Risk of Mortality with a Bloodstream Infection Is Higher in the Less Severely Ill at Admission
http://www.100md.com
美国呼吸和危急护理医学 2005年第3期
Food and Drug Administration, Division of Anti-Infective Drug Products, Rockville
Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine
Epidemiology Section, Veterans Affairs Maryland Health Care System
Department of Hospital Epidemiology and Infection Control, The Johns Hopkins Hospital
Division of Infectious Diseases, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
Correspondence and request for reprints should be addressed to Mary-Claire Roghmann, M.D., M.S., VA Maryland Health Care System, 100 N. Greene St. (Lower level), Baltimore, MD 21201. E-mail: mroghman@epi.umaryland.edu
ABSTRACT
Rationale: Health careeCassociated bloodstream infections are common in critically ill patients; however, investigators have had difficulty in quantifying the clinical impact of these infections given the high expected mortality among these patients. Objective: To estimate the impact of health careeCassociated bloodstream infections on in-hospital mortality after adjusting for severity of illness at critical care admission. Method: A cohort of medical and surgical intensive care unit patients. Measurements: Severity of illness at admission, bloodstream infection, and in-hospital mortality. Main Results: Among the 2,783 adult patients, 269 developed unit-associated bloodstream infections. After adjusting for severity of illness, patients with a lower initial severity of illness who developed an infection had a greater than twofold higher risk for in-hospital mortality (hazard ratio [HR] = 2.42, 95% confidence interval [CI] 1.70, 3.44) when compared with patients without infection and with a similar initial severity of illness. In contrast, patients with a higher initial severity of illness who subsequently developed an infection did not have an increased risk for in-hospital mortality (HR = 0.96, 95%CI 0.76, 1.23) when compared with patients without infection but with a similar initial severity of illness. Conclusions: These results suggest that these infections in less ill patients have a higher attributable impact on subsequent mortality than in more severely ill patients. Focusing interventions to prevent bloodstream infections in less severely ill patients would be expected to have a greater benefit in terms of mortality reduction.
Key Words: adults bloodstream infection cohort study intensive care unit mortality
Bloodstream infections (BSIs) are a common health careeCassociated infection among intensive care unit (ICU) patients (1, 2). Most BSIs are categorized as being due to intravascular catheters; and catheter-associated bloodstream infections represent approximately 15% of all ICU infections (2). The use of intravascular catheters has become more common in hospitalized patients both inside and outside the ICU (3). The Center for Disease Control and Prevention's Hospital Infection Control Practices Advisory Committee recently published guidelines for preventing intravascular catheter associated bloodstream infections (4). These recommendations include, but are not limited to, surveillance for bloodstream infections, the use of full barrier drapes with catheter insertion and appropriate skin preparation, and if infection control measures are not successful, the use of antiseptic or antimicrobial impregnated catheters. These and other interventions are time consuming and increase costs; therefore, it is important to quantify the impact of BSIs to justify implementing their use.
Estimates of the excess mortality due to bloodstream infections fall most often between 35 and 60%, but range from 5 to 80% (5eC14). This wide range of mortality estimates illustrates the difficulty in separating the BSI mortality from mortality due to the severity of patients' underlying disease processes (15, 16). However, the use of well validated severity-of-illness measures that predict hospital or ICU mortality before the BSI can minimize this confounding (17). The objective of our study was to quantify the attributable impact of ICU-associated BSIs on the in-hospital mortality of medical and surgical ICU patients while adjusting for the severity of their illness upon admission to the ICU. Identifying a group of patients that would benefit most from a reduction in BSI incidence could lead to cost-effective use of measures to reduce the risk of BSIs. Some of the results of this study have been previously reported in the form of an abstract (18).
METHODS
Setting
This prospective cohort study was conducted in a population of adult patients from five ICUs (three surgical [n = 30 beds, 19 beds, and 10 beds] and two medical [n = 25 beds and 10 beds) in three tertiary care institutions in Baltimore, Maryland: Johns Hopkins Hospital ( 1,100 beds), University of Maryland Medical System ( 500 beds), and Baltimore Veterans Affairs Medical Center ( 150 beds) from August 1998 to April 2000. Patients admitted to participating ICUs were included in the study if they were older than 18 years of age and stayed in the ICU for more than 48 hours.
Data Collection
Research assistants prospectively collected clinical data on all patients via chart review and were unaware of patient outcomes at the time of data collection. Certified infection control professionals prospectively identified all BSIs as a part of infection control surveillance in the ICUs. Data on disposition at discharge were obtained retrospectively from administrative databases.
Definitions
Eligible patients with cultured blood growing organisms (a positive blood culture) obtained more than 48 hours after admission to the ICU, and which was unrelated to infection present on ICU admission, had an ICU-associated BSI. BSIs were then classified on the basis of suspected etiology as either "primary" or "secondary" using CDC National Nosocomial Infection Surveillance System definitions (19) (see the online supplement for further details).
APACHE II scores were calculated on all patients in the participating ICUs during the first 24 hours of admission to the unit (20). Age, sex, date(s) of hospital and ICU admission and discharge, admitting diagnosis, surgical procedures, and history of underlying medical conditions were collected prospectively during the patient's admission.
Mortality was assessed at the time of discharge from the acute care hospital. Patient discharge disposition was noted as: discharged home, discharged to a long-term care facility, deceased, or other disposition (not otherwise specified).
Statistical Analysis
We compared categorical variables using chi-square and Fisher's exact tests. We compared continuous variables using Student's t tests. We categorized patient APACHE II scores on the basis of precedents set in previous literature (21). We performed unstratified and stratified analyses to determine the unadjusted and adjusted associations between the development of a bloodstream infection in the ICU and in-hospital mortality. We tested for effect modification using the Breslow-Day test for homogeneity (p < 0.05 level). If we did not detect effect modification, we evaluated for confounding. We suspected confounding if the Mantel-Haenszel common relative risk (RR) differed by 10% or more from the unadjusted relative risk found in the unstratified analysis of the association between BSI status and in-hospital mortality.
We then constructed Cox proportional hazard models based on time in the ICU until death or censoring, defined as discharge from the hospital. We included BSI status as a time-dependent variable, which identified BSI status at the time cultured blood grew organisms. Thus, for those with BSIs, the time variable is time from cultured blood with organisms to death or censoring; for those without, time is from admission to the ICU to death or censoring. Additional models evaluated the effect of previously identified effect modifying and confounding variables.
RESULTS
Between August 1998 and April 2000, 2,811 adult patients were admitted to the ICU and stayed for more than 48 hours. Twenty-eight of these patients were admitted with BSIs and thus excluded from further analysis. Of the remaining 2,783 patients, 269 had documented ICU-associated bloodstream infections during their ICU stay. Table 1 provides descriptive information about the study population. Ten percent of the study population (n = 269) developed ICU-associated BSIs a median of 10 days from ICU admission (range 3eC89 days). When stratified by severity of illness of admission (APACHE < 20; 20), there were no significant differences in duration of time to BSI (median 10 days vs. 10 days, p = 0.57, Wilcoxon). Sixty-eight percent of these patients had primary BSIs, out of which 95% were noted to have had a central line in place at the time the bloodstream infection was diagnosed. The major pathogens causing BSIs (both primary and secondary) were as follows: Enterococcus species (29%), coagulase-negative staphylococci (24%), gram-negative organisms (17%), Candida species (13%), and Staphylococcus aureus (13%).
Table 2 provides a comparison of ICU patients with and without BSIs. Patients with BSIs were significantly more likely to die during their hospital admission. In addition, they were more ill on admission as judged by higher APACHE II scores. Patients with BSIs were more likely to have been admitted to a hospital floor for more than 48 hours before admission to the ICU. Furthermore, patients with BSIs were significantly more likely to: be younger, have cirrhosis, have received a solid organ transplant, and be immunosuppressed than patients without BSIs.
Table 3 shows variables significantly associated with in-hospital mortality. They included: older age, female sex, hospital admission for more than 48 hours before ICU admission, admission to a medical ICU (versus a surgical ICU), and not having surgery during the hospital admission and higher APACHE II score. Four percent of ICU patients with an APACHE score of 0 to 9 died during hospitalization; 13% of patients with a score of 10 to 19 died; 29% of patients with a score of 20 to 29 died; and 47% of patients with a score 30 died. Comorbid conditions associated with in-hospital mortality included: end-stage renal disease, cirrhosis, HIV-positive status, being on immunosuppressive therapy, being on dialysis, and not having coronary artery disease/peripheral vascular disease.
Patients with BSIs were three times more likely to die in-hospital than patients without BSIs (RR 3.12, 95% confidence interval [CI] 2.72eC3.56). Stratified analyses of the association between BSI status and in-hospital mortality were performed on patient variables significantly associated with both BSI status and in-hospital mortality, or solely associated with in-hospital mortality to test for effect modification and confounding (see Table E1 in the online supplement). Effect modification is the ability of a variable to change the relationship, as measured by the RR, between a risk factor (BSI) and an outcome (in-hospital mortality); for example, asbestos exposure may be an effect modifying factor for the relationship between cigarette smoking and lung cancer. Cigarette smokers exposed to asbestos have a higher risk for lung cancer than cigarette smokers not exposed to asbestos. Effect modification in our analysis was noted for the APACHE II score (Stratum 1 APACHE II < 20: RR 6.44, 95% CI 5.00eC8.34; Stratum 2 APACHE II 20: RR 1.91, 95% CI 1.63eC2.24; Breslow Day test p < 0.01) and HIV infection (see online supplement). We chose to exclude the patients with HIV infection from further analysis because of the small number of patients with HIV infection. Confounding was noted for two variables: being admitted to the hospital more than 48 hours before ICU admission and cirrhosis (Table E1).
We compared time to death in HIV-negative patients with BSI to those without BSI stratified by their APACHE score at ICU admission. In those with an APACHE score less than 20, the curves significantly diverged (p 0.01, Log Rank test). In those with an APACHE score greater than or equal to 20, the curves were not significantly different (p = 0.57, Log Rank test). Table 4 displays the results of the proportional hazard models for time to in-hospital mortality in HIV-negative patients; BSI is used as a time-dependent variable in the model. Patients with a BSI and a low admission APACHE II score (< 20) had 2.42 times the risk of death in-hospital compared with patients without a BSI and a low admission APACHE II score. However, in patients with a high admission APACHE II score ( 20), the hazard ratio did not show an increased risk of in-hospital mortality (HR 0.96). For each increase in age by 1 year, the mortality rate increased by 1% in the model. Cirrhosis and admission to the hospital for more than 2 days before ICU admission were also found to significantly increase the risk of mortality.
If BSIs are causally associated with death, then BSIs due to more virulent bacteria (e.g., S. aureus and gram-negative bacilli) would have a stronger association with mortality than BSIs due to less virulent bacteria (e.g., coagulase-negative staphylococci). Among those patients with a low admission APACHE II score (< 20), those with a virulent organism were over seven times more likely to die compared with patients without BSIs (RR 7.43, 95% CI 5.74eC9.62, p 0.01). In comparison, those with BSIs due to less virulent bacteria and a low admission APACHE score had a lower risk of dying (RR 4.10, 95% CI 2.34eC7.13, p 0.01). This increase in risk with an increase in virulence of the organism was not seen among patients with a high admission APACHE score ( 20). Among those patients with a high admission APACHE II score ( 20), those with a virulent organism were 1.93 times more likely to die compared with those without BSIs (RR 1.93, 95% CI 1.63eC2.28, p 0.01). Those with BSIs due to less virulent bacteria were 1.86 times more likely to die compared with those without BSIs (RR 1.86, 95% CI 1.38eC2.52, p 0.01).
DISCUSSION
In this large cohort of patients admitted to ICUs, mortality was up to seven times higher among patients who developed BSIs than those who did not. In contrast to traditional thinking, we found that less severely ill ICU patients who develop an ICU-associated BSI had a higher mortality than their counterparts who did not develop a BSI. This risk was significantly higher than that seen among more ill ICU patients who developed a BSI. Age, cirrhosis, and being in the hospital longer than 48 hours before ICU admission were also independent risk factors for mortality.
Our study findings that mortality is higher among patients with ICU-associated BSIs are consistent with other studies of BSIs and mortality in intensive care unit patients (6, 10eC14). Smith and coworkers demonstrated a one-and-a-half times increased risk among medical ICU patients at a Veterans Affairs Medical Center (13). Pittet and colleagues found a greater than three times increased risk of death among their patients with BSI (6). Renaud and associates showed that the odds of death among their patients with BSI were more than four times those of patients without BSI (11). Our study findings are unique because we describe an interesting interaction between ICU patients' severity of illness at admission and their risk of in-hospital mortality if they develop a BSI. Other studies looking at the impact of ICU complications on in-hospital mortality should consider testing for this type of interaction.
Measuring the impact of an ICU complication on an outcome such as mortality is difficult because the measurement of the patient's underlying risk of mortality is imprecise. Still, we believe that our findings are biologically plausible. Patients with higher severity of illness may have many reasons for increased mortality. The addition of a BSI may not greatly increase severely ill patients' overall risk of mortality. Clinically, we know a cirrhotic patient with a gastrointestinal bleed who requires an ICU admission has a high risk of mortality. The addition of a BSI to this patient's list of life-threatening problems may be inconsequential. One may postulate that severely ill patients have an impaired cytokine response to microbial antigens such that proinflammatory cytokines, normally induced during acute bacteremia, are less able to wreak their havoc. This could occur either through a reduction in cytokine-producing cells following chemotherapy or immunosuppressive therapy, or the induction of tolerance to microbial pathogens secondary to a permeable or "leaky" gut. Although the pathophysiologic mechanism is not clear, this observation merits further investigation.
Our study is methodologically strong. To our knowledge, this is the largest cohort study to assess the association between mortality and ICU-associated BSIs. The closest in size was the study by Renaud and coworkers of 2,201 patients, of whom 96 unique patients developed ICU-associated bloodstream infections (11). We used a standardized severity-of-illness scoring system (the APACHE II system) that is well validated in predicting ICU and hospital mortality (20). We measured severity of illness at admission to the ICU before development of the BSI. Given the fact that we derived our cohort from three tertiary care, teaching hospitals, we believe that this study is generalizable to most tertiary care ICU populations.
The major limitation of our study is that it is observational. We attempted to control for important confounding variables such as severity of illness at ICU admission, but there may still be hidden bias due to the observational nature of the study. Because of the difficulty in determining whether an infection was directly or indirectly related to a patient's death, we can only infer that the bloodstream infection was the important factor that increased the risk of mortality. In support of our supposition, we found that the risk of death was greater among patients with bloodstream infections caused by more virulent organisms. It is important to note that certain research questions can only be answered with observational studies for both ethical and practical reasons. For the question at hand, we feel that we used the best methodology available to us.
In conclusion, we found that ICU patients who have a lower severity of illness and develop a BSI are at significantly higher increased risk for in-hospital mortality compared with ICU patients with higher severity of illness who develop a BSI. Although only a third of the BSIs occurred in patients with a lower severity of illness, the impact of the BSI was twice as high in this population. This study further clarifies the relationship between bloodstream infections and in-hospital mortality among ICU patients. Our study supports implementing interventions to prevent bloodstream infections in less severely ill patients in the ICU, as well as at-risk patients on general medical and surgical floors. Infection control efforts have long been focused in the intensive care unit because of the higher risk of infection in ICU patients. The results of this study suggest that decisions on using infection control interventions might be more cost-effectively driven by using both the impact of infections on specific patient populations and the overall risk of infection in that patient population.
Acknowledgments
The authors thank Dr. Alan S. Cross for contributing his ideas on the biological plausibility of our findings.
This research was supported by # UR8/CCU315092eC03 from the Center for Disease Control and Prevention for Epicenters for the Prevention of Health careeCassociated Infections.
The views expressed in this paper do not necessarily reflect those of the U.S. Food and Drug Administration.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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Pittet D. Nosocomial bloodstream infections. In: Wenzel RP, editor. Prevention and control of nosocomial infections, 2nd ed. Baltimore, MD: Williams & Wilkins; 1993. pp. 512eC555.
Pittet D, Tarara D, Wenzel RP. Nosocomial bloodstream infection in critically ill patients: excess length of stay, extra costs, and attributable mortality. JAMA 1994;271:1598eC1601.
Kreger BE, Craven DE, Carling PC, McCabe WR. Gram-negative bacteremia: III. Reassessment of etiology, epidemiology and ecology in 612 patients. Am J Med 1980;68:332eC343.
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Smith RL, Meixler SM, Simberkoff MS. Excess mortality in critically ill patients with nosocomial bloodstream infections. Chest 1991;100:164eC167.
Diekema DJ, Beekmann SE, Chapin KC, Morel KA, Munson E, Doern GV. Epidemiology and outcome of nosocomial and community-onset bloodstream infection. J Clin Microbiol 2003;41:3655eC3660.
Cosgrove SE, Carmeli Y. Studies of bloodstream infection outcomes: reading between the lines. Infect Control Hosp Epidemiol 2003;24:884eC886.
Wenzel RP. The mortality of hospital-acquired bloodstream infections: need for a new vital statistic Int J Epidemiol 1988;17:225eC227.
Haley RW. Measuring the costs of nosocomial infections: methods for estimating economic burden on the hospital. Am J Med 1991;91:32SeC38S.
Kim PW, Keelaghan EF, Langenberg P, Perl TM, Roghmann M. Bloodstream infections during ICU admissions increase in-hospital mortality. Interscience Conference on Antimicrobial Agents and Chemotherapy, 2004; Washington DC.
Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988;16:128eC140.
Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818eC829.
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Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine
Epidemiology Section, Veterans Affairs Maryland Health Care System
Department of Hospital Epidemiology and Infection Control, The Johns Hopkins Hospital
Division of Infectious Diseases, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland
Correspondence and request for reprints should be addressed to Mary-Claire Roghmann, M.D., M.S., VA Maryland Health Care System, 100 N. Greene St. (Lower level), Baltimore, MD 21201. E-mail: mroghman@epi.umaryland.edu
ABSTRACT
Rationale: Health careeCassociated bloodstream infections are common in critically ill patients; however, investigators have had difficulty in quantifying the clinical impact of these infections given the high expected mortality among these patients. Objective: To estimate the impact of health careeCassociated bloodstream infections on in-hospital mortality after adjusting for severity of illness at critical care admission. Method: A cohort of medical and surgical intensive care unit patients. Measurements: Severity of illness at admission, bloodstream infection, and in-hospital mortality. Main Results: Among the 2,783 adult patients, 269 developed unit-associated bloodstream infections. After adjusting for severity of illness, patients with a lower initial severity of illness who developed an infection had a greater than twofold higher risk for in-hospital mortality (hazard ratio [HR] = 2.42, 95% confidence interval [CI] 1.70, 3.44) when compared with patients without infection and with a similar initial severity of illness. In contrast, patients with a higher initial severity of illness who subsequently developed an infection did not have an increased risk for in-hospital mortality (HR = 0.96, 95%CI 0.76, 1.23) when compared with patients without infection but with a similar initial severity of illness. Conclusions: These results suggest that these infections in less ill patients have a higher attributable impact on subsequent mortality than in more severely ill patients. Focusing interventions to prevent bloodstream infections in less severely ill patients would be expected to have a greater benefit in terms of mortality reduction.
Key Words: adults bloodstream infection cohort study intensive care unit mortality
Bloodstream infections (BSIs) are a common health careeCassociated infection among intensive care unit (ICU) patients (1, 2). Most BSIs are categorized as being due to intravascular catheters; and catheter-associated bloodstream infections represent approximately 15% of all ICU infections (2). The use of intravascular catheters has become more common in hospitalized patients both inside and outside the ICU (3). The Center for Disease Control and Prevention's Hospital Infection Control Practices Advisory Committee recently published guidelines for preventing intravascular catheter associated bloodstream infections (4). These recommendations include, but are not limited to, surveillance for bloodstream infections, the use of full barrier drapes with catheter insertion and appropriate skin preparation, and if infection control measures are not successful, the use of antiseptic or antimicrobial impregnated catheters. These and other interventions are time consuming and increase costs; therefore, it is important to quantify the impact of BSIs to justify implementing their use.
Estimates of the excess mortality due to bloodstream infections fall most often between 35 and 60%, but range from 5 to 80% (5eC14). This wide range of mortality estimates illustrates the difficulty in separating the BSI mortality from mortality due to the severity of patients' underlying disease processes (15, 16). However, the use of well validated severity-of-illness measures that predict hospital or ICU mortality before the BSI can minimize this confounding (17). The objective of our study was to quantify the attributable impact of ICU-associated BSIs on the in-hospital mortality of medical and surgical ICU patients while adjusting for the severity of their illness upon admission to the ICU. Identifying a group of patients that would benefit most from a reduction in BSI incidence could lead to cost-effective use of measures to reduce the risk of BSIs. Some of the results of this study have been previously reported in the form of an abstract (18).
METHODS
Setting
This prospective cohort study was conducted in a population of adult patients from five ICUs (three surgical [n = 30 beds, 19 beds, and 10 beds] and two medical [n = 25 beds and 10 beds) in three tertiary care institutions in Baltimore, Maryland: Johns Hopkins Hospital ( 1,100 beds), University of Maryland Medical System ( 500 beds), and Baltimore Veterans Affairs Medical Center ( 150 beds) from August 1998 to April 2000. Patients admitted to participating ICUs were included in the study if they were older than 18 years of age and stayed in the ICU for more than 48 hours.
Data Collection
Research assistants prospectively collected clinical data on all patients via chart review and were unaware of patient outcomes at the time of data collection. Certified infection control professionals prospectively identified all BSIs as a part of infection control surveillance in the ICUs. Data on disposition at discharge were obtained retrospectively from administrative databases.
Definitions
Eligible patients with cultured blood growing organisms (a positive blood culture) obtained more than 48 hours after admission to the ICU, and which was unrelated to infection present on ICU admission, had an ICU-associated BSI. BSIs were then classified on the basis of suspected etiology as either "primary" or "secondary" using CDC National Nosocomial Infection Surveillance System definitions (19) (see the online supplement for further details).
APACHE II scores were calculated on all patients in the participating ICUs during the first 24 hours of admission to the unit (20). Age, sex, date(s) of hospital and ICU admission and discharge, admitting diagnosis, surgical procedures, and history of underlying medical conditions were collected prospectively during the patient's admission.
Mortality was assessed at the time of discharge from the acute care hospital. Patient discharge disposition was noted as: discharged home, discharged to a long-term care facility, deceased, or other disposition (not otherwise specified).
Statistical Analysis
We compared categorical variables using chi-square and Fisher's exact tests. We compared continuous variables using Student's t tests. We categorized patient APACHE II scores on the basis of precedents set in previous literature (21). We performed unstratified and stratified analyses to determine the unadjusted and adjusted associations between the development of a bloodstream infection in the ICU and in-hospital mortality. We tested for effect modification using the Breslow-Day test for homogeneity (p < 0.05 level). If we did not detect effect modification, we evaluated for confounding. We suspected confounding if the Mantel-Haenszel common relative risk (RR) differed by 10% or more from the unadjusted relative risk found in the unstratified analysis of the association between BSI status and in-hospital mortality.
We then constructed Cox proportional hazard models based on time in the ICU until death or censoring, defined as discharge from the hospital. We included BSI status as a time-dependent variable, which identified BSI status at the time cultured blood grew organisms. Thus, for those with BSIs, the time variable is time from cultured blood with organisms to death or censoring; for those without, time is from admission to the ICU to death or censoring. Additional models evaluated the effect of previously identified effect modifying and confounding variables.
RESULTS
Between August 1998 and April 2000, 2,811 adult patients were admitted to the ICU and stayed for more than 48 hours. Twenty-eight of these patients were admitted with BSIs and thus excluded from further analysis. Of the remaining 2,783 patients, 269 had documented ICU-associated bloodstream infections during their ICU stay. Table 1 provides descriptive information about the study population. Ten percent of the study population (n = 269) developed ICU-associated BSIs a median of 10 days from ICU admission (range 3eC89 days). When stratified by severity of illness of admission (APACHE < 20; 20), there were no significant differences in duration of time to BSI (median 10 days vs. 10 days, p = 0.57, Wilcoxon). Sixty-eight percent of these patients had primary BSIs, out of which 95% were noted to have had a central line in place at the time the bloodstream infection was diagnosed. The major pathogens causing BSIs (both primary and secondary) were as follows: Enterococcus species (29%), coagulase-negative staphylococci (24%), gram-negative organisms (17%), Candida species (13%), and Staphylococcus aureus (13%).
Table 2 provides a comparison of ICU patients with and without BSIs. Patients with BSIs were significantly more likely to die during their hospital admission. In addition, they were more ill on admission as judged by higher APACHE II scores. Patients with BSIs were more likely to have been admitted to a hospital floor for more than 48 hours before admission to the ICU. Furthermore, patients with BSIs were significantly more likely to: be younger, have cirrhosis, have received a solid organ transplant, and be immunosuppressed than patients without BSIs.
Table 3 shows variables significantly associated with in-hospital mortality. They included: older age, female sex, hospital admission for more than 48 hours before ICU admission, admission to a medical ICU (versus a surgical ICU), and not having surgery during the hospital admission and higher APACHE II score. Four percent of ICU patients with an APACHE score of 0 to 9 died during hospitalization; 13% of patients with a score of 10 to 19 died; 29% of patients with a score of 20 to 29 died; and 47% of patients with a score 30 died. Comorbid conditions associated with in-hospital mortality included: end-stage renal disease, cirrhosis, HIV-positive status, being on immunosuppressive therapy, being on dialysis, and not having coronary artery disease/peripheral vascular disease.
Patients with BSIs were three times more likely to die in-hospital than patients without BSIs (RR 3.12, 95% confidence interval [CI] 2.72eC3.56). Stratified analyses of the association between BSI status and in-hospital mortality were performed on patient variables significantly associated with both BSI status and in-hospital mortality, or solely associated with in-hospital mortality to test for effect modification and confounding (see Table E1 in the online supplement). Effect modification is the ability of a variable to change the relationship, as measured by the RR, between a risk factor (BSI) and an outcome (in-hospital mortality); for example, asbestos exposure may be an effect modifying factor for the relationship between cigarette smoking and lung cancer. Cigarette smokers exposed to asbestos have a higher risk for lung cancer than cigarette smokers not exposed to asbestos. Effect modification in our analysis was noted for the APACHE II score (Stratum 1 APACHE II < 20: RR 6.44, 95% CI 5.00eC8.34; Stratum 2 APACHE II 20: RR 1.91, 95% CI 1.63eC2.24; Breslow Day test p < 0.01) and HIV infection (see online supplement). We chose to exclude the patients with HIV infection from further analysis because of the small number of patients with HIV infection. Confounding was noted for two variables: being admitted to the hospital more than 48 hours before ICU admission and cirrhosis (Table E1).
We compared time to death in HIV-negative patients with BSI to those without BSI stratified by their APACHE score at ICU admission. In those with an APACHE score less than 20, the curves significantly diverged (p 0.01, Log Rank test). In those with an APACHE score greater than or equal to 20, the curves were not significantly different (p = 0.57, Log Rank test). Table 4 displays the results of the proportional hazard models for time to in-hospital mortality in HIV-negative patients; BSI is used as a time-dependent variable in the model. Patients with a BSI and a low admission APACHE II score (< 20) had 2.42 times the risk of death in-hospital compared with patients without a BSI and a low admission APACHE II score. However, in patients with a high admission APACHE II score ( 20), the hazard ratio did not show an increased risk of in-hospital mortality (HR 0.96). For each increase in age by 1 year, the mortality rate increased by 1% in the model. Cirrhosis and admission to the hospital for more than 2 days before ICU admission were also found to significantly increase the risk of mortality.
If BSIs are causally associated with death, then BSIs due to more virulent bacteria (e.g., S. aureus and gram-negative bacilli) would have a stronger association with mortality than BSIs due to less virulent bacteria (e.g., coagulase-negative staphylococci). Among those patients with a low admission APACHE II score (< 20), those with a virulent organism were over seven times more likely to die compared with patients without BSIs (RR 7.43, 95% CI 5.74eC9.62, p 0.01). In comparison, those with BSIs due to less virulent bacteria and a low admission APACHE score had a lower risk of dying (RR 4.10, 95% CI 2.34eC7.13, p 0.01). This increase in risk with an increase in virulence of the organism was not seen among patients with a high admission APACHE score ( 20). Among those patients with a high admission APACHE II score ( 20), those with a virulent organism were 1.93 times more likely to die compared with those without BSIs (RR 1.93, 95% CI 1.63eC2.28, p 0.01). Those with BSIs due to less virulent bacteria were 1.86 times more likely to die compared with those without BSIs (RR 1.86, 95% CI 1.38eC2.52, p 0.01).
DISCUSSION
In this large cohort of patients admitted to ICUs, mortality was up to seven times higher among patients who developed BSIs than those who did not. In contrast to traditional thinking, we found that less severely ill ICU patients who develop an ICU-associated BSI had a higher mortality than their counterparts who did not develop a BSI. This risk was significantly higher than that seen among more ill ICU patients who developed a BSI. Age, cirrhosis, and being in the hospital longer than 48 hours before ICU admission were also independent risk factors for mortality.
Our study findings that mortality is higher among patients with ICU-associated BSIs are consistent with other studies of BSIs and mortality in intensive care unit patients (6, 10eC14). Smith and coworkers demonstrated a one-and-a-half times increased risk among medical ICU patients at a Veterans Affairs Medical Center (13). Pittet and colleagues found a greater than three times increased risk of death among their patients with BSI (6). Renaud and associates showed that the odds of death among their patients with BSI were more than four times those of patients without BSI (11). Our study findings are unique because we describe an interesting interaction between ICU patients' severity of illness at admission and their risk of in-hospital mortality if they develop a BSI. Other studies looking at the impact of ICU complications on in-hospital mortality should consider testing for this type of interaction.
Measuring the impact of an ICU complication on an outcome such as mortality is difficult because the measurement of the patient's underlying risk of mortality is imprecise. Still, we believe that our findings are biologically plausible. Patients with higher severity of illness may have many reasons for increased mortality. The addition of a BSI may not greatly increase severely ill patients' overall risk of mortality. Clinically, we know a cirrhotic patient with a gastrointestinal bleed who requires an ICU admission has a high risk of mortality. The addition of a BSI to this patient's list of life-threatening problems may be inconsequential. One may postulate that severely ill patients have an impaired cytokine response to microbial antigens such that proinflammatory cytokines, normally induced during acute bacteremia, are less able to wreak their havoc. This could occur either through a reduction in cytokine-producing cells following chemotherapy or immunosuppressive therapy, or the induction of tolerance to microbial pathogens secondary to a permeable or "leaky" gut. Although the pathophysiologic mechanism is not clear, this observation merits further investigation.
Our study is methodologically strong. To our knowledge, this is the largest cohort study to assess the association between mortality and ICU-associated BSIs. The closest in size was the study by Renaud and coworkers of 2,201 patients, of whom 96 unique patients developed ICU-associated bloodstream infections (11). We used a standardized severity-of-illness scoring system (the APACHE II system) that is well validated in predicting ICU and hospital mortality (20). We measured severity of illness at admission to the ICU before development of the BSI. Given the fact that we derived our cohort from three tertiary care, teaching hospitals, we believe that this study is generalizable to most tertiary care ICU populations.
The major limitation of our study is that it is observational. We attempted to control for important confounding variables such as severity of illness at ICU admission, but there may still be hidden bias due to the observational nature of the study. Because of the difficulty in determining whether an infection was directly or indirectly related to a patient's death, we can only infer that the bloodstream infection was the important factor that increased the risk of mortality. In support of our supposition, we found that the risk of death was greater among patients with bloodstream infections caused by more virulent organisms. It is important to note that certain research questions can only be answered with observational studies for both ethical and practical reasons. For the question at hand, we feel that we used the best methodology available to us.
In conclusion, we found that ICU patients who have a lower severity of illness and develop a BSI are at significantly higher increased risk for in-hospital mortality compared with ICU patients with higher severity of illness who develop a BSI. Although only a third of the BSIs occurred in patients with a lower severity of illness, the impact of the BSI was twice as high in this population. This study further clarifies the relationship between bloodstream infections and in-hospital mortality among ICU patients. Our study supports implementing interventions to prevent bloodstream infections in less severely ill patients in the ICU, as well as at-risk patients on general medical and surgical floors. Infection control efforts have long been focused in the intensive care unit because of the higher risk of infection in ICU patients. The results of this study suggest that decisions on using infection control interventions might be more cost-effectively driven by using both the impact of infections on specific patient populations and the overall risk of infection in that patient population.
Acknowledgments
The authors thank Dr. Alan S. Cross for contributing his ideas on the biological plausibility of our findings.
This research was supported by # UR8/CCU315092eC03 from the Center for Disease Control and Prevention for Epicenters for the Prevention of Health careeCassociated Infections.
The views expressed in this paper do not necessarily reflect those of the U.S. Food and Drug Administration.
This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org
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