Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an Intensive Care Unit

Research Article

Prospective evaluation of the prognostic scores for cirrhotic patients admitted to an Intensive Care Unit Eric Levesque1, Emir Hoti1, Daniel Azoulay1,2,3, Philippe Ichaï1,2,4, Houssam Habouchi1, Denis Castaing1,2,4, Didier Samuel1,2,4, Faouzi Saliba1,2,4,⇑ 1

AP-HP Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France; 2Univ Paris-Sud, UMR-S 785, Villejuif, France; 3 Inserm, Unité 1004, 94800 Villejuif, France; 4Inserm, Unité 785, 94800 Villejuif, France

Background & Aims: Cirrhotic patients admitted to an Intensive Care Unit (ICU) have a poor prognosis. Identifying patients in whom ICU care will be useful can be challenging. The aim of this study was to assess the predictive value of prognostic scores with respect to mortality and to identify mortality risk factors. Methods: Three hundred and seventy-seven cirrhotic patients admitted to a Liver ICU between May 2005 and March 2009 were enrolled in this study. Their average age was 55.5 ± 11.4 years. The etiology of cirrhosis was alcohol (68%), virus hepatitis (18%), or mixed (5.5%). The main causes of hospitalization were gastrointestinal hemorrhage (43%), sepsis (19%), and hepatic encephalopathy (12%). Results: ICU and in-hospital mortality rates were 34.7% and 43.0%, respectively. Infection was the major cause of death (81.6%). ROC curve analysis demonstrated that SOFA (0.92) and SAPS II (0.89) scores calculated within 24 h of admission predicted ICU mortality better than the Child–Pugh score (0.79) or MELD scores with (0.79–0.82) or without the incorporation of serum sodium levels (0.82). Statistical analysis showed that the prognostic severity scores, organ replacement therapy, and infection were accurate predictors of mortality. On multivariate analysis, mechanical ventilation, vasopressor therapy, bilirubin level at admission, and infection were independently associated with ICU mortality.

Keywords: Cirrhosis; Prognostic scores; Intensive Care Unit; Outcome; Mortality; Model for End-Stage Liver Disease. Received 1 February 2011; received in revised form 24 May 2011; accepted 17 June 2011; available online 9 August 2011 ⇑ Corresponding author. Address: Réanimation, Centre Hépato-Biliaire, Hôpital Paul Brousse, 12 avenue Paul-Vaillant-Couturier, 94804 Villejuif, France. Tel.: +33 1 45 59 64 12; fax: +33 1 45 59 38 57. E-mail address: [email protected] (F. Saliba). Abbreviations: ICU, Intensive Care Unit; SOFA, Sequential Organ Failure Assessment; APACHE, Acute Physiology and Chronic Health Evaluation; MELD, Model for End-Stage Liver Disease; TIPS, Transjugular Intrahepatic Portosystemic Shunt; UNOS, United Network for Organ Sharing; MELD-Na, Model for End-Stage Liver Disease with incorporation of serum sodium; iMELD, Integrated Model for EndStage Liver Disease; MESO, Model for End-Stage Liver Disease to Sodium index; SAPS II, Simplified Acute Physiology Score; ROC, Receiver Operating Characteristic; MARS, Molecular Adsorbent Recirculating System; RRT, Renal Replacement Therapy; AUROC, Area Under Receiver Operating Characteristic; SIRS, Systemic Inflammatory Response Syndrome; CFU, Colony Forming Units; CPIS, Clinical Pulmonary Infection Score.

Conclusions: For cirrhotic patients admitted to the ICU, SAPS II, and SOFA scores predicted ICU mortality better than liver-specific scores. Mechanical ventilation or vasopressor therapy, bilirubin levels at admission and infection in patients with advanced cirrhosis were associated with a poor outcome. Ó 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Introduction Cirrhotic patients admitted to an Intensive Care Unit (ICU) have a poor prognosis, with mortality rates ranging from 36% to 86% [1–4]. In addition, management of these patients requires that a significant percentage of the total ICU care budget is devoted to a subgroup of cirrhotic patients who will eventually not survive [5,6]. To identify patients in whom aggressive treatment may offer recovery, or those who may benefit from a transfer to an ICU or from liver transplantation, has always been a challenge for intensivists and hepatologists. To this end, several prognostic scores [7,8] have been proposed, including the Child–Pugh, which until now has been the most widely utilized liver-specific score [9,10]. However, the discriminatory power of this score relative to mortality in cirrhotic patients admitted to the ICU is inferior to that of general ICU scores (SOFA or APACHE) [11]. This might be due, at least in part, to the fact that the Child–Pugh score does not include any markers of renal function. Recently, the Model for End-Stage Liver Disease (MELD) score, initially developed for cirrhotic patients treated with Transjugular Intrahepatic Portosystemic Shunt (TIPS) [12], has been applied widely to predict mortality across a broad spectrum of liver diseases. Thus, the MELD score was implemented in 2002 by the United Network for Organ Sharing (UNOS) as a tool to estimate the severity of liver disease, the mortality of patients on waiting lists for liver transplantation and subsequently for the allocation of liver grafts. The MELD score has been associated with 3-month mortality in patients on the waiting list. Despite its potential benefits, relatively few studies have analyzed the predictive value of the MELD score in cirrhotic patients admitted to an Intensive Care Unit [13–15]. Moreover, hyponatremia, as a surrogate of portal hypertension, has now been recognized as an important

Journal of Hepatology 2012 vol. 56 j 95–102

Research Article prognostic factor in patients with liver cirrhosis [16]. Several MELD models incorporating serum sodium (Na+) levels (the MELD-Na [16], iMELD [17], and MESO [18]) have been shown to improve prognostic accuracy in cirrhotic patients awaiting liver transplantation [19,20]. However, only one study has evaluated these modified versions (MELD combined with serum sodium) in cirrhotic patients admitted to an ICU and observed a similar discrimination ability of MELD-Na and MELD to predict in-hospital mortality [15]. To evaluate the performance of these scores as predictive tools of mortality in patients with cirrhosis in an ICU, we compared the Child–Pugh classification, liver-specific prognostic models (MELD and MELD combined with serum sodium) and two ICU prognostic scores [the Simplified Acute Physiology Score (SAPS II) [21] and Sequential Organ Failure Assessment (SOFA)] [22]. In addition, we looked for specific factors that might predict mortality in patients with cirrhosis admitted to an ICU.

Statistical analysis

Patients and methods Patients This prospective cohort study was performed in the Liver Intensive Care Unit (15 beds) at Paul Brousse University Hospital. This is a tertiary referral unit that has been highly specialized in liver diseases since 1970. The unit is run by hepatologists, intensivists, and liver surgeons. Between May 2005 and March 2009, 377 consecutive cirrhotic patients requiring intensive monitoring and/or treatment that could not be provided outside an ICU were enrolled. All patients were P18 years of age and had histologically-proven or clinically diagnosed cirrhosis (e.g. portal hypertension with ascites, esophageal varices, or encephalopathy). Cirrhotic patients admitted to the Liver ICU before or following any type of surgery were excluded from this study.

Data The following clinical and demographic data were collected: age, gender, etiology of cirrhosis, and primary diagnosis at ICU admission including variceal bleeding, encephalopathy, sepsis, and hepatorenal syndrome. The SAPS II [21] and initial Sequential Organ Failure Assessment (SOFA) [22] were determined within 24 h of admission to determine the severity of the acute illness. These scores have been validated to predict survival in general ICU populations. The SAPS II system is based on age, chronic health status, admission status, and an acute physiological score including systolic blood pressure, heart rate, body temperature, Glasgow coma score, urine output, serum sodium, serum potassium, serum urea, serum bicarbonate, serum bilirubin, white blood cell count, and arterial oxygen tension or alveolar–arterial oxygen tension gradient. The SOFA comprises scores for six organ systems (respiratory, cardiovascular, hepatic, renal, coagulation, and neurological) graded from 0 to 4 according to normal function or the degree of dysfunction. The severity of liver disease at ICU admission was graded using the Child– Pugh classification [20]. All other prognostic models (MELD, MELD-Na, iMELD, and MESO index) were calculated based on the laboratory results obtained on the day of admission. The following equations were used to calculate the severity scores: – MELD: 9.6  log [creatinine (mg/dl)] + 3.8  log [bilirubin (mg/ dl)] + 11.2  log (INR) + 6.43 [23] The MELD score ranges from 6 to 40, with higher values indicating more severe disease. – MELD-Na: MELD + 1.59  (135  Na) (with Na between 135 and 120 mmol/L) [16]. – iMELD: MELD + (0.3  age)  (0.7 + Na) + 100 [17]. – MESO index: [MELD/Na (mmol/L)]  10 [18]. During our study, organ failure was defined as a SOFA score of 3 or 4 for the organ concerned [22] (Cardiovascular: need for epinephrine or norepinephrine or dopamine >5 lg/kg/min; Respiratory: PaO2/FiO2 <200 mmHg with respiratory

96

support; Renal: creatinine >300 lmol/L or urine output <500 ml/day; Hematology: platelet count <50  103/mm3; Hepatic: bilirubin >102 mmol/L; Central Nervous system: Glasgow coma score <9). At admission and during follow-up in the ICU, systematic screening for infection included chest X-rays, biological parameters (leukocytes, C-reactive protein), clinical features (temperature, signs of shock), and cultures of blood, sputum, urine, and ascites. Infection at admission was defined as an infection occurring within the first 48 h following admission to the ICU. A diagnosis of infection was based on the following criteria: (1) spontaneous bacterial peritonitis was defined when the ascitic fluid neutrophil count was >250/mm3, (2) positive urine culture for urinary tract infection, (3) positive blood cultures (two blood cultures for Staphylococcus epidermidis) for bacteremia, (4) a suspicion of pneumonia was based on combined criteria including elevated leukocytes (>12,000/mm3), elevated C-reactive protein (>50 mg/L), fever or hypothermia (<36.5 °C or >38.5 °C), tracheal secretions, a need for oxygen supply or mechanical ventilation, lung infiltrates or opacities on a chest X-ray. For all prospectively identified episode of pneumonia, modified Clinical Pulmonary Infection Score (mCPIS) was calculated retrospectively [24,25]. Pneumonia was confirmed by a positive microbial diagnosis (with a threshold of 104 Colony Forming Units/ml (CFU/ml) for bronchoalveolar lavage cultures or 106 CFU/ml in the case of tracheal aspiration [26]) when available or a mCPIS P5.

Data are expressed as mean ± SD. The Mann–Whitney U-test was used to compare continuous variables and Chi-square for categorical variables. Univariate and multivariate Cox regression hazard analysis models were used to determine independent, significant, predictive factors of ICU mortality. Survival rates were calculated using the Kaplan–Meier method on day 60 after ICU admission and groups were compared with the log-rank test. None of the patient was lost. Median follow-up was 8 months (2–36 months). Statistical analyses were performed using Statview 5.0 for Macintosh (SAS Institute Inc., Cary, NC, USA). A ROC curve analysis software (MedCalc version 10.2.0.0, for windows) was used to determine the Receiver Operating Characteristic (ROC) curve. To identify which score had the best discrimination capacity to predict ICU mortality, Areas Under Receiver Operating Characteristics curve (AUROC) were compared [27]. Sensitivity, specificity, and positive and negative predictive values were determined for MELD, SOFA, and SAPS II. Cut-off values were identified using the highest Youden index (sensitivity + specificity 1) [28]. A p value of less than 0.05 was considered to be statistically significant.

Results Patients Between May 2005 and March 2009, 377 consecutive cirrhotic patients admitted to our ICU were enrolled in this study. The characteristics of these patients are shown in Table 1. The median age was 55.5 ± 11.4 years; 73% were men and the liver disease concerned was most frequently alcohol-related (68%). The most common primary diagnoses at ICU admission were: acute variceal bleeding (43%), severe infection (19%), or hepatic encephalopathy (13%). Among the patients with alcoholic cirrhosis, 39 patients (14%) had a histologically proven severe acute alcoholic hepatitis. Follow-up to 60 days or time of death was completed for the whole cohort. In this series, none of the patient was lost. Five patients were transferred to another hospital (ICU discharge). Three died within 60 days and considering living in ICU and died in hospital. The cumulative incidence of mortality was 34.7% (131 out of 377 patients) in the Liver ICU and 43% (162 out of 377 patients) in the hospital. The results of the univariate analysis performed on all 377 cirrhotic patients admitted, in order to the ICU to determine predictive factors of ICU mortality, are presented in Table 2. There were no significant differences in age and gender between the survivor and non-survivor groups. The primary diagnosis at admission to the ICU differed significantly between the

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JOURNAL OF HEPATOLOGY Table 1. Clinical characteristics of 377 cirrhosis patients admitted to an ICU. Data are expressed as mean ± S.D.

Variable Age (years, mean ± SD)

Patients (n = 377) 55.5 ± 11.4

Gender (M/F)

277/100

Length of ICU stay (days, mean ± SD)

9.7 ± 11.3

Length of hospital stay (days, mean ± SD)

23.0 ± 26.4

Cause of cirrhosis Alcoholic

258 (68%)

Hepatitis B

15 (4%)

Hepatitis C

52 (14%)

Alcoholic + Hepatitis

21 (6%)

Others

31 (8%)

Primary ICU admission Acute variceal bleeding Severe infection

162 (43%) 72 (19%)

Hepatic encephalopathy

47 (13%)

Hepatorenal syndrome type I

19 (5%)

Other

77 (20%)

Prognostic scores at ICU admission (mean ± SD) SAPS II

45.6 ± 21.2

SOFA

9.4 ± 4.9

Child Pugh

10.5 ± 2.3

Child Pugh category (A/B/C)

25/89/263

MELD

24.9 ± 10.8

MELD Na

29.7 ± 13.8

MESO

1.9 ± 0.8

iMELD

48.1 ± 13.2

Biological parameters at admission Serum sodium (mmol/L)

133.9 ± 6.8

Serum creatinine (µmol/L)

155.6 ± 138.8

Bilirubin T (µmol/L)

169.7 ± 193.9

INR Mortality

3.02 ± 2.39

ICU

131 (34.7%)

Hospital

162 (42.9%)

SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; MELD, Model for End-Stage Liver Disease; MESO, the MELD to sodium index; iMELD, the integrated MELD; MELD-Na, the MELD with the incorporation of serum sodium; ICU, Intensive Care Unit.

two groups (p <0.001). Patients admitted with acute variceal bleeding and hepatic encephalopathy had better prognosis for survival, respectively 76.5% and 74.5%, whereas patients admitted for infection had a cumulative survival in the ICU of 36.2%. In the subgroup of patients with severe acute histologically proven alcoholic hepatitis, the ICU and hospital mortality rate were 61% and 74%, respectively. Among the surviving patients, five patients underwent liver transplantation within 5–356 days after ICU admission.

Patients with cirrhosis who died during their ICU stay displayed significantly higher values on all prognostic scores at admission when compared to those who survived (Table 2). Receiver Operating Characteristic curves were used to evaluate the power of the scores (Fig. 1A and B). SOFA and SAPS II scores calculated 24 h after ICU admission were found to be the most reliable systems relative to survival, with AUROC values of 0.92 (SE 0.01, 95% CI 0.89–0.95) and 0.89 (SE 0.2, 95% CI 0.86–0.93), respectively. The AUROC of SOFA score was not statistically different from the AUROC of SAPS II score (p = 0.1). General prognostic scores had the highest AUROC values when compared to liver-specific prognostic models (p <0.01 with each of these scores). No differences were seen between the MELD and the different models incorporating serum sodium (p >0.05). The Child–Pugh score had the lowest AUROC (0.79, SE 0.02, 95% CI 0.74–0.84). Using the highest Youden Index [28], we determined the most discriminative cut-off point (for each prognostic score) from the different ROC curves. Different datasets were calculated based on the cut-off values for the SAPS II, SOFA, and MELD scores, which were 47.5, 10.5, and 28.5, respectively (Table 3). Fig. 2(A–C) shows the cumulative survival rates for the study population dichotomized by the cut-off point which discerned patients who would die in the ICU with a p <0.001. We also observed a significant difference in cumulative survival at 60 days between the three Child–Pugh categories (A–C) (Fig. 2D). At admission to the ICU, 71% (270/377) of patients presented with failure of one or more organs. The number of organ failures at admission (as defined by the SOFA score) was significantly related to ICU mortality, with a rate ranging from 2.8% in patients without organ failure to 90.6% in patients with three or more organ failures. At admission, 30.5% (n = 115) of the patients needed an organ support. Eighty eight patients (23.3%) were treated with vasopressors (e.g. epinephrine, norepinephrine, dobutamine, or dopamine >5 lg/kg/min). Eighty seven patients (23.1%) required mechanical ventilation. The main reasons for endotracheal intubation and mechanical ventilation at admission were: respiratory insufficiency secondary to infection in 38 cases (including 16 patients with pneumonia), hemorrhagic shock in 19 cases, airway protection (endoscopy) in 10 cases, and hepatic encephalopathy in eight cases. ICU stay During their stay in the ICU, a total of 172 patients (45.6%) required intubation and mechanical ventilation. In addition to the patient who required mechanical ventilation at admission, 85 other patients were intubated during their ICU stay including 69 patients for respiratory insufficiency due to an infection (mainly pneumonia, n = 59) and hepatic encephalopathy (n = 10). There was no difference in ICU mortality between the patients who were intubated for airway protection (including encephalopathy) and those who were intubated for respiratory failure. One hundred and fifty four patients (40.8%) needed vasopressor therapy (epinephrine, norepinephrine, dobutamine, or dopamine >5 lg/kg/min) for septic or hemorrhagic shock. Thirty nine patients required Renal Replacement Therapy (RRT) during their ICU stay. The Molecular Adsorbent Recirculating System (MARSÒ) was used in 36 patients (9.5%) with severe progressive jaundice, hepatic encephalopathy, hepatorenal syndrome, or any combination of these syndromes. The number of organ sup-

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Research Article Table 2. Predictive factors of ICU mortality determined by univariate analysis in 377 cirrhosis patients admitted to an ICU. The Area Under the Receiver Operating Characteristic Curve (AUROC) value of prognostic scores at ICU admission were: SOFA, 0.92; SAPS II, 0.89; MELD, 0.82; MESO, 0.82; iMELD, 0.81; MELD-Na, 0.79; Child– Pugh, 0.79. Data are expressed as mean ± S.D.

Non-Survivors (n = 131) 56.1 ± 10.2

p value

Age (years, mean ± SD)

Survivors (n = 246) 55.2 ± 11.9

Gender (M/F)

179/67

98/33

0.67

Alcoholic

163 (66)

95 (73)

Hepatitis B

10 (4)

5 (4)

Hepatitis C

37 (15)

15 (11)

Alcoholic + Hepatitis

13 (5)

8 (6)

Others

23 (10)

8 (6)

124 (51)

38 (29)

Variable

Cause of cirrhosis n (%)

0.64

Primary diagnosis ICU admission n (%) Acute variceal bleeding

0.49

<0.0001

Severe infection

26 (10)

46 (35)

Hepatic encephalopathy

35 (14)

12 (9)

Hepatorenal syndrome type I

11 (5)

8 (6)

Other

50 (20)

27 (21)

Laboratory data Serum sodium (mmol/L)

134.4 ± 6.1

133.2 ± 7.9

0.02

Serum creatinine (µmol/L)

126.9 ± 131.4

209.3 ± 136.9

<0.001

Serum bilirubin (mmol/L)

124.8 ± 157.9

253.9 ± 224.8

<0.001

INR

2.34 ± 1.26

4.29 ± 3.30

<0.001

Mechanical ventilation

18 (7)

69 (52)

<0.001

Vasopressor therapy*

18 (7)

70 (53)

<0.001

Organ support at admission

Prognostic scores at ICU admission SAPS II

35.4 ± 13.7

64.9 ± 19.3

<0.0001

SOFA

6.8 ± 3.1

14.2 ± 4.0

<0.0001

Child Pugh

9.7 ± 2.2

12.0 ± 1.8

<0.0001

Child Pugh category (A/B/C)

24/81/141

1/8/122

<0.0001

MELD

20.7 ± 9.5

32.8 ± 8.2

<0.0001

MELD Na

24.8 ± 12.4

38.7 ± 11.6

<0.0001

MESO

1.6 ± 0.7

2.48 ± 0.6

<0.0001

iMELD

43.2 ± 11.4

57.3 ± 11.4

<0.0001

Mechanical ventilation

45 (18)

127 (97)

<0.0001

Vasopressor therapy*

30 (12)

124 (95)

<0.0001

Renal replacement therapy

4 (2)

35 (27)

<0.0001

Molecular adsorbent recirculating system

18 (7)

18 (14)

0.04

Clinical feature during ICU n (%)

SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; MELD, Model for End-Stage Liver Disease; MESO, the MELD to sodium index; iMELD, the integrated MELD; MELD-Na, the MELD with the incorporation of serum sodium; ICU, Intensive Care Unit. ⁄ Vasopressors: epinephrine, norepinephrine, dobutamine, or dopamine >5 lg/kg/min.

ports (mechanical ventilation, vasopressor therapy, RRT, and MARSÒ) during the ICU stay was significantly related to ICU mortality, which ranged from 2.2% (patients not requiring organ support) to 96.1% in patients requiring the support of three or more organs (Fig. 3). The length of ICU stay in survivor patients was statistically significantly shorter than in non-survivor patients (7.5 ± 7.8 days vs. 13.8 ± 15.1 days, p <0.0001). 98

Infections One hundred and sixty-nine patients (44.8% of the total study population) had obvious infection as already defined. Infection was present in 72 patients at their admission to the Liver ICU, related to pneumonia in 51% of cases (n = 37) or spontaneous bacterial peritonitis in 21% of cases (n = 14).

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JOURNAL OF HEPATOLOGY A

B

1.0

0.8 Sensitivity

Sensitivity

0.8 0.6 SAPSII SOFA MELD CP

0.4 0.2 0.0 0.0

Factors associated with mortality: multivariate logistic regression analyses

1.0

0.2

0.4 0.6 0.8 1-Specificity

0.6 iMELD MELDNa MELD MESO

0.4 0.2

1.0

0.0 0.0

0.2

0.4 0.6 0.8 1-Specificity

A logistic regression analysis with mortality as the end-point was performed using categorical and/or continuous variables. Prognostic scores at admission were excluded from this analysis to prevent any risk of colinearity. Table 4 shows that bilirubin at admission, infection at admission or acquired during the ICU stay, mechanical ventilation and vasopressor therapy were independently related to ICU mortality.

1.0

Fig. 1. Receiver Operating Characteristic (ROC) curves for (A) SAPS II, SOFA, MELD, Child–Pugh and for (B) MELD, MELD-Na, MESO, iMELD in 377 cirrhotic patients admitted to an ICU.

Among the organisms identified in the 37 communityacquired pneumonia, gram negative bacilli were the most frequent (10 out of the 21 isolates, mainly Escherichia coli) and gram positive cocci in 9 out of the 21 isolates (Streptococcus pneumoniae and Staphylococcus aureus). The most frequent organism isolate in spontaneous bacterial peritonitis were E. coli (n = 5), Enterobacter spp. (n = 3) and streptococcus (n = 3). Ninety-seven patients developed a hospital-acquired infection at the following sites: respiratory infections (n = 55, 56%); bacteremia (n = 26; 26.8%) and others including spontaneous bacterial peritonitis and urinary tract infections (n = 16; 16.5%). The most frequent organism causing acquired pneumonia were E. coli and Enterobacter spp. (n = 21; 38%), Pseudomonas (n = 8; 14.5%), and Staphylococcus (n = 8; 14.5%). Staphylococcus was the main organism identified in the hospital acquired bacteremia. In this cohort, the fungal infections impacted on ICU mortality. Among the 20 patients with a fungal positive sample, 18 died during their ICU stay (90%) and one patient within 2 months following ICU discharge. The distribution of fungal infections associated Pneumocystis Juroveci pneumonia in two patients, candidemia in four patients, pulmonary aspergillosis in six patients, and positive tracheal aspirate samples for candida colonization (n = 9). The presence of infection was strongly associated with poor survival at 2 months (Fig. 4A). In the subgroup of patients with infection, we observed a similar cumulative survival between patients with an infection at admission and patients with hospital-acquired infection (Fig. 4B). In addition, in 107 patients (81.6%), the infection (pneumonia, spontaneous bacterial peritonitis, or septicemia) is the cause of death. Of these, 46 patients (43%) presented with sepsis at admission to the ICU. In the other 61 patients, mortality was secondary to hospital-acquired infection.

Discussion The main result of this study is that the SAPS II and SOFA scores performed better than standard MELD, MELD incorporating sodium levels and the Child–Pugh score to predict ICU mortality in cirrhotic patients admitted to an ICU. Our findings agree with those of Cholongitas et al. [11]. In their meta-analysis grouping 21 cohorts from studies published during the past 20 years, these authors observed that liver function was not the main determinant of outcome in cirrhotic patients with multi-organ failure, so that an organ failure score such as SOFA could be more useful in predicting outcome [11]. Nevertheless, for several decades, Child–Pugh remained the most widely-used score despite its major limitation i.e. it does not include other organ dysfunctions known to highly contribute to mortality rates in critically ill cirrhotic patients [29]. Recognizing the problems inherent in the Child–Pugh score, two recent studies evaluated the performance of the MELD score (a liver prognostic score that includes renal function) in cirrhotic patients admitted to an ICU [13,14]. Both studies reported that the MELD is a reliable scoring system to predict mortality in patients with decompensated cirrhosis. In addition, the MELD and SOFA scores had similar discriminatory power (AUROC = 0.81 and 0.83, respectively) [13]. Although we found a discriminatory power for the MELD (AUROC = 0.83) that was similar to those reported by these two studies, we observed that the SOFA score was more effective in predicting ICU mortality (AUROC = 0.92), which was in line with the findings of other studies [4,6,30]. The MELD model does not include any surrogate of portal hypertension, the complications of which are a frequent cause of admission to an ICU. To make up for this deficiency, Na values have now been added to the MELD score [16]. Indeed, in patients with liver cirrhosis, hyponatremia is a common event that correlates with the severity of portal hypertension [16,31–33]. To date, this concept has only been evaluated by one study in decompensated cirrhotic patients [34], which reported that the three variants of MELD scores incorporating Na levels improved the

Table 3. Prediction of subsequent ICU mortality in 377 cirrhotic patients after the first day of ICU admission.

Scoring system

Cut-off point

Youden Index

Sensitivity (%)

Specificity (%)

PPV (%)

NPV (%)

SOFA MELD SAPS II

10.5 28.5 47.5

0.67 0.50 0.65

79 72 83

87 78 81

78 63 70

88 84 91

SAPS, Simplified Acute Physiology Score; SOFA, Sequential Organ Failure Assessment; MELD, Model for End-Stage Liver Disease; PPV, positive predictive value; NPV, negative predictive value.

Journal of Hepatology 2012 vol. 56 j 95–102

99

100 82.5% 80 p <0.001

60 40

24.7% SAPS II <47.5 SAPS II ≥47.5

20 0 0

10

<47.5

223

212

201

190

189

187

184

≥47.5

104

88

66

50

42

50

38

Cumulative survival rate (%)

No. of patients at risk:

B

60

p <0.001

60 40

19.4%

SOFA <10.5 SOFA ≥10.5

20 0 0

10

<10.5

243

227

214

204

202

200

196

≥10.5

134

73

53

36

29

27

26

Cumulative survival rate (%)

20 30 40 50 From admission to ICU (Days)

60

100 78.9%

80 p <0.001

60 40

28.2% MELD <28.5 MELD ≥28.5

20 0 0

10

<28.5

228

206

198

189

185

183

180

≥28.5

149

94

69

51

46

44

42

Cumulative survival rate (%)

96.1 77.9

80 60 40 20 2.2

5.8

0 (n = 178)

1 (n = 52)

0 2 (n = 95)

3 or more (n = 52)

Number of organ support during ICU stay

80.7%

80

20 30 40 50 From admission to ICU (Days)

60

100 96.0% 84.3%

80 p <0.001

60

48.2%

40

Child A Child B Child C

20 0 0

10

No. of patients at risk:

20 30 40 50 From admission to ICU (Days)

60

Child A

24

23

23

23

23

23

23

Child B

89

85

79

78

78

77

75

Child C

255

189

163

137

129

126

123

Fig. 2. Cumulative survival in 377 cirrhotic patients admitted to an ICU according to (A) SAPS II (solid curve, SAPS II >47.5 and dashed curve SAPS II <47.5), (B) SOFA (solid curve, SOFA >10.5 and dashed curve SOFA <10.5), (C) MELD score (solid curve, MELD >28.5 and dashed curve MELD <28.5), and (D) category of Child–Pugh (A, B or C) after the first day of ICU admission.

prognostic value of MELD at 3, 6, and 12 months. The present study is the first to show that models incorporating Na levels do not predict ICU mortality better than MELD alone in such 100

100

Fig. 3. Correlation between the number of organ supports required (during the ICU stay) and ICU mortality in 377 cirrhotic patients (p <0.005).

No. of patients at risk:

D

20 30 40 50 From admission to ICU (Days)

100

No. of patients at risk:

C

Percentage of mortality (%)

A

Cumulative survival rate (%)

Research Article

patients. Recently, using only the MELD-Na model and studying a smaller cohort, Das et al. reported results similar to ours [15]. The higher MELD values obtained in our cohort (when compared to those found by Jiang et al. [34]) might explain this difference. As mentioned above, the performance of scores to predict ICU mortality can partly be explained by the inclusion in these models of surrogate variables related to organ dysfunction and not just the variable related to liver severity (Na+, bilirubin, or INR). During our study, cirrhotic patients admitted to an ICU had a mortality rate approaching 90% if they experienced the failure of more than three organs or if they required more than two types of organ support or replacement therapy (mechanical ventilation, vasopressor therapy, RRT, or MARS). Based on our logistic regression models, organ support (mechanical ventilation and vasopressor therapy) was an independent predictor of mortality in our population. Like other authors, we also observed that infection in cirrhotic patients was an independent predictor of mortality [35–37]. Infection has also been associated with significantly more intensive support [36]. This concept is consistent with similar studies showing a close relationship between mortality and SIRS, considering that 46–60% of infected patients with cirrhosis will develop SIRS [38–40]. The cause of ICU admission is associated with the prognosis of patients. In our experience, patients admitted in ICU for acute variceal bleeding or hepatic encephalopathy had a markedly improved ICU survival of 76.5% vs. 36.2% for patients admitted for infection indication. However, in comparison with recent studies, in our work, the ICU mortality rate for the subgroup of patients with acute variceal bleeding is high [41,42]. However, our situation of tertiary university intensive care unit may cause a selection bias in the patient recruitment, including more patients with failure to control variceal bleeding, rebleeding, hemorrhagic shock, and patients transferred for salvage TIPS. In an era of advanced organ-targeted therapies in critical care, we believe that the key issue is to ensure a more aggressive management of cirrhotic patients before the onset of organ dysfunction. In this situation, admission to the ICU of cirrhotic patients is not futile and can result in survival rates as high as 65%. In addition, because prognostic models can predict a better outcome in cirrhotic patients when assessed 48 h after admission [43], we believe that all cirrhotic patients should be admitted to an ICU and then rapidly reassessed. However, the criteria for this reassessment need to be defined, but they should include prognostic scores (to evaluate organ failure) and additional factors (primary ICU diagnosis, sepsis, organ support). In this regard, Gildea et al.

Journal of Hepatology 2012 vol. 56 j 95–102

JOURNAL OF HEPATOLOGY Cumulative survival rate (%)

A

prognosis for non-critically ill cirrhotic patients with additional factors such as infection, organ failure or organ support) could be applied during the decision-making process on whether to withdraw or pursue care for cirrhotic patients in an ICU.

100 80.8%

80 p <0.001

60 40

32.0%

Conflict of interest

Infection No-infection

20 0 0

10

20

30 Days

40

50

60

Infection group

208

182

175

172

171

169

168

No-infection group

169

118

92

68

60

57

54

B

Cumulative survival rate (%)

No. of patients at risk:

The authors who have taken part in this study do not have any relationship with the manufacturers of the drugs involved either in the past or present and did not receive any funding from the manufacturer to carry out this research. References

100 80 p = 0.32

60

32.0%

40 20

31.9%

Infection at admission Hospital acquired infection

0 0

10

20

30 Days

40

50

60

At admission group

72

41

34

29

26

25

23

Hospital aquired group

97

77

58

39

34

32

31

No. of patients at risk:

Fig. 4. Cumulative survival in 377 cirrhotic patients admitted to an ICU according to the development of infection during the ICU stay. Day 0 is the day of admission to the ICU.

Table 4. Factors independently associated with ICU mortality in 377 cirrhotic patients admitted in an ICU.

Odds ratio 50.3

95% CI

p

8.99-281

<0.001

Vasopressor therapy

11.9

3.77-37.03

<0.001

Infection

3.51

1.35-9.15

0.01

Bilirubin

1.006

1.003-1.01

0.0005

Mechanical ventilation

whose study included 420 cirrhotic patients admitted to a medical ICU, showed that those with three risk factors had a 1 month mortality rate of 92%, compared to 11% for patients with no risk factors [7]. The risk factors applied during the present study were a prognostic score (APACHE III score) of >90, organ support (requirement for vasopressors), and biological parameters which increased during sepsis (severity of jaundice). In conclusion, our data show that the prognosis for cirrhotic patients admitted to an ICU depends on both the severity of hepatic and extra-hepatic organ dysfunctions and the primary diagnosis at admission. With a positive predictive value of only 78%, we believe that the influence of prognostic scores on decisions to admit (or not to admit) patients with cirrhosis to an ICU should be minimal, and that these scores should not constitute a preadmission screening tool. It is difficult to predict outcome in cirrhotic ICU patients, and a combination of prognostic scores such as SOFA (developed in large and heterogeneous ICU populations) and MELD (developed to predict the short-term

[1] Shellman RG, Fulkerson WJ, DeLong E, Piantadosi CA. Prognosis of patients with cirrhosis and chronic liver disease admitted to the medical intensive care unit. Crit Care Med 1988;16:671–678. [2] Singh N, Gayowski T, Wagener MM, Marino IR. Outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality. J Gastroenterol 1998;33:73–79. [3] Aggarwal A, Ong JP, Younossi ZM, Nelson DR, Hoffman-Hogg L, Arroliga AC. Predictors of mortality and resource utilization in cirrhotic patients admitted to the medical ICU. Chest 2001;119:1489–1497. [4] Chen YC, Tsai MH, Ho YP, Hsu CW, Lin HH, Fang JT, et al. Comparison of the severity of illness scoring systems for critically ill cirrhotic patients with renal failure. Clin Nephrol 2004;61:111–118. [5] Wong LL, McFall P, Wong LM. The cost of dying of end-stage liver disease. Arch Intern Med 1997;157:1429–1432. [6] Wehler M, Kokoska J, Reulbach U, Hahn EG, Strauss R. Short-term prognosis in critically ill patients with cirrhosis assessed by prognostic scoring systems. Hepatology 2001;34:255–261. [7] Gildea TR, Cook WC, Nelson DR, Aggarwal A, Carey W, Younossi ZM, et al. Predictors of long-term mortality in patients with cirrhosis of the liver admitted to a medical ICU. Chest 2004;126:1598–1603. [8] Rabe C, Schmitz V, Paashaus M, Musch A, Zickermann H, Dumoulin FL, et al. Does intubation really equal death in cirrhotic patients? Factors influencing outcome in patients with liver cirrhosis requiring mechanical ventilation. Intensive Care Med 2004;30:1564–1571. [9] Child C, Turcotte J. The liver and portal hypertension. In: Child CI, editor. Surgery and portal hypertension. Philadelphia, PA: Saunders; 1964. p. 50–58. [10] Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973;60:646–649. [11] Cholongitas E, Senzolo M, Patch D, Shaw S, Hui C, Burroughs AK. Review article: scoring systems for assessing prognosis in critically ill adult Cirrhotics. Aliment Pharmacol Ther 2006;24:453–464. [12] Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864–871. [13] Cholongitas E, Senzolo M, Patch D, Kwong K, Nikolopoulou V, Leandro G, et al. Risk factors, sequential organ failure assessment and model for endstage liver disease scores for predicting short term mortality in cirrhotic patients admitted to intensive care unit. Aliment Pharmacol Ther 2006;23:883–893. [14] Yu JW, Wang GQ, Li SC. Prediction of the prognosis in patients with acuteon-chronic hepatitis using the MELD scoring system. Gastroenterol Hepatol 2006;21:1519–1524. [15] Das V, Boelle PY, Galbois A, Guidet B, Maury E, Carbonell N, et al. Cirrhotic patients in the medical intensive care unit: early prognosis and long-term survival. Crit Care Med 2010;38:2108–2116. [16] Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008;359:1018–1026. [17] Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005;41:32–39. [18] Biggins SW, Kim WR, Terrault NA, Saab S, Balan V, Schiano T, et al. Evidencebased incorporation of serum sodium concentration into MELD. Gastroenterology 2006;130:1652–1660. [19] Luca A, Angermayr B, Bertolini G, Koenig F, Vizzini G, Ploner M, et al. An integrated MELD model including serum sodium and age improves the

Journal of Hepatology 2012 vol. 56 j 95–102

101

Research Article [20]

[21]

[22]

[23]

[24]

[25]

[26] [27]

[28] [29]

[30]

[31]

102

prediction of early mortality in patients with cirrhosis. Liver Transpl 2007;13:1174–1180. Huo TI, Wang YW, Yang YY, Lin HC, Lee PC, Hou MC, et al. Model for endstage liver disease score to serum sodium ratio index as a prognostic predictor and its correlation with portal pressure in patients with liver cirrhosis. Liver Int 2007;27:498–506. Le Gall JR, Lemeshow S, Saulnier F. A new Simplified Acute Physiology Score (SAPS II) based on a European/North American multicenter study. JAMA 1993;270:2957–2963. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonça A, Bruining H, et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine. Intensive Care Med 1996;22:707–710. Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al. United Network for Organ Sharing Liver Disease Severity Score Committee. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91–96. Luna CM, Blanzaco D, Niederman MS, et al. Resolution of ventilatorassociated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome. Crit Care Med 2003;31:676–682. Pugin J, Auckenthaler R, Mili N, et al. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic ‘‘blind’’ bronchoalveolar lavage fluid. Am Rev Respir Dis 1991;143:1121–1129. Meduri GU, Chastre J. The standardization of bronchoscopic techniques for ventilator-associated pneumonia. Chest 1992;102:557S–564S. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837–845. Youden WJ. Index for rating diagnostic tests. Cancer 1950;3:32–35. Du Cheyron D, Bouchet B, Parient JJ, Ramakers M, Charbonneau P. The attributable mortality of acute renal failure in critically ill patients with liver cirrhosis. Intensive Care Med 2005;31:1693–1699. Tsai MH, Peng YS, Lien JM, Weng HH, Ho YP, Yang C, et al. Multiple organ system failure in critically ill cirrhotic patients. A comparison of two multiple organ dysfunction/failure scoring systems. Digestion 2004;69:190–200. Samuel D. MELD-Na as a prognostic score for cirrhotic patients: hyponatremia and ascites are back in the game. J Hepatol 2009;50:836–841.

[32] Ginès A, Escorsell A, Ginès P, Saló J, Jiménez W, Inglada L, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993;105:229–236. [33] Arroyo V, Rodés J, Gutiérrez-Lizárraga MA, Revert L. Prognostic value of spontaneous hyponatremia in cirrhosis with ascites. Am J Dig Dis 1976;21:249–256. [34] Jiang M, Liu F, Xiong WJ, Zhong L, Chen XM. Comparison of four models for end-stage liver disease in evaluating the prognosis of cirrhosis. World J Gastroenterol 2008;14:6546–6550. [35] Moreau R, Hadengue A, Soupison T, Kirstetter P, Mamzer MF, Vanjak D, et al. Septic shock in patients with cirrhosis: hemodynamic and metabolic characteristics and intensive care unit outcome. Crit Care Med 1992;20:746–750. [36] Karvellas CJ, Pink F, McPhail M, Austin M, Auzinger G, Bernal W, et al. Bacteremia, acute physiology and chronic health evaluation II and modified end stage disease are independent predictors of mortality in critically ill nontransplanted patients with acute on chronic liver failure. Crit Care Med 2010;38:121–126. [37] Cho JH, Park KH, Kim SH, Bang JH, Park WB, Kim HB, et al. Bacteremia is a prognostic factor for poor outcome in spontaneous bacterial peritonitis. Scand J Infect Dis 2007;39:697–702. [38] Cazzaniga M, Dionigi E, Gobbo G, Fioretti A, Monti V, Salerno F. The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome. J Hepatol 2009;51:475–482. [39] Thabut D, Massard J, Gangloff A, Carbonell N, Francoz C, Nguyen-Khac E, et al. Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure. Hepatology 2007;46:1872–1882. [40] Plessier A, Denninger MH, Consigny Y, Pessione F, Francoz C, Durand F, et al. Coagulation disorders in patients with cirrhosis and severe sepsis. Liver Int 2003;23:440–448. [41] Carbonell N, Pauwels A, Serfaty L, Fourdan O, Levy VG, Poupon R. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology 2004;40:652–659. [42] Bittencourt PL, Farias AQ, Strauss E, Mattos AA, et al. Variceal bleeding: consensus meeting report from the Brazilian Society of Hepatology. Arq Gastroenterol 2010;47:202–216. [43] Cholongitas E, Betrosian A, Senzolo M, Shaw S, Patch D, Mamousou P, et al. Prognostic models in cirrhotics admitted to intensive care units better predict outcome when assessed at 48 h after admission. J Gastroenterol Hepatol 2008;23:1223–1227.

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