 LABORATORY INVESTIGATIONS Anesthesiology 2006; 104:73–9 © 2005 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Statistical Prediction of the Type of Gastric Aspiration Lung Injury Based on Early Cytokine/Chemokine Profiles Alan D. Hutson, Ph.D.,* Bruce A. Davidson, B.S.,† Krishnan Raghavendran, M.D.,‡ Patricia R. Chess, M.D.,§ Alan R. Tait, Ph.D., Bruce A. Holm, Ph.D.,# Robert H. Notter, M.D., Ph.D.,** Paul R. Knight, M.D., Ph.D.†† Background: Unwitnessed gastric aspiration can be a diagnos- tic dilemma, and early discrimination of different forms may help to identify individuals with increased risk of development of severe clinical acute lung injury or acute respiratory distress syndrome. The authors hypothesized that inflammatory medi- ator profiles could be used to help diagnose different types of gastric aspiration. Methods: Diagnostic modeling using a newly modified re- ceiver operator characteristic approach was applied to recently published data from our laboratory on lavaged inflammatory mediators from rodents given intratracheal normal saline, hy- drochloric acid, small nonacidified gastric particles, or a com- bination of acid and small gastric particles. Multiple animal groups and postaspiration times of injury were analyzed to gauge the applicability of the predictive approach: rats (6 and 24 h), C57/BL6 wild-type mice (5 and 24 h), and transgenic mice on the same background deficient in the gene for monocyte chemoattractant protein 1 (MCP-1 [/] mice; 5 and 24 h). Results: Overall, the four types of aspiration were correctly discriminated in 85 of 96 rats (89%), 72 of 78 wild-type mice (92%), and 59 of 73 MCP-1 (/) mice (81%) by models that used a maximum of only two mediators. The severe “two-hit” aspirate of the combination of acid and small gastric particles was correctly predicted in 21 of 24 rats, 23 of 23 wild-type mice, and 21 of 21 MCP-1 (/) mice. Specific best-fit mediators or mediator pairs varied with aspirate type, animal type, and time of injury. Cytokines and chemokines that best predicted the combination of acid and small gastric particles were cytokine- induced neutrophil chemoattractant 1 (6 h) and MCP-1 (24 h) in rats, tumor necrosis factor /macrophage inflammatory pro- tein 2 (5 h) and tumor necrosis factor /MCP-1 (24 h) in wild- type mice, and tumor necrosis factor /macrophage inflamma- tory protein 2 (5 h) and tumor necrosis factor /keratinocyte- derived cytokine (24 h) in MCP-1 (/) mice. Conclusions: These results support the potential feasibility of developing predictive models that use focused measurements of inflammatory mediators to help diagnose severe clinical forms of unwitnessed gastric aspiration, such as the combination of acid and small gastric particles, that may have a high risk of progres- sion to acute lung injury/acute respiratory distress syndrome. ASPIRATION of gastric contents causes lung injuries ranging from mild, subclinical pneumonitis to severe, progressive respiratory failure with associated high mor- tality. Gastric aspiration is common in unconscious pa- tients, with a reported occurrence of 1 in every 2,000 – 4,000 anesthetic cases. 1–3 The true incidence of clinical gastric aspiration is thought to be even higher, because many episodes are unwitnessed and manifest as unex- plained pulmonary dysfunction. 1 Further complicating the difficulty in diagnosis is the predisposition of pa- tients who have had an aspiration event to development of a secondary bacterial pneumonia, 1,4 which in many cases gives rise to similar respiratory deficits and symp- toms. A severe course associated with clinical acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) occurs in 10 –30% of witnessed gastric aspiration cases. 1,3 ALI/ARDS associated with gastric aspiration has a high mortality and accounts for up to 20% of all deaths attributable to anesthesia. 1,3 A recent National Heart, Lung and Blood Institute working group report empha- sized the importance of developing improved cellular and molecular methods in combination with animal and human studies to better understand the pathogenesis of ALI/ARDS and associated conditions, including gastric aspiration. 5 The current study focuses on the use of predictive models incorporating data on inflammatory mediators in lung lavage to help diagnose different forms of gastric aspiration. In the clinical setting, the composition of aspirated gastric material can vary considerably and may include low pH secretions, food particulate material of varying size, and bacteria from colonized stomach or oropharyn- geal flora. The specific form of aspiration is thought to be highly important in determining the severity and progression of lung injury in patients. A severe and more progressive form of ALI/ARDS is likely in patients if food particulate material is present along with acid during gastric aspiration. 6–8 The presence of food particles can be noted visually during witnessed aspiration or at the time of patient intubation, but in many instances (includ- ing all cases of unwitnessed aspiration), this is not pos- sible. Patients with severe forms of aspiration may also have increased sensitivity to iatrogenic factors such as hyperoxia or early mechanical ventilation, which are known to worsen the severity of aspiration lung injury in animals. 9,10 The ability to accurately diagnose different forms of gastric aspiration would identify at-risk sub- groups of patients and also potentially assist in develop- * Associate Professor, Department of Biostatistics, † Assistant Professor, De- partment of Anesthesiology, ‡ Assistant Professor, Departments of Anesthesiol- ogy and Surgery, # Professor, Departments of Pharmacology and Pediatrics, † Professor, Departments of Anesthesiology and Microbiology, State University of New York at Buffalo, Buffalo, New York. § Associate Professor, ** Professor, Department of Pediatrics, University of Rochester, Rochester, New York.  Associate Professor, Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan. Received from the Department of Anesthesiology, State University of New York at Buffalo, Buffalo, New York. Submitted for publication March 10, 2005. Accepted for publication July 21, 2005. Supported in part by grant Nos. HL-48889 (to Dr. Knight and Mr. Davidson), AI-46534 (to Dr. Knight and Mr. Davidson), HL-03910 (to Dr. Chess), and HL56176 (to Drs. Notter, Holm, and Chess) from the National Institutes of Health, Bethesda, Maryland, and by a New York Strategically Targeted Academic Research Faculty Development Grant (to Dr. Holm), Buffalo, New York. Address reprint requests to Dr. Knight: State University of New York Buffalo School of Medicine, 245 Biomedical Research Building, 3435 Main Street, Buffalo, New York 14214. Address electronic mail to: pknight@buffalo.edu. Individual article reprints may be purchased through the Journal Web site, www.anesthesiology.org. 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