Diabetes and Acute Respiratory Distress Syndrome: Can We Finally Believe the Epidemiology?* Annette Esper, MD, MSc

In the most recent prospective observational study of patients with at-risk diagnoses in this issue of Critical Care Medicine, Yu et al (9) investigate further the association between diabetes and ARDS. As a result of their large sample size (« = 3,860 subjects) and rigorous methods, this study definitively confirms the inverse relationship between diabetes and ARDS and expands our knowledge by demonstrating that the protective associaMarc Moss, MD tion occurs in patients with all types of diabetes. Furthermore, Division of Pulmonary Sciences this study verifies that the presence of diabetes does not impact and Critical Care Medicine 60-day mortality in those patients in whom ARDS develop. Department of Medicine The mechanisms responsible for this association between University of Colorado, Denver diabetes and ARDS remain unclear; however, the influence of Aurora, CO diabetic medications, hyperglycemia, and the impact of the metabolic syndrome on inflammation may intersect to alter the he acute respiratory distress syndrome (ARDS) is a lifedevelopment of ARDS (10). The effect of acute hyperglycemia threatening disorder that occurs in critically ill patients on the development of ARDS is conflicting. Although hyperwith a variety of heterogeneous diagnoses. Although glycemia exacerbates inflammation and injury, studies have ARDS-associated mortality has declined over the years, mortalnot demonstrated an association between acute hyperglycemia ity remains high at approximately 25-40%. Previous epidemioand the development of ARDS (1). Therefore, the association logical studies identified at-risk diagnoses that are associated between diabetes and VUIDS may involve nonglycemic facwith an increased susceptibility for developing ARDS; however, tors. For example, a variety of medications commonly used in only 20-40% of patients with these at-risk diagnoses (such as patients with diabetes may contribute to the protective effects sepsis, trauma, or aspiration) progress to ARDS. Therefore, of diabetes on the development of ARDS. Prior clinical studies other factors may alter the progression to ARDS, such as the have reported that medications, such as aspirin and statins, are presence of preexisting chronic comorbid conditions. independently associated with a decreased risk of ARDS (11, One common comorbid condition encountered in the 12). However, the study by Yu et al (9) reported that these medicritically ill population, diabetes mellitus, has previously cations do not account for the protective effect of diabetes on been reported to influence the development of ARDS. IniARDS development. As Yu et al (9) acknowledged, the lack of tially, a prospective study of critically ill patients with septic an association of these medications may be accounted for by the shock revealed a decreased risk of ARDS in diabetics when low prevalence of and potential misclassification of their use. compared with nondiabetics (25% vs 47%, respectively, p = The study has multiple strengths. Yu et al (9) performed a 0.03), a finding that persisted even after adjustment for potenlarge observational study in patients at risk for the development tial confounding factors (1). Subsequently, other studies have of ARDS that allows for examination of multiple potential explored the relationship between diabetes and the develconfounders including the type of diabetes, acute hyperglyceopment of ARDS and reported very similar findings (2-7), mia, and a variety of diabetes medications. They used estabexcept for one study in patients undergoing high-risk surgery lished criteria to classify^ the different types of diabetes, and that found diabetics were more likely to develop postoperative they also underwent training regarding the radiographie criacute lung injury (8). teria for ARDS in order to minimize misclassification. The study also has some important limitations. Although they used predefined criteria to differentiate type 1 and type 2 diabet*See also p. 2720. ics, 23% of the patients with diabetes remained unclassified. Key Words: acute lung injury; acute respiratory distress syndrome; In addition, blood glucose levels were only collected within the comorbid conditions; diabetes; hyperglycemia first 24 hours of ICU admission. Therefore, the impact of gluDr. Esper's institution received grant support from National Heart, Lung cose control and glucose variability could not be examined. As and Blood Institute (K23 career development award, 1K23HL103842). Dr. Moss' institution received grant support from the National Institutes of hemoglobin AlC levels were not available, patients with previHealth (NIH) (K24 HL 089223). Drs. Moss and Esper received support ously undiagnosed diabetes may have been misclassified as not for article research from NIH. having diabetes. Therefore, obtaining hemoglobin AlC levels Copyright © 2013 by the Society of Critical Care Medicine and Lippincott would potentially improve the identification and classification Williams & Wilkins of diabetes in these critically ill patients. DOI: 10.1097/CCM.0b013e31829cb06b Division of Pulmonary and Critical Care Departnnent of Medicine Emory University Atlanta, GA

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December 2013 • Volume 41 • Number 1 2

Editorial

What may account for the conflicting results from the previous studies regarding the protective effect of diabetes on the susceptibility to develop ARDS? The most likely etiology is the difference in the patient populations enrolled into the various studies. Almost all of the studies demonstrating a protect effect of diabetes on the development of ARDS enrolled patients with specific well-defined at-risk diagnoses, such as septic shock (1, 3). The one study that did not confirm the association between diabetes and ARDS enrolled general ICU patients (13). Therefore, the effects of diabetes may not be generalizable to all ICU patients. Another etiology of the conflicting results may be related to different study designs. Retrospective studies were more likely to identify no association between diabetes and the development of ARDS, likely due to imprecise definitions resulting in nondifferential misclassification. It has been 13 years since the original observation reporting an association between diabetes and a decreased susceptibility to develop ARDS. Despite several confirmatory publications in this area, the validity of these epidemiological results was still considered to be uncertain. One reason for this persistent uncertainty is that the scientific community is generally reluctant to accept new ideas. This cautionary and somewhat skeptical approach to research is usually justified, as the results of many published studies are eventually determined to be false (14). Relevant to the critical care community, the results of several landmark clinical trials including intensive insulin therapy and activated protein C were not replicated in subsequent studies. However, based on several confirmatory studies including the most recent report by Yu et al (9), the protective effect of diabetes on the development of ARDS appears to have been confirmed. There are likely multiple mechanisms by which diabetes attenuates the susceptibility to develop ARDS (15). It is time to move forward and identify the specific molecular pathways involved in this epidemiological association. Ultimately, this research will strive to develop novel protective measures or therapies that will diminish the susceptibility to develop ARDS in patients with and without diabetes.

REFERENCES 1. Moss M, Guidot DM, Steinberg KP, et al: Diabetic patients have a decreased incidence of acute respiratory distress syndrome. Crit Care Med 2000; 28:2187-2192 2. Gong MN, Thompson BT, Williams P, et al: Clinical predictors of and mortality in acute respiratory distress syndrome: Potential role of red cell transfusion. Crit Care Med 2005; 33:1191 -1198 3. Iscimen R, Cartin-Ceba R, Yilmaz M, et al: Risk factors for the development of acute lung injury in patients with septic shock: An observational cohort study. Crit Care Med 2008; 36:151 8-1522 4. Esper AM, Moss M, Martin GS: The effect cf diabetes mellitus on organ dysfunction with sepsis: An epidemiological study. Crit Care 2009; 13:R18 5. Gong MN, Bajwa EK, Thompson BT, et al: Body mass index is associated with the development of acute respiratory distress syndrome. Thorax 20^0; 65:44-50 6. Trillo-Alvarez C, Cartin-Ceba R, Kor DJ, et al: Acute lung injury prediction score: Derivation and validation in a population-based sample. Eur Respir i 2011 ; 37:604-609 7. Gajic O, Dabbagh O, Park PK, et al; U.S. Critical Illness and Injury Trials Group: Lung Injury Prevention Study Investigators (USCIITGLIPS): Early identification of patients at risk of acute lung injury: Evaluation of lung injury prediction score in a multicenter cohort study. Am J Respir Crit Care Med 2011 ; 1 83:462-470 8. Kor DJ, Warner DO, Alsara A, et al: Derivation and diagnostic accuracy of the surgical lung injury prediction model. Anesthesiology 2011; 115:117-128 9. Yu S, Christiani DC, Thompson BT, et al: Role of Diabetes in the Development of Acute Respiratory Distress Syndrome. Crit Care Med 2013; 41:2720-2732 10. Honiden S, Gong MN: Diabetes, insulin, and development of acute lung injury. Crit Care Med 2009; 37:2455-2464 11. Sigurdsson GH, Vallgren S, Christenson JT: Influence of aspirin and steroids on acute lung injury after i.v. injection of a sclerosing agent. Acta Chir Scand 1989; 155:163-170 12. Eriioh JM, Talmor DS, Cartin-Ceba R, et al: Prehospitalization antiplatelet therapy is associated with a reduced incidence of acute lung injury: A population-based cohort study. Chest 2011; 139:289-295 13. Koh GC, Vlaar AP, Hofstra JJ, et al: In the critically ill patient, diabetes predicts mortality independent of statin therapy but is not associated with acute lung injury: A cohort study. Crit Care Med 2012; 40:1835-1843 14. loannidis JP: Why most published research findings are false. PLoS Med 2005; 2:e124 15. Moss M, Standiford TJ: Leptin in fibroproliferative acute respiratory distress syndrome: Not just a satiety factor. Am J Respir Crit Care Med 20] :; 183:1443-1444

The Guest Who Would Not Leave' Glenn Wortmann, MD, FACP, FIDSA Infectious Diseases Section MedSfar Washington Hospital Center Washington, DC

*See also p. 2733. Keywords: Acinetobacter; infection control; multidrug-resistant bacteria Dr. Wortmann lectured for the Speakers Bureau for Astellas. Copyright © 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM.0b013e31829cb097

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cinetobacter species, in particular Acinetobacter baumannii complex (ABC), has emerged as a successful, predominantly nosocomial, pathogen. The organism is a strictly aerobic Gram-negative bacterium, with the complex consisting of several closely related genospecies (1). Although some reports suggest that certain genospecies are associated with greater resistance to antibiotics and higher mortality in bacteremic patients, most clinical laboratories simply report the identified organism as ABC (2). ABC is ubiquitous and can be recovered from the environment, as well as healthy human skin (3,4). The organism has also been well reported to www.ccmjoumal.org

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Diabetes and acute respiratory distress syndrome: can we finally believe the epidemiology?

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