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Incidence and Prognosis of Early Hepatic Dysfunction in Critically Ill Patients—A Prospective Multicenter Study

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Incidence and Prognosis of Early Hepatic Dysfunction in Critically Ill Patients—A Prospective Multicenter Study Incidence and prognosis of early hepatic dysfunction in critically ill patients—A prospective multicenter study Ludwig Kramer, MD; Barbara Jordan, MSc; Wilfred Druml, MD; Peter Bauer, PhD; Philipp G. H. Metnitz, MD, PhD, DEAA; for the Austrian Epidemiologic Study on Intensive Care, ASDI Study Group, Vienna, Austria Objective: In critically ill patients, hepatic dysfunction is re- stays (5 vs. 3 days; p < .001) and increased hospital mortality garded as a late organ failure associated with poor prognosis. We (30.4% vs. 16.4%; p < .001). Hepatic dysfunction was also asso- investigated the incidence and prognostic implications of early ciated with higher observed-to-expected mortality ratios (1.02 vs. hepatic dysfunction (serum bilirubin >2 mg/dL within 48 hrs of 0.91; p < .001). Multiple logistic regression analysis showed an admission). independent mortality risk of hepatic dysfunction (odds ratio, Design: Prospective, multicenter cohort study. 1.86; 95% confidence interval, 1.71–2.03; p < .001), which ex- Setting: Thirty-two medical, surgical, and mixed intensive care ceeded the impact of all other organ dysfunctions. A case-control units. study further confirmed these results: Patients with early hepatic Patients: A total of 38,036 adult patients admitted consecu- dysfunction exhibited significantly increased raw and risk-ad- tively over a period of 4 yrs. justed mortality compared with control subjects. Interventions: None. Conclusions: Our results provide strong evidence that early Measurements and Main Results: Excluding patients with pre- hepatic dysfunction, occurring in 11% of critically ill patients, -and acute or acute-on-chronic presents a specific and independent risk factor for poor progno (%1.8 ;691 ؍ existing cirrhosis (n (we identified 4,146 patients sis. (Crit Care Med 2007; 35:1099–1104 ,(%0.3 ,108 ؍ hepatic failure (n (10.9%) with early hepatic dysfunction. These patients had dif- KEY WORDS: hepatic failure; liver; outcome; bilirubin; epidemi- ferent baseline characteristics, longer median intensive care unit ology epatic dysfunction is tradi- evated serum activity of aspartate amino- ies have specifically investigated hepatic tionally considered to indi- transferase or alkaline phosphatase (4, 5), dysfunction (12). cate poor outcome in criti- such variability in definitions has precluded Considering the pivotal and possibly cally ill patients, but no an accurate overall assessment of hepatic underappreciated role of the liver in the Hlarge systematic investigation into its ex- pathogenesis of systemic inflammatory re- dysfunction in critically ill patients. act incidence and prognostic relevance Unlike ascites, transaminases, or alka- sponse syndrome, sepsis, and multiorgan has been performed (1). Since no physi- line phosphatase activity, serum bilirubin failure (13), we hypothesized that early he- ologic variable allows for early detection is a stable and powerful marker of hepatic patic dysfunction, in the absence of preex- of hepatic dysfunction, current diagnos- dysfunction, with elevated levels reflect- isting liver disease, independently increases tic criteria are based on laboratory tests, ing impairment in the energy-consuming mortality in critically ill patients. To test mostly serum bilirubin levels (for review, processes of heme metabolism, conjuga- this hypothesis, we analyzed a large pro- see Ref. 2). Although some authors have tion, and bile secretion (6). Serum biliru- spective database of patients admitted to used more specific definitions, such as Austrian multidisciplinary intensive care bin is a key component of prognostic hepatic encephalopathy, ascites (3), or el- units (ICUs) between 1999 and 2003. The scores for patients with chronic liver dis- study protocol was approved by institu- ease (7) and cirrhosis (8) (including the tional review. Since no additional interven- Child-Pugh classification and the Model From the Departments of Medicine IV (LK), Core tions were performed and no individualized Unit for Medical Statistics and Informatics, Section of for End-Stage Liver Disease score) and data were analyzed, the need for individual Medical Statistics (BJ, PB), Department of Medicine III also of prognostic models in patients with informed consent was waived. (WD), and Department of Anesthesiology and General acute liver failure (9). Bilirubin levels are Intensive Care (PGHM), Medical University of Vienna, Vienna General Hospital, A-1090 Vienna, Austria. also used in scoring algorithms for as- MATERIALS AND METHODS Supported, in part, by a grant for statistical anal- sessing prognosis in critically ill patients ysis from the Fund of the Austrian National Bank, (for review, see Ref. 10). Since clinical Database. Data were collected by the Aus- project 10995 ONB. jaundice tends to develop only several trian Center for Documentation and Quality As- The authors have not disclosed any potential con- surance in Intensive Care Medicine (ASDI), a flicts of interest. days after hepatic injury ensues, hepatic nonprofit organization that has established an Copyright © 2007 by the Society of Critical Care dysfunction is traditionally considered a intensive care database and benchmarking Medicine and Lippincott Williams & Wilkins late event in sepsis and multiorgan fail- project (14, 15). The prospectively collected data DOI: 10.1097/01.CCM.0000259462.97164.A0 ure (11). Only comparatively small stud- included sociodemographic data, such as age, Crit Care Med 2007 Vol. 35, No. 4 1099 gender, and comorbid conditions; causes of ICU Institute, Cary, NC). Unless otherwise specified, gated independent associations between early admission according to a predefined list of med- descriptive results are expressed as median and hepatic failure and mortality using a case- ical and surgical diagnoses (16); severity of ill- first and third quartiles. Student’s t-test or Wil- control design. After patients with preexisting ness, as measured by the Simplified Acute Phys- coxon’s rank-sum test if appropriate was used to cirrhosis or acute hepatic failure—which are iology Score (SAPS) II (17); numbers and compare quantitative variables between groups. known to have increased mortality—had been severity of organ dysfunction, as measured by The chi-square test was used for categorical vari- excluded from the population of patients with the Logistic Organ Dysfunction system (LOD) ables. A p value of Ͻ.05 (two-sided) was consid- bilirubin Ͼ2 mg/dL, patients with early hepatic (18); level of provided care, as measured by the ered significant. Observed-to-expected mortality dysfunction were identified (n ϭ 4,146). For Simplified Therapeutic Intervention Scoring ratios were calculated by dividing the number of each of these patients, a control patient was System-28 (19); length of ICU and hospital stay; observed deaths per group by the number of chosen, using gender, age (Ϯ5 yrs), and biliru- and outcome data, including survival status at SAPS II-predicted deaths per group. Ninety-five bin-corrected SAPS II scores (calculated as orig- ICU and hospital discharge. percent confidence intervals were calculated ac- inal SAPS II score minus the allocated bilirubin A total of 42,394 patients were admitted to cording to Hosmer and Lemeshow (20). points) as matching criteria. Matching controls the 32 ICUs during the study period. For pa- Two logistic regression models were con- were found for all but eight patients. ICU was tients who were admitted more than once structed to explore the influence of several used as an additional matching criterion to min- (n ϭ 1,923), only the first admission was eval- static and dynamic variables on vital status at imize the influence of ICU-specific factors on uated. Patients who were Ͻ18 yrs of age (n ϭ hospital discharge (hospital mortality) as the prognosis. Matching controls from the same ICU 774), those with records that lacked an entry dependent variable. Univariate analysis was were found for 3,942 patients. Conditional logis- in the field “hospital outcome” (n ϭ 460), and performed using Student’s t-tests for contin- tic regression was then performed to show the those without a valid SAPS II score (n ϭ uous variables and chi-square for categorical influence of early hepatic dysfunction on mor- 1,201) were excluded, leaving 38,036 patients variables to assess those related to mortality. A tality. for analysis (Fig. 1). set of predefined variables affecting ICU mor- Data Quality. To assess the reliability of tality were entered into the logistic regression data collection, we sent an independent ob- models. Moreover, ICU was added as a dummy RESULTS server to each unit to obtain SAPS II data from variable to adjust for the effect of different the clinical charts of a random sample of pa- treatment centers. From univariate analysis, A total of 38,036 consecutive ICU ad- tients. Variance-component analyses with the age, gender, diagnosis, organ failure scores, missions were included in the cohort (Ta- random factors “units,” “patients within and bilirubin values Ͼ2 mg/dL within 48 hrs ble 1). Data quality was satisfactory with units,” and “observers within units” were per- of admission (indicating early hepatic dysfunc- respect to both completeness of records formed (SAS, procedure varcomp) as previ- tion) were entered as dummy variables. A sec- and interrater variability. The median ously described (14). To assess completeness ond model was constructed in a similar way, of documentation, we also calculated the but instead of the dummy variable, abnormal number of missing variables necessary number of missing variables
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