Critical care and cirrhosis: outcome and benefit Julia Wendon, William Bernal, Chris Willars and Georg Auzinger

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1 Critical care and cirrhosis: outcome and benefit Julia Wendon, William Bernal, Chris Willars and Georg Auzinger Institute of Liver Studies, Kings College Hospital, Denmark Hill, London, UK Correspondence to Julia Wendon, Institute of Liver Studies, Kings College Hospital, Denmark Hill, SE5 9RS London, UK Tel: ; Current Opinion in Critical Care 2011, 17: Purpose of review The incidence of cirrhosis is growing steadily and this cohort of patients will present in ever-greater numbers to critical care with acute decompensation, usually secondary to an inter-current event or following elective surgery. This review examines the evidence for treatment options and outcomes. Recent findings Outcome of cirrhotics presenting with end-organ dysfunction is steadily improving and their outcomes are not as poor as sometimes suggested. Treatment options for variceal bleeding and renal dysfunction are evolving and outcomes improving. Summary Critical care support should be offered to patients with cirrhosis and in high-risk variceal bleed patients transhepatic portosystemic shunt should be considered. Keywords alcoholic hepatitis, cirrhosis, hepatic encephalopathy, renal failure, variceal bleed Curr Opin Crit Care 17: ß 2011 Wolters Kluwer Health Lippincott Williams & Wilkins Introduction The management of cirrhosis has been radically changed over the years both transplantation, resulting in 5-year survival of greater than 70%. In addition, management of the complications of cirrhosis has progressed with improved outcome and quality of life. Critical care support for patients with cirrhosis has traditionally been viewed with a degree of scepticism, with an inevitably poor prognosis being envisaged. Without question, these patients do have an underlying chronic disease process; however, their prognosis is probably no worse and perhaps better than many other patients with chronic disease processes. Specifically, improvements have impacted on management of varices, renal dysfunction and understanding and treatment options of hepatic encephalopathy. The management and prognosis of hepatocellular carcinoma have also improved significantly, with multiple therapeutic options available, arterial chemoembolization, resection and Serafanib. Hepatological scoring systems Prognosis of liver disease in a ward and outpatient environment is well delineated for populations, although not individuals, by use of Child-Pugh score and Model for End-stage Liver Disease (MELD) score [1,2]. Child- Pugh Score provides a score between 1 and 3 for each of the following: degree of encephalopathy, ascites, bilirubin level, albumin and coagulation as measured by the International Normalized Ratio (INR). MELD score, developed for predicting survival following transhepatic portosystemic shunt (TIPS), incorporates bilirubin, INR and creatinine. It has been shown to be a useful predictor of survival in cirrhosis [3] with a variety of complications and is used in the United States and much of Europe to determine minimal listing criteria and offer of organs to patients on the liver transplant waiting list. Varices Control of the airway of patients with acute variceal haemorrhage has not been subject to a controlled trial. However, elective intubation and ventilation of patients with active variceal haemorrhage or in those with encephalopathy who require endoscopic therapy is essential. It provides the endoscopist with an optimal scenario for haemostasis and prevents the substantial risk of micro/macroaspiration and subsequent chest sepsis that is otherwise likely. Antibiotics are indicated in the management of acute variceal bleeding, evidence demonstrating decreased risk of rebleed and decreased mortality [4,5]. In addition, thromboelastography may be usefully applied as an adjunct to assess risk of rebleeding [5]. Optimal endoscopic control is achieved with banding therapy for oesophageal varices and glue for gastric varices. The combination of vasocontrictor therapy such as terlipressin, for 5 days, along with endoscopic therapy as compared with terlipressin alone decreases risk of rebleeding but does not affect survival [6]. The use of ß 2011 Wolters Kluwer Health Lippincott Williams & Wilkins DOI: /MCC.0b013e32834ab06f

2 534 Critical care outcomes terlipressin has also been shown to be cost-effective in respect of prehospital management [7]. The identification of patients who are likely to fail endoscopic therapy needs to be considered early in their clinical course, with recourse to other therapeutic options such as TIPS shunting. If portal pressure measurements are available, those with a pressure more than 20 mmhg have significantly improved prognosis if offered TIPS shunting, as compared with ongoing endoscopic therapy. The low-risk group with portal pressure less than 20 mmhg had a more than 80% 12-month survival, whereas the high-risk group with pressure more than 20 mmhg had a survival of more than 70% if they proceeded to TIPS compared with 40% in those managed endoscopically [8]. Many centres do not have this facility available to them within the first h of admission and recent work has suggested this high-risk group, who may benefit form TIPS shunting, may be identified by Child-Pugh Score. Eighty percent of Child-Pugh C patients will have a portal pressure more than 20 mmhg. Risk of rebleed can also be predicted by active bleeding at the time of endoscopy and more than 4 U blood transfusion in the first 24 h [9]. Procaccini et al. [10] recently reported TIPS vs. cyanoacrylate glue injection in the management of gastric varices. In this single centre study of 105 patients, there was no difference in survival comparing the two treatment options. A recent study compared early TIPS shunt (offered to Child-Pugh C Score 10 13, or active bleeding at endoscopy if Child-Pugh 7 9) with drug therapy and endoscopic band ligation and demonstrated significantly improved 24-month survival in the TIPS group (>80 vs. 60%) [11 ]. It would thus appear appropriate to admit patients with variceal haemorrhage to a critical care environment to facilitate resuscitation, well tolerated endoscopic management and decision-making in regard of TIPS shunting. Renal failure The management of renal failure in association with cirrhosis is based on volume loading with 20% albumin and vasoconstrictor therapy [12,13]. A recent metaanalysis has demonstrated survival benefit for this modality of treatment [14 ]. The perception is, and remains, however, that prognosis once hepatorenal failure is established remains poor, and may preclude admission to critical care, once renal replacement therapy is required. Of concern in this regard is that treatment is often commenced late, when creatinine is significantly elevated and urine output low, and these factors are associated with worse outcome [15]. Key points Outcome of cirrhotics presenting with end-organ dysfunction is steadily improving and their outcomes are not as poor as sometimes suggested. Treatment options for variceal bleeding and renal dysfunction are evolving and outcomes improving. Critical care support should be offered to patients with cirrhosis, and in high-risk variceal bleed patients transhepatic portosystemic shunt should be considered. Terlipressin has been shown to improve free water clearance when administered to those with ascites alone; thus, earlier treatment may be beneficial [16]. Furthermore, the development of renal dysfunction will impair renal ammonia clearance, which may impact on risk of hepatic encephalopathy. The inevitably poor prognosis that is reported in patients with coexistent renal failure and cirrhosis needs to be questioned following the recent publication demonstrating wide variation in 90-day survival depending upon the causation of the acute renal dysfunction [17 ]. Parenchymal nephropathy carried the best outcome (80%), followed by hypovolaemia (50%), infection (35%) and lastly hepatorenal failure (18%). It is important, therefore, not to consider all patients with renal failure to have an inevitable mortality and refuse admission, with inevitable mortality. Treatment with vasoactive drug therapy and albumin therapy has been reported as being beneficial in responders in several trials and a recent meta-analysis of both type I and II hepatorenal failure demonstrated a mortality benefit in favour of treatment with drug and albumin [14 ]. The prognosis of a cirrhotic population requiring renal replacement therapy and intensive care was examined by Fang et al. [18]. They reported developing an MBRS (mean arterial blood pressure, bilirubin, respiratory and systemic inflammatory scores) score (mean arterial blood pressure < 80 mmhg, bilirubin > 80 mmol/l, respiratory failure and sepsis; allocating one point for each factor). Scores of 0 and 1 were associated with survival of 62 and 58%, survival feel to 10% for a score of 3 with all patients dying with a score of 4. Risk, Injury, Failure, Loss, End-stage kidney disease (RIFLE) score has also been examined [19]. Cirrhotics admitted to critical care without renal failure had a survival of 60%, RIFLE I had a 20% survival, whereas all those with RIFLE F and R died. Survivors and nonsurvivors were separated by a Sequential Organ Failure Assessment (SOFA) score on day 1 in a similar

3 Critical care and cirrhosis: outcome and benefit Wendon et al. 535 manner to that described by Wehler et al. [20]; 8 or lower and survival was more than 80%, whereas scores of 9 and above were associated with a mortality of more than 90%. Cholongitas et al. [21] examined a variety of scores in 412 cirrhotics admitted to critical care. SOFA score had the best discrimination (area under the curve 0.84) and Acute Physiology and Chronic Health Evaluation (APACHE) II had the best calibration. RIFLE score had optimal sensitivity to predict death during follow-up but overall did not perform as well as the other scores, such as SOFA or APACHE. Cardio-respiratory failure Intubation and ventilation may be required for decreased conscious level or hypoxaemia. Analysis of cirrhotics admitted to critical care has shown a significant effect of inspired oxygen (FiO 2 ), suggesting that hypoxaemia is in itself a poor prognostic factor vs. ventilation per se [22,23]. The aetiology of hypoxaemia should be sought because that resulting from hepatopulmonary syndrome (shunting and diagnosed on contrast echo) will be different from that of acute lung injury. Recent data has shown good outcome for those transplanted with severe hepatopulmonary syndrome, albeit requiring prolonged periods of ventilator support. Cardiac dysfunction normally presents as a high output state with impaired peripheral resistance, with cirrhotic cardiomyopathy being seen as cirrhosis progresses [24]. Echocardiography is useful in excluding portopulmonary syndrome (portal hypertension and pulmonary hypertension) and assessing function of both the right and left ventricle and volume status [25]. Portopulmonary syndrome needs to be assessed by right heart catheter studies and response to treatment gauged [22]. Transplantation is an option and outcome is optimized in those who have been treated and responded to therapy (Sidenafil, Bosanten, prostaglandins). Many patients will require vasopressor support. Studies had suggested a moderate incidence of adrenal dysfunction (as assessed by response to adrenocorticotropic hormone) [26] in the critically ill cirrhotic population and uncontrolled data had suggested potential beneficial outcome with treatment. A recent randomized control of trial of steroids did not demonstrate any outcome benefit, although there was a decrease in vasopressor dose and reversal of shock, but overall no decrease in vasopressor-free days [27 ]. Hepatic encephalopathy Encephalopathy can be challenging to manage in a ward environment, and its presence is associated with a worse outcome than in those who do not develop encephalopathy. Hepatic encephalopathy in a ward environment is likely to result in impaired outcome due to poor compliance with therapy secondary to their agitation and confusion. In addition, they are at increased risk of sepsis particularly respiratory due to microaspiration when conscious level is decreased. Hepatic encephalopathy can resolve with remarkable speed or can persist for prolonged periods. Admission to a critical care environment allows close monitoring of airway competence; intubation will be required for those with falling Glasgow Coma score and agitation levels to such a degree as to make patients a danger to themselves. In a recent study of patients with grade III/IV hepatic encephalopathy, inflammatory response rather than arterial ammonia levels separated survivors from nonsurvivors. Differences in survival were reflected by systemic inflammatory response syndrome, SOFA, MELD and APACHE II scores. No differences were seen in arterial ammonia levels [28]. Increased ammonia concentrations have been shown, however, to impair neutrophil function [29]. Use ofthemolecular Adsorbent Recycling System(MARS) extracorporeal support system has been shown to decrease time to improvement in level of encephalopathy in a randomized controlled trial in chronic liver disease [30]. The study did not impact on survival, but was not powered to do so. Recent abstract presentations at the European Liver Meeting showed data using both MARS and Prometheus in decompensated liver cirrhosis. The MARS study showed improved level of encephalopathy but did not demonstrate overall survival benefit. The Prometheus system overall did not impact on survival, but subgroup analysis suggested benefit in groups with type I hepatorenal syndrome and MELD score more than 30. Protein restriction has previously been suggested as beneficial; however, the work of Cordoba et al. [31] showed no difference in resolution of hepatic encephalopathy when comparing groups on a high vs. restricted protein intake, and indeed the protein restricted group had negative protein balance as compared with the normal protein group. Ammonia lowering therapies, such as L-ornithine L-arginine, have not been assessed in critically ill cirrhotics but may potentially have a role. More important, however, is the need to address and treat possible aetiological factors, sepsis, dehydration, variceal bleed or administration of neuroactive drugs as examples. Alcoholic hepatitis Alcoholic hepatitis has been almost entirely examined in a ward-based environment. The scoring systems that

4 536 Critical care outcomes have developed over the years have allowed delineation of those patients who are most likely to respond to therapy [32 ]. The Glasgow Hepatitis Score [33] (based upon white blood cell, bilirubin, age, coagulation and urea) also delineates survivors from nonsurvivors, in addition to defining that group who are most likely to respond to steroids. French investigators have also described the Lille criteria incorporating a delta fall in steroids over the first 2 weeks of treatment, in addition to age, renal function, INR, baseline bilirubin and albumin, as being highly predictive of outcome [34 36]. Elective surgery Patients with cirrhosis are increasingly being admitted to critical care areas following elective surgical procedures, either as a planned admission or following decompensation. Thirty and 90-day mortality can be predicted from baseline MELD score [37,38]; in those undergoing cardiac surgery mortality is also related to severity of underlying disease, with reasonable survivals being recorded in Child-Pugh A patients. Scoring systems Although hepatological scoring systems, such as MELD or Child-Pugh score, seem optimal for assessing prognosis in a ward or outpatient setting, physiologically based scoring systems seem to offer an optimal prognostication in the critical care area. The most studied is that of the SOFA score, offering optimal prediction at 3 days as opposed to on admission [20,39]. Interestingly, aetiology of liver disease per se does not impact on outcome, although overall outcome for those admitted with variceal haemorrhage appears better than for those admitted with sepsis and multiple organ failure. Scoring systems have been developed by the Royal Free Group incorporating bilirubin, lactate, FiO 2, urea and number of failing organ systems (as defined by SOFA) [40]. Studies by Gunsar et al. [41] have also demonstrated the importance of nutritional status in determining outcome. Cholongitas et al. [40] examined 128 patients, of whom 98% were ventilated, with an overall Child-Pugh score of 11 and MELD score of 23, with an overall mortality of 54%. All scores performed better at 48 h as opposed to on admission and the SOFA cutoff was 10, as opposed to 9 in the original article by Wehler et al. [20]. A more recent publication is that of Das et al. [42]; they examined 138 cirrhotics on day 1 and 88 on day 3. These authors adapted the original SOFA score and noted improved sensitivity and positive predictive capacity if haematological organ failures were excluded, and scores assessed on day 3 vs. day 1. Conclusion These data overall would suggest that treatment options and support for patients with cirrhosis are improving over time and the dreadful prognosis that is associated with this cohort needs to be reassessed. Prediction, in terms of groups, is best made on day 2 or 3 following admission as opposed to on day of admission or prior to admission. With the advent of further support options, it is likely that prognosis and survival will further improve, be it by stabilization of function and/or transplantation in some instances. Acknowledgement Conflicts of interest There are no conflicts of interest. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp ). 1 Cholongitas E, Papatheodoridis GV, Vangeli M, et al. Systematic review: the model for end-stage liver disease should it replace Child-Pugh s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther 2005; 22: Kamath PS, Kim WR. The model for end-stage liver disease (MELD). Hepatology 2007; 45: Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology 2001; 33: Brown MR, Jones G, Nash KL, et al. Antibiotic prophylaxis in variceal hemorrhage: timing, effectiveness and Clostridium difficile rates. World J Gastroenterol 2010; 16: Chau TN, Chan YW, Patch D, et al. Thrombelastographic changes and early rebleeding in cirrhotic patients with variceal bleeding. Gut 1998; 43: Lo GH, Chen WC, Wang HM, et al. Low-dose terlipressin plus banding ligation versus low-dose terlipressin alone in the prevention of very early rebleeding of oesophageal varices. Gut 2009; 58: Combier E, Levacher S, Letoumelin P, et al. 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N Engl J Med 2010; 362: Randomized controlled trial of TIPS shunting in cirrhotics who are at high risk of rebleeding. Demonstrates significant mortality benefit. 12 Arroyo V, Fernandez J. Pathophysiological basis of albumin use in cirrhosis. Ann Hepatol 2011; 10 (Suppl 1):S Arroyo V, Fernandez J, Gines P. Pathogenesis and treatment of hepatorenal syndrome. Semin Liver Dis 2008; 28: Gluud LL, Christensen K, Christensen E, Krag A. Systematic review of randomized trials on vasoconstrictor drugs for hepatorenal syndrome. Hepatology 2010; 51: Good meta-analysis showing benefit of albumin and vasoactive drugs in treatment of hepatorenal failure.

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