PREDICTING PROGNOSIS AMONG CIRRHOTIC PATIENTS: CHILD-PUGH VERSUS APACHE III VERSUS MELD SCORING SYSTEMS

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1 Phil J Gastroenterol 2006; 2: PREDICTING PROGNOSIS AMONG CIRRHOTIC PATIENTS: CHILD-PUGH VERSUS APACHE III VERSUS MELD SCORING SYSTEMS Ira I Yu, Luis Abola Section of Gastroenterology, Department of Internal Medicine, University of the East Ramon Magsaysay Memorial Medical Center Quezon City, Philippines Background: Prognosis of acutely ill cirrhotic patients is influenced by the dysfunction of both hepatic and extrahepatic systems. The Child-Pugh (CP) scoring is still the cornerstone in the prognostic evaluation of cirrhotic patients. However, it has some drawbacks due to disregard of cardiac, renal, pulmonary, and other organ systems. The Acute Physiology, Age and Chronic Health Evaluation (APACHE) III and Model for End Stage Liver Disease (MELD) have been proposed as tools to predict mortality risk because of the limited predictive accuracy of the Child-Pugh system. Objectives: To evaluate the prognostic accuracy of CP vs. APACHE III vs. MELD for predicting inhospital mortality among decompensated cirrhotic patients and to determine the clinical and biochemical variables that may be predictive of mortality Methods: The survival/mortality of 64 cirrhotic patients admitted from January 2002 to June 2003 were respectively studied. The CP, MELD, and APACHE III scores were computed for each patient within the first 24 hours of their admission. Patient disposition was classified as either survival or demise. Numerical (continuous) variables were reported as mean + SD, and group comparisons between survivors and non-survivors were carried out using the independent sample t test. Univariate analysis and multiple forward stepwise logistic regressions were used to identify clinical and biochemical parameters directly correlated with mortality. Finally, sensitivity, specificity, positive predictive and negative predictive values were computed for the three prognostic scoring systems. Results: 29 patients died (45.3%) due to cirrhosis-related (73.4%) and non-cirrhosis related conditions (26.6%). CP, APACHE and MELD mean scores of survivors (5.9, 25.6 and 4.4 respectively) were lower than non-survivors (8.2, 54.8 and 11.1, respectively) (p<0.001). Sensitivity of CP, APACHE and MELD were almost comparable (88.6%, 85.7% and 85.7% respectively), however, APACHE showed the best specificity (86.2%) compared with CP (69.0%) and MELD (75.9%). Likewise, the APACHE system has the highest negative predictive value (88.2%). The overall predictive accuracy of APACHE was 6.2% and 4.6% greater than the CP and MELD scores. By multiple logistic regression, only WBC count (p=0.023), BUN (p=0.03) and presence of encephalopathy (p=0.007) were significantly correlated with mortality. Conclusion: The APACHE III scoring system is superior to Child-Pugh and MELD scoring systems for prognosticating in-hospital mortality among decompensated cirrhotic patients. Keywords: hepatic decompensation, in-hospital mortality among cirrhotics, prognostic scoring system.

2 20 Yu I, Abola L INTRODUCTION In 1964, Child and Turcotte described a prognostic model for assessment of surgical risk in cirrhotic patients. Pugh et al proposed a modification of this model in The modified Child-Pugh (CP) prognostic index has been used extensively to risk stratify patients with cirrhosis and to evaluate efficacy of therapeutic procedures. At present, the CP classification is by far the most widely applied and reported system as it is easy to use at the bedside. Over the years, many clinical and biochemical parameters have been suggested in order to more accurately estimate the prognosis of cirrhotic patients and correctly predict their short and medium term survival. The short-term prognosis of acutely ill patients with cirrhosis is influenced by the degree of hepatic insufficiency and by the dysfunction of extrahepatic organ systems. 1 The lack of evaluation of cardiac, renal, pulmonary, acid-base and electrolyte status, and disregard for important associated factors, limit the predictive accuracy of the Child-Pugh system. Recently, the study group at the Mayo Clinic introduced a new scoring system, the Model for End Stage Liver Disease (MELD), to evaluate the prognosis of patients undergoing TIPS 2, 3. They then generalized its application to patients with different stages of cirrhosis to evaluate their short term survival prognosis. 4 The MELD score takes into consideration objective parameters (serum creatinine, prothrombin time INR, serum bilirubin) and is computed with a statistically derived coefficient on a continuous scale with no upper or lower limits, thus avoiding many drawbacks of the Child-Pugh scoring system. 5 TheAcute Physiology Age and Chronic Health Evaluation System (APACHE) III is a physiologically based system that was developed and refined by Knauss and associates. It was originally designed to estimate probability of death among critically ill hospitalized adults in the intensive care setting, cirrhotic and noncirrhotic patients alike. 6,7 Recently, Butt et al reported its use in cirrhotic patients in comparison with Child-Pugh score outside of the intensive care setting. 8 OBJECTIVES 1. To evaluate the prognostic accuracy of Child-Pugh versus APACHE III versus MELD scoring systems for predicting mortality among hospitalized decompensated cirrhotic patients. 2. To determine clinical and biochemical variables that may be predictive of mortality. PATIENTS AND METHODS Cirrhotic patients admitted or referred to the Section of Gastroenterology of the University of the East Ramon Magsaysay Memorial Medical Center, a tertiary hospital, from January 2002 to June 2003 were respectively studied. Data collected included demographics; etiology of cirrhosis; indication for hospital admission; presence or absence of ascites and encephalopathy; and the corresponding Child- Pugh, MELD, and APACHE III scores. The diagnosis of cirrhosis was made by clinical evaluation (n= 61) or histologically (n= 3). The clinical diagnosis of cirrhosis was made by a history of portal hypertension excluding other etiology, impaired liver function tests, impaired clotting parameters, ultrasonographic or computer tomographic criteria. The Child-Pugh, MELD and APACHE III scores were computed for each patient on admission. The MELD score was calculated according to the original formula proposed by the Mayo clinic group. 9 The APACHE III score was computed by recording and summing points for the potential physiologic measurements (pulse rate, mean blood pressure, temperature, respiratory rate, hematocrit, white blood cell count (WBC), serum creatinine, urine output, blood urea nitrogen (BUN), serum sodium, serum albumin, bilirubin, blood glucose, neurologic status), age, and chronic health evaluation. If multiple co-morbid conditions are present, the condition with the highest risk point was scored. Points for the potential physiologic measurements reflect the worst (most abnormal) value during the initial 24 hours of hospital admission. 10 Arterial blood gas analysis was not performed routinely and hence this variable was not included in the

3 Child-Pugh Scoring 21 calculation of the APACHE III score. The principal study outcome was hospital mortality rate. The cause of death was also determined. Statistical Analysis. Categorical variables were reported as frequency and percentage. Numerical (continuous) variables were reported as mean + SD, and group comparisons between survivors and non-survivors were carried out using the independent sample t test. Univariate analysis and multiple forward stepwise logistic regressions were used to identify clinical and biochemical parameters directly correlated with mortality. Finally, sensitivity, specificity, positive predictive and negative predictive values were computed for the three prognostic scoring systems. RESULTS A total of 64 patients (male - 44 (68.8%), female - 20 (31.2%), mean age 56.12) were included in the study. Indication for hospital admission was mostly due to upper gastrointestinal bleeding (30.8%) (Table 1). Other reasons for hospitalization were encephalopathy (21.8%), spontaneous bacterial peritonitis (SBP) (3.8%) and ascites (21.8%). Other reasons for admission were fever, cough, anorexia, and body weakness. There were several patients who were found to have more than one problem on admission; hence, these reasons for admission were also tallied separately. Majority of the cirrhosis were due to viral hepatitis (48.4%) (29 chronic hepatitis B cases and 2 chronic hepatitis C). The second most common cause of cirrhosis was chronic alcoholism (37.5%). There were 9 patients (14.1%) whose exact cause of cirrhosis was not determined because hepatitis markers were not performed either due to financial limitations or the patients expired prior to the testing. Mean CP, MELD and APACHE scores were 6.9, 7.4 and 38.8, respectively. 45.3% of the study population died. The mean time of death was 7.4 days. 34.4% of the patients died because of cirrhosis-related complications (hepatic encephalopathy, hepatorenal syndrome, sepsis, and Table 1: Baseline Clinical Characteristics of Patients Sex N % Male Female Etiology of Cirrhosis Alcohol Hepatitis Others Indication for Admission GI Bleeding Encephalopathy SBP Ascites Others Child-Pugh Class A B C Disposition Alive Expired Cirrhosis related Non-liver related bleeding esophageal varices), while 26.6% of the patients died because of non-liver-related causes (myocardial infarction, congestive heart failure). Table 2 presents the comparative details of various prognostic indices included in the 3 scoring systems among survivors and nonsurvivors. Mean Child-Pugh, MELD and APACHE III scores were significantly different

4 22 Yu I, Abola L between survivors (5.9, 4.4 and 25.6, respectively) and non-survivors (8.2, 11.1, and 54.8 respectively ) (p<0.001). Univariate analysis was performed on all variables contained in Child-Pugh, MELD and APACHE III scores. A p value less than 0.05 was considered statistically significant. This analysis revealed that increasing levels of blood glucose, serum creatinine, prothrombin time INR, blood urea nitrogen (BUN), WBC, respiratory rate, pulse rate, ascites and encephalopathy were significantly associated with increased risk of death. Similarly, decreased levels of albumin, mean arterial pressure (MAP) and urine output increased the probability of death. However, on multivariate forward stepwise logistic regression, an elevated WBC count (p=0.02, OR 1.2)and BUN (p=0.003, OR 1.2) and the presence of encephalopathy (p<0.001, OR 18.6) were the only factors significantly associated with death. To evaluate to what extent the 3 scoring systems were valid in predicting hospital mortality, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. (Table 3) Receiver operating characteristic (ROC) curves were used to determine the cut off values for all the scoring systems using the best sensitivity and specificity Table 2: Patient Characteristics Subdivided According to Survival Survivors Non-survivors p value CP <0.001 MELD <0.001 APACHE <0.001 Table 3: Prediction of Hospital Mortality in discriminating patients who survived and those who died.) The sensitivity of CP, MELD and APACHE were almost similar (88.6%, 85.7%, and 85.7% respectively). However, APACHE had the highest specificity (86.2%). Similarly, the positive predictive value of the 3 scoring systems were almost the same, but the highest negative predictive value was that using the APACHE III scoring system. The overall predictive accuracy of APACHE III was higher (85.9%) than Child-Pugh (79.7%) and MELD (81.3%). DISCUSSION The ability to objectively estimate patient risk for mortality or other important outcomes is a challenging undertaking for clinical research. The Child-Pugh system is an important component of the prognostic evaluation of cirrhotic patients, although, this traditional scoring has several shortcomings. This issue intensified the search for a continuous disease severity score system that used more objective, readily verifiable parameters, which could be validated as a measure of liver disease severity, or predictor of mortality. APACHE III and MELD scoring systems had been found individually to be superior over Child-Pugh in some reports In this study, the aim was to evaluate the short term prognostic ability of the 3 scoring systems in comparison with each other. Previous studies had only compared Child-Pugh versus MELD or APACHE III. None had attempted to compare all 3 systems together. In this retrospective study, it was shown that APACHE III was an excellent prognostic system for predicting in-hospital mortality among decompensated cirrhotic patients. The Child- Scoring System Cut-off value Sensitivity (%) Specificity (%) Predictive Accuracy PPV (%) NPV (%) Child-Pugh MELD APACHE Legend: PPV, positive predictive value; NPV, negative predictive value

5 Child-Pugh Scoring 23 Pugh score uses two very subjective variables in its calculation - portosystemic encephalopathy and ascites. It is well known that physical assessment of ascites is not very accurate when compared to the much more sensitive imaging studies such as ultrasound. Minimal ascites, in fact, may not be detectable by mere bedside examination, and this may result in a lower CP score when missed. Even more problematic is the assessment of hepatic encephalopathy. Clinicians may vary in their threshold for considering encephalopathy. Even the examination for the presence of asterixis as a qualifier for encephalopathy is not very accurate. MELD and APACHE III use objective variables in their computation. This, the authors think, is one reason why MELD and APACHE III did better than CP. Furthermore, while it is true that to some extent, CP score indicates the severity of the underlying liver disease, it is not at the present time, the best tool for predicting mortality in cirrhotic patients with multisystem organ failure. MELD uses prothrombin time INR, serum bilirubin, and serum creatinine levels while APACHE III went further by incorporating parameters that measured the pulmonary, cardiac, electrolyte, acid-base, and neurologic status of the patient. An increased number of comorbid conditions, the authors believe, contributed to a poorer prognosis, and hence, should never be disregarded in any outcome probabilistic model. End stage liver disease or events such as bleeding, infection, and high dose diuretic therapy have effects on renal function and may cause functional renal impairment. In patients presenting with a high CP class, the impact of impaired renal function on survival is well known. 9 More than 70% of our patients were of CP Class A or B. Univariate analysis revealed that increasing levels of BUN, creatinine and decreasing level of urine output correlated with mortality. This finding suggests that a deteriorating renal function is a prognostic marker even in patients with relatively good liver synthetic function. However, on multivariate analysis, while the value of BUN as an independent predictor of mortality was confirmed, neither the level of creatinine nor urine output had any prognostic significance. This may have been due to the small sample size of this study. Bacterial infections are a frequent and severe complication of cirrhosis. 14,15 Cirrhotic patients have an acquired immune deficiency because of dyshomeostasis and malnutrition. All host defense systems are compromised. Compared to the background population, the mortality of infections is more than 20x increased in cirrhosis. 16,17 In comparison to the limited clinical variables contained in CP and MELD, WBC as a rough guide to the level of septicemia, has always been incorporated in all APACHE scoring systems (both II and III). Moreover, the result of the multivariate logistic analysis showed that an elevated WBC count was associated with inhospital mortality. However, for any prognostic scoring system to be clinically useful, it should also be easy to use at the bedside. Child-Pugh and MELD are relatively easier to do because of the fewer data needed. APACHE III system is a more complicated model, although, majority of the parameters used in the calculation of APACHE III are requested on admission, especially among critically ill patients. Still, because of the complexity in arriving at the APACHE III score, hesitations in routinely using it is the major hindrance in achieving wide popularity. The present study is limited by the omission of the arterial blood gas examination. As this study is a retrospective study, blood gas examination was not routinely done on all of the patients. This in effect might have produced lower APACHE scores. The exclusion of this parameter might also lead to a different multivariate analysis. CONCLUSION/RECOMMENDATION The present data showed that APACHE III has the highest overall predictive accuracy among the three scoring systems. However, since there is no such thing as 100% accuracy in any probabilistic estimate outcome model, it is prudent to say, that these scoring systems should always go hand in hand with critical clinical analysis and good decisionmaking.

6 24 Yu I, Abola L REFERENCES 1. Wehler, M, Kokosha J, Reulbach U, Hahn EG, Strauss R. Short Term Prognosis in Critically Ill Patients With Cirrhosis Assessed by Prognostic Scoring Systems. Hepatology Aug; 34(2): Malinchoc M, Kamath PS, Gordon FD, et al. A Model to Predict Poor survival In Patients Undergoing Transjugular Intrahepatic Portosystemic Shunts. Hepatology 2000; 31: Angermayr B, Cejan M, Karnel E, et al. Child Pugh versus MELD Score In Predicting Survival In Patients Undergoing Transjugular Intrahepatic Portosystemic Shunt. Gut 2003; 52: Kamath PS, Wiesner RH, Malinchoc M, et al. A Model To Predict Survival In Patients With End Stage Liver Disease. Hepatology 2001; 33: Wiesner RH, McDiarmid SV, Kamath PS, et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl 2001;7: Aggarwal A, Ong J, Younossi Z, Nelson D, Hoffman- Hogg L, Arroliga A. Predictors of Mortality and Resource Utilization in Cirrhotic Patients Admitted To The Medical ICU. Chest 2001; 119: Zimmerman JE, Wagner DP, Seneff MG, Becker RB, Sun X, Knaus WA. Intensive Care Unit Admission With Cirrhosis: Risk-Stratifying Patient Groups and Predicting Individual Survival. Hepatology 1996 June; 23(6): Butt A, Khan AA, Alam A, Shah SW, Shafqat F, Naqvi AB. Predicting Hospital Mortality in Cirrhotic Patients: Comparison of Child-Pugh and Acute Physiology, Age and Chronic Health Evaluation (APACHE III) Scoring Systems. Am J Gastroenterology December; 93 (12): Botta F, Giannini E, Romagnoli P, et al. MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: A European study. Gut. 2003; 52: Knaus, W, Wagner DP, Draper EA, et al. The APACHE III Prognostic System. Risk Prediction of Hospital Mortality for Critically Ill Hospitalized Adults. Chest December; 100(6): Afessa, B. and Kubilis, P. Upper Gastrointestinal Bleeding in Patients With Hepatic Cirrhosis: Clinical Course and Mortality Prediction. Am J Gastroenterology February; 95(2): Weisner, R, Edwards E, Freeman R, et al. Model for End Stage Liver Disease (MELD) and Allocation of Donor Livers. Gastroenterology January; 124: Chalasani N, Kahi CJ, Francois F, et al. Mayo clinic end-stage liver disease model (MELD) for predicting patient outcomes following acute variceal bleeding. Hepatology 2001;34:345A. 14. Caly WR, Strauss E. A Prospective Study of Bacterial Infections In Patients With Cirrhosis. J Hepatology 1993 July; 18 (3): Campillo B, Richardet J-P, Kheo T, Duperyron C. Nosocomial Spontaneous Bacterial Peritonitis and Bacteremia in Cirrhotic Patients: Impact Of Isolate Type On Prognosis And Characteristic Of Infection. Clinical Infectious Disease. 2002; 35: Foreman M, Mannino D, Moss M. Cirrhosis As A Risk Factor For Sepsis and Death: Analysis of the National Hospital Discharge Survey. Chest 2003; 124: Vilstrup H. Cirrhosis and Bacterial Infections. Rom J Gastroenterol 2003 Dec; 12 (4):

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