Supplementary Online Content

Roquilly A, Mahe PJ, Seguin P, et al. Hydrocortisone Therapy for Patients With Multiple Trauma: The Randomized Controlled HYPOLYTE Study. JAMA. 2011;305(12):1201-1209.

eAppendix. Clinical Definitions eFigure 1. Kaplan-Meier Curves for Hospital Acquired Pneumonia Patients eFigure 2. Kaplan-Meier curves for duration of mechanical ventilation and duration of ICU hospitalization eTable 1: Modifiable Risk Factors of Hospital Acquired Pneumonia eTable 2: Types of Pathogens Involved in Hospital Acquired Pneumonia at Day 28 eTable 3: Cause of Deaths eTable 4: Outcomes for Patients With Adapted Corticosteroid Function

This supplementary material has been provided by the authors to give readers additional information about their work.

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Appendix. Clinical Definitions Aspiration pneumonia: pneumonia that occurs in the first 48 hours after trauma and that had been incubating at the time of admission 1. Cardiac insufficiency: dyspnea (stage 2 or higher according to the New York Heart Association score) with echocardiography abnormalities. Chronic pulmonary insufficiency: symptomatic pulmonary disease associated with altered results following functional lung exploration. Corticosteroid function: assessment with a corticotropin test: assessment of basal cortisolemia immediately before corticotropin (0.25 mg) infusion followed by cortisolemia assessment 30 and 60 minutes later. Delta of cortisolemia was calculated as: [Maximal cortisolemia Basal cortisolemia]. Corticosteroid insufficiency: basal cortisolemia level below 15 g/dl (413 nmol/l) 2 and/or a maximal delta below 9 g/dl (248 nmol/l) 3. Adapted corticosteroid function: basal cortisolemia level above 15 g/dl and a delta above 9 g/dl (248 nmol/l) after adrenal stimulation. Hospital-Acquired Pneumonia1: the presence of at least two signs (body fever greater than 38C; leukocytosis greater than 12000/ml or leukopenia below 4000/ml; purulent pulmonary secretions) associated with the appearance of a new infiltrate or changes in an existing infiltrate on chest X-ray. The diagnosis must have been confirmed by a lower respiratory tract sample using a quantitative culture with a predefined positive threshold (104 cfu/ml for a bronchoalveolar lavage or nonbronchoscopic sample; 103 cfu/ml for a protected specimen brush). Hospital-acquired pneumonia (HAP) was defined as pneumonia that occurs 48 hours after admission, which had not been incubating at the time of admission. Immunosuppression: immunosuppressive agent (anti-graft rejection, glucocorticoid, anti-tumor necrosis factor alpha agent, cyclosporine, cyclophosphamide), Human Immunodeficiency Virus, cancer. Infections (others): Tracheobronchitis 1: association of at least two signs (fever above 38.0C, leukocytosis above 12000/ml, or purulent pulmonary secretions) with isolation of bacteria from a lower respiratory tract sample without changes in chest X-Ray. Urinary tract infection: fever above 38.2C associated with leukocyturia (>10000/ml) and bacteriuria (>103 UFC/ml) without other infection. Bacteriemia: one positive blood culture (two positive blood cultures for Staphiloccocus coagulase negative). Surgical wound infection: sputum from surgical incision or dehiscence associated with fever. Obesity: Body Mass Index (weigh/height2) above 30. Organ failure Acute Lung Injury 4: ratio of arterial oxygen tension to inspired oxygen fraction (PaO2/FiO2) between 200 and 300 with bilateral infiltrates on chest X-ray without elevation of left atrial pressure. Acute Respiratory Distress Syndrome 4: ratio of arterial oxygen tension to inspired oxygen fraction (PaO2/FiO2) below 200 with bilateral infiltrates on chest X-ray without elevation of left atrial pressure. Acute kidney injury 5: oliguria (<0.3 ml/kg/hour for 24 hours or more) or increase in basal creatinemia of more than 300%. Hematologic insufficiency 6: platelet count below 50000/ml. Hepatic insufficiency: bilirubinemia above 50 mmol/l associated with a prothrombin time below 40%. Shock: hypotension (systolic arterial pressure below 90 mmHg) refractory to vascular filling with vasoactive drugs requirement.

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References 1. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005; 171, 388-416. 2. Cohan P, Wang C, McArthur DL et al. Acute secondary adrenal insufficiency after traumatic brain injury: a prospective study. Crit Care Med 2005; 33, 23582366. 3. Annane D, Bellissant E. Prognostic value of cortisol response in septic shock. Jama 2000; 284, 308-309. 4. Abraham E, Matthay MA, Dinarello CA et al. Consensus conference definitions for sepsis, septic shock, acute lung injury, and acute respiratory distress syndrome: time for a reevaluation. Crit Care Med 2000; 28, 232-235. 5. Uchino S, Bellomo R, Goldsmith D, Bates S, Ronco C. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med 2006; 34, 1913-1917. 6. Antonelli M, Moreno R, Vincent JL et al. Application of SOFA score to trauma patients. Sequential Organ Failure Assessment. Intensive Care Med 1999; 25, 389-394.

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eFigure 1. Kaplan-Meier Curves for Hospital Acquired Pneumonia Patients

Hazard Ratio = 0.82 ; IC95% = 0.23 2.93 ; P = 0.76 Comparison of Hydrocortisone group versus Placebo with a stratified cox model (N= 17 in the hydrocortisone group, N=19 in the placebo). Analyses of patients with an adapted corticosteroid function left untreated when the result of the corticotropin test was available

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eFigure 2. Kaplan-Meier curves for duration of mechanical ventilation and duration of ICU hospitalization Patients A. Duration of Mechanical Ventilation

Hazard Ratio = 1.20 ; IC95% = 0.48; 3.02 ; P = 0.6944 Comparison of Hydrocortisone group versus Placebo with a stratified cox model (N= 17 in the hydrocortisone group, N=19 in the placebo). Analyses of patients with an adapted corticosteroid function left untreated when the result of the corticotropin test was available

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B: ICU Length of Stay

Hazard Ratio = 1.13 ; IC95% = 0.42; 3.04 ; P = 0.8112 Comparison of Hydrocortisone group versus Placebo with a stratified cox model (N= 17 in the hydrocortisone group, N=19 in the placebo). Analyses of patients with an adapted corticosteroid function left untreated when the result of the corticotropin test was available

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eTable 1. Modifiable Risk Factors of Hospital Acquired Pneumonia

all patients (ITT) CIRCI patients (mITT) Adapted corticosteroid Interventions Hydrocortisone (n=73) Placebo (n=76) Pvalue Hydrocortisone (n=56) Placebo (n=57) Pvaluesa function (n=36) Antibiotic prophylaxis no. (%) Duration of antibiotic prophylaxis (days) median (IQR) Oropharyngeal decontamination no. (%) Enteral nutrition at day 7 no. (%) Stomach ulcer prevention no. (%) Proclive > 30 no. (%) Protocol for glycemia control no. (%) 63 (86.3) 5 (2-6) 44 (61.1) 64 (88.9) 43 (59.7) 62 (87.3) 68 (94.4) 65 (85.5) 4.5 (2-6) 47 (61.8) 69 (90.8) 56 (73.7) 67 (88.2) 71 (94.7) 0.89 0.97 0.93 0.70 0.07 0.88 1 49 (87.5) 5 (2-6) 32 (57.1) 49 (87.5) 37 (66.1) 48 (87.3) 55 (98.2) 50 (87.7) 5 (2-6) 36 (63.2) 53 (93.0) 41 (71.9) 50 (87.7) 52 (92.9) 0.97 0.51 0.51 0.33 0.50 0.94 0.36 29 (80.6) 3 (2-6) 23 (65.7) 31 (88.6) 21 (60.0) 31 (88.6) 32 (91.4)
a

P-valuesb P-valuesc

0.35 0.69 0.80 0.47 0.24 1 1

0.37 0.95 0.42 1 0.56 1 0.16

Abbreviations: ITT: intention to treat analysis; mITT: modified intention to treat analysis; CIRCI: Critical Illness-Related Corticosteroid Insufficiency; IQR: interquartile range. Hydrocortisone b c versus Placebo ; Placebo versus Adapted Corticosteroid Function ; Hydrocortisone versus Adapted Corticosteroid Function.

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eTable 2. Types of Pathogens Involved in Hospital Acquired Pneumonia at Day 28

Pathogens no. (%) Early onset pneumonia (J0-J8) Staphylococus aureus methicillin susceptible Staphylococus aureus methicillin resistant Streptococcus pneumoniae Haemophilius influenzae Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Others Late onset pneumonia (J9-J28) Staphylococus aureus methicillin susceptible Staphylococus aureus methicillin resistant Streptococcus pneumoniae Haemophilius influenzae Escherichia coli Klebsiella pneumoniae Pseudomonas aeruginosa Others All patients (ITT) Hydrocortisone Placebo (n=73) (n=76) 21 10 (48) 1 (5) 1 (5) 6 (29) 5 (24) 1 (5) 1 (5) 3 (14) 7 2 (29) 0 0 0 4 (57) 0 2 (29) 2 (29) 32 12 (38) 0 1 (3) 12 (38) 6 (19) 1 (3) 0 6 (19) 15 7 (47) 0 1 (7) 0 2 (13) 0 1 (7) 7 (47) CIRCI patients (mITT) Hydrocortisone Placebo (n=56) (n=57) 17 9 (53) 0 0 4 (24 ) 5 (29) 1 (6 ) 1 (6 ) 2 (12 ) 5 1 (20) 0 0 0 2 (40) 0 2 (40) 0 26 11 (42) 0 0 10 (38) 5 (19) 1 (4) 0 6 (23) 12 7 (58) 0 1 (8) 0 1 (8) 0 0 5 (42) Adapted corticosteroid function (n=36) 10 2 (20) 1 (10) 2 (20) 4 (40) 1 (10) 0 0 1 (10) 5 1 (20) 0 0 0 3 (60) 0 1 (20) 4 (80)

Abbreviations: ITT: intention to treat analysis; mITT: modified intention to treat analysis; CIRCI: Critical Illness-Related Corticosteroid Insufficiency;

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eTable 3. Cause of Death

All patients (ITT) Hydrocortisone (n=73) N (%) Cause of death Hemorrhage or intracranial hypertension Trauma and infection Withdrawing of life sustaining therapies Timing of death Death < 48 hours (hemorrhage or intracranial hypertension) 2 days < Death < 28 days 2 (2.7) 4 (5.5) 1 (1.3) 3 (3.9) 2 (3.6) 4 (7.1) 0 (0) 3 (5.4) 1 (2.8) 0 (0) 2 (2.7) 3 (4.1) 1 (1.4) 2 (2.6) 2 (2.6) 0 (0) 2 (3.6) 3 (5.3) 1 (1.8) 1 (1.8) 2 (3.6) 0 (0) 1 (2.8) 0 (0) 0 (0) Placebo (n=76) CIRCI patients (mITT) Hydrocortisone (n=56) Placebo function (n=57) (n=36) Adapted corticosteroid

Abbreviations: ITT: intention to treat analysis; mITT: modified intention to treat analysis; CIRCI: Critical Illness-Related Corticosteroid Insufficiency;

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eTable 4. Outcomes for Patients With Adapted Corticosteroid Function

Hydrocortisone (n=17) Number of HAP 0 1 2 HAP per treatment (day 8) General population Severe head trauma No severe head trauma ISS < 30 ISS 30 Vasoactive drugs Duration (days) Norepinephrine Delta in the 24 first hours (g/kg/min) Epinephrine Dobutamine Mechanical ventilation-free days Length of ICU stay (days) Other infections Tracheobonchitis 2 (11.8) 0 0.2159 2 (0-4.5) 10 (62.5) -0.03 0.14 0 0 13.3 10.4 23.0 19.9 1 (0-3) 11 (57.9) -0.09 0.27 0 0 13.0 10.0 20.9 14.0 0.6102 0.7817 0.4744 / / 0.9282 0.7207 4 (23.53) 3 (30.0) 1 (14.3) 3 (25.0) 1 (20.0) 7 (36.84) 4 (57.14) 3 (25.0) 5 (35.7) 2 (40.0) 0.3867 0.3500 1 0.6828 1 11 (64.7) 6 (35.3) 0 11 (57.9) 7 (36.8) 1 (5.3) 0.5140 Placebo (n=19) P-values

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Adapted corticosteroid function eTable 4 (cont) Urinary Tract Infection Bacteriemia Surgical wound infection Organ failures ARDS or ALI Acute Kydney Injury Myocardial insufficiency Hepatic insufficiency Hematologic insufficiency Death Etomidate infusion prior to inclusion Metabolic tolerance Hyperglycemia (180 mg/dl) Hyperkaliemia ( 5.0 mmol/l) Hypernatremia (150 mmol/l) Hypokaliemia ( 3.0 mmol/l) Hyponatremia (130 mmol/l) Gastrointestinal bleeding or digestive perforation 1 (6.3) 0 1 (6.3) 1 (6.3) 0 0 1 (5.3) 1 (5.3) 3 (15.8) 0 0 0 1 1 0.6081 0.4571 / / 0 1 (6.3) 0 0 0 1 (5.9) 8 (50) 3 (15.8) 2 (10.5) 0 0 0 1 (5.3) 7 (36.8) 0.2336 1 / / / 1 0.4333 Hydrocortisone (n=17) 1 (5.9) 0 0 Placebo (n=19) 0 0 2 (10.5) P-values 0.4722 / 0.4873

Abbreviations: HAP : Hospital Acquired Pneumonia; ISS : Injury Severity Score ; ARDS : Acute Respiratory Distress Syndrom, ALI : Acute Lung Injury.

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