AJRCCM Articles in Press. Published on February 13, 2003 as doi:10.1164/rccm.200210-1196OC
ACUTE RESPIRATORY DISTRESS SYNDROME AFTER BACTEREMIC SEPSIS DOES NOT INCREASE MORTALITY PHILIPPE EGGIMANN*, STEPHAN HARBARTH*, BARA RICOU§, STEPHANE HUGONNET*, KARIN FERRIERE*, PETER SUTER§, DIDIER PITTET* Authors' affiliations: * Infection Control Program, Department of Medicine §
Division of Surgical Intensive Care,
Department of Anesthesiology, Pharmacology & Surgical Intensive Care The University of Geneva Hospitals, Geneva, Switzerland Correspondence and requests for reprints should be addressed to: Prof. Didier Pittet, M.D., M.S. Infection Control Program The University of Geneva Hospitals, 1211 Geneva 14, Switzerland Phone: +41-22-372-9828 - Fax: +41-22-372-3987 E-mail:
[email protected] Financial support: Educational grant from the Department of Anesthesiology, Pharmacology & Surgical Intensive Care, University of Geneva Hospitals. Running head: Mortality of ARDS following sepsis Word count: 2,333 text words; 2 Tables; 1 Figure; 41 references Submitted to: Am J Resp Crit Care Med. Descriptor: 2 (ARDS and sepsis, patient studies) This article has an online data supplement, which is accessible from this issue’s table of contents online at www.atsjournals.org
21 Copyright (C) 2003 by the American Thoracic Society.
ABSTRACT To determine whether acute respiratory distress syndrome (ARDS) complicating bacteremic sepsis independently affects mortality in critically ill patients, we conducted a 3-year retrospective cohort study in a surgical intensive care unit. We included all consecutive patients with blood culture-positive sepsis and measured organ dysfunctions and mortality. Among 4,530 admissions, 196 cases of bacteremic sepsis were recorded. ARDS occurred in 31 (16%) of these patients. The case-fatality rate was 58% in patients with ARDS, compared to 31% in patients without ARDS. Using Cox proportional hazards regression with timedependent variables, the unadjusted hazard ratio for death was 1.8 (95% confidence interval [CI], 1.0 - 3.2). After adjusting for comorbid factors present before onset of sepsis, the hazard ratio was 2.2 (95% CI; 1.2 - 3.9). After further adjustment was made for nonpulmonary organ dysfunctions and microbiologic factors that were independently associated with mortality, the adjusted hazard ratio for ARDS was 0.6 (95% CI; 0.3 - 1.2). Among critically ill surgical patients, ARDS complicating bacteremic sepsis remains common, but it is not independently associated with short-term mortality, after adjusting for severity of illness and non-pulmonary organ dysfunctions evolving after onset of sepsis.
Count: 189 words Key words: Acute lung injury / Critical care / Prognosis / Respiratory failure / Sepsis
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INTRODUCTION Sepsis remains an important cause of morbidity and mortality among hospitalized patients. Acute respiratory failure after onset of sepsis is common and can be associated with adverse outcomes (1-4). To explain the high case-fatality rate among critically ill patients with sepsis and acute respiratory distress syndrome (ARDS), investigators have hypothesized that prognosis may be determined by the severity of underlying conditions that also predispose patients to ARDS, and by simultaneous, non-pulmonary complications, usually related to multiple organ failure (4, 5). Russell and coworkers (6) have suggested in a prospective, observational study that, although pulmonary dysfunction is a frequent complication among septic patients, the severity of lung injury and hypoxemia may not be correlated with an increased risk of mortality. By contrast, Martin and Bernard stated in a recently published textbook chapter that respiratory dysfunction related to sepsis is associated with significant independent mortality (7). To test the hypothesis that severe pulmonary dysfunction complicating sepsis has no independent impact on mortality in critically ill patients, we conducted a 3-year retrospective cohort study using survival regression methods and examined the independent effect of ARDS on mortality in 196 critically ill patients with blood culture-positive sepsis.
MATERIAL AND METHODS (546 WORDS) Study cohort This study was conducted at the surgical intensive care unit of the University of Geneva Hospitals, which is a 22-bed referral unit, admitting over 1,500 patients per year (8). The source population consisted of all patients admitted between June 1, 1994, and May 31, 1997. Patients were included if they had microbiologically confirmed bacteremia or fungemia with signs of sepsis, i.e. "bacteremic sepsis" (9).
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Data Collection and Definitions A list of all potential study subjects with an episode of bacteremia or fungemia during the study period was generated from computerized files of the microbiology laboratory. We recorded on a detailed data collection form patient demographics, comorbidities, vital signs, respiratory parameters, routine blood tests, organ dysfunctions and results of microbiological cultures after onset of sepsis (8). Patients' severity of underlying illness was classified according to McCabe and Jackson (10). Patients’ comorbidities were recorded according to the index proposed by Charlson et al. (11). The severity of the patients' condition was measured according to the Simplified Acute Physiology Scoring II system (12) and the Acute Physiology and Chronic Health Evaluation II score (13). Further details about exclusion criteria and data retrieval are listed in the online data supplement. The time of onset of bacteremic sepsis was defined as the time when the first positive blood culture was drawn. Bacteremic sepsis was defined as a systemic inflammatory response syndrome (see online data supplement) associated with positive blood cultures, the latter being characterized by the presence of viable microorganisms (e.g., bacteria or fungi) in the blood (9). Pneumonia required the presence of new radiographic infiltrates, coupled with identification of a significant amount (>103 cfu/mL) of at least one pathogen in a culture of broncho-alveolar lavage fluid and clinical evidence of infection (14). Beginning at the first day of blood culture-positive sepsis, we recorded organ dysfunctions according to the type and number of days of dysfunction, based on preestablished definitions (15-17). ARDS was defined according to established criteria as acute onset respiratory failure with presence of bilateral diffuse chest infiltrates, a PaO2/FiO2 ≤ 200 mm Hg with a pulmonary wedge pressure ≤ 18 mm Hg, and presence of a recognized predisposing factor for ARDS (16, 18). Definitions of other organ failures can be found in the online data supplement.
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Statistical Analysis We graphically explored mortality by plotting Kaplan-Meier survival curves and performed Cox proportional hazards regression to evaluate risk factors associated with mortality and to properly adjust for length of stay (19). We adjusted for baseline characteristics and comorbidity in a first survival model. In a second survival model, severity of illness at onset of sepsis and microbiologic variables were also included. Moreover, non-pulmonary organ dysfunctions were added as time-dependent covariates so that comparisons between patients with or without organ dysfunctions were made at comparable intervals after onset of bacteremic sepsis (20). Variables with a p-value ≤ 0.20 in the univariable analyses were candidates for the multivariable analysis, as well as the main variable of interest (ARDS). The strength of the association between prognostic variables and death was expressed as hazard ratios, and their corresponding 95% confidence intervals (CI) were calculated. More details on the development of the Cox proportional hazard model and the statistical analysis of important interaction terms can be found in the online data supplement.
RESULTS Among 4,530 admissions, 196 cases of blood culture-positive sepsis were recorded (incidence, 4.3%). The causative pathogens are shown in Table E1 of the online data supplement. The mean Acute Physiology and Chronic Health Evaluation II score at admission to the unit was 21.4 ± 8.4; the mean age of study subjects was 56.9 ± 17.1 years. Forty-eight (24.5%) patients were women. Median length of stay in the intensive care unit was 11 days (interquartile range, 5 to 22). The majority of patients (n=153, 78%) underwent surgery before admission to the intensive care unit. Cardiovascular disease (n=48, 24%), gastrointestinal disease (n=42, 21%), and multiple trauma (n=38, 19%) were
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the most frequent reasons for admission. ARDS occurred in 31 bacteremic patients (16 %). As expected, bacteremic patients with ARDS had greater comorbidity and severity of illness (Table 1). The case-fatality rate was 58% (18/31) in patients with ARDS, compared with 31% (51/165) in patients without. The Figure illustrates survival curves for both cohorts. The unadjusted hazard ratio for death was 1.8 (95% CI, 1.0 - 3.2; p = 0.03 by the log-rank test). The follow-up period for the 196 patients represented 2,087 patient-days. During that time interval, at least one organ dysfunction was present during 890 patient-days. The timing and cumulative prevalence of the different organ dysfunctions is illustrated in Figure E1 (see Online Data Supplement). The most frequent organ dysfunctions in terms of organfailure days were neurologic dysfunction (460 days, 22%), ARDS (327 days, 16%), renal failure (211 days, 10%), and septic shock (182 days, 9%). Among the 31 patients with ARDS, respiratory failure was associated with no other organ dysfunction in 2 patients, with one additional, non-pulmonary organ dysfunction in 8, with 2 or 3 non-pulmonary organ dysfunctions in 12, and with ≥ 4 non-pulmonary organ dysfunctions in 9 patients. After adjusting for baseline factors and comorbidities (Table 2, model 1), ARDS was still associated with an increased mortality rate (adjusted hazard ratio, 2.2; 95% CI, 1.2 3.9). We then included microbiologic variables and non-pulmonary organ dysfunctions that were associated with mortality on bivariate analysis (Table 2, model 2). After including these variables in a multivariable survival model, the risk of death was significantly correlated with neurologic dysfunction (hazard ratio, 6.7; 95% CI, 3.4 - 13.0), shock (hazard ratio, 4.2; 95% CI, 2.4 - 7.5), cardiac dysfunction (hazard ratio, 2.2; 95% CI, 1.2 - 4.3), and the score of the Simplified Acute Physiology Scoring II system at onset of sepsis (hazard ratio per 1-point increase, 1.03; 95% CI, 1.01-1.05). Appropriate antimicrobial therapy was independently associated with decreased mortality (hazard ratio, 0.5; 95% CI, 0.3 - 0.8). After adjusting for the above-mentioned independent risk factors for mortality, ARDS was
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not associated with an increased risk of death (adjusted hazard ratio, 0.6; 95% CI, 0.3 1.2). In a separate analysis, we confirmed these results for the lack of association between ARDS and mortality after excluding 29 patients (15%) who were censored or died within 2 days after onset of bacteremic sepsis (adjusted hazard ratio, 0.7; 95% CI, 0.3 - 1.3). To assess whether the effect of ARDS on survival was affected by possible interactions with other non-pulmonary organ dysfunctions, we added several interaction terms to the Cox regression model. For instance, for the interaction of ARDS with neurologic failure, the p-value of the interaction term was 0.65. The multiplicative terms for other interactions were also not statistically significant (e.g., interaction of ARDS with cardiac failure, p =0.23; interaction of ARDS with liver failure, p = 0.74; interaction of ARDS with shock, p = 0.33).
DISCUSSION Despite a large body of research about ARDS, no study has specifically assessed, after adjustment for evolving organ dysfunctions and severity of illness, the independent shortterm mortality of patients with ARDS complicating bacteremic sepsis. Our results confirm the hypothesis that ARDS, while it may be a good marker of the severity of the underlying disease, is rarely the direct cause of death in septic patients. These data suggest that septic patients who subsequently develop ARDS do not die from respiratory failure, but rather from non-pulmonary organ dysfunctions, such as cardiac or neurologic failure leading to refractory shock and multi-organ failure (4, 6, 21). Thus, improvements in outcome of septic patients with ARDS may depend more on treatment of sepsis and multi-organ failure than on oxygenation measures and ventilation strategies (22). The association between acute respiratory failure and mortality has been extensively studied in patients with mechanical ventilation and ARDS, showing contradictory results (4,
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23-25). Several authors found that the presence of ARDS with sepsis leading to mechanical ventilation was independently associated with mortality (24, 26-28). Others showed that death of septic patients with ARDS is more frequently associated with refractory sepsis and multi-organ failure, suggesting that the degree of respiratory system failure and severity of lung injury are not independent predictors of outcome (1, 4, 5, 21, 22, 29, 30). For instance, Ferring et al (22) looked at 129 patients who developed ARDS with a case-fatality rate of 52% and found that sepsis and multi-organ failure was the primary cause of death (49%), followed by respiratory failure (16%). Our results suggest that death in septic patients can not be attributed to the development of respiratory failure, but to the severity of underlying illness and to the nonpulmonary organ failures developing after the onset of sepsis. It is to note, however, that the 95% confidence interval surrounding the effect of ARDS on the risk of death in our study overlap that reported by other studies (24, 27, 28). For instance, in the study performed by Esteban et al. (24), the odds ratio of mortality after ARDS was 1.4 (95% CI, 1.0 - 2.0). According to the limited number of observations in this paper, we cannot completely refute the results obtained previously. Long-term evaluation of critically ill patients with ARDS complicating sepsis has been performed in at least two studies (27, 31), showing again incoherent results. Perl et al. (27) found that development of ARDS after suspected gram-negative sepsis independently increased the long-term likelihood of death (hazard ratio, 2.3; 95% CI, 1.1 - 4.8). By contrast, Davidson et al. (31) assessed in a prospective, matched cohort study the effect of ARDS on long-term survival and concluded that, if sepsis or trauma patients survive to hospital discharge, ARDS does not independently increase their risk of subsequent death (hazard ratio, 1.0; 95% CI, 0.5 - 2.1). Our study results complement the findings by Davidson et al. (31), since in the latter study no information was given about in-hospital mortality and non-pulmonary organ dysfunctions evolving after onset of sepsis. In further
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distinction to Davidson et al., we included detailed patient-level data about microbiologic factors and appropriateness of antimicrobial therapy in the final Cox regression model. Hitherto, reported biological data focusing on ARDS after bacteremic sepsis has been limited (3, 32). Meduri et al. showed that for patients with ARDS secondary to sepsis, the likelihood of death was correlated with the degree of pulmonary and extra-pulmonary inflammation, estimated by measuring levels of different cytokines in broncho-alveolar lavage fluids and plasma (33, 34). Thus, elevated systemic inflammatory reaction may be causally related to outcome in septic patients with ARDS (3). Conversely, clinical studies confirmed that non-pulmonary organ dysfunction due to systemic inflammation markedly decreases survival in patients with ARDS (23). Several features may have contributed to the low adjusted risk of death in patients with ARDS evolving after onset of bacteremic sepsis. Attending physicians in charge of the unit have a large experience with ARDS management (35-37). Furthermore, new strategies were progressively introduced in the management of these patients during the last 10 years, such as protective lung ventilation (36), less sedation and early detection of ventilatorassociated pneumonia (38). Moreover, the institution is very active in trying to improve the quality of critical care (39, 40). There are several limitations to this study, most importantly, the relatively small number of patients with ARDS included. However, this report represents one of the largest reported studies of ARDS complicating blood culture-positive sepsis. Secondly, this experience may not be representative for patients with culture-negative sepsis or patients in other settings such as medical or pediatric intensive care units. Nevertheless, the comorbidities were diverse, and likely represent a patient population encountered in other surgical intensive care units. Thirdly, we cannot exclude that non-pulmonary organ dysfunctions related to systemic infection started already more than 24 hours before blood culture positivity. Future studies may use better indicators of early systemic infection to
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assess the interacting effects of different organ-dysfunctions at the earliest possible moment (41). Finally, our study design did not allow us to examine in detail the hypothesis that lung inflammation due to ARDS may contribute to non-pulmonary organ dysfunctions. However, we looked at the interactions between ARDS and the development of important organ dysfunctions and did not retrieve statistically significant interaction terms. Despite these limitations, our study presents a new perspective on the effect of ARDS on risk of death in septic patients and provides a strong quantitative basis on this subject. Our results refute the hypothesis that severe lung injury after bacteremic sepsis is associated with significant independent mortality. Important strengths of our study were the availability of detailed data on evolving organ dysfunctions and the use of advanced regression methods with time-dependent co-variables, which allowed to adjust for the time interval between onset of bacteremic sepsis and discharge or death. Overall, our results suggest that although ARDS after bacteremic sepsis remains a common complication, it may not be independently associated with short-term mortality.
Acknowledgments: The authors would like to thank Peter Rohner for assistance in retrieving microbiologic data, Nadia Colaizzi for her help with data management and Rosemary Sudan for editorial assistance.
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TABLE
1: BASELINE CHARACTERISTICS OF 196
PATIENTS WITH BACTEREMIC SEPSIS
Acute Respiratory
All Other
P
Distress
Patients
Value
Syndrome
with Sepsis
(n=31)
(n=165)
54 (45 - 66)
57 (48 - 72)
0.13
Male gender (n, %)
23 (74)
125 (76)
0.85
Emergency admission (n, %)
13 (42)
64 (39)
0.74
18 (7 - 41)
10 (5 - 21)
0.02
Ultimately or rapidly fatal disease (n, %)
10 (32)
32 (19)
0.1
Charlson comorbidity index ≥ 2 (n, %)
14 (45)
56 (34)
0.23
Cardiac disease (n, %)
3 (10)
45 (27)
0.04
Gastrointestinal disease (n, %)
5 (16)
37 (22)
0.44
Trauma (n, %)
7 (23)
31 (19)
0.62
Neurologic disease (n, %)
2 (6)
24 (15)
0.38
Infectious disease (n, %)
4 (13)
10 (6)
0.24
Respiratory disease (n, %)
4 (13)
6 (4)
0.05
Other (n, %)
6 (19)
12 (7)
0.04
Pneumonia (n, %)
12 (39)
44 (27)
0.17
Gastrointestinal tract (n, %)
6 (19)
24 (15)
0.49
Catheter-associated bacteremia (n, %)
3 (10)
32 (19)
0.20
Urinary tract (n, %)
0 (0)
7 (4)
0.24
10 (32)
58 (35)
0.76
Characteristic
Mean age (years, IR)
Median length of stay in the intensive care unit (days, IR)
Primary admission diagnosis
Source of infection
Other or unknown source (n, %)
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(Table 1 continued)
APACHE II score At admission (mean ± SD)
25 (9)
21 (8)
0.009
At onset of sepsis (mean ± SD)
27 (9)
21 (8)
