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Clinical Investigations in Critical Care |

Cirrhosis as a Risk Factor for Sepsis and Death*: Analysis of the National Hospital Discharge Survey FREE TO VIEW

Marilyn G. Foreman; David M. Mannino; Marc Moss
Author and Funding Information

*From the Department of Medicine (Dr. Foreman), Division of Pulmonary and Critical Care, Morehouse School of Medicine, Atlanta, GA; Respiratory Health Branch (Dr. Mannino), The Centers of Disease Control and Prevention, Atlanta, GA; and the Department of Medicine (Dr. Moss), Division of Pulmonary and Critical Care, Emory University School of Medicine, Atlanta, GA.

Correspondence to: Marilyn G. Foreman, MD, FCCP, Morehouse School of Medicine, 720 Westview Dr, SW, Atlanta, GA 30310; e-mail: foremam@msm.edu



Chest. 2003;124(3):1016-1020. doi:10.1378/chest.124.3.1016
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Published online

Study objectives: The unfavorable influence of cirrhosis on survival in the critically ill has been supported by several single-center reports. Variations in case mix, the technological capabilities of individual facilities, and differences in organizational staffing and structure could limit the extrapolation and generalization of these data to other institutions. To assess the impact of a diagnosis of cirrhosis on outcomes of sepsis, sepsis-related mortality, and respiratory failure in hospitalized patients, we analyzed data from the National Hospital Discharge Survey (NHDS) from 1995 to 1999 to determine its national consequence.

Design: Secondary analysis of an existing national database.

Patients or participants: Based on NHDS estimates, 175 million hospital discharges occurred during the 5-year period of study. One percent (1.7 million) of these hospitalizations involved a diagnosis of cirrhosis.

Interventions: None.

Measurements and results:After adjustments for age, race, and gender, cirrhotic individuals are significantly more likely to die while hospitalized (adjusted risk ratio [RR], 2.7; 95% confidence interval [CI], 2.3 to 3.1), to have hospitalizations associated with sepsis (adjusted RR, 2.6; 95% CI, 1.9 to 3.3), and to die from sepsis (adjusted RR, 2.0; 95% CI, 1.3 to 2.6). Additionally, cirrhosis is associated with an increased RR for acute respiratory failure (adjusted RR, 1.4; 95% CI, 1.1 to 1.8) and death from acute respiratory failure (adjusted RR, 2.6; 95% CI, 1.5 to 3.6).

Conclusions: In this national database of hospital discharge information, a diagnosis of cirrhosis is strongly associated with an increased risk of sepsis, acute respiratory failure, sepsis-related mortality, and acute respiratory failure-related mortality.

In 1998, > 25,000 deaths in the United States were due to cirrhosis, achieving the designation as the 10th most common cause of mortality.1 More than 95% of all cirrhosis deaths result from the toxic effect of prolonged alcohol abuse.2 With differing perspectives, several studies36 have analyzed outcomes in cirrhosis patients who require intensive care (Table 1 ). These single-center reports may have excelled in the systematic collection of epidemiologic data, but they may not be wholly applicable to the general population. In fact, they may reflect the biases or specialties of the reporting institution such as tertiary referral centers or liver transplant services. To determine the national impact of a diagnosis of cirrhosis on the development of sepsis, sepsis-related mortality, and acute respiratory failure, we evaluated the National Hospital Discharge Survey (NHDS), which is a global reflection of hospital utilization in the United States.

Survey Design

The NHDS is an annual survey conducted by the National Center for Health Statistics. Published continually since 1965, the NHDS collects medical information from a 1% sample of hospital discharge records from non-Federal, short-stay hospitals in the 50 states and the District of Columbia. General medical or surgical hospitals with average stays for all patients of < 30 days and hospitals with six or more beds for patient use are eligible. Military, Federal, Veterans Administration hospitals, and hospital units from penal institutions are not included.

Annually, approximately 270,000 inpatient records from 500 hospitals of varying sizes are surveyed. The NHDS uses a complex, modified, three-stage probability design to ensure a representative national sampling.7 The hospital sample is periodically updated to reflect changes in the eligibility of participating hospitals or changes in hospital demographics such as mergers. The data collected include race, gender, age, marital status, hospital admission date, hospital discharge date, diagnoses, procedures, zip code, expected source of payment, and dates of surgery. Statistics are computed from a multistage estimation procedure that includes population-weighting adjustments to generate unbiased national estimates.

The NHDS database was examined over a 5-year period from 1995 to 1999. To ensure that all patients with cirrhosis were captured, the data were abstracted for first-listed and all-listed mentions of cirrhosis and portal hypertension. Subjects were identified utilizing International Classification of Diseases, ninth revision, clinical modification (ICD9-CM) codes 571 for cirrhosis and 572.3 for portal hypertension. ICD9-CM code 571 includes alcoholic fatty liver, acute alcoholic hepatitis, alcoholic cirrhosis of the liver, alcoholic liver damage, chronic hepatitis not due to viral hepatitis, chronic persistent hepatitis, cirrhosis without mention of alcohol, biliary cirrhosis, other chronic nonalcoholic liver disease, and unspecified chronic liver disease without mention of alcohol. Individuals with sepsis were identified with the following ICD9-CM codes: all sepsis, 038.0 to 038.9; Gram-positive sepsis, 038.0 to 038.2; and Gram-negative sepsis, 0.38.4. In addition, subjects with acute respiratory failure were identified with ICD9-CM codes 518.82, 518.5, and 799.1.

Statistical Analysis

All analyses were performed using a statistical software package (SAS, SAS Institute, Cary, NC; or SUDAAN, Research Triangle Institute, Research Triangle Park, NC). SUDAAN was used to adjust for the complex sample design in calculating the variances and confidence intervals. Comparisons to noncirrhotic individuals were adjusted for age, race, and gender. The SUDAAN procedure RATIO was used to determine both the adjusted and unadjusted ratios of death, sepsis, Gram-positive sepsis, Gram-negative sepsis, and sepsis-associated death among subjects hospitalized with any mention of cirrhosis to those with no mention of cirrhosis.

The NHDS estimated that there was a total of 175 million hospital discharges nationally during the period 1995 to 1999. Of those hospital discharges, 1.7 million (1%) were associated with a diagnosis of cirrhosis. In the cirrhosis subset, 97% of the hospital discharges were identified by the ICD9-CM code for cirrhosis and 3% were coded for portal hypertension alone. In the final analysis, the patients with cirrhosis were primarily white (79%) and male (59%), with a mean (± SD) age of 56 ± 17 years (Table 2 ).

Individuals with cirrhosis were more likely to have a diagnosis of sepsis during their hospitalization when compared to patients without a diagnosis of cirrhosis (Table 3 ). A diagnosis of sepsis was listed concurrently in 4.6% of the patients with cirrhosis (79,800 of 1.7 million hospitalizations) and in only 1.9% of those patients without cirrhosis (3.3 million of 173 million hospitalizations). Cirrhotic individuals were more likely to have Gram-positive or Gram-negative infections listed concurrently on their hospital discharge information. In the subset with cirrhosis, Gram-negative infections occurred in 1.44% (24,900 of 1.7 million hospitalizations). By comparison, the frequency of Gram-negative infections among those patients without cirrhosis was 0.41% (713,000 of 173 million hospitalizations). With patients with cirrhosis, Gram-positive infections occurred in 1.61% (27,700 of 1.7 million hospitalizations) compared to 0.53% among patients without cirrhosis (926,900 of 173 million). After adjusting for age, race, and gender, individuals with cirrhosis were 2.6 times more likely to be septic (95% confidence interval [CI], 1.9 to 3.3), 3.5 times more likely to have Gram-positive infections (95% CI, 1.8 to 5.1), and 2.8 times more likely to have Gram-negative infections (95% CI, 2.1 to 3.6) while hospitalized.

A modest increase in the risk of acute respiratory failure (ARF) was noted among individuals with cirrhosis. ARF occurred in 4.7% of hospitalizations (81,500 of 1.7 million hospitalizations) among individuals with cirrhosis compared to 3% of hospitalizations (5.2 million of 173 million hospitalizations) among those without cirrhosis. The adjusted risk ratio (RR) for ARF was 1.4 (95% CI, 1.1 to 1.8). Additionally, cirrhotic individuals with ARF were 2.6 times more likely to die during the hospitalization when compared to noncirrhotic individuals with ARF (95% CI, 1.5 to 3.6) [Table 4 ] .

A diagnosis of cirrhosis substantially increased the risk of all-cause mortality during hospitalization. Death occurred in 128,400 individuals with cirrhosis (7.5%), and in 2.3% of individuals without cirrhosis (4 million of 173 million hospitalizations). Cirrhotic patients were therefore 2.7 times more likely to die during hospitalization (95% CI, 2.3 to 3.1). In the subset of patients with sepsis, the adjusted RR for sepsis-related mortality was 2.0 (95% CI, 1.3 to 2.6). The most frequent primary hospital discharge diagnoses for cirrhosis decedents are presented in Table 5 .

With the novel application of an existing national database to analyze critical care outcomes, we have documented the substantial negative impact of a diagnosis of cirrhosis on the risk of sepsis, acute respiratory failure, and death during hospitalization. Hospitalized patients with cirrhosis are nearly three times more likely to die when compared to patients without a diagnosis of cirrhosis. Cirrhotic patients are more likely to have a concurrent diagnosis of Gram-positive or Gram-negative sepsis, with a high mortality rate when sepsis is associated with the hospitalization. In addition, we also observed similar associations between cirrhosis and acute respiratory failure.

With mortality rates ranging from 37 to 98%, several studies (Table 1) have documented high mortality rates for patients with cirrhosis who require admission to the ICU. Similar to our study, other investigators89 also have reported that bacterial infections and respiratory disease are important causes of death in cirrhotic individuals. The mechanisms for the increased morbidity and mortality in hospitalized cirrhotic patients with infection and critical illness may be immunologic, mechanical, or pharmacological. The immunologic abnormalities in patients with alcoholic cirrhosis are multiple and varied. Abnormalities exist in both cell-mediated and humoral immunity. As the primary source of C3 complement synthesis, the disruption of the normal hepatic architecture with diffuse fibrosis commonly results in acquired hypocomplementemia with defective opsonization.10 Abnormal lymphocyte function may be manifested by decreased responsiveness to phytohemagglutinin, defects in delayed-type hypersensitivity, and abnormal T-cell and B-cell function caused by malnutrition.10 Disruption of the reticuloendothelial system leads to a diminished ability of the liver to clear pathogens from the portal venous system.10 Similarly, the altered intestinal motility, bacterial overgrowth, increased intestinal permeability, and bacterial translocation seen with spontaneous bacterial peritonitis may correlate with the bacterial translocation observed in multiorgan failure, sepsis, hemorrhagic shock, and surgical stress.11 The explanation for the high incidence of respiratory infections is also likely to be multifactorial. Mechanical factors such as alterations in consciousness with diminished cough from encephalopathy or intoxication and restriction of basilar lung expansion from ascites may promote respiratory complications. However, abnormal respiratory cellular function has been demonstrated in studies of cirrhotic individuals, finding impaired cytokine release from stimulated alveolar macrophages,12 reduced alveolar macrophage phagocytic ability,13 and discordance between peripheral and alveolar T-lymphocyte subsets.14 Last, the treatment of serious infections must take into consideration the susceptibility of cirrhotic individuals to drug-related complications as a result of alterations in drug metabolism and clearance. One common drug-related complication is aminoglycoside nephrotoxicity, but coagulopathies and bleeding from broad-spectrum therapy with β-lactam antibiotics also may occur.15

Large national databases1617 have been used to examine the epidemiology of sepsis and acute respiratory failure. TenHoor and colleagues16 analyzed the risk factors for ARDS using decedent data from the National Mortality Followback Study. Cirrhosis and sepsis were factors resulting in an increased proportional mortality ratio, which is a measure of the relative importance of an exposure to a specific cause of death. Patients with cirrhosis and sepsis were more likely to die with ARDS compared to individuals with ARDS who did not have cirrhosis or sepsis. Using national data, our study provides additional confirmation of the relative importance of infectious complications as a cause of death in patients with cirrhosis. Infectious etiologies (eg, septicemia and pneumonia) were listed as the primary hospital discharge diagnosis for 11.2% of the cirrhosis decedents (Table 5) . Other studies of sepsis have documented changing trends in epidemiology and have attempted to estimate the extent of its economic impact. Septicemia, the outcome measurement used by the Centers for Disease Control and Prevention for vital statistics, was the 10th leading cause of death in 1999.,18 Significantly, the age-adjusted death rate for septicemia increased nearly 7%. Angus and colleagues17 have used large administrative data sets for a similar purpose. Linking hospital discharge data from seven large states with information from several medical agencies, Angus et al17 estimated an annual expenditure of $16.7 billion for severe sepsis, with a prediction that the incidence will increase 1.5% annually.17

Our study has the following limitations. Although the NHDS is a national study, only 1% of all hospital discharges are included. Since individuals are not assigned a unique identifier, multiple hospital admissions by single individuals cannot be accounted for in the final analysis. In addition, attempts to explore possible etiologies of the associations are limited by the information that is included in the database. For example, the incidence of Gram-positive infections in cirrhotic individuals may be due to a line-related infection resulting from the greater use of central venous catheterization, but the database was not designed for this type of inquiry. Inherently, studies of this type also cannot be assessed for type and appropriateness of care. Stratification by severity of illness or by severity of cirrhosis cannot be accomplished with this database. Last, acute hepatic dysfunction is a potentially lethal complication of multiorgan dysfunction syndrome (MODS). Interposing mortality from MODS-related hepatic dysfunction with mortality from cirrhosis could influence the outcomes of sepsis and death. The inappropriate inclusion of mortality from MODS could lead to erroneous conclusions about the relationship between cirrhosis and poor outcomes during hospitalization. For this reason, the database also was analyzed for ICD9-CM code 570, acute and subacute necrosis of the liver (ie, hepatic failure). Only 18,000 hospital discharges were coded for acute hepatic failure, and only 1% of hospital discharges were concurrently coded with ICD9-CM code 570 (for hepatic failure) and ICD9-CM code 571 (for cirrhosis and chronic liver disease). Therefore, the relative infrequence of the acute hepatic failure diagnosis and concurrent coding lessens the possibility that this type of miscoding could account for the increased incidence of sepsis and death.

In conclusion, our study demonstrates that patients with cirrhosis have a higher risk of infections and are more likely to die as a result of those infections. On a national level, the preexistence of cirrhosis is a predictor of poor outcome when hospitalization is required for episodes of sepsis. Additional studies are required to determine the factors that predispose cirrhotic individuals to serious infections and the extent to which these factors are modifiable.

Abbreviations: ARF = acute respiratory failure; CI = confidence interval; ICD9-CM = International Classification of Diseases, ninth revision, clinical modification; MODS = multiorgan dysfunction syndrome; NHDS = National Hospital Discharge Survey; RR = risk ratio

This research was supported by the National Institute on Alcohol Abuse and Alcoholism (grant R21 AA12779-02).

Table Graphic Jump Location
Table 1. Cirrhosis and Critical Care Outcomes*
* 

APACHE = acute physiology and chronic health evaluation; MV = mechanical ventilation; ICCO = intensive care cirrhosis outcome score; MICU = medical ICU.

Table Graphic Jump Location
Table 2. Cirrhosis Demographics from NHDS, 1995 to 1999
* 

Values given as mean ± SD.

 

Race was not specified in 317,800 cases.

Table Graphic Jump Location
Table 3. Impact of Cirrhosis in NHDS, 1995 to 1999
Table Graphic Jump Location
Table 4. Cirrhosis and ARF in NHDS, 1995 to 1999
* 

95% CI, 1.1 to 1.8.

 

95% CI, 1.5 to 3.6.

Table Graphic Jump Location
Table 5. Primary Diagnosis at Discharge for Cirrhosis Decedents in the NHDS, 1995 to 1999
National Center for Health Statistics. Vital Health Stat 13, No. 145.
 
Saadatmand, F, Stinson, FS, Grant, BF, et al Liver cirrhosis mortality in the United States, 1970 – 97. December 2000; US Department of Health and Human Services, Public Health Service, National Institutes of Health; National Institute on Alcohol Abuse and Alcoholism. Bethesda, MD: Surveillance Report No. 54.
 
Shellman, RG, Fulkerson, WJ, deLong, E, et al Prognosis of patients with cirrhosis and chronic liver disease admitted to the medical intensive care unit.Crit Care Med1988;16,671-678. [PubMed] [CrossRef]
 
Singh, N, Gayowski, T, Wagener, MM, et al Outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality.J Gastroenterol1998;33,73-79. [PubMed]
 
Aggarwal, A, Ong, JP, Younossi, ZM, et al Predictors of mortality and resource utilization in cirrhotic patients admitted to the medical ICU.Chest2001;119,1489-1497. [PubMed]
 
Zauner, C, Schneeweiss, B, Schneider, B, et al Short-term prognosis in critically ill patients with liver cirrhosis: an evaluation of a new scoring system.Eur J Gastroenterol Hepatol2000;12,517-522. [PubMed]
 
Dennison, C, Pokras, R. Design and operation of the National Hospital Discharge Survey: 1988 redesign. Vital and Health Statistics, Series 1, No. 39.  US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Atlanta, GA:.
 
Caly, WR, Strauss, E A prospective study of bacterial infections in patients with cirrhosis.J Hepatol1993;18,353-358. [PubMed]
 
Rosa, H, Silverio, AO, Perini, RF, et al Bacterial infection in cirrhotic patients and its relationship with alcohol.Am J Gastroenterol2000;95,1290-1293. [PubMed]
 
Johnson, DH, Cunha, BA Infections in cirrhosis.Infect Dis Clin North Am2001;15,363-371. [PubMed]
 
Ramachandran, A, Balasubramanian, KA Intestinal dysfunction in liver cirrhosis: its role in spontaneous bacterial peritonitis.J Gastroenterol Hepatol2110;16,607-612
 
Gosset, P, Wallaert, B, Canva-Delacambre, JF, et al Impaired secretion and mRNA expression of monokines by alveolar macrophages from nonsmoking patients with alcoholic liver cirrhosis.J Infect Dis1995;171,743-746. [PubMed]
 
Wallaert, B, Aerts, C, Colombel, JF, et al Human alveolar macrophage antibacterial activity in the alcoholic lung.Am Rev Respir Dis1991;144,278-283. [PubMed]
 
Wallaert, B, Colombel, JF, Prin, L, et al Bronchoalveolar lavage in alcoholic liver cirrhosis: T-lymphocyte subsets and immunoglobulin concentrations.Chest1992;101,468-473. [PubMed]
 
Westphal, J-F, Jehl, F, Vetter, D Pharmacological, toxicologic, and microbiological considerations in the choice of initial antibiotic therapy for serious infections in patients with cirrhosis of the liver.Clin Infect Dis1994;18,324-335. [PubMed]
 
TenHoor, T, Mannino, DM, Moss, M Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.Chest2001;119,1179-1184. [PubMed]
 
Angus, DC, Linde-Zwirble, WT, Lidicker, J, et al Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.Crit Care Med2001;29,1303-1310. [PubMed]
 
Hoyert, DL, Arias, E, Smith, BL, et al Deaths: final data for 1999.Natl Vital Stat Rep2001;49,1-113
 

Figures

Tables

Table Graphic Jump Location
Table 1. Cirrhosis and Critical Care Outcomes*
* 

APACHE = acute physiology and chronic health evaluation; MV = mechanical ventilation; ICCO = intensive care cirrhosis outcome score; MICU = medical ICU.

Table Graphic Jump Location
Table 2. Cirrhosis Demographics from NHDS, 1995 to 1999
* 

Values given as mean ± SD.

 

Race was not specified in 317,800 cases.

Table Graphic Jump Location
Table 3. Impact of Cirrhosis in NHDS, 1995 to 1999
Table Graphic Jump Location
Table 4. Cirrhosis and ARF in NHDS, 1995 to 1999
* 

95% CI, 1.1 to 1.8.

 

95% CI, 1.5 to 3.6.

Table Graphic Jump Location
Table 5. Primary Diagnosis at Discharge for Cirrhosis Decedents in the NHDS, 1995 to 1999

References

National Center for Health Statistics. Vital Health Stat 13, No. 145.
 
Saadatmand, F, Stinson, FS, Grant, BF, et al Liver cirrhosis mortality in the United States, 1970 – 97. December 2000; US Department of Health and Human Services, Public Health Service, National Institutes of Health; National Institute on Alcohol Abuse and Alcoholism. Bethesda, MD: Surveillance Report No. 54.
 
Shellman, RG, Fulkerson, WJ, deLong, E, et al Prognosis of patients with cirrhosis and chronic liver disease admitted to the medical intensive care unit.Crit Care Med1988;16,671-678. [PubMed] [CrossRef]
 
Singh, N, Gayowski, T, Wagener, MM, et al Outcome of patients with cirrhosis requiring intensive care unit support: prospective assessment of predictors of mortality.J Gastroenterol1998;33,73-79. [PubMed]
 
Aggarwal, A, Ong, JP, Younossi, ZM, et al Predictors of mortality and resource utilization in cirrhotic patients admitted to the medical ICU.Chest2001;119,1489-1497. [PubMed]
 
Zauner, C, Schneeweiss, B, Schneider, B, et al Short-term prognosis in critically ill patients with liver cirrhosis: an evaluation of a new scoring system.Eur J Gastroenterol Hepatol2000;12,517-522. [PubMed]
 
Dennison, C, Pokras, R. Design and operation of the National Hospital Discharge Survey: 1988 redesign. Vital and Health Statistics, Series 1, No. 39.  US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics. Atlanta, GA:.
 
Caly, WR, Strauss, E A prospective study of bacterial infections in patients with cirrhosis.J Hepatol1993;18,353-358. [PubMed]
 
Rosa, H, Silverio, AO, Perini, RF, et al Bacterial infection in cirrhotic patients and its relationship with alcohol.Am J Gastroenterol2000;95,1290-1293. [PubMed]
 
Johnson, DH, Cunha, BA Infections in cirrhosis.Infect Dis Clin North Am2001;15,363-371. [PubMed]
 
Ramachandran, A, Balasubramanian, KA Intestinal dysfunction in liver cirrhosis: its role in spontaneous bacterial peritonitis.J Gastroenterol Hepatol2110;16,607-612
 
Gosset, P, Wallaert, B, Canva-Delacambre, JF, et al Impaired secretion and mRNA expression of monokines by alveolar macrophages from nonsmoking patients with alcoholic liver cirrhosis.J Infect Dis1995;171,743-746. [PubMed]
 
Wallaert, B, Aerts, C, Colombel, JF, et al Human alveolar macrophage antibacterial activity in the alcoholic lung.Am Rev Respir Dis1991;144,278-283. [PubMed]
 
Wallaert, B, Colombel, JF, Prin, L, et al Bronchoalveolar lavage in alcoholic liver cirrhosis: T-lymphocyte subsets and immunoglobulin concentrations.Chest1992;101,468-473. [PubMed]
 
Westphal, J-F, Jehl, F, Vetter, D Pharmacological, toxicologic, and microbiological considerations in the choice of initial antibiotic therapy for serious infections in patients with cirrhosis of the liver.Clin Infect Dis1994;18,324-335. [PubMed]
 
TenHoor, T, Mannino, DM, Moss, M Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study.Chest2001;119,1179-1184. [PubMed]
 
Angus, DC, Linde-Zwirble, WT, Lidicker, J, et al Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.Crit Care Med2001;29,1303-1310. [PubMed]
 
Hoyert, DL, Arias, E, Smith, BL, et al Deaths: final data for 1999.Natl Vital Stat Rep2001;49,1-113
 
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