complications \200 \200 Jakob SM, Clinical review: splanchnic ischaemia Crit Care 2002; 6: 306 \200\22312. Bowel infarction Liver dysfunction. Hepatic arterial \202 ow increases at times of reduce d portal venous \202 ow, thereby maintain- ing hepatic perfusion; however, this compensat ory mechanism is limited, after which further decreases in splanchnic and/or systemic \202 ow lead to liver failure. Sepsis Systemic in \202 ammatory response leading to multi- organ failure Kirton OC, Windsor J, Wedderburn R, et al. Failure of splanchnic resuscitation in the acute ly injured trauma patient correlates with multiple organ system failure and length of stay in the ICU. Chest 1998; 113: 1064 \200\2239. Lisbon A. Dopexamine, dobutamine and dopamine increase splanchnic blood \202 ow: what is the evidence? Chest 2003; 123: 460S \200\2233S \200 Malbrain MLNG, Chiumello D. Prevalence of intra-abdominal hypertension in critically ill pa tients: a multicentre epidemiologi- cal study. Intensive Care Med 2004; 30: 822 \200\2239. Meier-Hellmann A, Reinhart K, Bredle DL, et al. Therapeutic options for the treatment of im paired gut function. J Am Soc Neprhol 2001; 12: S65 \200\2239.3S Outcome Medical management may suf \201 ce in some cases; usually surgery is necessary and frequently life saving. However, survival is 10 \200\22325% once the in \202 ammatory re sponse is fully developed. Stechmiller JK, Treloar D, Allen N. Gut dysfunction in critically ill patients: a review of the literature. Am J Crit Care 1997; 6: 204 \200\2239. Zakaria R, Garrison RN, Spain DA, e t al. Intraperitoneal resuscita- tion improves intestinal blood flow following haemorrhagic shock. Ann Surg 2003; 237: 704 \200\22311. Further reading Ivatury RR, Diebel L, Porter JM, et al. Intra-abdominal hypertension and th e abdominal compartment syndrome. Surg Clin North Am 1997; 77: 783 \200\223800. 344 S MUDAN & A RIGA Abdominal hypertension (IAH) and abdominal compartment syndrome Our understanding of intra-abdominal hypertension (IAH) and the awareness of the potentiall y deleterious effects of abdominal compartment syndrome has increased mark- edly over the p ast decade The anterior abdominal wall is compliant and distends to permit accommodation of a sudden increase in the intra- abdominal mass without a substantial increase in the IAP. However, as elasticity plateaus, further increase in the intra-abdominal contents will lead to a rise in the pres- sure. The standard method for the measurement of IAP is directly by needle puncture into the abdominal cavity, e.g. at laparoscopy or during peritoneal dialys is. Indirect meas- urements can be obtained through a urinary bladder cath- eter or a ballo on-tipped catheter inserted into the stomach. Normal IAP is 5 \200\2237 mmHg in the critica lly ill patient. IAH is de \201 ned as a sustained or repeated pathological elevation of I AP >12mm Hg. IAH is graded as follows: Parenchymal compression leads to infection. Pulmonary oedema follows and increased risk of ventilator-associated lung injury. 2 Cardiovascular: compression of the IVC and portal vein results in reduced venous return t o the heart, a down and right shift of the Starling curve and commensurate fall in cardiac output. Decompression of the abdomen is shown to reverse the problem and improve cardiac fu nction. 3 Renal: reduced cardiac output and tamponade of the kid- neys combine to reduce renal perf usion. Tamponade is suf \201 cient to reduce renal perfusion if the abdominal pressure exc eeds 15mm Hg and results in anuria at IAP >30 mmHg. 4 Alimentary system: IAH reduces hepatic and splanchnic blood \202 ow causing liver dysfu nction and deterioration in gut function, mucosal acidosis and loss of gut barrier function 5 CNS: there is a correlation between IAP and ICP. Increased IAP lead to increased intratho racic pressure, increased venous pressure and impedes venous return from the brain, causing a rise in the ICP. I II III IV IAP 12 \200\22315mm Hg IAP 16 \200\22320mm Hg IAP 21 \200\22325mm Hg IAP >25mm Hg Management The reported mortality risk associated with abdominal compartment syndrome is 43 %, and so it is important to be aware of, diagnose and treat the problem. Appropriate treat ment is based on 4 principles. 1 Serial monitoring of IAP 2 Optimization of organ function and systemic perfusion. 3 Medical therapy to reduce IAP can address the intra- abdominal co ntents by emptying the luminal contents of the intestine through gastric decompression and bowel purgation. Reduction of tissue oedema should be addressed. Intra-abdominal collection s should be drained if possible. Abdominal wall tone can be reduced and, especially if ther e is pain or agitation, analgesia and seda- tion might be suf \201 cient. The use of neuro muscular block- ade to cause muscle relaxation may be required but is associated with incre ased ventilator-associated problems and ICU-related muscle wasting. The APP is calculated by the mean arterial pressure minus the intra-abdominal pressure; APP = MAP \200\223 IAP. The diag- nosis of abdominal compartment syndrome is made when the pe ak IAP is >20mm Hg and/or the APP is <50mm HG during a minimum of two standardized measurem ents and there is associated single or multiple organ failure which was not previously pres ent. Etiology of IAH/ abdominal compartment syndrome The causes of raised IAP and IAH can be bro ken down to 4 main groups: 1 Surgical. Post-operative intra-abdominal or retroperito- neal hemorrhage, reduction of a large hernia, abdomi- nal closure under excessive tension (e.g. oedematous or distended bowel), ileus secondary to leak or intra- abdominal leak/collection . prolonged pneumoperito- neum during laparoscopy. 4 Surgical decompression should be considered for refrac- tory IAH where the IAP is >20mm H g or IAP is >15mm Hg and with evidence of organ dysfunction or ischaemia. Surgical decompression of the abdomen leads to the prob- lem of how to manage the open abdo men. Intra-abdominal viscera such as the small bowel can be inspected directly for viabilit y or for perforation/leakage. However, an open abdomen exudes \202 uid and makes the nurs ing challenge more dif \201 cult, especially with regard to skin and wound care. Exposed b owel tends to desiccate and, combined with frequent dressing changes and contact with prost hetic materials, leads to serosal damage and the potential for bowel injury and \201 stul a formation. Fluid losses from the open abdomen are significant, and include the protein eq uivalent of 2g of nitrogen/day. This should be considered when thinking about \202 uid an d electrolyte replacement. The reported \201 stula rate for patients with the open abdome n in the ICU is 18%, and 2 Medical. Peritoneal dialysis, intra-abdominal infections, acute pancreatitis, ascites, ps eudo-obstruction, general- ized oedema from in \202 ammatory process occurring out- side a bdomen. 3 Post-traumatic. Traumatic bleeding, visceral oedema from aggressive \202 uid resuscitat ion and external compression from body cast (e.g. MAST). 4 Burns. Third space loss from leaky capillaries and high volume \202 uid resuscitation. Pathophysiology of organ dysfunction. IAH adversely affects several organ systems. 1 Respir atory: lung compliance is reduced as is thoracic volume due to pressure on the diaphragm fr om below. The reduction in lung volume results in basal atelectasis. 345 CHAPTER 20.14 IAH and abdominal compartment syndrome wall musculature. Reconstruction may involve the use of mesh prostheses, skin grafts and ti ssue expansion. the incidence of anastomotic failure in this setting is 10%. In the event of \201 stulat ion, then the management should involve an appropriate surgical team, \202 uid and electr olyte replacement, nutritional control, control of \201 stula ef \202 uent, relief of di stal obstructions and possibly the use of octreotide. The problems of management of the ope n abdomen have led to the use of several wound management systems. The Bogota bag, for exam ple, can be sutured to the wound edges and has a tendency to rip and result in evisceration at a critical time. The currently preferred techniques are the Sandwich Pack Dressing and negative pressure suction therapy, as well as a dynamic closure system . Once the acute pro blem is over, the abdomen may be closed up, but primary closure may not be feasible if ther e has been extensive tissue loss or retraction of the abdominal Further reading Cheatham ML, Malbrain ML, Kirkpatrick A, et al. Results from the Internatio nal Conference of Experts on Intra-abdominal Hypertension and Abdominal Compartment Syndrom e II. Recommendations. Intensive Care Med 2007; 33: 951 \200\22362 De Laet I, Malbrain ML. Current insights, I Intra-abdominal hyper- tension and abdominal co mpartment syndrome. Med Intensiva 2007; 31: 88 \200\22399. Malbrain ML, De Laet I, Cheatham M. Consensus conference de \201 ni- tions and recommendat ions on intra-abdominal hypertension (IAH) and the Abdominal compartment syndrome (ACS) \200\224the long road to the \201 nal publications, how did we get there? Acta Clin Belg Suppl 2007; 1: 44 \200\22365. This page intentionally left blank 347 Chapter 21 Hepatic disorders Chapter contents Jaundice 348 Acute liver failure 350 Hepatic encephalopathy 352 Chronic liver failure 354 A bnormal liver function tests 356 348 M COWAN, S THOMSON, & T RAHMAN Jaundice Jaundice (icterus) is the accumulation of bile pigments in serum and tissues including scle rae and skin. Jaundice is usually clinically detectable once serum bilirubin exceeds 50 mo l/l. Hyperbilirubinaemia in the absence of primary hepatobiliary disease is common in the c ritically ill, occur- ring in 30% of patents spending >48h on the general ITU. Table 21.1.1 Common causes of drug hepatotoxicity Trazodone Valproic acid Mixed Amitryptiline Azathioprine Carbamazepine Clindamycin Enalapri l Nitrofurantoin Phenobarbital Hepatocellular Acarbose Allopurinol Amiodarone Baclofen Disul \201 ram Fluoxetine HAART Ha lothane Herbals including black cohosh, green tea extract, kava kava, germander Isoniazid K etoconazole Lisinopril Losartan Methotrexate NSAIDs Omeprazole Paroxetine Pyrazinamide Rifa mpicin Risperidone Sertraline Statins Tetracyclines Causes of jaundice The causes of jaundice are classically divided into pre- hepatic, hepato cellular and cholestatic causes, but overlap is common, especially in the critically ill. Pre-hepatic jaundice Pre-hepatic jaundice occurs when the liver \200\231s capacity to proce ss bilirubin is exceeded. This is either related to excess breakdown of haem pigments in re d cells or con- genital abnormalities in the bilirubin conjugation pathway or bile salt exp ort pump malfunction. Common causes of intravascular haemolysis include haemoglobinopathies , red cell membrane defects, microangiopathic haemolytic anae- mia, drugs and sepsis. Becau se unconjugated bilirubin is not water soluble, it does not appear in the urine. Gilbert \200\231s syndrome is a benign condition affecting 2 \200\2237% of the UK population and is characterized by mild unconjugated hyperbilirubinaemia in response to fasting or stress. C ritical illness will almost inevitably precipitate hyperbilirubinaemia in patients with Gil bert \200\231s syndrome. Investigations including liver enzymes are normal. Other causes of congenital hyper- bilirubinaemia including Dubin \200\223Johnson, Rotor or Crigler \200 \223 Najjar syndromes are rare. Mutations of the genes encoding the bile salt export pump u nderlying the familial intrahepatic cholestasis syndromes, which cause progressive cholesta sis and liver damage, have recently been characterized. Phenytoin Sulfonamides Verapamil Cholestatic Amoxicillin-clavulanate Anabolic steroids Clop idogrel Erythromycin Irbesartan Oestrogens Phenothiazines Terbina \201 ne Tricyclics Intrahepatic jaundice Jaundice may be caused by hepatocellular dysfunction or intrahepatic cholestasis. Any cause of acute or chronic liver injury may cause jaundice. The most common causes in the UK are acute viral hepatitis (hepatitis A virus (HAV), CMV, EBV, rarely HBV or HCV) and drug reactions. Acute hepa- titis with renal failure may complicate leptospiros is. Congestive hepatopathy occurs secondary to right heart failure or constrictive pericard itis. A salient cause of acute hepatocellular jaundice on the ITU is following an episode o f hypotension, including that sustained secondary to hypovolaemia, or cardiac dysrhythmia. Jaundice may also occur both as a harbinger and as a marker of sepsis in the critically ill patient. Idiosyncratic drug reactions may be predominantly hepato- cellular (characterized by an elevated alanine aminotrans- ferase (ALT)/aspartate aminotransferase (AST)) or chole static (rise in alkaline phosphatase). Drug-induced liver injury is unpredictable and may b e dif \201 cult to diag- nose since there can be considerable latency between drug intake and clinical presentation. Common hepatotoxic drugs are summarized in Table 21.1.1. Biliary strictures: \200 \200 \200 Extrinsic compression: \200 \200 \200 Cholangiocarcinoma Benign biliary stricture Primary sclerosing cholangitis Pancreatic carcinoma Pancreatitis pseudocyst Hilar lymphadenopathy History and examination Jaundice is a symptom, not a diagnosis. A cause for jaundice must a lways be sought. In hepatic and post-hepatic causes of jaundice, enterohepatic circulation of bile products is interrupted, hence stools will be pale whilst the urine is dark seconda ry to conjugated bilirubin. Pruritis is common. Right upper quadrant pain suggests either b iliary obstruction or liver capsular stretching. Biliary obstruction may be com- plicated b y cholangitis with fevers, rigors and features of sepsis. A history of biliary surgery or t rauma may be apparent. Risk factors for acute viral hepatitis should be sought. A full drug history including the use of over-the-counter, herbal or Chinese remedies, and recreationa l drug use is important. Stigmata of chronic liver disease may be observed. Hepatome- galy is uncommon in chronic liver disease and suggests hepatic congestion, or in \201 ltration. Splenomegaly suggests long- standing liver disease complicated by portal hypertension. A p alpable gallbladder is suggestive of malignant biliary obstruction. Extrahepatic jaundice Extrahepatic jaundice occurs as a consequence of obstruc- tion of the biliary tree distal to the biliary canaliculi. This may be secondary to: \200 Gallstone disease: \200 \200 Common bile duct stones Cystic duct stones (Mirizzi \200\231s syndrome) 349 CHAPTER 21.1 Jaundice Investigations Blood tests LFTs con \201 rm the diagnosis of jaundice and may differenti- ate between an obstructive and hepatocellular cause. Tests of liver synthetic function (alb umin, prothrombin time) are important to stratify the severity of the liver injury. De \201 ciency of fat-soluble vitamins, including vitamin K, is common in cholestasis, so clot ting may be deranged in the absence of signi \201 cant synthetic dysfunction. In this inst ance, the prothrombin time corrects rapidly with (IV) vitamin K supplementation. Viral stud ies (HAV IgM, HBVsAg, HCV Ab, CMV IgM, EBV IgM) should be tested in acute cases of jaundice . In early acute hepatitis C, antibody testing may be falsely negative. If clinical suspici on remains high, the diagnosis can be con- \201 rmed by testing for viral RNA. critically ill patients are on multiple medications, this is rarely possible, but efforts s hould be made to stop as many drugs as possible or substitute for less hepatotoxic agents. In most cases of drug-induced hepatitis, the AST falls by 50% within 8 days of stopping the culprit drug, but liver injury may worsen or follow a protracted course. In chole- static dug injury, it may take several months for LFTs to normalize. Rechallenge should not be per formed. In cases of potential adverse effects secondary to antituberculous or antiretrovira l drug regimens, expert advice should be sought. Extrahepatic cholestasis Sepsis is common in biliary obstruction, and broad-spec- trum anti biotics with Gram-negative cover should be given. Coagulopathy corrects with parenteral vit amin K. Decompression and drainage of the biliary tree is a priority in extrahepatic biliar y obstruction. For patients who are stable, ERCP performed under sedation or general anaes- thesia will allow dilatation and stenting of strictures and diagnostic cytology. ERCP is a ssociated with a risk of pan- creatitis, hemorrhage and cholangitis. In a recent audit of E RCP practice in England, >60% mortality was seen in patients of ASA class 5. Patients who a re too unstable to tolerate ERCP should be referred for radiological percuta- neous biliary drainage, with a view to de \201 nitive drainage and internalization once their clinical condition has improved. Imaging In the normal patient population, ultrasound is a sensitive method of diagnosing bi liary obstruction, with a diagnostic accuracy of up to 79% for common bile duct stones. The technique is less accurate in the critically ill where biliary dyskinesia is common, but i t is portable, non-invasive and does not require IV contrast, making it a suitable \201 r st-line investigation. CT imaging may diagnose the presence and level of biliary obstructio n and is better at visualizing the pancreas than ultrasound. Magnetic resonance cholangio- pancreatography (MRCP) is a highly T2-weighted MRI of the biliary tree that has impressive accuracy for the diagno- sis of biliary tract stones. MRCP is of limited applicability to t he critically ill. Pruritis Itching is common in obstructive jaundice. Troublesome symptoms may respond to ora l antihistamines or cholesty- ramine (4g tds). Treatment In pre-hepatic jaundice the underlying cause should be identified and treated app ropriately. For intrahepatic causes of jaundice, care is supportive with treatment of the u nderlying condition. Further reading Brienza N, Dal \201 no L, Cinnella G, et al. Jaundice in critical illness: promoting factors of a concealed reality. Intensive Care Med 2006; 32: 267 \200\22374. Williams EJ, Taylor S, Fairclough P, et al. Are we meeting the stand- ards set for endoscop y? Results of a large-scale prospective sur- vey of endoscopic retrograde cholangiopancreat ograph practice. Gut 2007; 56: 821 \200\2239. Drug reactions All drugs with the potential to cause jaundice or hepato- toxicity should be withdrawn. In practice on the ITU where 350 M COWAN, S THOMSON, & T RAHMAN Acute liver failure Acute liver failure is a rare syndrome de \201 ned as the onset of liver dysfunction (mani fest as jaundice, coagulopathy and encephalopathy) in a patient without known liver disease and an illness of <6 months duration. With the exception of a few rare causes, acute deter ioration of chronic liver disease is not included in this de \201 nition. Although the inc i- dence has declined following the introduction of blister packs and legislation limiting the amount that can be purchased, the most common cause of acute liver failure in the UK re mains secondary to overdose of paracetamol (acetami- nophen). In 20% of cases no cause can be identi \201 ed. The etiology of acute liver failure is summarized in Table 21.2.1. The presence of encephalopathy is required to diagnose liver failure, but this is an ominous, and frequently late, sign. Jaundice and synthetic dysfunction in a patient not known to suf fer from liver disease should therefore be treated seriously. Acute liver failure is denote d hyperacute if the time from onset of jaundice to encephalopathy is <7 days, subacute if > 4 weeks, and acute for intermediate durations. Even with modern supportive care and emergen cy liver transplantation, mortality may exceed 50% even in specialist units. Patients \200 \231 relatives should be counseled accordingly. and exclude hepatic venous thrombosis. Slit lamp examina- tion is useful to detect Kayser \200\223Fleischer rings in acute Wilson disease. A CT brain scan may be considered to exclu de other causes of deteriorating conscious level. A liver biopsy, usually via the transjugu lar route, may be help- ful in the assessment of Wilson disease, autoimmune hepa- titis or in \201 ltrative hepatic malignancy, if the diagnosis is not clear from non-invasive testi ng. Medical management There is a risk of rapid deterioration in acute liver failure and theref ore patients should be nursed in a high depend- ency environment and monitored closely for signs of decreasing conscious level. The advice of the local liver transplant center should be sought with a view to an early transfer. Patients with acute liver failure are nursed s upine with 20 head-up tilt. GI bleeding is a recognized complication of acute liver failu re, and prophylaxis against stress-induced gastric ulceration is routine. Mild hypothermia may prevent increased ICP in severe liver failure. Nutrition/metabolic Feeding, preferably enterally, should be instituted early. Hypo- and hy perglycaemia are common, and tight blood sugar control with IV glucose and insulin is impor tant. Hypo-magnesaemia, hypophosphataemia and hypokalae- mia are common and may require con tinuous supplemen- tation. Lactic acidosis secondary to acute liver failure is an independe nt predictor of poor prognosis. Hyperlactaemia should be treated by ensuring adequate tissu e perfusion. Severe lactic acidosis may be treated by high volume haemo \201 ltration. History and examination The history and examination should be directed to \201 nding the cause of the liver injury, identifying any co-morbidities that may in \202 uence the clini cal course (including social fac- tors that might contraindicate liver transplantation) and assessing the degree of damage to the liver and associated organ systems. A detailed drug history including use of over-the-counter and herbal medication should be taken. Any risk f actors for exposure to waterborne or blood- borne hepatitis viruses including a travel hist ory should be investigated. Other important questions include a family history of liver dis ease, organ-speci \201 c autoimmune syn- dromes, symptoms and risks for malignancy. Episod es of hypotension or collapse may be apparent. There should be no signs of chronic liver di sease on exam- ination. The liver may be enlarged or collapsed. A careful examination for t he presence or absence of encephalopa- thy should be undertaken. The pregnancy-related syn- dromes associated with acute liver failure occur in the third trimester. Sepsis Sepsis, secondary to bacteria and fungi, is a common cause of clinical deterioration and death. Infections should be treated promptly and aggressively. Prophylactic broad- spe ctrum antibiotics with or without antifungals may reduce the risk of cerebral oedema. Encephalopathy Sedatives should be avoided if at all possible in the con- scious patient du e to the risk of accumulation. Sleep distur- bance and disorientation may be signs of encep halopathy. Routine prophylaxis against seizures is not proven to be helpful. Propofol is th e maintenance sedative of choice once mechanical ventilation is required. Investigations Recommended blood tests are summarized in Table 21.5.5. Liver imaging with u ltrasound or CT will assess liver volume Coagulopathy There is a risk of bleeding secondary to coagulopathy and thrombocytopaenia. V vitamin K is usually given. Clotting factor support should be avoided in the absence of ac tive bleeding unless the decision to list the patient for emergency liver transplantation h as been made since this obscures one of the most important prognostic features. Venous and even arterial puncture or canulation is not an indication for clotting factor support. Table 21.2.1 Common causes of acute liver failure Drug toxicity (including paracetamol, amphetamine/ecstasy) Acute viral hepatitis (hepatitis A, B, E) Wilson disease Autoimmune hepatitis Acute fatty liver of pregnancy, HELLP syndrom e Acute hepatic ischaemia Budd \200\223Chiari syndrome Malignant in \201 ltration (lymphom a, breast and gastric cancers) Toxins (Amanita) Seronegative acute liver failure Cardiovascular Hypotension is common, and care must be taken to main- tain renal and cerebr al perfusion. Most patients are volume de \201 cient at the time of presentation and requi re aggressive \202 uid resuscitation. Initial \202 uid replacement should be with collo id rather than crystalloid. There is no need for sodium 351 CHAPTER 21.2 Acute liver failure restriction in acute liver failure. SVR is low, and hypotension resistant to volume replace ment should be managed with vasopressor inotropes such as norepinephrine. Central venous ac cess and monitoring is recommended in this situ- ation. Pulmonary artery catheterization is not routine. Table 21.2.2 UK criteria for listing for super-urgent liver transplantation Acetaminophen-induced acute liver failure, either: 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.