Towards prevention of acute lung injury: frequency and outcomes of emergency department patients at risk- a multicenter ...

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Title:
Towards prevention of acute lung injury: frequency and outcomes of emergency department patients at risk- a multicenter cohort study
Physical Description:
Mixed Material
Language:
English
Creator:
Hou, Peter C.
Elie-Turenne, Marie-Carmelle
Mitani, Aya
Barry, Jonathan M.
Kao, Erica Y.
Cohen, Jason E.
Frendl, Gyorgy
Publisher:
Springer Open Journal(International Journal of Emergency Medicine)

Notes

Abstract:
Background: Few emergency department (ED) evaluations on acute lung injury (ALI) have been carried out; hence, we sought to describe a cohort of hospitalized ED patients at risk for ALI development. Methods: Patients presenting to the ED with at least one predisposing condition to ALI were included in this study, a subgroup analysis of a multicenter observational cohort study (USCIITG-LIPS 1). Patients who met ALI criteria within 6 h of initial ED assessment, received end-of-life care, or were readmitted during the study period were excluded. Primary outcome was frequency of ALI development; secondary outcomes were ICU and hospital mortality. Results: Twenty-two hospitals enrolled 4,361 patients who were followed from the ED to hospital discharge. ALI developed in 303 (7.0 %) patients at a median onset of 2 days (IQR 2–5). Of the predisposing conditions, frequency of ALI development was highest in patients who had aortic surgery (43 %) and lowest in patients with pancreatitis (2.8 %). Compared to patients who did not develop ALI, those who did had higher ICU (24 % vs. 3.0 %, p < 0.001) and hospital (28 % vs. 4.6 %, p < 0.001) mortality, and longer hospital length of stay (16 vs. 5 days, p < 0.001). Among the 22 study sites, frequency of ALI development varied from less than 1 % to more than 12 % after adjustment for APACHE II. Conclusions: Seven percent of hospitalized ED patients with at least one predisposing condition developed ALI. The frequency of ALI development varied significantly according to predisposing conditions and across institutions. Further research is warranted to determine the factors contributing to ALI development.
General Note:
Publication of this article was funded in part by the University of Florida Open-Access publishing Fund. In addition, requestors receiving funding through the UFOAP project are expected to submit a post-review, final draft of the article to UF's institutional repository, IR@UF, (www.uflib.ufl.edu/UFir) at the time of funding. The institutional Repository at the University of Florida community, with research, news, outreach, and educational materials.
General Note:
Hou et al. International Journal of Emergency Medicine 2012, 5:22 http://www.intjem.com/content/5/1/22; Pages 1-12
General Note:
doi:10.1186/1865-1380-5-22 Cite this article as: Hou et al.: Towards prevention of acute lung injury: frequency and outcomes of emergency department patients at-risk – a multicenter cohort study. International Journal of Emergency Medicine 2012 5:22

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Web files Appendices 1. Material and Methods: Study Flow 2. Material and Methods: Definition of clinical variables (in cluding references) 3. Table 1 & 2 comparing US versus Non-US study sites 4. Table 1 & 2 comparing Prospective versus Retrospective study sites in the US 5. Acknowledgement

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Appendix 1 Materials and Methods: Study Flow Reviewallhospital admissionseachday (excludepatientswithALI/ARDS at presentation) Doespatienthaveoneofthesehighriskconditions? -sepsis, severesepsis, pancreatitis, shock -high-risktrauma, high-risksurgery -pneumoniaoraspiration FILL OUT FORM 1 (BASELINE) Stop YesNo Followpatienteverydayuntildischarge fromhospital collectfluid balance day1-4. collecttransfusiondata (numberofunits) -DoesABG getdone? Check ifPaO2/FIO2 ratio < 300 notALI/ARDS No Yes Check CXR: bilateral pulmonaryedema? notALI/ARDS NoYes Isthereleftatrialhypertension? notALI/ARDS YesNo notALI/ARDS Yes No ALI/ARDS STUDY FLOW FILL OUT FORM 2 (HOSPITAL AND OUTCOME)

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Appendix 2 Materials and Methods: Definitions of clinical variables Alcohol abuse: Known diagnosis of chronic alcoholism or a previous admi ssion for alcohol detoxification or alcohol withdrawal; daily alcohol con sumption of >14 drinks a week; or >5 drinks binges 1 Tobacco exposure: Patients or surrogates were asked about used of tobacco produc ts in the number of cigarettes and also the amount per day and the years of smoking, in order to report pack-years. United States Department of Health and Human Se rvices, Substance Abuse and Mental Health Services Administration ( http://www.samhsa.gov/index.aspx ). Former smoker is defined if the patient quits 30 or more days before admission Diabetes mellitus: Documentation of diabetes in the clinical record bas ed on the 2007 American Diabetes Association Statement of the Expert Committ ee on the Diagnosis and Classification of Diabetes Mellitus 7 : 1. Symptoms of diabetes plus casual plasma glucose conc entration >200 mg/dl. Casual is defined as any time of day without regard to time since last mea l. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. OR 2. FPG >126 mg/dl. Fasting is defined as no caloric intake fo r at least 8 h. OR

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3. 2-h postload glucose > 200 mg/dl during an OGTT. The test s hould be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water. Chronic interstitial lung disease: As defined by the American Thoracic Society/European Respiratory Society International Multidisciplinary Co nsensus Classification of the Idiopathic Interstitial Pneumonias 10 as a group of disorders of known causes (collagen vascula r disease, environmental or drug related) as well as disorders of unkn own cause. The latter include idiopathic interstitial pneumonias (IIPs), granulomato us lung disorders (e.g., sarcoidosis), and other forms of interstitial lung disease (ILD) includ ing lymphangioleiomyomatosis (LAM), pulmonary Langerhans' cell histiocytosis/histiocytosis X (HX), and eosinophilic pneumonia. The most important distinction among the idiopathic intersti tial pneumonias is that between idiopathic pulmonary fibrosis and the other interstitial pneumonias (IPs), which include nonspecific interstitial pneumonia (a provisional term ), desquamative interstitial pneumonia, pneumonia, and lymphocytic interstitial pneumonia. respira tory bronchiolitis-associated interstitial lung disease, acute interstitial pneumoni a, cryptogenic organizing pneumonia. Cirrhosis: Cirrhosis represents a late stage of progressive hepatic fibrosis characterized by distortion of the hepatic architecture and the formatio n of regenerative nodules. The gold standard for diagnosis of cirrhosis is with a liver biops y, however, liver biopsy is not necessary if the clinical, laboratory, and radiologic data strongly suggest the presence of cirrhosis. An example would be a patient with ascites, severe coagulopa thy, and a shrunken nodular appearing liver on ultrasonography 12 Cancer, lymphoma and leukemias: as defined by the National Cancer Institute in the Ter ms & Definitions MP/H Coding Rules (http://www.cancer.gov/s earch/results.aspx)

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Carcinoma cancer that begins in the skin or in tissues that line or cover internal organs. Sarcoma cancer that begins in bone, cartilage, fat, muscle blood vessels, or other connective or supportive tissue. Leukemia cancer that starts in blood-forming tissue such as the bone marrow and causes large numbers of abnormal blood cells to be produced an d enter the blood. Lymphoma and myeloma cancers that begin in the cells of the immune sy stem Central nervous system cancers cancers that begin in the tissues of the brain an d spinal cord. Metastasis : The spread of cancer from one part of the body to ano ther. A tumor formed by cells that have spread is called a "metastatic tumor or a "metastasis." The metastatic tumor contains cells that are like those in the origin al (primary) tumor. AIDS: Defined by the CDC 20 as all patients in categories A3, B3, C1-C3 from the t able below are reported as AIDS based upon prior AIDS-indicator con ditions and/or a CD4 cell count <200/mm3. AIDS-indicator conditions include three new entri es added to the 1987 case definition: recurrent bacterial pneumonia, invasive cervi cal cancer, and pulmonary tuberculosis. Symptomatic conditions not included in category C that (a ) are attributed to HIV infection or indicate a defect in cell-mediated immunity or (b) are conditions considered to have a clinical course or to require management that is complicated by HIV infection. Examples of B conditions include but are not limited to baciliary angiomatosis; thr ush; vulvovaginal candidiasis that is persistent, frequent or poorly responsive to therapy; cervical dysplasia (moderate or severe); cervical carcinoma in situ; constitutional symptoms such as fever (38.5¡C) or diarrhea for more than one month; oral hairy leukoplakia; and herpes zoste r involving two episodes or more than one dermatome.

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Immunosuppression: defined as therapy with immunosuppressants, chemotherapy, radiation or long term/recent high dose of steroids; or active leukemi a, lymphoma or AIDS 22 Heart Failure: Documentation of heart failure in the clinical recor d as defined by the ACC/AHA 2005 Guideline Update for the Diagnosis and Managemen t of Chronic Heart Failure in the Adult: a report of the American College of Card iology/American Heart Association Task Force on Practice Guidelines(Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in co llaboration with the American College of Chest Physicians and the International Societ y for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society 6 Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disor der that impairs the ability of the ventricle to fill with or eject blood. HF is defined as a clinical sy ndrome that is characterized by specific symptoms (dyspnea and fatigue) in the medical history an d signs (edema, rales) on the physical examination. There is no single diagnostic test for HF because it is largely a clinical diagnosis that is based on a careful history and physical examinatio n. The clinical syndrome of HF may result from disorders of the pericardium, myocardium, endocardium, or great vessels, but majority of patients with HF has symptoms due to an impai rment of LV myocardial function. Heart failure may be associated with a wide spectrum of LV functional abnormalities, which may range from patients with normal LV size and preser ved EF to those with severe dilatation and/or markedly reduced EF. In most patients, abnormaliti es of systolic and diastolic dysfunction coexist, regardless of EF. COPD: Documentation in the clinical record of COPD based on the Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstr uctive Pulmonary Disease NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop Summary 8 : COPD is a disease state characterized by airflow li mitation that is not fully

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reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. A diagnosis of COPD should be considered in any patient who has symptoms of cough, sput um production, or dyspnea, and/or a history of exposure to risk factors for the disease. The d iagnosis is confirmed by spirometry. The presence of a post-bronchodilator FEV 1 < 80% of the predicted value in combination with an FEV 1 /FVC < 70% confirms the presence of airflow limitation that is not fully reversible. Where spirometry is unavailable, the diagnosis of COPD should be made using all available tools. Clinical symptoms and signs, such as abnormal shortness of breath and incr eased forced expiratory time, can be used to help with the diagnosis. A low peak flow is consistent with COPD, but has poor specificity because it can be caused by other lung diseases and by poor performance. In the interest of improving the diagnosis of COPD, eve ry effort should be made to provide access to standardized spirometry. Chronic cough and sputum production often precede the development of airflow limitation by many years, although not all individuals with cough and sputum production go on to develop COPD. Chronic kidney disease: The National Kidney Foundation Kidney Disease Outcom es Quality Initiative (NKF-K/DOQI) workgroup has defined CKD as the f ollowing 13 which has been accepted internationally 14 : the presence of markers of kidney damage for 3 months, as defined by structural or functional abnormalities of the kidne y with or without decreased glomerular filtration rate (GFR), that can lead to decreased GFR, manifest by either pathological abnormalities or other markers of kidney damage, including a bnormalities in the composition of blood or urine, or abnormalities in imaging tests; or the presence of GFR <60 mL/min/1.73 m2 for 3 months, with or without other signs of kidney damage as described above. Pneumonia: be defined according to three different categories as es tablished by the 2005 International Sepsis Forum Consensus Conference on Defi nitions of Infection in the Intensive

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Care Unit: Microbiologically confirmed : The patient must have a new or progressive radiographic infiltrate, along with a high clinical suspic ion of pneumonia plus a definite cause established by the recovery of a probable etiologic agent from a) an uncontaminated specimen (blood, pleural fluid, transtracheal aspirate, or transth oracic aspirate); b) the recovery from respiratory secretions of a likely pathogen that does n ot colonize the upper airways (e.g., Mycobacterium tuberculosis Legionella species, influenza virus, or Pneumocystis jiroveci (carinii ); c) recovery of a likely/possible respiratory pathoge n in high concentrations using quantitative cultures of a lower respiratory tract sam ple (endotracheal aspirate, BAL, or protected specimen brush); or d) positive serology. Probable : The patient must have a new or progressive radiographic infiltrate along with a high clinical suspic ion of pneumonia plus detection (by staining or culture) of a likely pulmonary pathogen in respi ratory secretions (expectorated sputum, endotracheal or bronchoscopic aspirate, or quantit atively cultured bronchoscopic BAL fluid or brush catheter specimen), but in concentration s below the diagnostic threshold, or the presence of a negative lower respiratory tract culture i f collected within 72 hrs after starting a new antibiotic regimen. Possible : Abnormal chest radiograph of uncertain cause, in a pati ent with a low or moderate clinical suspicion of pneumonia, but with microbiological or serological evidence of definite or probable pneumonia 23 Given the timing of our evaluation (hospital admission) the microbiologic proof not be possible and not be required and a practical CDC definition be app lied: 1) Chest radiographs showing new or progressive infiltrate, c onsolidation, cavitation or pleural effusion AND 2) Either of: i. New onset purulent sputum and/or change in its character,

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OR ii. IF AVAILABLE: 1. positive blood culture or isolation of pathogen from specime n obtained by transtracheal space, bronchial brushing or biopsy and/or is olation of virus or viral antigen detection from respiratory secreti ons 2. diagnostic single antibody titer (IgM) or fourfold incr ease in sera (IgG) for pathogen 3. histopathological evidence of pneumonia Sepsis: Suspected or documented infection in the presence of more than one of the following clinical manifestations: (1) a body temperature greater than 38¡C or less than 36¡C; (2) a heart rate greater than 90 beats per minute; (3) tachypnea, manifested by a respiratory rate greater tha n 20 breaths per minute, or hyperventilation, as indicated by a PaCO2 of less than 32 mm Hg; and (4) an alteration in the white blood cell count, such as a c ount greater than 12,000/cu mm, a count less than 4,000/cu mm, or the presence of more than 10 percent immature neutrophils ("bands") 24 Shock: We defined shock as recommended by the 2006 International Cons ensus Conference on Hemodynamic Monitoring in Shock and Implications for Ma nagement 25 : Presence of hypotension with evidence of inadequate tissue perfusion on phy sical examination (altered mental status not explained by other causes other than the hemodynamic status and urine output less than 0.5 ml/Kg/min). Hypotension was defined as a syst olic blood pressure (SBP) < 90mmHg, or SBP decrease of 40 mmHg from baseline, or mean arterial pressure (MAP) < 65mmHg 25 We expanded the definition of shock in the absence of hy potension when shock is suggested by history and physical examination; according to the c onsensus recommendation 25 In this case, markers of inadequate perfusion were used and defi ned as follows: central venous oxygen saturation (ScvO2) or mixed venous oxygen saturation (SvO2) less than 70% 26 blood

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lactate levels greater than 4 mmol/L 26 in the absence of known acute or chronic liver disease, increased base deficit < -4 26 and blood pH less than 7.32 26 Septic shock : Sepsis in the presence of shock 24 that is defined as hypotension with evidence of inadequate tissue perfusion: systolic blood pressure (SBP) < 90m mHg, or SBP decrease of 40 mmHg from baseline, or mean arterial pressure (MAP) < 65m mHg 25 Hypovolemic shock: presence of shock as previously described, in the setting of clinical documented volume loss and resolution of hypotension and n ormalization of markers of tissue hypoperfusion after resuscitation with fluid or blood products or surgical intervention to obtain vascular control when appropriate 25, 27 There must not be convincing evidence for a primary alternative diagnosis of cardiogenic or distributive sh ock 27 Cardiogenic shock: presence of shock as previously described, in the setting of clinical documented inadequate tissue perfusion due to cardiac dysfunct ion. The most common etiology is an acute myocardial infarction (MI) with left vent ricular failure, but it can also be caused by mechanical complications, such as acute mitral regurgitat ion or ventricular septal defect, hypertrophic cardiomyopathy, valvular disease, or myocardi tis 28, 29 Aspiration: witnessed or suggestive history of inhalation of food or r egurgitated gastric contents 30 Acute pancreatitis: Defined by the Practice Guidelines in Acute Pancreatitis as two of the following three features: 1) abdominal pain characteristic of acute pancreatitis, 2) serum amylase and/or lipase >/ 3 times the upper limit of normal, and 3) characteristic findings of acute pancreatitis on CT scan 31

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Trauma: presence of lung contusion, blast injury, fracture of two or more long bones, traumatic brain injury and smoke inhalation 35 .Near drowning: Submersion accident with at least temporary survival (near drowning), or water rescue or remov al of victim from water (save) 32 Heat stroke: is defined as a core body temperature in e xcess of 40.5C (105F) with associated central nervous system dysfunction in the setting of a large environmental heat load that cannot be dissipated 33 High risk surgery: defined as any of the following procedures 36, 37 : All cardiac and aortic vascular procedures (excluding endo vascular procedures) Noncardiac thoracic surgery including esophageal and pulmonary (excluding thoracoscopic surgery) Acute abdomen Orthopedic spine surgeries Mechanical ventilation(MV): Invasive and non-invasive mechanical ventilation for mor e than 1 hour, except for post operative patients requiring MV for l ess than 12 hours after the surgery and patients who use chronic non-invasive ventilation treatme nt for obstructive sleep apnea (OSA) were excluded 46, 47 Glasgow Coma Scale: defined according to the original description by Teasdale and collaborators 49 Inspired oxygen concentration FIO 2 and arterial oxygen tension PaO 2 : When arterial blood gases are not available, FIO 2 and PaO 2 was estimated from oxygen saturation (SaO 2 ) and FIO 2 according to Rice at al 52 .An SaO 2 / FIO 2 value of 235 corresponds with P/F ratio of 200 while S/F

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value of 315 corresponds with P/F ratio of 300. In non-intubat ed patients approximate FIO 2 were estimated based on oxygen flow and device type.

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51. Ely EW, Inouye SK, Bernard GR, et al. Delirium in m echanically ventilated patients: Validity and reliability of the Confusion Assessment Me thod for the intensive care unit (CAM-ICU). Journal of the American Medical Associati on 2001;286(21):2703-10. 52. Rice TW, Wheeler AP, Bernard GR, Hayden DL, Schoenfe ld DA, Ware LB. Comparison of the SpO2/FiO2 Ratio and the PaO2/FiO2 Ratio in Patient s with Acute Lung Injury or Acute Respiratory Distress Syndrome. Chest 2007.

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Appendix 3 Table 1: Demographics, Predisposing conditions, and Risk modifiers Variable Total (n=4361) US sites (n=4233) Non US sites (n=128) P-value Demographics Median age (Q1, Q3) 56.0 (41.0, 71.0) 56.0 (41.0, 71.0) 57.0 (38.5, 68.5) 0.396 Male, no. (%) 2422 (55.5%) 2332 (55.1%) 90 (70.3%) < 0.001 Caucasian (n=4220), no. (%), 2608 (61.8%) 2608 (63.7%) 0 (0.0%) < 0.001 Weight (n=3905), median (Q1, Q3) 76.5 (63.5, 91.0) 76.5 (63.5, 91.6) 76.5 (65.0, 88.0) 0.523 PBW(n=3551), median (Q1, Q3) 63.8 (64.7, 73.0) 63.8 (54.6, 73.0) 65.9 (56.9, 70.5) 0.874 Admission source (n=4311), no. (%) < 0.001 Home 3331 (77.3%) 3249 (77.7%) 82 (64.1%) Nursing facility 338 (7.8%) 338 (8.1%) 0 (0.0%) Outside ED 440 (10.2%) 423 (10.1%) 17 (13.%) Other 202 (4.7%) 173 (4.1%) 29 (22.7%) APACHE II (Q1, Q3) 10.0 (6.0, 15.0) 10.0 (5.0, 15.0) 13.5 (7.0, 19.0) < 0.001 Predisposing conditions Shock 395 (9.1%) 391 (9.2%) 4 (3.1%) 0.018 Aspiration 210 (4.8%) 202 (4.8%) 8 (6.3%) 0.442 Sepsis 1806 (41.4%) 1795 (42.4%) 11 (8.6%) < 0.001 Pancreatitis 323 (7.4%) 308 (7.3%) 15 (11.7%) 0.059 Pneumonia 1227 (28.1%) 1189 (28.1%) 38 (29.7%) 0.692 High risk trauma Traumatic brain injury 490 (11.2%) 474 (11.2%) 16 (12.5%) 0.646 Smoke inhalation 27 (0.6%) 27 (0.6%) 0 (0.0%) 1.000 Near drowning 3 (0.1%) Lung contusion 188 (4.3%) 179 (4.2%) 9 (7.0%) 0.124 Multiple fractures 330 (7.6%) 307 (7.3%) 23 (18.0%) < 0.001 High risk surgery Thoracic (noncardiac) 5 (0.1%) 5 (0.1%) 0 (0.0%) 1.000 Orthopedic spine 17 (0.4%) 14 (0.3%) 2 (2.34%) 0.012 Acute abdomen 295 (6.8%) 273 (6.5%) 22 (17.2%) < 0.001 Cardiac surgery 20 (0.5%) 12 (0.3%) 8 (6.3%) < 0.001 Aortic vascular 14 (0.3%) 11 (0.3%) 3 (2.3%) < 0.001 Emergency surgery 339 (7.7%) 302 (7.1%) 37 (28.9%) < 0.001 Risk Modifiers Alcohol abuse 421 (9.7%) 417 (9.9%) 4 (3.1%) 0.011 Obesity (n=3508) 1020 (29.1%) 996 (29.5%) 24 (18.8%) 0.009 Chemotherapy 158 (3.6%) 157 (3.7%) 1 (0.8%) 0.091

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Diabetes mellitus 1042 (23.9%) 1020 (24.1%) 22 (17.2%) 0.071 Smoking (n=4019) 0.222 None 2060 (51.3%) 2005 (51.5%) 55 (43.7%) Former 888 (22.1%) 856 (22.0%) 32 (25.4%) Active 1071 (26.7%) 1032 (26.5%) 39 (31.0%) RR (n=4137), median (Q1,Q3) 20.0 (18.0, 24.0) 20.0 (18.0, 24.0) 20.0 (16.0, 24.0) 0.057 Tachypnea (n=4137), no. (%) 315 (7.6%) 304 (7.6%) 11 (8.7%) 0.632 SpO2 (n=4361), median (Q1, Q3) 97.0 (94.0, 99.0) 97.0 (94.0, 99.0) 97.0 (93.0, 98.0) 0.541 SpO2 >95% (n=4361) 1203 (27.6%) 1166 (27.6%) 37 (28.9%) 0.734 FiO2 (n=4361), median (Q1, Q3) 0.2 (0.2, 0.3) 0.2 (0.2, 0.3) 0.4 (0.2, 0. 5) < 0.001 FiO2 >0.35 (n=4796), no. (%) 841 (19.3%) 757 (17.9%) 76 (59.4%) < 0.001 Albumin (n=2423), median (Q1, Q3) 3.5 (2.9, 4.0) 3.5 (2.9, 4.0) 3.8 (3.3, 4.1) 0.173 Hypoalbuminemia (n=2423), no. (%) 945 (47.1%) 939 (47.3%) 6 (30.0%) 0.123 pH (n=1499), median (Q1, Q3) 7.4 (7.3, 7.4) 7.4 (7.3, 7.4) 7.4 (7.3, 7.4) 0.043 Acidosis (pH <7.35), no. (%) 476 (45.9%) 435 (46.9%) 41 (37.3%) 0.056 PRW: Predicted Body Weight; RR: Respiratory Rate; Tachyp nea = RR > 30; SpO2: Oxygen Saturation; FiO2: Fraction of Inspired Oxygen

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Table 2: Hospital Course and Outcomes Variable Total (n=4361) US sites (n=4233) Non US sites (n=128) Pvalue ALI 303 (7.0%) 266 (6.3%) 37 (28.9%) < 0.001 ICU admission, no. (%) 2320 (53.2%) 2217 (52.4%) 103 (80.5%) < 0.001 ICU LOS (n=2320), median (Q1, Q3) 2.0 (1.0, 5.0) 2.0 (1.0, 5.0) 5.0 (2.0, 17.0) < 0.001 Hospital LOS (n=4361), median (Q1, Q3) 6.0 (3.0, 10.0) 6.0 (3.0, 10.0) 13.5 (7.0, 26.5) < 0.001 Vasopressors use, no. (%) 448 (10.3%) 408 (9.6%) 40 (31.3%) < 0.001 Acute hemodialysis (n=4290), no. (%) 148 (3.5%) 140 (3.4%) 8 (6.3%) 0.084 ICU mortality, no. (%) 194 (4.5%) 174 (4.1%) 20 (15.6%) < 0.001 Hospital mortality, no. (%) 272 (6.2%) 249 (5.9%) 23 (18.0%) < 0.001 Mechanical ventilation (n=4223) 1299 (30.8%) 1206 (29.5%) 93 (72.7%) < 0.001 Invasive (n=4228), no. (%) 997 (23.6%) 906 (22.1%) 91 (71.1%) < 0.001 Invasive duration (n=932), median (Q1, Q3) 3.0 (1.0, 8.0) 3.0 (1.0, 8.0) 4.0 (1.0, 19.0) 0.011 Mode: Volume Control 762 (83.9%) 691 (84.5%) 71 (78.9%) 0.099 Mode: Pressure Control 111 (12.2%) 94 (11.5%) 17 (18.9%) TV/PBW (n=768), median (Q1, Q3) 8.3 (7.4, 9.5) 8.2 (7.3, 9.5) 8.6 (7. 9, 9.6) 0.031 TV/PBW (n=768) > 8, no. (%) 456 (59.4%) 391 (57.7%) 65 (72.2%) 0.016 TV/PBW (n=768) 6-8, no. (%) 272 (35.4%) 248 (36.6%) 24 (26.7%) TV/PBW (n=768) < 6, no. (%) 40 (5.2%) 39 (5.8%) 1 (1.1%) Plateau Pressure (n=435), median (Q1, Q3) 19.0 (16.0, 24.0) 20.0 (17.0, 25.0) 15.9 (14.0, 18.0) < 0.001 PEEP, (n=916), median (Q1, Q3) 5.0 (5.0, 5.5) 5.0 (5.0, 5.0) 5.0 (5.0, 6.0) 0.018 Non-invasive (n=4146), no. (%) 470 (11.3%) 460 (11.5%) 10 (7.9%) 0.211 Non-invasive duration (n=461), median (Q1, Q3) 2.0 (1.0, 5.0) 2.0 (1.0, 5.0) 2.0 (2.0, 3.0) 0.745 ICU: Intensive Care Unit; LOS: Length of Stay; TV: Ti dal Volume; PBW: Predicted Body Weight; PEEP: Peak End-Expiratory Pressure

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Appendix 4 Table 1: Demographics, Predisposing conditions, and Risk modifiers Variable US sites (n=4233) Prospective (n=3981) Retrospective (n=252) Pvalue Demographics Median age (Q1, Q3) 56.0 (41.0, 71.0) 56.0 (42.0, 72.0) 52.0 (40.5, 65.0) 0.011 Male, no. (%) 2332 (55.1%) 2163 (54.3%) 169 (67.1%) < 0.001 Caucasian (n=4220), no. (%), 2608 (63.7%) 2429 (63.1%) 179 (73.7%) < 0.001 Weight (n=3905), median (Q1, Q3) 76.5 (63.5, 91.6) 76.4 (63.5, 91.6) 76.8 (64.0, 91.2) 0.958 PBW(n=3551), median (Q1, Q3) 63.8 (54.6, 73.0) 63.8 (54.6, 73.0) 66.0 (56.9, 73.7) 0.018 Admission source (n=4311), no. (%) < 0.001 Home 3249 (77.7%) 3079 (78.2%) 170 (69.7%) Nursing facility 338 (8.1%) 325 (8.3%) 13 (5.3%) Outside ED 423 (10.1%) 383 (9.7%) 40 (16.4%) Other 173 (4.1%) 152 (3.9%) 21 (8.6%) APACHE II (Q1, Q3) 10.0 (5.0, 15.0) 10.0 (6.0, 14.0) 11.0 (5.0, 17.0) 0.295 Predisposing conditions Shock 391 (9.2%) 353 (8.9%) 38 (15.1%) 0.001 Aspiration 202 (4.8%) 130 (3.3%) 72 (28.6%) < 0.001 Sepsis 1795 (42.4%) 1717 (43.1%) 78 (31.0%) < 0.001 Pancreatitis 308 (7.3%) 294 (7.4%) 14 (5.6%) 0.278 Pneumonia 1189 (28.1%) 1105 (27.8%) 84 (33.3%) 0.056 High risk trauma Traumatic brain injury 474 (11.2%) 472 (11.9%) 2 (0.8%) < 0.001 Smoke inhalation 27 (0.6%) 21 (0.5%) 6 (2.4%) 0.004 Near drowning Lung contusion 179 (4.2%) 152 (3.8%) 27 (10.7%) < 0.001 Multiple fractures 307 (7.3%) 273 (6.9%) 34 (13.5%) < 0.001 High risk surgery Thoracic (noncardiac) 5 (0.1%) 5 (0.1%) 0 (0.0%) 1.000 Orthopedic spine 14 (0.3%) 14 (0.4%) 0 (0.0%) 1.000 Acute abdomen 273 (6.5%) 258 (6.5%) 15 (6.0%) 0.741 Cardiac surgery 12 (0.3%) 12 (0.3%) 0 (0.0%) 1.000 Aortic vascular 11 (0.3%) 10 (0.3%) 1 (0.4%) 0.491 Emergency surgery 302 (7.1%) 285 (7.2%) 17 (6.8%) 0.805 Risk Modifiers Alcohol abuse 417 (9.9%) 360 (9.0%) 57 (22.6%) < 0.001 Obesity (n=3508) 996 (29.5%) 939 (29.5%) 57 (28.4%) 0.722 Chemotherapy 157 (3.7%) 154 (3.9%) 3 (1.2%) 0.029

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Diabetes mellitus 1020 (24.1%) 973 (24.4%) 47 (18.7%) 0.037 Smoking (n=4019) < 0.001 None 2005 (51.5%) 1896 (51.9%) 109 (46.0%) Former 856 (22.0%) 839 (23.0%) 17 (7.2%) Active 1032 (26.5%) 921 (25.2%) 111 (46.8%) RR (n=4137), median (Q1,Q3) 20.0 (18.0, 24.0) 20.0 (18.0, 24.0) 26.0 (19.0, 32.0) < 0.001 Tachypnea (n=4137), no. (%) 304 (7.6%) 280 (7.1%) 24 (30.0%) < 0.001 SpO2 (n=4361), median (Q1, Q3) 97.0 (94.0, 99.0) 97.0 (94.0, 98.0) 96.0 (93.0, 98.0) < 0.001 SpO2 >95% (n=4361) 1166 (27.6%) 1070 (26.9%) 96 (38.1%) < 0.001 FiO2 (n=4361), median (Q1, Q3) 0.2 (0.2, 0.3) 0.2 (0.2, 0.3) 0.5 (0.3, 1.0) < 0.001 FiO2 >0.35 (n=4796), no. (%) 757 (17.9%) 669 (16.8%) 88 (34.9%) < 0.001 Albumin (n=2423), median (Q1, Q3) 3.5 (2.9, 4.0) 3.5 (3.0, 4.0) 2.8 (2.5, 3.5) < 0.001 Hypoalbuminemia (n=2423), no. (%) 939 (47.3%) 881 (46.3%) 58 (71.6%) < 0.001 pH (n=1499), median (Q1, Q3) 7.4 (7.3, 7.4) 7.4 (7.3, 7.4) 7.4 (7.3, 7.4) 0.982 Acidosis (pH <7.35), no. (%) 435 (46.9%) 383 (46.9%) 52 (46.9%) 0.995 PRW: Predicted Body Weight; RR: Respiratory Rate; Tachyp nea = RR > 30; SpO2: Oxygen Saturation; FiO2: Fraction of Inspired Oxygen

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Table 2: Hospital Course and Outcomes Variable US sites (n=4233) Prospective (n=3981) Retrospective (n=252) Pvalue ALI 266 (6.3%) 241 (6.1%) 25 (9.9%) 0.014 ICU admission, no. (%) 2217 (52.4%) 2137 (53.7%) 80 (31.8%) < 0.001 ICU LOS (n=2320), median (Q1, Q3) 2.0 (1.0, 5.0) 2.0 (0.0, 5.0) 4.0 (3.0, 8.0) < 0.001 Hospital LOS (n=4361), median (Q1, Q3) 6.0 (3.0, 10.0) 5.0 (3.0, 10.0) 7.0 (4.0, 14.0) < 0.001 Vasopressors use, no. (%) 408 (9.6%) 382 (9.6%) 26 (10.3%) 0.707 Acute hemodialysis (n=4290), no. (%) 140 (3.4%) 129 (3.3%) 11 (4.4%) 0.363 ICU mortality, no. (%) 174 (4.1%) 161 (4.0%) 13 (5.2%) 0.388 Hospital mortality, no. (%) 249 (5.9%) 233 (5.9%) 16 (6.4%) 0.745 Mechanical ventilation (n=4223) 1206 (29.5%) 1090 (27.6%) 116 (83.5%) < 0.001 Invasive (n=4228), no. (%) 906 (22.1%) 810 (20.5%) 96 (69.1%) < 0.001 Invasive duration (n=932), median (Q1, Q3) 3.0 (1.0, 8.0) 3.0 (1.0, 7.0) 4.0 (2.0, 9.0) 0.006 Mode: Volume Control 691 (84.5%) 596 (82.6%) 95 (99.0%) < 0.001 Mode: Pressure Control 94 (11.5%) 93 (12.9%) 1 (1.0%) TV/PBW (n=768), median (Q1, Q3) 8.2 (7.3, 9.5) 8.3 (7.3, 9.6) 8.0 (7.4, 9.1) 0.230 TV/PBW (n=768) > 8, no. (%) 391 (57.7%0 348 (58.3%) 43 (53.1%) 0.556 TV/PBW (n=768) 6-8, no. (%) 248 (36.6%) 214 (35.9%) 34 (42.0%) TV/PBW (n=768) < 6, no. (%) 39 (5.8%) 35 (5.9%) 4 (4.9%) Plateau Pressure (n=435), median (Q1, Q3) 20.0 (17.0, 25.0) 21.0 (17.0, 26.0) 20.0 (17.0, 24.0) 0.661 PEEP, (n=916), median (Q1, Q3) 5.0 (5.0, 5.0) 5.0 (5.0, 5.0) 5.0 (5.0, 6.0) 0.008 Non-invasive (n=4146), no. (%) 460 (11.5%) 425 (10.8%) 35 (44.3%) < 0.001 Non-invasive duration (n=461), median (Q1, Q3) 2.0 (1.0, 5.0) 2.0 (1.0, 4.0) 5.0 (3.0, 13.0) < 0.001 ICU: Intensive Care Unit; LOS: Length of Stay; TV: Ti dal Volume; PBW: Predicted Body Weight; PEEP: Peak End-Expiratory Pressure

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Appendix 5 : Acknowledgement USCIITG LIPS1 participating centers and corresponding inve stigators Mayo Clinic Rochester, Minnesota : Adil Ahmed MD, Ognjen Gajic MD, Michael Malinchoc MS, Daryl J Kor MD, Bekele Afessa, MD, Rodrigo Cartin-Ceba, MD, De partments of Internal Medicine, Health Sciences Research, and Anesthesiology University of Missouri, Columbia : Ousama Dabbagh, MD, MS, FCCP, FASSM, Assistant Pro fessor of Clinical Medicine, Associate Fellowship Program Director, Diplomat, American Board of Sleep Medicine; Nena Kallenbach, Administrative Assistant University of Michigan, Ann Arbor : Pauline K. Park, MD, FACS, FCCS, Co-Director, Surg ical Intensive Care Unit, Associate Professor, Surgery, Julie Harris, Clinical Research Coordinator; Lena Napolitano, MD; Krishnan Raghavendran, MBBS; Robert C. Hyzy, MD; Ja mes Blum, MD; Christy Dean University of Texas Southwestern Medical Center in Dalla s, Texas : Adebola Adesanya, MD; Srikanth Hosur, MD; Victor Enoh, MD, Department of Anesthesiology, Division of Critical Care Medicine University of Medicine and Dentistry of New Jersey : Steven Y. Chang, PhD, MD, Assistant Professor, MICU Director, Pulmonary and Critical Care Medicine; A mee Patrawalla, MD, MPH; Marie Elie, MD Brigham and Women's Hospital : Peter C. Hou, MD, Jonathan M. Barry, BA, Erica Kao Ian Shempp, BS, Atul Malhotra, MD, Jason Cohen, Gyorgy Frendl, MD, PhD, D epartments of Emergency Medicine, Surgery, Internal Medicine, and Anesthesiology Perioperative and Pain Medicine, Division of Burn, Trauma, and Surgical Critical Care Wright State University Boonshoft School of Medicine & Miama Va lley Hospital : Harry Anderson, III, MD, Professor of Surgery; Kathryn Tchorz, MD, Associa te Professor of Surgery; Mary C. McCarthy, MD, Professor of Surgery; David Uddin, PhD, DABCC, CI P, Director of Research Wake Forest University Health Sciences, Winston-Salem, NC : J. Jason Hoth, MD, Assistant Professor of Surgery; Barbara Yoza, PhD, Study Coordinator University of Pennsylvania : Mark Mikkelsen, MD, MSCE, Assistant Professor of M edicine, Pulmonary, Allergy and Critical Care Division; Jason D. Christie, MD; David F. Gaieski, MD; Paul Lanken, MD; Nuala Meyer, MD; Chirag Shah, MD Temple University School of Medicine : Nina T. Gentile, MD, Associate Professor and Dir ector, Clinical Research, Department of Emergency Medicine, Temple Univers ity School of Medicine; Karen Stevenson, MD, Resident, Department of Emergency Medicine; Brent F reeman, BS, Research Coordinator; Sujatha Srinivasan, MD, Resident, Department of Emergency Medici ne Mount Sinai School of Medicine : Michelle Ng Gong, MD, MS, Assistant Professor, Pulmon ary, Critical Care and Sleep Medicine, Department of Medicine Beth Israel Deaconess Medical Center, Boston, Massachus etts : Daniel Talmor, MD, Director of Anesthesia and Critical Care, Associate Professor of Anaesthesia, Harvard Medical School; S. Patrick Bender MD; Mauricio Garcia MD Massachusetts General Hospital Harvard Medical School : Ednan Bajwa, MD, MPH, Assistant Professor; Atul Malhotra, MD, Associate Professor; B. Taylor Thom pson, Associate Professor; David C. Christiani, MD, MPH, Professor University of Washington, Harborview : Timothy R. Watkins, MD, Acting Instructor, Departmen t of Medicine, Division of Pulmonary and Critical Care Medicine; Steven Deem, MD; Miriam Treggiari, MD, MPH Mayo Clinic Jacksonville : Emir Festic, MD; Augustine Lee, MD; John Daniels, MD Akdeniz University, Antalyia, Turkey : Melike Cengiz, MD, PhD; Murat Yilmaz, MD Uludag University, Bursa, Turkey : Remzi Iscimen, MD Bridgeport Hospital, Yale New Haven Health : David Kaufman, MD, Section Chief, Pulmonary, Critica l Care & Sleep Medicine, Medical Director, Respiratory The rapy Emory University : Annette Esper, MD; Greg Martin, MD University of Illinois at Chicago : Ruxana Sadikot, MD, MRCP University of Colorado : Ivor Douglas, MD

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Johns Hopkins University : Jonathan Sevransky, MD, MHS, Assistant Professor of Medicine, Medical Director, JHBMC MICU We would also like to acknowledge help and support of Rob Taylo r (Vanderbilt University, Nashville, TX) and Joseph J Wick (Mayo Clinic) for the availabilit y and maintenance of REDcap database.



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ORIGINALRESEARCHOpenAccessTowardspreventionofacutelunginjury: frequencyandoutcomesofemergency departmentpatientsat-risk – amulticenter cohortstudyPeterCHou1,2,3,4,15*,Marie-CarmelleElie-Turenne5,6,AyaMitani3,7,16,JonathanMBarry2,3,17,EricaYKao1,3,18, JasonECohen8,9,19,GyorgyFrendl3,4,7,20,OgnjenGajic10,11,12,21andNinaTGentile13,14,22OnBehalfofUSCritical IllnessandInjuryTrialsGroup:LungInjuryPreventionStudyInvestigators(USCIITG – LIPS1)AbstractBackground: Fewemergencydepartment(ED)evaluationsonacutelunginjury(ALI)havebeencarriedout;hence, wesoughttodescribeacohortofhospitalizedEDpatientsatriskforALIdevelopment. Methods: PatientspresentingtotheEDwithatleastonepredisposingconditiontoALIwereincludedinthis study,asubgroupanalysisofamulticenterobservationalcohortstudy(USCIITG-LIPS1).PatientswhometALI criteriawithin6hofinitialEDassessment,receivedend-of-lifecare,orwerereadmittedduringthestudyperiod wereexcluded.PrimaryoutcomewasfrequencyofALIdevelopment;secondaryoutcomeswereICUandhospital mortality. Results: Twenty-twohospitalsenrolled4,361patientswhowerefollowedfromtheEDtohospitaldischarge.ALI developedin303(7.0%)patientsatamedianonsetof2days(IQR2 – 5).Ofthepredisposingconditions,frequency ofALIdevelopmentwashighestinpatientswhohadaorticsurgery(43%)andlowestinpatientswithpancreatitis (2.8%).ComparedtopatientswhodidnotdevelopALI,thosewhodidhadhigherICU(24%vs.3.0%, p <0.001) andhospital(28%vs.4.6%, p <0.001)mortality,andlongerhospitallengthofstay(16vs.5days, p <0.001).Among the22studysites,frequencyofALIdevelopmentvariedfromlessthan1%tomorethan12%afteradjustmentfor APACHEII. Conclusions: SevenpercentofhospitalizedEDpatientswithatleastonepredisposingconditiondevelopedALI. ThefrequencyofALIdevelopmentvariedsignificantlyaccordingtopredisposingconditionsandacrossinstitutions. FurtherresearchiswarrantedtodeterminethefactorscontributingtoALIdevelopment.BackgroundAdultrespiratorydistresssyndrome(ARDS)wasfirst describedbyAshbaugh[1]in1967.Sincethen,thedefinitionandcriteriaforthissyndromehaveevolved.Atthe 1994American – EuropeanConsensusConference(AECC), expertsagreedtothefollowingterminology:Acutelunginjury(ALI)wasdefinedastheacuteonsetofhypoxemia [PaO2/FiO2(partialpressureofarterialoxygen/fractional concentrationofinspiredoxygen) 300mmHg]andbilateralinfiltratesonfrontalchestx-ray(Figure1),intheclinicalabsenceofleftatrialhypertension(orwhenmeasured, pulmonary-arterywedgepressure<18mmHg)[2].ARDS isthemoresevereformofALIwithhypoxemiaat 200mmHgorless[2-4].IntheUS,approximately150,000 to190,600casesofALIoccurannually,withanassociated mortalityrateof38to44%,3.6millionhospitaldays, andlong-termfunctionaldisabilitiesandcostafterintensivecareunit(ICU)discharge[5-8].Pathophysiologically,ALIisclassicallycharacterizedbyanincreased *Correspondence: phou@partners.org1DepartmentofEmergencyMedicine,BrighamandWomen ’ sHospital, Boston,MA,USA2DivisionofBurn,Trauma,andSurgicalCriticalCare,BrighamandWomen ’ s Hospital,Boston,MA,USA Fulllistofauthorinformationisavailableattheendofthearticle 2012Houetal.;licenseeSpringer.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproduction inanymedium,providedtheoriginalworkisproperlycited.Hou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22 http://www.intjem.com/content/5/1/22

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permeabilityofthealveolar-capillarymembraneresulting intheinfluxofprotein-richedemafluidintotheair spaces,andetiologiesofALIaremyriad,includingdirect(pulmonary)andindirect(extrapulmonary)causes [3,4,9].ImportanceDespitenumerousrandomizedcontrolledtrials,alung protectivestrategyduringmechanicalventilation remainstheonlytherapyshowntoimprovesurvivalin patientswithestablishedALI[3,4,10-12].Accordingto the “ two-hit ” modelofALIdevelopmentbeforeALI becomesclinicallyapparent,apre-ALIstateexistsfollowingthefirstinjurytothelungs.TheUnitedStates CriticalIllnessandInjuryTrialsGroup-LungInjuryPreventionStudy(USCIITG-LIPS1)investigatorsfocused ondefiningpatientcharacteristicsthatwouldallowusto identifythesepatientsbeforeovertALIdevelops.Interventionsdeliveredinthisearlyphaseofcarecanoffer potentialpreventionofALI.Asmostclinicalstudiesin ALIhaveprimarilyfocusedonmechanicallyventilated patients,insightintoapotentiallypreventablephaseof ALIpriortoitsdevelopmentiscurrentlylacking[13,14]. DatasuggestthatALIisrarelypresentatthetimeofinitialEmergencyDepartment(ED)evaluation;however,a searchintopemergencymedicinejournalsyieldedmany casereportsofpatientspresentingwithALI[15-18].In reality,manyEDpatientsmayhaveunrecognizedALI andpossessmanypredisposingconditionsforALIdevelopment.Recently,aNationalHeartLungBloodInstitute WorkshopReportonfutureclinicalresearchinALI recommendedtocontinuethedevelopmentofstrategies toperformALIpreventiontrialsandobservational studiesofpatientswithoutALIundergoingprolonged mechanicalventilation[19].Followingtheparadigmof traumateamcareformajortrauma,activationofthe cardiaccatheterizationlaboratoryteamforST-elevation myocardialinfarctionandacutestroketeamsforischemicstroke,andearlygoal-directedtherapyforsevere sepsis,clinicalbenefitmaybederivedfromearlyidentificationofandpreventativeinterventionsforpatientsat riskofdevelopingALI.GoalofthisinvestigationWeevaluatedthefrequencyofALIdevelopmentinatriskhospitalizedEDpatientsamongthestudysites, describedthepredisposingconditionsandriskmodifiers ofALIdevelopment,anddeterminedtheattributionof ALItohospitalmortality.MethodsStudydesignThisisasubgroupanalysisofdatafromamulticenter, observationalcohortstudy,theUnitedStatesCriticalInjuryandIllnessTrialsGroup-LungInjuryPrevention Study1(USCIITG-LIPS1)[20,21].Allparticipating studysitesreceivedapprovalfromtheirrespectivelocal institutionalreviewboard.Thestudyflowdiagramis illustratedinAdditionalfile1:Appendix1.StudysettingFromMarchthroughAugust2009,22centers(20 Americanand2Turkishhospitals)enrolledpatients withatleastoneALIpredispositionadmittedfromthe ED.Patientswereenrolledprospectivelyat19studysites andretrospectivelyat3sites.SelectionofparticipantsConsecutiveadultEDpatientsadmittedtoacademicand communityacutecarehospitalswereeligibleforthe studyiftheypresentedwithoneormore apriori definedconditionspredisposingtoALI(shock,aspiration,sepsis,pancreatitis,pneumonia,high-risktrauma: traumaticbraininjury,smokeinhalation,neardrowning, lungcontusion,multiplefractures;high-risksurgery: thoracic,spine,acuteabdomen,cardiac,aorticvascular; andemergencysurgery).Patientswereexcludedwhen ALIwaspresentatinitialassessment,iftheyweretransferredfromanin-patientsetting,diedintheED,admittedforcomfortorhospicecare,orre-admittedduring thestudyperiod.Hospitaladmissionlogswerereviewed tominimizethepossibilitythatpatientswithpredisposingconditionsweremissed.AfteridentificationofatriskEDpatients,theywerefollowedthroughtheir hospitalizationprospectivelyin19hospitals.Inthethree hospitalsthatenrolledretrospectively,investigators Figure1 Chestx-rayrepresentingacutelunginjury. Hou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page2of12 http://www.intjem.com/content/5/1/22

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followedthesameprotocolanddefinitions,butdata werecollectedafterpatientdischarge.DatacollectionandprocessingBaselinecharacteristics,includingdemographics,comorbidities,andclinicalvariables,werecollectedduringthe first6hofinitialEDevaluation.Predisposingconditions andALIriskmodifierswereidentifiedandcollected. Predisposingconditionswerepre-defined,andALIrisk modifiersincluded:alcoholabuse,obesitychemotherapy, diabetesmellitus,smoking,tachypnea,hypoxemia,oxygensupplementation,hypoalbuminemia,andacidosis. De-identifiedsubjectinformationwasenteredateach centerintothesecure,password-protectedNIH-supported webform(REDCaphttp://www.project-redcap.org). Electronicrangechecksandvalidationruleswereutilized toeliminateerroneousdataentryandartifactsinnumericvalues.Priortostudyinitiationateachsite,investigatorsandstudycoordinatorsreviewedthedefinitionsof eachriskfactor(seeAdditionalfile1:Appendix2)and receivedmandatorystructuredonlinetrainingforALI assessment.Briefly,indeterminingifachestradiograph isconsistentwithALI,assessmentbeginswithinterpretabilityofthex-rayfollowedbyevaluationforbilateral opacitiesgenerallydescribedasinfiltratesconsistentwith pulmonaryedema.Onlywhenthebilateralopacitiesare notfullyexplainedbynon-qualifyingopacities(i.e.,pulmonaryfibrosis)andnotlimitedtothelowerlungzones withnormalparenchymaaboveisthechestradiograph consistentwithALI.Inaddition,aformaltrainingsession wasprovidedduringthe2009USCIITGmeetingin Nashville,TN.Theprincipalinvestigatorsfromeachsite wereresponsiblefordatacollectionandentry,aswellas qualitycontrol.OutcomemeasuresTheprimaryoutcomewasthedevelopmentofAECCdefinedALIduringthehospitaladmissionofat-riskED patients.SecondaryoutcomesincludedtimetoALIdevelopment;proportionanddurationofinvasiveand non-invasivemechanicalventilation;vasopressorrequirement;acuterenalfailurerequiringhemodialysis; andICUandhospitallengthofstayandmortality.PrimarydataanalysisTheStrengtheningtheReportingofObservationalStudiesinEpidemiology(STROBE)guidelineswerefollowed inthedesignandreportingofthisobservationalstudy [22].PCHandAManalyzedthedata,whichweresummarizedasnumber(inpercentage)andmedian(with inter-quartilerange).Missingdatawerecodedexplicitly asdescribedandhandledbyusinglogicexpression. Continuousvariablesweredichotomizedatthemedian. Theoddsratiosand95%confidenceintervalswere computedfromperforminglogisticregression.Statistical significancewassetat0.05forregressionanalysis.FrequencyofALIwascalculatedpernumberofEDpatients presentingwithpredisposingconditionatthetimeof hospitaladmission. Inordertoevaluateoursecondaryoutcomemeasures, wecomparedhospitalandICUmortalityandlengthof staybetweenEDpatientsatriskwhodevelopedALIand thosewhodidnot.Todeterminethemortalityburden attributedtothedevelopmentofALI,weperformeda logisticregressionanalysisadjustedforthebaseline AcutePhysiologyandChronicHealthEvaluation(APACHEII)score[23].Inaddition,wedescribedthe utilizationanddurationofinvasiveandnon-invasive mechanicalventilation,andperformedanexploratory analysiscomparingpatientswhodidanddidnotdevelop ALIwithrespecttotheirinitialventsettings,specifically tidalvolumeperpredictedbodyweight,plateaupressure,andpositiveendexpiratorypressure(PEEP).Lastly, weillustratedthefrequencyofALIdevelopmentfor eachpredisposingcondition,athospitaldayonset,and ateachhospitalsetting.AllstatisticalanalysiswasperformedinSAS9.2(SASInstitute,Cary,NC).SensitivityanalysisSiteswithretrospectivedataandextremefrequenciesof ALIdevelopmentwereexcluded,andasensitivityanalysisoftheprospectivecohortfromtheentireEDcohort wasperformed.ResultsanddiscussionResults CharacteristicofstudysubjectsTwenty-twocentersscreened5,992,excluded166 patientswithALIatadmissionandothercriteria,and enrolled5,584patientswithatleastoneALIpredisposition,ofwhich4,361patientswereadmittedfromthe ED(Figure2).ALIDevelopedwithin48HofAdmissioninAt-Risk PatientsandMarkedlyIncreasedMortalityALIdevelopedin303(7.0%)admittedEDpatientswith amedianof2days,inter-quartilerange(IQR)2 – 5days. AmongpatientswhodevelopedALI,asubsetof198 (65.3%)mettheARDScriteria.Thefollow-uptohospitaldischargewascompleteinallpatients.Baseline characteristics,severityofillness,andpredisposingconditionsandALIriskmodifiersdifferedbetweenpatients whodidandthosewhodidnotdevelopALI(Table1). PatientswhodevelopedALIweremorelikelymaleand heavier,andhadahigherAPACHEIIscore.Themajorityofpatientshadallmeasurementsavailableatthetime ofhospitaladmissionexceptforserumalbumin ( n =2,423)andarterialpH( n =1,499).AsthesetestsareHou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page3of12 http://www.intjem.com/content/5/1/22

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usuallyorderedbasedonclinicalsuspicion,missingdata wereconsiderednormal(i.e.,ifserumalbuminorarterialpHwasnotmeasured,hypoalbuminemiaandacidosis werecodedasabsent),similarlytoAPACHEscorecalculation.TheoddsratiosforALIdevelopmentwere highestinriskmodifiersoftachypneaandafractionof inspiredoxygen35%orgreater;andinpredisposing conditionsofaorticvascular,cardiac,andspinalsurgeries,near-drowning,andsmokeinhalation.However,the numbersofsubjectsinsomeofthesecategorieswere smallcomparedtoothers.ThefrequencyofALIvaried accordingtopredisposingconditionwiththehighest rateoccurringafteremergentaorticsurgery(42.9%)and thelowestrateoccurringinpancreatitis(2.8%) (Figure3). Outcomedataforthestudycohortareshownin Table2.Morethanhalfoftheentirecohortand91%of patientswhodevelopedALIweretreatedintheICU; and31%oftheentirecohortand95%ofpatientswith ALIwereeitherinvasivelyornon-invasivelymechanicallyventilated.Comparedtoat-riskpatientswhodidnot developALI,thosewhodevelopedALIweremorelikely tobeventilatedinvasively(88%vs19%)andnoninvasively(30%vs10%),respectively.Similarly,comparingtopatientswhodidnotdevelopALI,thosewho didhadincreasedresourceutilizationasreflectedin morevasopressorusage(38%vs8%),ahigherpercentageofacutehemodialysisrequirement(11%vs3%), andlongerICU(9vs2days)andhospital(16vs5days) lengthsofstays.Moreimportantly,patientswhodevelopedALIhadincreasedICU(24%vs3%)andhospital (28%vs5%)mortality.Whenadjustedforseverityof illnessusingtheAPACHEIIscore,thedevelopmentof ALImarkedlyincreasedtheriskofin-hospitaldeathby morethanfour-fold[OR4.45,95%CI(3.23,6.14)]. ThevariationinthefrequencyofALIdevelopment amongthe22studysitesisillustratedinFigure4.Even afteradjustmentforeachsite ’ sAPACHEIIscore,asignificantvariationinthefrequencyofALIdevelopment remained.Byexcludingtheoneoutlier(44%),thefrequencyofALIdevelopmentvariedfrom0.7to12.8%. Sincethedatasetisfairlylarge,theutilizationofinvasivemechanicalventilationandonsetofALIdevelopmentwereexplored.Figure5providesadescriptionof ALIdevelopmentandinitiationofinvasivemechanical ventilationbyhospitalday.Themajorityofpatientswho developedALIandwhoreceivedinvasivemechanical ventilationdidsowithinthefirst2daysafterhospital admission.AsillustratedinFigure6,themajorityof patientswhodevelopedALIhadinitiationofinvasive mechanicalventilationonthedayofALIonset.Unfortunately,nodatawererecordedregardingtheexacttiming (inhoursandminutes)andthereasonforinitiationofinvasivemechanicalventilationwithrespecttotheonsetof ALIdevelopment.AlthoughrelativelyfewpatientsdevelopedALIpriortoinitiationofinvasivemechanical ventilation,manydevelopedALIadayormoreafter initiationofinvasivemechanicalventilation. 5992 patients with at least one predisposing condition at the time of ED evaluation or hospital admission for elective high-risk surgery 5584 enrolled 4361 ED subgroup 303 ALI 4058 No ALI Exclusions: 166 ALI on admission, 124 in-patient transfers, 44 readmissions, 28 comfort care, 46 other (died in the ED, prisoner, incomplete record) Hospital admission for elective surgery Figure2 Patientenrollmentflowdiagram. Hou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page4of12 http://www.intjem.com/content/5/1/22

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Table1Demographics,predisposingconditions,andriskmodifiersintotal,noALI,ALIVariableTotal( n =4361)NoALI( n =4058)ALI( n =303)OR(95%CI)P-value Demographics Medianage(Q1,Q3)56.0(41.0,71.0)56.0(41.0,71.0)54.0(41.0,67.0)0.99(0.99,1.00)0.050 Male,no.(%)2,422(55.5%)2222(54.8%)200(66.0%)1.60(1.26,2.05)<0.001 Caucasian(n=4220),no.(%),2608(61.8%)2424(61.8%)184(62.0%)1.01(0.79,1.28)0.956 Weight(n=3905),median(Q1,Q3)76.5(63.5,91.0)76.0(63.5,91.0)83.2(69.2,96..0)1.84(1.43,2.37)<0.001 PBW(n=3551),median(Q1,Q3)63.8(64.7,73.0)63.8(54.6,73.0)66.1(56.4,75.0)1.42(1.10,1.84)0.007 Admissionsource(n=4311),no.(%) Home3,331(77.3%)3,125(78.0%)206(68.2%)1.00 Nursingfacility338(7.8%)322(8.0%)16(5.3%)0.75(0.45,1.27)0.002 OutsideED440(10.2%)396(9.9%)44(14.6%)1.69(1.20,2.37)0.253 Other202(4.7%)166(4.1%)36(11.9%)3.29(2.23,4.84)<0.001 APACHEII(Q1,Q3)10.0(6.0,15.0)9.0(5.0,14.0)15.0(10.0,21.0)1.11(1.09,1.13)<0.001 Predisposingconditions Shock395(9.1%)327(8.1%)68(22.4%)3.30(2.46,4.42)<0.001 Aspiration210(4.8%)176(4.3%)34(1.2%)2.79(1.89,4.11)<0.001 Sepsis1,806(41.4%)1,684(41.5%)122(40.3%)0.95(0.75,1.21)0.674 Pancreatitis323(7.4%)314(7.7%)9(3.0%)0.37(0.19,0.72)0.003 Pneumonia1,227(28.1%)1,127(27.8%)100(33.0%)1.28(0.99,1.64)0.051 High-risktrauma Traumaticbraininjury490(11.2%)445(11.0%)45(14.9%)1.42(1.02,1.97)0.040 Smokeinhalation27(0.6%)20(0.5%)7(2.3%)4.78(2.00,11.38)<0.001 Neardrowning3(0.1%)2(0.1%)1(0.3%)6.72(0.61,74.27)0.120 Lungcontusion188(4.3%)161(4.0%)27(8.9%)2.37(1.55,3.63)<0.001 Multiplefractures330(7.6%)304(7.5%)26(8.6%)1.16(0.76,1.76)0.489 High-risksurgery Thoracic(noncardiac)5(0.1%)4(0.1%)1(0.3%)3.36(0.37,30.12)0.280 Orthopedicspine17(0.4%)13(0.3%)4(1.3%)4.16(1.35,12.85)0.013 Acuteabdomen295(6.8%)268(6.6%)27(8.9%)1.38(0.91,2.09)0.125 Cardiacsurgery20(0.5%)14(0.3%)6(2.0%)5.84(2.23,15.30)<0.001 Aorticvascular14(0.3%)8(0.2%)6(2.0%)10.23(3.53,29.68)<0.001 Emergencysurgery339(7.7%)282(7.0%)57(18.8%)3.10(2.27,4.24)<0.001 Riskmodifiers Alcoholabuse421(9.7%)381(9.4%)40(13.2%)1.47(1.04,2.08)0.031 Obesity( n =3,508)1,020(29.1%)929(28.6%)91(35.0%)1.34(1.03,1.75)0.029 Chemotherapy158(3.6%)145(3.6%)13(4.3%)1.21(0.68,2.16)0.520 Diabetesmellitus1,042(23.9%)987(24.3%)55(18.2%)0.69(0.51,0.93)0.016 Smoking( n =4,019) None2,060(51.3%)1,931(51.6%)129(47.1%)1.00 – Former888(22.1%)829(22.1%)59(21.5%)1.07(0.78,1.47)0.644 Active1,071(26.7%)985(26.3%)86(31.4%)1.31(0.98,1.74)0.089 RR( n =4,137),median(Q1,Q3)20.0(18.0,24.0)20.0(18.0,24.0)22.0(18.0,27.0) Tachypnea( n =4,137),no.(%)315(7.6%)269(6.8%)52(18.8%)3.18(2.29,4.40)<0.001 SpO2( n =4,361),median(Q1,Q3)97.0(94.0,99.0)97.0(94.0,99.0)95.0(92.0,98.0) SpO2<95%( n =4,361)1,203(27.6%)1,076(26.5%)127(41.9%)2.17(1.56,3.02)<0.001 FiO2( n =4,361),median(Q1,Q3)0.2(0.2,0.3)0.2(0.2,0.3)0.4(0.2,1.0) FiO2>0.35( n =4,796),no.(%)841(19.3%)688(17.0%)153(50.5%)4.92(3.87,6.25)<0.001 Albumin( n =2,423),median(Q1,Q3)3.5(2.9,4.0)3.5(3.0,4.0)3.2(2.4,3.7) Hou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page5of12 http://www.intjem.com/content/5/1/22

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SensitivityanalysesWhendatafromthetwonon-USstudysiteswereremoved ( n =4,233)fromtheanalysis(seeAdditionalfile1:Appendix3),ALIdevelopedin266(6.3%)patientswithamedian of2days(IQR2 – 5days)afteradmissiontothehospital. ThefrequencyofALIvariedaccordingtopredisposing conditionwiththehighestrateofALIoccurringafteraorticsurgery(36.4%)andthelowestrateoccurringinpancreatitis(2.9%).Baselinecharacteristics,severityofillness, predisposingconditionsandALIriskmodifiers,andsecondaryoutcomesremaineddifferentbetweenpatientswho didandthosewhodidnotdevelopALI.However,there werenosignificantdifferencesinthegroupcharacteristics fromtheUSstudysiteswhencomparingtotheentire cohort. Inaddition,whendatafromthethreeretrospectiveUS studysiteswereremoved( n =3,981)fromourdescriptiveanalysis(seeAdditionalfile1:Appendix4),ALI developedin241(6.1%)patientswithamedianof2days (IQR2 – 4days)afteradmissiontothehospital.ThefrequencyofALIvariedaccordingtopredisposingconditionwiththehighestrateofALIoccurringafteraortic surgery(40%)andthelowestrateoccurringinpancreatitis(2.4%).Baselinecharacteristics,severityofillness, predisposingconditionsandALIriskmodifiers,andsecondaryoutcomesmaintainedtheirdifferencesbetween patientswhodidanddidnotdevelopALI.However, therewerenosignificantdifferencesinthegroupcharacteristicswhencomparingtheprospectiveUSsitesand theentireUScohort. Table1Demographics,predisposingconditions,andriskmodifiersintotal,noALI,ALI (Continued)Hypoalbuminemia( n =2,423),no.(%)945(47.1%)838(45.6%)107(64.5%)2.17(1.56,3.02)<0.001 pH( n =1,499),median(Q1,Q3)7.4(7.3,7.4)7.4(7.3,7.4)7.3(7.2,7.4) Acidosis(pH<7.35),no.(%)476(45.9%)364(43.3%)112(56.6%)1.70(1.25,2.33)<0.001PRW:Predictedbodyweight;RR:respiratoryrate;tachypnea=RR>30;SpO2:oxygensaturation;FiO2:fractionofinspiredoxygen. Figure3 FrequencyofALIDevelopmentVarieswithPredisposingCondition. Hou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page6of12 http://www.intjem.com/content/5/1/22

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Effectsofinitialventilatorsettingsonthedevelopmentof ALISincethereisgrowingevidencetosuggestthatalung protectivestrategywithlowtidalvolumeventilationmay beprotectiveinat-riskpatients,weexploredtheeffect oftheinitialventsettingonALIdevelopment[24,25]. Weevaluatedtheinitialtidalvolumedividedbypredictedbodyweight(TV/PBWincc/kg)in768patients Table2Hospitalcourseandoutcomesfortotal,NoALI,andALIVariableTotal( n =4,361) NoALI(n =4,058)ALI( n =303)OR(95%CI)P-value ICUadmission,no.(%)2,320(53.2%)2,043(50.3%)277(91.4%)10.50(6.99,15.77)<0.001 ICULOS( n =2,320),median(Q1,Q3)2.0(1.0,5.0)2.0(0.0,4.0)9.0(5.0,17.0)19.12(9.79,37.38)<0.001 HospitalLOS(n=4361),median(Q1,Q3)6.0(3.0,10.0)5.0(3.0,9.0)16.0(9.0,26.0)8.60(5.94,12.36)<0.001 Vasopressorsuse,no.(%)448(10.3%)334(8.2%)114(37.6%)6.73(5.20,8.71)<0.001 Acutehemodialysis( n =4,290),no.(%)148(3.5%)115(2.9%)33(11.0%)4.15(2.76,6.23)<0.001 ICUmortality,no.(%)194(4.5%)120(3.0%)74(24.4%)10.61(7.71,14.59)<0.001 Hospitalmortality,no.(%)272(6.2%)188(4.6%)84(27.7%)7.90(5.90,10.56)<0.001 Mechanicalventilation( n =4,223)1,299(30.8%)1,013(25.8%)286(94.7%)51.29(30.85,85.28)<0.001 Non-invasive( n =4,146),no.(%)470(11.3%)387(10.0%)83(30.1%)3.87(2.93,5.11)<0.001 Non-invasiveduration( n =461),median(Q1,Q3)2.0(1.0,5.0)2.0(1.0,5.0)3.0(2.0,5.5)1.29(0.73,2.25)0.379 Invasive( n =4,228),no.(%)997(23.6%)730(18.6%)267(88.4%)33.40(23.27,47.94)<0.001 Invasiveduration( n =932),median(Q1,Q3)3.0(1.0,8.0)2.0(1.0,5.0)8.0(4.0,15.0)6.53(4.52,9.42)<0.001 TV/PBW( n =768),median(Q1,Q3)8.3(7.4,9.5)8.4(7.5,9.7)8.1(7.3,9.2)0.70(0.51,0.96)0.029 Plateaupressure( n =435),median(Q1,Q3)19.0(16.0,24.0)19.0(15.0,23.0)21.0(17.0,27.2)1.77(1.17,2.69)0.007 PEEP( n =916),median(Q1,Q3)5.0(5.0,5.5)5.0(5.0,5.0)5.0(5.0,8.0)2.30(1.32,4.01)0.003 Mode:Volumecontrol762(83.9%)561(86.4%)201(77.6%)1.00 – Mode:Pressurecontrol111(12.2%)63(9.7%)48(18.5%)2.13(1.41,3.20)0.010ICU:Intensivecareunit;LOS:lengthofstay;TV:tidalvolume;PBW:predictedbodyweight;PEEP:peakend-expiratorypressure. Figure4 FrequencyofALIDevelopmentVariesbyInstitution. Hou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page7of12 http://www.intjem.com/content/5/1/22

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whounderwentinvasivemechanicalventilation(Table2). Comparingthosewhodidnot,patientswhodeveloped ALIreceivedasignificantlowerinitialTV/PBW[8.1vs 8.4,OR0.70(95%CI0.51-0.96), p =0.029]buthada significantlyhigherplateaupressure[21vs19,OR1.77 (95%CI1.17-2.69), p =0.007]andpeakend-expiratory pressure(PEEP)[OR2.30(95%CI1.32-4.01), p =0.003]. Regardingthemodeofmechanicalventilation,asignificantlyhigherproportionofpatientswhodevelopedALI wasinitiatedonpressurecontrolventilation[OR2.13 (95%CI1.41-3.2), p =0.01]andnon-invasiveventilation [OR3.87(95%CI2.93-5.11), p <0.001]comparedto thosewhodidnotdevelopALI;incontrast,nosignificantdifferencewasfoundinthosewhounderwentinitial volumecontrolventilation.LimitationsOurstudycarriesthelimitationsofobservationalcohort studiesandthoseinherenttoclinicalresearchwithALI: inter-observerreliabilityofportablechestX-rayinterpretation,ALIimitators,andconsistencyindetermining exclusionofleftatrialhypertensionastheprincipal causeofpulmonaryedema[26-28].Weinstituteda mandatorystructuredtraininginALIassessmentand heldthesite-principalinvestigatorsresponsiblefor qualitycontrol.Thesemeasureswereintendedtomitigatetheselimitations. RegardingthevariationinthefrequencyinALIdevelopmentamongthestudysites,twonon-USsiteshadthe highestrateandcouldbeexplainedbydifferencesin theirhealth-caredeliverysystem,specificallyemergency medicalcareandcriticalcareservices,andpossibly populationandenvironmentalfactors.Whenthedata fromthesetwonon-UScenterswereexcluded,nosignificantdifferenceinthefrequencyofALIdevelopment ( p =0.216)wasfoundbetweentheUSsites.Inaddition, thevastmajorityofpatientswereenrolledprospectively ensuringclosefollow-upandreducingtheriskofmisclassificationfrommedicalrecordreview.Whendata fromthosecentersenrollingretrospectivelywere excluded,nosignificantdifferenceinthefrequencyof ALIdevelopment( p =0.665)wasfoundcomparingthe prospectiveUSsitestotheentireUScohort.Hence,althoughasignificantvariationinthefrequencyofALI developmentacrossinstitutionswasfound,theUSsites andtheprospectivelyenrollingUSsiteswerenotsignificantlydifferentwheneachsubgroupwascomparedto theentirecohort.DiscussionEventhoughALIisclassifiedasararedisease[29],itis amajorpublichealthconcern.Itis,however,unclear howmuchifvariationsininitialmanagementofALIpronepatientsbyemergencyphysicianscontributetoits development.Toourknowledge,thisisthelargest detailedstudyofacohortofhospitalizedadultED patientsatriskforALIdevelopment.Thestrengthsof thisstudyincludethelargesamplesizefromageographicallydiversepopulationofpatientsatbothacademic andcommunityhospitals.Usingroutinelyavailableclinicaldata,weidentifiedEDpatientsatriskforALIdevelopmentearlyinthecourseoftheirillness.Theearly identificationofpredisposingconditionsandriskmodifiersaswellassubsequentinterventionsintheEDand ICUmaypotentiallypreventdiseasedevelopmentby minimizingoravoidingsecondaryinsults. Interestingly,inourstudywefoundthatALIdevelopedwithlowerfrequenciesthanpreviouslyreported followingconditionsrecognizedtopredisposepatientsat riskforALIsuchas:aspiration,pneumonia,sepsis,and trauma[30,31].Thismaybeexplainedbythefactthat ourpatientswereenrolledearly(intheED)withoutany signsofALI(withatleastonepredisposingfactor present)andweexcludedthosewhodevelopedALI within6hofEDpresentation,whilethoseotherstudies enrolledpatientsuponICUadmission.Consistentwith ourfindings,arecentstudybyFergusonetal.showed that7%ofpatientswithsepsis,2%ofpatientswith pancreatitis,10%ofpatientswithpneumonia,and15% Figure5 PercentageofALIDevelopmentandInvasive MechanicalVentilationOnsetbyHospitalDay. Figure6 DaysbetweenOnsetofALIDevelopmentandInvasive MechanicalVentilation. Hou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page8of12 http://www.intjem.com/content/5/1/22

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ofpatientswithwitnessedaspirationdevelopedALI[32]. Similarly,themajorityofpatientswithpredisposingconditionsneverdevelopedALI,andmanywerenotadmittedtotheICU. Ourinclusioncriteriarequiredthepresenceofatleast oneALIriskfactoratthetimeofhospitaladmission,potentiallymissingthepatientswhoacquireapredisposing conditionandreceivedasecondaryinjurylaterinthe hospitalstay.Wecannotruleoutthataminorityofour patientsidentifiedashighriskwerealreadyprogressing todevelopfull-blownALIatthetimeofenrollment,althoughtheexclusionofthosewhodevelopedALIwithin 6hofEDpresentationintendedtominimizethispossibility.However,wedobelievethatearlieridentification ofsuchpatientswouldalsobeofbenefit,andcouldhelp limittheprogressionofALIdevelopmentandimprove patientoutcomesbyalertingproviderstomakeefforts tolimitsecond-hitexposures.Tosupportthisnotion,a population-basedstudyinOlmstedCounty,Minnesota, hasrecentlyshownasteadydeclineinARDSincidence. Thiswasattributableentirelytoareducedincidenceof hospital-acquiredARDSandsuggeststhatrecent improvementsinprevention,earlyrecognition,andcriticalcaredeliverymayinpartberesponsibleforthis[33]. FromOlmstedCounty ’ sexperience,majorsystem changeswithinthehospitalthroughouttheyearswere progressivelymade.Theseincludeelectronicmedical recordswithcomputerizedorderentrytomonitordata andinstitutedecisionsupport,restrictivetransfusion protocolwithleukoreductionandmaledonorpredominantplasmatransfusion,respiratorytherapyprotocolon limitinginitialvolumeaccordingtopredictedbody weightonallpatients,increasedstaffingofintensivists with24-honsite,sepsisresuscitationprotocolsand teams,rapidresponseteams,standardizationofinpatient pneumoniacare,andstaffeducationandtraining. RegardingpotentialinterventionsthatmayaffectthedevelopmentofALI,achecklistforlunginjuryprevention (CLIP)hasbeenproposedanddevelopedbyexpertsin thefield[34].TheCLIPdomains(andelements)consist ofroutineICUpracticesofmorbiditypreventionandinclude:respiratorysupport(lungprotectivestrategies, minimizingoxygentoxicity)[12,24,25];aspirationprecautions(rapidsequenceintubation,head-of-bedelevation,oralcarewithchlorhexidine)[35-37];infection control(earlyandappropriateantibiotictherapy,source control,preventionofnosocomialinfectiontransmission)[38];fluidmanagement(earlyfluidresuscitationin severesepsisandsepticshock,fluidrestrictionafter shockresolution)[39,40];transfusionmanagement(restrictiveredbloodcelltransfusionthreshold,transfusion guidelinesforbloodproducts)[40,41];andcommunication(validatedstructuredhandoffssuchasSBAR:situation,background,assessment,andrecommendation) [42].AsacontinuuminthecareofthecriticallyillstartingintheEDandtransitioningtotheICU,allofthese domainsandmanyoftheseproposedelementsarebeing followedtoacertainextent,butinconsistentlyas reflectedinourownexperientialobservationsandpracticevariations.However,suchaproposedchecklistwill requirevalidationforitsutilityinadherencetobest practicesandALIprevention.ConclusionsManyEDpatientswhoarehospitalizedhaveriskfactors forALIdevelopment.Inthiscohort,wefound7%of EDpatientswithatleastonepredisposingcondition developedALI,andthereisvariationinthefrequencyof ALIdevelopmentacrossstudysites.Inaddition,more resourcesareutilizedinpatientswhododevelopALI, andmoreimportantly,ALIsignificantlyincreasedthe patient ’ sriskofdeathinthehospital.Hence,istherea roleforemergencyphysiciansinthemanagementof patientsatriskforALIdevelopment? Currently,pre-plannedancillarystudiesareongoingto explorepotentialdifferencesindevelopmentofALIat differenthospitalsettings,indifferentdisease-related groups,andtheirspecifictreatmentmodalities.In addition,acutelunginjurypreventiontrialsarebeing proposed.Furtherresearchisalsowarrantedtodevelop apredictionmodeltoidentifyhospitalizedEDpatients atriskofALIdevelopmentatanearlystageintheir illness.AdditionalfileAdditionalfile1: WebfilesAppendices[43-94]. Abbreviations AECC:American-Europeanconsensusconference;ALI:acutelunginjury; APACHE:acutephysiologyandchronichealthevaluation;ARDS:acute respiratorydistresssyndrome;CLIP:checklistforlunginjuryprevention; ED:emergencydepartment;ICU:intensivecareunits;LIPS:lunginjury predictionscore;PEEP:positiveendexpiratorypressure;PBW:predictedbody weight;TV:tidalvolume;USCIITG-LIPS1:UnitedStatesCriticalInjuryand IllnessTrialsGroup-LungInjuryPreventionStudy1;VALI:ventilator-associated lunginjury. Competinginterests TheSTARCenterprovidedinternalfunding(Dr.Frendl),researchstaff,and biostatisticalsupport,BrighamandWomen ’ sHospital,Boston,MA.Dr.Gajicis supportedinpartbygrantsfromtheNationalHeart,Lung,andBlood InstituteHL78743-01A1;NationalCenterforResearchResources1KL2 RR024151.Dr.GentileissupportedinpartbygrantsfromtheNational InstituteofNeurologicalDisordersandStroke5U10NS059039-04.Therestof theauthorshavenodisclosuresorconflictofinterest. Authors'contributions PCH,MCE,OG,andNTGconceivedthestudy,designedthereview,and supervisedtheconductofthereviewanddatacollection.GFobtained researchfunding.PCH,AM,andOGextractedandmanagedthedataand performedqualitycontrolofthedata.AMprovidedstatisticaladviceon studydesign,andallauthorsanalyzedthedata.PCHdraftedthemanuscript, andallauthorsprovidedsignificantcontributionstoitsrevision.PCHtakesHou etal.InternationalJournalofEmergencyMedicine 2012, 5 :22Page9of12 http://www.intjem.com/content/5/1/22

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responsibilityforthepaperaswhole.Allauthorsreadandapprovedthefinal manuscript. Acknowledgments USCriticalIllnessandInjuryTrialsGroup:LungInjuryPreventionStudy Investigators(seeAdditionalfile1:Appendix5). Authordetails1DepartmentofEmergencyMedicine,BrighamandWomen ’ sHospital, Boston,MA,USA.2DivisionofBurn,Trauma,andSurgicalCriticalCare, BrighamandWomen ’ sHospital,Boston,MA,USA.3SurgicalIntensiveCare UnitTranslationalResearch(STAR)Center,BrighamandWomen ’ sHospital, Boston,MA,USA.4HarvardMedicalSchool,Boston,MA,USA.5Departmentof EmergencyMedicine,UniversityofFloridaCollegeofMedicine,1329SW 16thStreet,GainesvilleFL32610,USA.6EmergencyDepartment,Shands UniversityofFlorida,MedicalCenter,Gainesville,FL,USA.7Departmentof Anesthesiology,PerioperativeandPainMedicine,BrighamandWomen ’ s Hospital,Boston,MA,USA.8DepartmentofEmergencyMedicine,Albany MedicalCenter,Albany,NY,USA.9AlbanyMedicalCollege,Albany,NY,USA.10DivisionofPulmonaryandCriticalCareMedicine,DepartmentofMedicine, MayoClinic,Rochester,MN,USA.11MultidisciplinaryEpidemiologyand TranslationalResearchinIntensiveCare(METRIC),MayoClinic,Rochester,MN, USA.12MayoMedicalSchool,Rochester,MA,USA.13Departmentof EmergencyMedicine,TempleUniversityHospital,Philadelphia,PA,USA.14TempleUniversitySchoolofMedicine,Philadelphia,PA,USA.15Harvard MedicalSchool,DepartmentofEmergencyMedicine&DivisionofBurn, Trauma,andSurgicalCriticalCare,DepartmentofSurgery,Brighamand Women ’ sHospital,75FrancisStreet,NevilleHouse312-B,Boston,MA02115, USA.16DepartmentofMedicine,StanfordHospitalsandClinics,300Pasteur Drive,Room:S102,MC:5110,Stanford,CA94305,USA.17DivisionofBurn, Trauma,andSurgicalCriticalCare,BrighamandWomen ’ sHospital,75Francis Street,Boston,\02115,USA.18DepartmentofEmergencyMedicine,Brigham andWomen ’ sHospital,75FrancisStreet,Boston,MA02115,USA.19Albany MedicalCenterEmergencyMedicineGroup,47NewScotlandAvenue,MC 139,Albany,NY12208,USA.20DepartmentofAnesthesiologyPerioperative andPainMedicine,BrighamandWomen'sHospital,75FrancisStreet,Boston, MA02115,USA.21PulmonaryandCriticalCareMedicine,MayoClinic,Old MarianHall,SecondFloor,Room115,200FirstSt.SW,Rochester,MN5590, USA.22DepartmentofEmergencyMedicine,TempleUniversityHospital, AdministrativeOffice,10thFloor,JonesHall,1316W.OntarioStreet, Philadelphia,PA19140,USA. 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