Sequential Organ Failure Assessment Score Predicts 3-Month Mortality after Molecular Adsorbent Recirculating System Dialysis

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1 Acta Nephrologica 25(2): 61-69, Original Article Sequential Organ Failure Assessment Score Predicts 3-Month Mortality after Molecular Adsorbent Recirculating System Dialysis Kuo-Chang Juan 1, *, Pei-Chun Fan 1, *, Ming-Hung Tsai 2, 3, Chang-Chyi Jenq 1, 3, Hsiang-Hao Hsu 1, 3, Ming-Yang Chang 1, 3, Ya-Chung Tian 1, 3, Chih-Hsiang Chang 1, 3, Cheng-Chieh Hung 1, 3, Ji-Tseng Fang 1, 3, Chih-Wei Yang 1, 3, and Yung-Chang Chen 1, 3 1 Kidney Research Center, Department of Nephrology 2 Division of Gastroenterology, Chang Gung Memorial Hospital, Taipei 3 Chang Gung University College of Medicine, Taoyuan, Taiwan, Republic of China Abstract BACKGROUND: Molecular adsorbent recirculating system (MARS) dialysis can prolong survival and improve multiple organ dysfunctions in patients with fulminant hepatic failure (FHF). However, further clinical data and experiences are needed to confirm the effectiveness of this therapeutic strategy. The prognostic factors and scoring systems for predicting outcome in liver failure patients undergoing MARS dialysis must also be identified. METHODS: This study retrospectively reviewed the medical records of 57 liver failure patients who received MARS dialysis at a tertiary care university hospital from January, 2003 to June, Demographic, clinical, and laboratory variables were recorded. Each patient was assessed using four scoring systems pre- and post-mars on Days 1, 2, and 3. RESULTS: The overall 90-day (after completion of all MARS dialysis sessions) survival rate was 21.1%. The Sequential Organ Failure Assessment (SOFA) score had better discriminatory power than Child-Pugh points, the model for end-stage liver disease (MELD), and the MELD plus sodium. Cumulative survival rates at 3-month follow-up after admission to intensive care unit (ICU) differed significantly (P < 0.05) between patients with SOFA scores 11 on post-mars treatment Day 3 and those with SOFA scores >11 on post-mars treatment Day 3. CONCLUSIONS: Though MARS improved laboratory parameters of hepatic detoxification in patients with FHF, the patients mortality remained unsatisfactorily high. Our experiences suggest that greater effort in finding a suitable liver donor is needed when using MARS in FHF. Of the four evaluated scoring systems, calculated SOFA scores on post-mars treatment Day 3 have the best discriminative power for predicting 3-month mortality following MARS treatment. (Acta Nephrologica 2011; 25: 61-69) KEY WORDS: liver transplantation, MARS (Molecular Adsorbent Recirculating System), SOFA (Sequential Organ Failure Assessment), Child-Pugh points, MELD (Model for End-stage Liver Disease) Introduction Despite recent therapeutic advances, fulminant hepatic failure (FHF) is associated with high morbidity and mortality rates. The accumulation of toxins during liver failure is likely an important mechanism responsible for the development of life-threatening complications (1-3). Notably, FHF results from loss of metabolic and synthetic hepatic function, rapidly leading to encephalopathy and multiple organ dysfunc- Corresponding author: Dr. Yung-Chang Chen, Division of Critical Care Nephrology, Chang Gung Memorial Hospital, No. 199, Tung Hwa North Rd., Taipei 105, Taiwan, R.O.C. Tel: ext. 8181, Fax: , cyc2356@gmail.com *Kuo-Chang Juan and Pei-Chun Fan contributed equally to this manuscript. Received: October 27, 2010; Revised: November 23, 2010; Accepted: March 17, 2011.

2 62 Juan, Fan, Tsai, Jenq, Hsu, Chang, Tian, Chang, Hung, Fang, Yang and Chen tions with mortality rates of roughly 90% (4). Currently, the only effective therapy for liver-failure patients is liver transplantation (5). The liver transplantation success rate has improved over the last decade. However; orthotopic liver transplantation is not readily available for most patients due to a shortage of livers. The management of this precipitating event in liver failure requires time to allow enough liver cells to regain regenerative function or for an organ to become available for transplant. Therefore, time is the crucial factor in successfully managing liver failure. The molecular adsorbent recirculating system (MARS), a type of albumin dialysis, is utilized as a bridging therapy to either optimize clinical status for liver transplantation or provide a resolution without liver transplantation (6-8). The Child-Pugh scoring system is widely adopted to risk-stratify cirrhotic patients and assess the efficacy of such therapeutic procedures as sclerotherapy, band ligation of varices, transjugular intrahepatic portosystemic shunt (TIPS) and surgery (9). The model for end-stage liver disease (MELD) score, initially developed to predict mortality in patients with cirrhosis undergoing TIPS (10), is also predictive of short-term cirrhotic mortality in other settings (11). Conversely, the MELD score does not include ascites in the model. Ascites is strongly correlated with mortality in cirrhotic patients (1). To improve the accuracy of MELD score, investigators have employed other potential prognostic markers. Serum sodium, a common laboratory test that is both objective and reproducible, is often associated with ascites and hepatorenal syndrome, both of which are highly predictive of mortality (12, 13). Therefore, the new MELD score plus sodium (MELD-Na) score (14) was developed for short-term outcome prediction. The Sequential Organ Failure Assessment (SOFA) score is a simple and objective score that allows for calculation of both the severity of organ dysfunction and the number of organ systems (respiratory, coagulatory, liver, cardiovascular, renal, and neurologic) involved (15). The score can measure individual or aggregate organ dysfunction and is currently used in intensive care units to characterize morbidity. Although originally designed for classifying organ failure rather than predicting outcomes, various investigations have identified a strong relationship between organ dysfunction and mortality (16-18). This study evaluates the improvement on multiple organ system dysfunction in patients with FHF by MARS dialysis, and compares liver-disease-specific scores (Child-Pugh points, and MELD and MELD-Na scores) and general intensive care unit (ICU) prognostic model (SOFA) on different days for predicting 3-month mortality for patients with FHF who had undergone MARS dialysis. Methods Patient Information and Data Collection This study was approved by the ethics committee and the need of informed consent was waived. This study retrospectively analyzed the data for 57 patients with FHF, treated with MARS albumin dialysis at our institution from January 2003 to June Pediatric patients (aged 18 years) were excluded. Retrospective data reviewed included the following: demographic data; laboratory variables; liver disease etiologies; indications for MARS dialysis; length of ICU stay and hospitalization and outcome. Child-Pugh points, MELD score, MELD-Na score, and SOFA score were employed to assess severity of illness on Day 1 of ICU admission, the day before MARS dialysis and on post-mars dialysis Days 1, 2, and 3. Study outcome was 3-month mortality rate after all MARS dialysis sessions. Follow-up at 3 months after MARS dialysis was made via reviews of patient records. Definitions of Scoring System The included patients were previously well. All of them presented with typical symptoms of FHF and developed hepatic encephalopathy within two weeks of the onset of jaundice (8). Liver disease severity at ICU admission was graded using the Child-Pugh, MELD, and MELD-Na scores. The MELD score was calculated by the following formula (0.957 ln[creatinine] ln[bilirubin] ln[international normalized ratio of prothrombin] ) 10 (11). To integrate serum sodium into the prognostic model, the MELD-Na score was calculated using the following formula developed by Biggins et al.: MELD (135 serum sodium), the minimum value for serum sodium is 120 mmol/l and the maximum is 135 mmol/l (13). Severity of illness was assessed by SOFA. Diagnosis at ICU admission and length of hospitalization before ICU admission were recorded as primary reasons for intensive care and duration of hospitalization before ICU admission, respectively. The worst physiological and biochemical values on the day of initial ICU admission were recorded. Patients were classified into the following groups: Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function, and End-stage renal failure (RIFLE) according to risk, injury, and failure categories (19-21). No patients met the criteria for loss of kidney function or end-stage renal disease categories. MARS Application and Patient Management The MARS system has been previously described

3 SOFA and MARS 63 in detail (6,8). Briefly, the MARS system is an extracorporal hemodiafiltration system that can eliminate albumin-bound toxins using albumin dialysis through a special membrane (MARS Flux, Teraklin AG, Rostock, Germany). The MARS system consists of a MARS monitor (Teraklin AG) and a conventional dialysis machine. The MARS monitor pumps the albumin dialysate in a closed loop at the same rate with the dialysis machine of 200 ml/min via the dialysis machine. The albumin dialysate is recirculated and recycled through a conventional dialyzer and two absorption columns (active charcoal and anion exchange resin). The blood circuit is established via a venousvenous access using a conventional hemodialysis double-lumen catheter inserted into the femoral vein. The MARS treatment was administered every other day. Each treatment session lasted 8 h. Treatment was discontinued when patients showed sustained clinical improvement or when patients were hemodynamically unstable, requiring volume loading and/or vasoactive drugs to maintain a MAP exceeding 65 mmhg. All patients were managed in the ICU. Patients were fully supported as dictated by their clinical condition; treatments included mechanical ventilation and inotropic agents. Other standard medical therapies included close monitoring of glucose levels, administration of empiric antibiotics unless there were specific culture results, lactulose for those with encephalopathy, renal replacement support for those with acute renal failure or ESRD. Statistics Continuous variables were summarized using means and standard deviation unless otherwise stated. All variables were tested for normal distribution using the Kolmogorov-Smirnov test. Means of continuous variables and normally distributed data were compared using the Student s t-test; otherwise, the Mann-Whitney U test was employed. Categorical data were tested by the chi-square test. Comparison between pre- and post-mars variables was carried out using the paired Student s t-test. Cumulative survival curves as a function of time were constructed using the Kaplan-Meier approach and compared via the log rank test. Calibration was assessed using the Hosmer- Lemeshow goodness-of-fit test to compare the number of observed and predicted deaths in risk groups for the entire range of death probabilities. Discrimination was explored using the area under a receiver operating characteristic curve (AUROC). Areas under two AUROC were compared using the nonparametric approach. The AUROC analysis was also performed to calculate cutoff values, sensitivity, specificity, and overall accuracy. Finally, cutoff points were calculated by obtaining the best Youden index (sensitivity + Native Liver Recovery N = 3 (5.26%) specificity 1). All statistical tests were two-tailed; a value of P < 0.05 was considered statistically significant. Subject Characteristics Enrolled patients (N = 57) Alive after LT N = 9 (15.79%) Bridge to Liver Transplantation N = 11 (19.3%) Survival at 90 days N = 12 (21.05%) Results Died before Liver Transplantation N = 43 (75.44%) Died after LT N = 2 (3.5%) Fig. 1. Outcome of enrolled patients in this study. LT, liver transplantation. The study population comprised 57 patients with FHF who underwent MARS dialysis between January 2003 and June Mean patient age was 51 years; 43 (75.4%) patients were male, and 14 (24.6%) were female. Overall 3-month survival rate was 21.1% (12/ 57). Twelve (21.1%) in-hospital patients survived, 9 (15.8%) received liver transplantation after MARS dialysis while 3 (5.3%) had a positive resolution of clinical conditions. Eleven (19.3%) of the 57 patients were bridged to liver transplantation. Of 46 patients, 43 died before/without transplantation primarily due to upper gastrointestinal bleeding, sepsis or multiple organ failure. The results of the study group are summarized in Fig. 1. Table 1 compares patient demographic data and clinical characteristics between 3-month survivors and non-survivors. No statistically significant predictors of 3-month mortality before MARS dialysis existed, including SOFA, Child-Pugh points, MELD score, MELD-Na score and RIFLE criteria. Moreover, no differences in age, sex, or length of ICU stay existed between 3-month survivors and non-survivors; however, length of hospital stay differed significantly between these two groups. Table 2 lists the causes of liver failure. Liver disease was largely attributed to hepatitis virus B infection. Table 3 lists laboratory data, and data for clinical characteristics and evaluation of disease severity before and after the first session of MARS dialysis. Significant improvement in blood urea nitrogen, serum creatinine, bilirubin and ammonia levels were noted

4 64 Juan, Fan, Tsai, Jenq, Hsu, Chang, Tian, Chang, Hung, Fang, Yang and Chen Table 1. Patient demographic data and clinical characteristics All Patients Survivors Non-survivors P value (n = 57) (n = 12) (n = 45) Age (years) 51 ± 2 50 ± 4 52 ± Gender (male/female) 43/14 9/3 34/ Body weight (kg) 67 ± 2 64 ± 3 68 ± Length of ICU stay (days) 27 ± 5 63 ± ± Length of hospital stay (days) 35 ± 6 82 ± ± DM (Yes/No) 11/46 2/10 9/ Ascites, ICU Day 1 (no/mild/moderate) 36/3/17 10/0/2 26/3/ Bilirubin, ICU Day 1 (mg/dl) 23 ± 2 24 ± 3 23 ± Albumin, ICU Day 1 (g/dl) 2.96 ± ± ± Na, ICU Day 1 (meq/l) 138 ± ± ± AST, ICU Day 1 (units/l) 785 ± ± ± ALT, ICU Day 1 (units/l) 960 ± ± ± PT, ICU Day 1 (INR) 4 ± 1 4 ± 1 4 ± Platelets, ICU Day 1 ( 10 3 /µl) 129 ± ± ± Leukocytes, ICU Day 1 ( 10 3 /µl) 10 ± 1 11 ± ± Hemoglobin, ICU first day (g/dl) 12 ± ± 1 13 ± Serum Creatinine on admission (mg/dl) 2 ± ± ± Serum Creatinine, ICU Day 1 (mg/dl) 2 ± ± ± Daily urine output, ICU f Day 1 (ml/day) 1128 ± ± ± RIFLE classification, ICU Day 1-Non ARF R category I category F category MAP on ICU admission (mmhg) 78 ± 2 84 ± 6 76 ± Sessions of MARS treatment 2.3 ± ± ± Child-Pugh points, ICU Day 1 (means ± SE) 11.5 ± ± 2 12 ± MELD score, ICU Day 1 (means ± SE) 35 ± 1 37 ± 2 34 ± MELD-Na score, ICU Day 1 (means ± SE) 35 ± 1 37 ± 2 35 ± SOFA, ICU Day 1 (means ± SE) 9.2 ± ± 1 9 ± Abbreviations: ICU, intensive care unit; DM, diabetes mellitus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; INR, international normalized ratio; MAP, mean arterial pressure; SE, standard error; MELD, model for end-stage liver disease; APACHE, Acute Physiology and Chronic Health Evaluation; SOFA, sequential organ failure assessment. following MARS dialysis. Additionally, MARS dialysis improved mean arterial pressure, coma scale, and prognostic scores including Child-Pugh points, MELD, MELD-Na and SOFA scores. No significant differences in serum albumin level, prothrombin time and sodium level existed between before and after the first session of MARS dialysis. Calibration, Discrimination, and Severity of Illness Scoring Systems Tables 4 shows the goodness-of-fit, as measured by the Hosmer-Lemeshow chi-square statistic for predicted mortality risk, and the predictive accuracy of the Child-Pugh points, MELD score, MELD-Na score and SOFA score in predicting 3-month mortality, respectively. Tables 4 also lists the discrimination for Child-Pugh points, MELD score, MELD-Na score and SOFA score for predicting 3-month mortality, respectively. The discriminatory power of the SOFA score was good and superior to that of Child-Pugh points, MELD, and MELD-Na score in predicting 3- month mortality. The AUROCs were largest for the SOFA score on Day 3 after all MARS dialysis sessions for predicting 3-month mortality (0.815 ± 0.070). Moreover, the AUROC of the SOFA score on Day 3 after all MARS dialysis sessions was a significantly better predictor (P < 0.05) of 3-month mortality than that of pre-mars dialysis Child-Pugh points, SOFA, MELD and MELD-Na scores.

5 SOFA and MARS 65 Table 2. Causes of liver failure and indications for MARS All Patients 3-month 3-month P value n (%) Survivors Non-survivors n (%) n (%) Cause of liver failure Hepatitis B 33 (58) 7 (58) 26 (58) Hepatitis C 3 (5) 1 (8) 2 (4) Drug 5 (9) 0 (0) 5 (11) Alcoholic + hepatitis B 1 (2) 0 (0) 1 (2) Hepatitis B + hepatitis C 2 (4) 1 (8) 1 (2) Alcoholic + hepatitis B + hepatitis C 1 (2) 0 (0) 1 (2) Hepatitis C + drug 1 (2) 0 (0) 1 (2) Alcoholic + drug 1 (2) 0 (0) 1 (2) Other causes + hepatitis B 3 (5) 0 (0) 3 (7) Other causes 7 (12) 3* (25) 4 # (9) Indications for MARS Bilirubin > 15 mg/dl 1 (2) 0 (0) 1 (2) Hepatic encephalopathy 4 (7) 0 (0) 4 (9) Bilirubin > 15 mg/dl + HE 35 (61) 6 (50) 29 (64) HE + renal failure 3 (5) 1 (8) 2 (4) Bilirubin > 15 mg/dl + RF + HE 10 (18) 3 (25) 7 (16) Bilirubin > 15 mg/dl + RF 3 (5) 2 (17) 1 (2) IICP + HE 1 (2) 0 (0) 1 (2) Abbreviations: MARS, molecular adsorbent recirculating system; HE, hepatic encephalopathy; RF, renal failure; IICP, increased intra-cranial pressure. *Klastin tumor post operation, autoimmune hepatitis, unknown. # Wilson s disease, primary biliary cirrhosis, biliary tract infection, systemic lupus erythematosus. Table 3. Score and clinical and laboratory data before and after the first session of MARS treatment Pre-MARS Post-MARS P value Mean arterial pressure (mmhg) 78 ± 3 96 ± 2 < Bilirubin (mg/dl) 26 ± 1 21 ± 1 < Albumin (g/dl) 3.1 ± ± PT (INR) 3.5 ± ± Ammonia 200 ± ± Creatinine (mg/dl) 2.4 ± ± 0.2 < Platelet (10 3 /µl) 92 ± 8 75 ± Na (meq/l) 143 ± ± AST (units/l) 481 ± ± ALT (units/l) 621 ± ± Comma scale 9.0 ± ± 0.5 < SOFA 11.0 ± ± MELD 38 ± 1 34 ± 1 < MELD-Na 38 ± 1 34 ± 1 < Child-Pugh points 12.1 ± ± 0.1 < Abbreviations: MARS, molecular adsorbent recirculating system; PT, prothrombin time; INR, international normalized ratio; AST, aspartate aminotransferase; ALT, alanine aminotransferase; SOFA, sequential organ failure assessment; MELD, model for end-stage liver disease.

6 66 Juan, Fan, Tsai, Jenq, Hsu, Chang, Tian, Chang, Hung, Fang, Yang and Chen Table 4. Calibration and discrimination for the scoring methods in predicting 3-month mortality Calibration Discrimination goodness-of-fit df P value AUROC ± SE 95% CI P value (X 2 ) SOFA On ICU Day ± 0.105* Pre-MARS ± 0.088* Post-MARS Day ± Post-MARS Day ± Post-MARS Day ± MELD On ICU Day ± 0.100* Pre-MARS ± Post-MARS Day ± Post-MARS Day ± Post-MARS Day ± MELD-Na On ICU Day ± 0.102* Pre-MARS ± Post-MARS Day ± Post-MARS Day ± Post-MARS Day ± Child-Pugh points On ICU Day ± 0.097* Pre-MARS ± 0.100* Post-MARS Day ± Post-MARS Day ± Post-MARS Day ± Abbreviations: NS, not significant; ICU, intensive care unit; df, degree of freedom; AUROC, areas under the receiver operating characteristic curve; SE, standard error; CI, confidence intervals; MARS, molecular adsorbent recirculating system; MELD, model for end-stage liver disease; SOFA, sequential organ failure assessment. * AUROC P < 0.05 vs. SOFA, Post-MARS Day 3. Indices for Predicting Short-Term Prognosis To assess the predictive value of selected cut-off points for predicting 3-month mortality, prediction sensitivity, specificity, and overall accuracy were determined. Tables 5 lists the data calculated using the cutoff point with the best Youden index. On Day 3 after all MARS dialysis sessions, the Youden index and overall accuracy for predicting 3-month mortality were higher for the SOFA score than for Child-Pugh points, MELD and MELD-Na scores. The cumulative survival rates in the study population differed significantly (P < 0.05) between patients with SOFA scores 11 and those with SOFA scores > 11 on Day 3 after all sessions of MARS dialysis (Fig. 2). Discussion The short-term (4 weeks to 6 months) mortality rates after MARS treatment varied considerably among the studies, ranging from 38 to 78.6% (6-8, 22-25). The overall 3-month mortality rate observed in this study was 78.9%, which was high compared with that of previous studies (6-8, 22-25). The high mortality may have been attributable to low mean sessions (2.3 ± 0.2) of MARS therapy (Table 1) and lack of liver donors. Indications for MARS dialysis in this study were primarily FHF associated with hepatitis B infection (74%), including hepatitis B with other possible causes of liver failure (Table 2), which were different from those in other non-asian studies. The principal clinical change noted after MARS dialysis was improvement in conscious level, mean arterial pressure, serum creatinine and serum bilirubin levels and the scoring systems (Table 3). Differences in number of MARS dialysis sessions undergone between survivors and non-survivors (3.2 ± 0.7 vs. 2.0 ± 0.2, respectively) were statistically significant (P = 0.047)

7 SOFA and MARS 67 Table 5. Prediction of subsequent 3-month mortality Predictive Cutoff Youden Sensitivity Specificity Overall Factors Point Index (%) (%) Accuracy (%) On admission SOFA MELD MELD-Na Child-Pugh points On ICU Day 1 SOFA MELD MELD-Na Child-Pugh points Post-MARS Day 1 SOFA MELD MELD-Na Child-Pugh points Post-MARS Day 2 SOFA MELD MELD-Na Child-Pugh points Post-MARS Day 3 SOFA MELD MELD-Na Child-Pugh points Abbreviations: MARS, molecular adsorbent recirculating system; MELD, model for end-stage liver disease; SOFA, sequential organ failure assessment. *Value giving the best Youden index for each period. Survival Rate P < 0.05 SOFA 11 (N = 16) SOFA > 11 (N = 41) Days after the Completion of All MARS Dialysis Sessions Fig. 2. Cumulative survival rate for 57 liver failure patients calculated using Sequential Organ Failure Assessment (SOFA) score on post-mars Day 3. (Table 1). This study also finds that SOFA score on Days 2 and 3 after MARS dialysis sessions were prognostically significant variables for patients with FHF who underwent MARS dialysis (Table 4). The SOFA score on Day 3 after all MARS dialysis sessions has the best Youden index and highest overall accuracy for predicting 3-month mortality (Table 5). A SOFA score of > 11 on Day 3 after all MARS dialysis sessions should be taken as an indicator of negative short-term outcome (Fig. 2). Additionally, critically ill patients with a baseline SOFA score exceeding 11 have more than 90% mortality (26, 27). Our previous studies demonstrated the good discriminative power and accuracy of SOFA score in independently predicting in-hospital mortality of critically ill cirrhotic patients without MARS therapy (28-30). For another 149 patients who received liver transplants, only SOFA scores calculated before liver transplantation were statistically significant predictors

8 68 Juan, Fan, Tsai, Jenq, Hsu, Chang, Tian, Chang, Hung, Fang, Yang and Chen of 3-month and 1-year post-transplant mortality, not Child-Pugh points, MELD scores or RIFLE criteria (31). A feature of FHF is disturbed systemic circulation characterized by marked arterial vasodilation in splanchnic circulation, which reduces total peripheral vascular resistance and arterial pressure while causing a secondary increase in cardiac output (32, 33). These abnormalities are implicated in several major cirrhotic complications such as more serious liver damage with jaundice, coagulopathy, hepatic encephalopathy, hepatorenal syndrome, hepatocardiac syndrome, and hepatopulmonary syndrome. The involvement of such abnormalities renders SOFA score an excellent tool for assessing the extent of organ dysfunction and predicting mortality. Analytical results obtained by this study confirm and extend these observations by demonstrating that the SOFA score for critically ill cirrhotic patients on Day 3 after MARS treatment had the best Youden index and highest overall accuracy in predicting 3-month outcome. On Day 3 after all MARS dialysis sessions, uncorrected multiple organ dysfunction results in delayed recovery of liver function and poor shortterm and/or post-liver transplantation prognosis. Both MELD score and Child-Pugh points were utilized to stratify prospective liver allograft recipients. The accuracy of the MELD score in predicting shortterm mortality in end-stage liver disease patients is well established (34). In this study, the AUROCs demonstrate that the discriminatory power of Child-Pugh points is superior to MELD and MELD-Na scores in predicting 3-month mortality (Table 4). Previous studies of prognostic models were mainly conducted in the United States and Europe. In Asia, chronic hepatitis B is the main cause of FHF. Asian studies suggested that there may be other important prognostic markers not considered in the MELD score. In 96 Chinese patients with decompensated cirrhosis due to chronic hepatitis B, hepatic encephalopathy and hypoalbuminemia were the most important factors predicting mortality. The Child-Pugh points may perform better than the MELD score in patients with chronic hepatitis B (35). In this study, no improvement of prothrombin time or reduction in platelet count was noted after MARS dialysis in our study (Table 3). As was consistent with previous observations in liver-failure patients (8, 25, 26), the prothrombin time which represents the synthetic function of the liver, did not change after MARS dialysis, as MARS dialysis replaces the excretory function of a failing liver, not its synthetic function. In previous reports, platelet counts decreased significantly after MARS treatment (8, 25, 26). The pathogenesis of thrombocytopenia is complex. Possible reasons include impaired platelet production, increased platelet destruction and sequestration of platelet to an enlarged spleen (32). Moreover, platelet consumption due to significant upper gastrointestinal bleeding before and during MARS dialysis is not uncommon in the patients with FHF in the ICU. Despite the encouraging results, potential limitations of this study should be mentioned. First, subjects were drawn from only one medical center; consequently, analytical results cannot be directly extrapolated to other patient populations. Second, as this study was retrospective, some laboratory data were unavailable. Third, the National Health Insurance program in Taiwan did not cover MARS treatment. Furthermore, liver transplantation, not MARS therapy, often offers the hope of prolonged survival and improved quality of life for critically ill patients with FHF. Unfortunately, although effective, the possibility of a transplant depends upon the availability of donor livers. A lack of donor livers and economic issues causing incomplete treatment with MARS partly explain the very poor outcomes of the 57 critically ill liver failure patients of this study. Finally, a high proportion of the patient population had hepatitis B (hepatitis B alone 63%; hepatitis B and C 4%; hepatitis B and alcoholism 4%); therefore, findings may have limited applicability to typical North American and European patients who have hepatitis C or are alcoholics. MARS dialysis is useful in decreasing temporarily the severity of multiple organ failure in FHF patients and as a bridge to liver transplantation. According to the data obtained in this study, we conclude that the SOFA score on Day 3 after all MARS dialysis sessions has the best Youden index of the four measures and highest overall prediction accuracy. 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