Abstract
Background: ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS. Methods: A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defined sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis. Results: Compared with patients with non-sepsis-related ARDS(n = 62), patients with sepsisrelated ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores(median, 78 vs 65, P<.0001). There were no differences in lung injury score, blood pH, PaO 2/FIO2 ratio, and PaCO2 on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower PaO 2/FIO2 ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P =.018), day 7(P =.004), and day 14(P =.004) (repeated-measures analysis, P =.011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P =.016), a lower successful extubation rate (53.6% vs 72.6%; P =.005), and fewer ICU-free days (P =.0001) and ventilator-free days (P =.003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). Conclusion: Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities.
Original language | English (US) |
---|---|
Pages (from-to) | 559-567 |
Number of pages | 9 |
Journal | Chest |
Volume | 138 |
Issue number | 3 |
DOIs | |
State | Published - Sep 1 2010 |
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine
- Cardiology and Cardiovascular Medicine
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In: Chest, Vol. 138, No. 3, 01.09.2010, p. 559-567.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS
AU - Sheu, Chau Chyun
AU - Gong, Michelle N.
AU - Zhai, Rihong
AU - Chen, Feng
AU - Bajwa, Ednan K.
AU - Clardy, Peter F.
AU - Gallagher, Diana C.
AU - Thompson, B. Taylor
AU - Christiani, David C.
N1 - Funding Information: Although sepsis as a cause of ARDS generally is associated with higher mortality than other risk factors, 15,16 to our knowledge, no study has comprehensively examined the clinical difference between sepsis-related and non-sepsis-related ARDS. Unlike previous studies, we considered ARDS developing in patients with pneumonia who also fulfilled sepsis criteria as sepsis-related ARDS, grouped all non-sepsis-related ARDS together, and took into account the reality that a fraction of ARDS may be caused by both septic and nonseptic injuries. Our study demonstrates significant differences between sepsis-related and non-sepsis-related ARDS in clinical features and outcomes. In general, patients with sepsis-related ARDS had a higher disease severity and worse clinical outcomes than those with non-sepsis-related ARDS. ARDS is a heterogeneous syndrome associated with complex interactions among the predisposing conditions, comorbidities, and genetic determinants. This heterogeneity leads to complexity and uncertainty in the study of this syndrome. 4 It is possible that clinical trials have not found a treatment effect that truly exists because a therapy that benefits one subgroup may not benefit another subgroup. 17 The genetic susceptibility to ARDS also shows differences among subgroups. 18 A better classification of ARDS subgroups, therefore, is crucial in the future research and management of ARDS. In 1998, Gattinoni and colleagues 19 first described the differences of underlying pathology, respiratory mechanics, and response to mechanical ventilation between pulmonary and extrapulmonary ARDS. However, later studies showed that there are no differences in mortality or ICU LOS between these two groups. 16,20–22 In the present study, we found significant differences in characteristics and outcomes between sepsis-related and non-sepsis-related ARDS. Our findings warrant further studies to understand whether these two ARDS subtypes may represent different syndromes. How sepsis-related ARDS differs pathophysiologically from non-sepsis-related ARDS remains largely unknown. Studies measuring circulating biomarkers in patients with ARDS showed that protein C level was lower in patients with sepsis-related ARDS than in those with non-sepsis-related ARDS, whereas procalcitonin, neopterin, von Willebrand factor antigen, soluble intercellular adhesion molecule-1, and soluble E-selectin levels were higher. 23–25 Plasma cytokines also vary among clinical risk factors because interleukin-6, −8, and −10 levels are known to be higher in patients with ARDS caused by sepsis and pneumonia. 26 These factors together suggest a higher degree of acute inflammation, endothelial cell activity, and coagulation activation in sepsis-related ARDS than in non-sepsis-related ARDS. Hemodynamics, ventricular function, and oxygen delivery and consumption, however, are not different between sepsis-related and non-sepsis-related ARDS. 23 Our study revealed no significant difference between sepsis-related and non-sepsis-related ARDS in baseline Pa o 2 /F io 2 ratio and severity of lung injury. However, patients with sepsis-related ARDS had lower serial Pao 2 /F io 2 ratios after ARDS diagnosis, indicating a poorer recovery from lung injury than patients with non-sepsis-related ARDS. We found diabetes to be more common in sepsis-related ARDS than in non-sepsis-related ARDS. Diabetes is associated with lower risk of developing ARDS, but how it may protect against ARDS remains unclear. 27,28 Studies have shown defects of neutrophil chemotactic, phagocytic, and microbicidal function in patients with diabetes. 29 Our finding is consistent with the premise that deficient neutrophil function may predispose these patients to severe infections but, conversely, may protect the lung from profound inflammation during severe infections. We identified seven independent predictors of ARDS mortality. From prior studies, age, APACHE III score, liver cirrhosis, and metastatic cancers are known predictors of ARDS mortality. 5,20,30–32 In a recent study, we found that higher admission serum bilirubin levels were associated with subsequent ARDS development and mortality. 33 The independent associations of admission serum glucose level and APC therapy with ARDS mortality have not been previously reported. Stress hyperglycemia is common in acute critical illnesses. Although admission hyperglycemia has been associated with increased mortality in critically ill patients, this association is not uniformly observed in all ICU populations, 34,35 with more evidence in surgical ICU patients but less in medical ICU patients. 34,36–38 Many studies demonstrating admission blood glucose level as an independent outcome predictor were carried out in patients with acute vascular problems like stroke, myocardial infarction, and coronary artery bypass grafting. 39–42 Interestingly, ARDS, with diffuse pulmonary microvascular damage as the pathologic hallmark, is also a syndrome of acute vascular illness. A randomized controlled trial of early blood glucose control in at-risk subjects is ongoing and will further clarify to role of hyperglycemia (or insulin therapy) on ARDS (trial registration: clinicaltrials.gov ; Identifier: NCT00605696 ). Recombinant human APC has both anticoagulant and antiinflammatory properties and is US Food and Drug Administration-approved for the treatment of high disease severity severe sepsis. Given that inflammation and coagulation both play important roles in the pathogenesis of ARDS 43,44 and that lower levels of plasma protein C were independent predictors of ARDS mortality, 45 APC may also be effective in treating ARDS. A recent phase II clinical trial showed that APC did not improve outcome in lower disease severity ALI but did improve dead space fraction. 46 Our study included patients with ARDS with greater severity of illness, of which 89% had sepsis. We found that treatment with APC was independently associated with decreased mortality. However, the survival benefit of APC in patients with ARDS might come from the effective treatment of severe sepsis or septic shock, not from effective treatment of ARDS per se. Of note, the effectiveness of APC for septic shock recently has been called into question, and an international trial of APC in septic shock is under way. 47 Hopefully, this trial will lead to a better understanding of the role of APC, if any, in sepsis-related ARDS. A major strength of this study is that it was conducted within a large, well-defined, two-center, multiple-ICU cohort of ARDS. All data were collected prospectively, thus avoiding recall biases. In addition, excluding from analyses patients with both septic-related and non-septic-related ARDS reduced possible bias from misclassification. Nevertheless, we acknowledge several limitations to our study. First, the number of patients with non-sepsis-related ARDS was relatively small largely due to the exclusion of 108 patients with both sepsis-related and non-sepsis-related ARDS. Second, we did not collect data for antibiotic appropriateness, time delay to the diagnosis of sepsis, and time to meeting resuscitation goals, all of which might affect the outcomes in critically ill patients. 48–50 Finally, patients with immunosuppression (other than secondary to steroids) were excluded in our study, thus generalization to populations including such patients should be made with caution. In summary, sepsis-related ARDS is associated with a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, longer ICU stay, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities. Our findings warrant further studies on potential pathophysiologic differences to understand whether sepsis-related and non-sepsis-related ARDS may represent different disease entities. Author contributions: Dr Sheu: contributed to the planning of the study, study design, data analyses and interpretation, and manuscript preparation and review. Dr Gong: contributed to the planning of the study, study design, assembly of the study patients, and manuscript preparation and review. Dr Zhai: contributed to the planning of the study, study design, and manuscript preparation and review. Dr Chen: contributed to the planning of the study, data analysis and interpretation, and manuscript preparation and review. Dr Bajwa: contributed to the planning of the study, assembly of study patients, and manuscript preparation and review. Dr Clardy: contributed to the planning of the study, assembly of study patients, and manuscript preparation and review. Dr Gallagher: contributed to the planning of the study, assembly of the study patients, and manuscript preparation and review. Dr Thompson: contributed to the planning of the study, assembly of the study patients, and manuscript preparation and review. Dr Christiani: contributed to the planning of the study, study design, and manuscript preparation and review. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Thompson reports financial support from Eli Lilly for his role as the co-principal investigator of the PROWESS-SHOCK study, a randomized trial of activated protein C vs placebo for septic shock. Drs Sheu, Gong, Zhai, Chen, Bajwa, Clardy, Gallagher, and Christiani have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Other contributions: We thank Thomas McCabe, Julia Shin, Hanae Fujii-Rios, Ian Taggart, and Kezia Ellison for patient recruitment; Andrea Shafer and Starr Sumpter for research support; Janna Frelich, Marcia Chertok, and Julie DelPrato for data management; and the patients and staff of the ICUs at Massachusetts General Hospital and Beth Israel Deaconess Medical Center.
PY - 2010/9/1
Y1 - 2010/9/1
N2 - Background: ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS. Methods: A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defined sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis. Results: Compared with patients with non-sepsis-related ARDS(n = 62), patients with sepsisrelated ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores(median, 78 vs 65, P<.0001). There were no differences in lung injury score, blood pH, PaO 2/FIO2 ratio, and PaCO2 on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower PaO 2/FIO2 ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P =.018), day 7(P =.004), and day 14(P =.004) (repeated-measures analysis, P =.011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P =.016), a lower successful extubation rate (53.6% vs 72.6%; P =.005), and fewer ICU-free days (P =.0001) and ventilator-free days (P =.003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). Conclusion: Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities.
AB - Background: ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS. Methods: A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defined sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis. Results: Compared with patients with non-sepsis-related ARDS(n = 62), patients with sepsisrelated ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores(median, 78 vs 65, P<.0001). There were no differences in lung injury score, blood pH, PaO 2/FIO2 ratio, and PaCO2 on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower PaO 2/FIO2 ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P =.018), day 7(P =.004), and day 14(P =.004) (repeated-measures analysis, P =.011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P =.016), a lower successful extubation rate (53.6% vs 72.6%; P =.005), and fewer ICU-free days (P =.0001) and ventilator-free days (P =.003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). Conclusion: Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities.
UR - http://www.scopus.com/inward/record.url?scp=77956817796&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77956817796&partnerID=8YFLogxK
U2 - 10.1378/chest.09-2933
DO - 10.1378/chest.09-2933
M3 - Article
C2 - 20507948
AN - SCOPUS:77956817796
SN - 0012-3692
VL - 138
SP - 559
EP - 567
JO - Chest
JF - Chest
IS - 3
ER -