Supplementary Appendix This appendix has been provided by the authors to give readers additional information about their work. Supplement to: Sprung CL, Annane D, Keh D, et al. Hydrocortisone therapy for patients with septic shock. N Engl J Med 2008;358:111-24.
Supplementary Appendix Table 1 Inclusion and Exclusion Criteria I. Inclusion Criteria (all 4 required at enrollment) * 1. Clinical evidence of infection within the previous 72 hours with either presence of polymorphonuclear cells in a normally sterile body fluid (excluding blood); culture or Gram stain of blood, sputum, urine or normally sterile body fluid positive for a pathogenic micro-organism; focus of infection identified by visual inspection (e.g. ruptured bowel with the presence of free air or bowel contents in the abdomen found at the time of surgery, wound with purulent drainage); or other clinical evidence of infection treated community acquired pneumonia, purpura fulminans, necrotising fascitis, etc. 2. Evidence of a systemic response to infection defined by the presence of two or more of the following signs within the previous 24 hours: fever (temperature >38.3 C) or hypothermia (rectal temperature < 35.6 C); tachycardia (heart rate of >90 beats/min); tachypnea (respiratory rate > 20 breaths/min, PaCO 2 <32 mmhg) or need for invasive mechanical ventilation; alteration of the white cell count >12,000 cells/mm 3, <4,000 cells/mm 3 or >10% immature neutrophils (bands). 3. Evidence of shock within the previous 72 hours (originally within the previous 24 hours) defined by (both A + B required): 1
A. a systolic blood pressure (SBP) < 90 mmhg or a decrease in SBP of more than 50 mmhg from baseline in previous hypertensive patients (for at least one hour) despite adequate fluid replacement OR need for vasopressors for at least one hour (infusion of dopamine 5 mcg/kg/min or any dose of epinephrine, norepinephrine, phenylephrine or vasopressin) to maintain a SBP 90 mmhg; and B. Hypoperfusion or organ dysfunction attributable to sepsis, including one of: 1. Sustained oliguria (urine output < 0.5 ml/kg/hr for a minimum of 1 hour); 2. Metabolic acidosis [ph of < 7.3, or arterial base deficit of 5.0 mmol/l, or an increased lactic acid concentration (> 2 mmol/l)]; 3. Arterial hypoxemia (PaO 2 /FIO 2 <280 in the absence of pneumonia) (PaO 2 /FIO 2 <200 in the presence of pneumonia); 4. Thrombocytopenia platelet count 100,000 cells/mm 3 ; 5. Acute altered mental status (Glasgow Coma Scale < 14 or acute change from baseline). 4. Informed consent according to local regulations * Patients had to be hypotensive or receiving vasopressors at the time of enrollment 2
II. Exclusion Criteria 1. Pregnancy 2. Age < 18 3. Underlying disease with a prognosis for survival < 3 months 4. Cardiopulmonary resuscitation within 72 hours before enrollment 5. Drug-induced immunosuppression, including chemotherapy or radiation therapy within 4 weeks before the study 6. Administration of chronic corticosteroids in the last 6 months or acute steroid therapy (any dose) within 4 weeks (including inhaled steroids) 7. Human immunodeficiency virus (HIV) positivity 8. Presence of an advanced directive to withhold or withdraw life sustaining treatment (i.e. DNR) 9. Advanced cancer with a life expectancy < 3 months 10. Acute myocardial infarction or pulmonary embolus 11. Another experimental drug study within the last 30 days 12. Moribund patients likely to die within 24 hours 13. Patients in the ICU > 2 months. 3
Supplementary Appendix Table 2 Type and site of infection and type of organism Characteristic Non Responders Responders All patients Hydrocortisone (N = 125) Placebo (N = 108) Hydrocortisone (N = 118) Placebo (N = 136) Hydrocortisone (N = 251) Placebo (N = 248) Type of infection - Community - acquired 68 (54) 55 (51) * 61 (52) * 71 (52) * 133 (53) * 127 (51) - Hospital - acquired 57 (46) 52 (48) * 56 (48) * 64 (47) * 117 (47) * 119 (48) - Post-surgery (within 7 days) 83 (66) 69 (64) 80 (68) 63 (46) 168 (67) 135 (54) Site of Infection - Lung 34 (27) 30 (28) 40 (34) 64 (47) * 76 (30) 95 (38) * - Gastrointestinal 63 (50) 62 (57) 55 (47) 52 (38) * 123 (49) 116 (47) * - Urinary tract 10 (8) 4 (4) 10 (9) 12 (9) * 20 (8) 17 (7) * - Soft tissue 11 (9) 8 (7) 5 (4) 9 (7) * 17 (7) 17 (7) * - Central Nervous System 2 (2) --- 2 (2) 2 (2) * 4 (2) 2 (1) * - Endocarditis 3 (2) 1 (1) --- 3 (2) * 3 (1) 4 (2) * - Gynecological 2 (2) 4 (4) 3 (3) 1 (1) * 5 (2) 5 (2) * - Bones/Joints 6 (5) 3 (3) --- 1 (1) * 6 (2) 4 (2) * - Bacteremia 11 (9) 8 (7) 6 (5) 14 (10) * 17 (7) 23 (9) * - Other 7 (6) 3 (3) 8 (7) 5 (4) * 15 (6) 9 (4) * - Unknown 4 (3) 4 (4) 5 (4) 1 (1) 9 (4) 5 (2) 4
Positive Culture - Gram-positive only 23 (18) 23 (21) 11 (9) 25 (18) 36 (14) 48 (19) - Gram-negative only 24 (19) 21 (19) 26 (22) 32 (24) 50 (20) 55 (22) - Gram-positive and Gram negative 25 (20) 26 (24) 20(17) 15 (11) 46 (18) 41 (17) - Fungus only 4 (3) 2 (2) 4 (3) 1 (1) 10 (4) 3 (1) - Anaerobes only 2 (2) 1 (1) 2 (2) 4 (3) 4 (2) 5 (2) - Other Mixed 15 (12) 14 (13) 13 (11) 17 (13) 28 (11) 32 (13) - Other 1 (1) --- 2 (2) 2 (2) 3 (1) 2 (1) - Pathogen unknown 31 (25) 21 (19) 40 (34) 40 (29) 74 (30) 62 (25) Gram-positive - Staph aureus methicillin sensitive 13 (10) 19 (18) 10 (9) 15 (11) 24 (10) 35 (14) - Staph aureus methicillin resistant 3 (2) 8 (7) 2 (2) 12 (9) 6 (2) 20 (8) - Staph coagulase negative 10 (8) 8 (7) 4 (3) 3 (2) 14 (6) 11 (4) - Streptococcus pneumoniae 3 (2) 3 (3) 4 (3) 2 (2) 7 (3) 5 (2) - Other Streptococcus species 17 (14) 9 (8) 14 (12) 16 (12) 31(12) 26 (11) - Enterococcus species 22 (18) 27 (25) 13 (11) 15 (11) 36 (14) 42 (17) - Clostridium species 3 (2) 2 (2) 1 (1) 2 (2) 4 (2) 4 (2) - Other Gram positive 1 (1) --- --- 2 (2) 1 (0) 2 (1) Gram- negative - Escherichia coli 34 (27) 31 (29) 35 (30) 25 (18) 69 (28) 56 (23) - Pseudomonas aeruginosa 7 (6) 11 (10) 5 (4) 7 (5) 12 (5) 18 (7) - Klebsiella pneumoniae 12 (10) 7 (7) 5 (4) 15 (11) 17 (7) 23 (9) - Other Enterobacter species 12 (10) 7 (7) 6 (5) 8 (6) 18 (7) 15 (6) 5
- Haemophilus influenzae 5 (4) 1 (1) 5 (4) 1 (1) 11 (4) 2 (1) - Anaerobes 8 (6) 10 (9) 6 (5) 7 (5) 14 (6) 16 (6) - Other Gram negative 21 (7) 25 (24) 18 (15) 31 (23) 39 (16) 58 (23) Fungus - Candida albicans 8 (6) 4 (4) 10 (9) 9 (7) 20 (8) 13 (5) - Other candida species 4 (3) 4 (4) 3 (3) 2 (1) 7 (3) 7 (3) - Yeast --- 1 (1) 4 (3) 2 (2) 4 (2) 3 (1) - Other 1 (1) --- 2 (2) 4 (3) 3 (1) 4 (2) Data are mean±sd for continuous variables or numbers of patients (percentages) for categorical variables. Staph- staphylococcus. *- 1 missing value, - 2 missing values. 6
Supplementary Appendix Table 3 Analysis by time of first study drug application after meeting baseline characteristics Treatment group Steroid Placebo Total N (%) N (%) N(%) Treatment start within 12 h Alive 125 (63.1) 128 (68.8) 253 (65.9) Died 73 (36.9) 58 (31.2) 131 (34.1) Total 198 (100.0) 186 (100.0) 384 (100.0) Treatment start between 12 to 24 h Alive 20 (80.0) 19 (79.2) 39 (79.6) Died 5 (20.0) 5 (20.8) 10 (20.4) Total 25 (100.0) 24 (100.0) 49 (100.0) Treatment start between 24 and 48 h Alive 11 (57.9) 18 (58.1) 29 (58.0) Died 8 (42.1) 13 (41.9) 21 (42.0) Total 19 (100.0) 31 (100.0) 50 (100.0) Treatment start between 48 and 72 h Alive 8 (100.0) 5 (83.3) 13 (92.9) Died 0 (0) 1 (16.7) 1 (7.1) Total 8 (100.0) 6 (100.0) 14 (100.0) Treatment start after more than 72 h Alive 1 (100.0) - 1 (100.0) Total 1 (100.0) - 1 (100.0) Total ITT population Alive 165 (65.7) 170 (68.8) 335 (67.3) Died 86 (34.3) 77 (31.2) 163 (32.7) Total 251 (100.0) 247 (100.0) 498 (100.0) 7