Table 1. Characteristics of the 37 Randomized Clinical Trials Included in the Meta-analysis of Corticosteroids vs Placebo or Standard Supportive Care in Adults With Sepsis.
| Study | Sites, No. | Patients, No. | Mean Age, y | Women, % | Type of Patient Population | Experimental Intervention | Primary Outcome |
|---|---|---|---|---|---|---|---|
| Klastersky et al,27 1971 | 1 | 85 | NR | CS: 39.1; PC: 51.3 | Severe sepsis and advanced cancer | Betamethasone 0.5 mg/kg every 12 h for 3 d | 30-d Mortality |
| Schumer,28 1976 | 1 | 172 | 50 | 3.5 | Septic shock | Group 1: methylprednisolone (30 mg/kg); group 2: dexamethasone (3 mg/kg); dose was repeated once in both groups after 4 h and had to be initiated at the time of diagnosis | Hospital mortality |
| Sprung et al,29 1984 | 2 | 59 | CS: 58; PC: 55 | CS: 14.3; PC: 18.2 | Septic shock | Group 1: methylprednisolone (30 mg/kg); group 2: dexamethasone (6 mg/kg); dose was repeated once in both groups after 4 h if shock persisted | Hospital mortality |
| Bone et al,30 1987 | 19 | 382 | CS: 53.0; PC: 53.6 | 38.5 | Sepsis or septic shock | Methylprednisolone bolus (30mg/kg) repeated every 6 h for 24 h | 14-d Septic shock |
| VASSCSG et al,31 1987 | 10 | 223 | CS: 60.9; PC: 60.6 | NR | Sepsis or septic shock | Methylprednisolone bolus (30 mg/kg) followed by 5 mg/kg/h for 9 h | 14-d Mortality |
| Luce et al,32 1988 | 1 | 75 | NR | NR | ARDS and sepsis | Methylprednisolone (30 mg/kg) every 6 h, 4 times | Prevention of ARDS |
| Bollaert et al,33 1998 | 2 | 41 | CS: 66; PC: 56 | CS: 31.8; PC: 36.8 | Septic shock | Hydrocortisone bolus (100 mg) every 8 h for 5 d, then tapered over 6 d | Shock reversal |
| Briegel et al,34 1999 | 1 | 40 | CS: 47; PC: 51 | CS: 55; PC: 40 | Septic shock | Hydrocortisone bolus (100 mg), followed by a continuous infusion of 0.18 mg/kg per hour until shock reversal, then tapered off | Shock reversal |
| Chawla and Kupfer,35 1999 | 1 | 44 | NR | NR | Septic shock | Hydrocortisone (100 mg) every 8 h for 3 d, then tapered over 4 d | Shock reversal |
| Annane et al,36 2002 | 19 | 300 | CS: 62; PC: 60 | CS: 36; PC: 30 | Septic shock | Hydrocortisone bolus (50 mg) every 6 h and fludrocortisone (50 μg) taken orally every 24 h for 7 d | 28-d Mortality |
| Yildiz et al,37 2002 | 1 | 40 | CS: 57.8; PC: 56.5 | CS: 43.8; PC: 56.3 | Sepsis, severe sepsis or septic shock | Prednisolone intravenous boluses 2 times daily at 6:00 am (5 mg) and at 6:00 pm (2.5 mg) for 10 d | 28-d Mortality |
| Keh et al,38 2003 | 1 | 40 | 52 | 65 | Septic shock | Hydrocortisone bolus (100 mg) followed by a continuous infusion of 10 mg/h for 3 d | Immune response |
| Confalonieri et al,39 2005 | 6 | 46 | CS: 60.4; PC: 66.6 | CS: 26.0; PC: 34.8 | Sepsis and community-acquired pneumonia | Hydrocortisone bolus (200 mg), followed by a continuous infusion of 10 mg/h for 7 d, then tapered off over 4 d | Improvement in Pao2:FIo2 |
| Oppert et al,40 2005 | 1 | 40 | CS: 59; PC: 47 | CS: 27.8; PC: 17.4 | Septic shock | Hydrocortisone bolus (50 mg), followed by continuous infusion of 0.18 mg/kg per hour up to cessation of vasopressor for ≥1 h, reduced to a dose of 0.02 mg/kg per hour for 24 h, then reduced by 0.02 mg/kg per hour every d | Time to cessation of vasopressor support |
| Tandan and Guleria,41 2005 | 1 | 51 | 51 | NR | Septic shock and adrenal insufficiency | Hydrocortisone (stated low dose but actual dose and duration NR) | 28-d Mortality or survival to hospital discharge |
| Rinaldi et al,42 2006 | 1 | 40 | CS68; PC: 66 | NR | Severe sepsis | Hydrocortisone (300 mg) daily as a continuous infusion for 6 d, then tapered off | Effect of steroids on urinary albumin/creatinine ratio |
| Cicarelli et al,43 2007 | 1 | 29 | CS: 69; PC: 61 | CS: 57.1; PC: 53.3 | Septic shock | Dexamethasone (0.2 mg/kg) given 3 times at intervals of 36 h | Improvement in Pao2:FIo2 |
| Meduri et al,44 2007 | 5 | 91 | CS: 59.1; PC: 54.5 | CS:29; PC:31 | ARDS and sepsis | Methylprednisolone loading dose of 1 mg/kg, followed by continuous infusion of 1 mg/kg per day from days 1-14, then 0.5 mg/kg per day from days 15-21, then 0.25 mg/kg per day from days 22-25, then 0.125 mg/kg per day from days 26-28 | Improvement in lung injury score at 7 d |
| Aboab et al,45 2008 | 1 | 23 | CS:55; PC:56 | CS: 60; PC: 61 | Septic shock | Hydrocortisone bolus (50 mg) every 6 h and fludrocortisone (50 μg) taken orally every 24 h for 7 d | Low- and high-normalized frequency components |
| Sprung et al,46 2008 | 52 | 499 | CS:63; PC:63 | CS: 34; PC: 33 | Septic shock | Hydrocortisone (50 mg) every 6 h for 5 d, then 50 mg every 12 h for 3 d, then 50 mg once daily for 3 d | 28-d Mortality |
| Hu et al,47 2009 | 1 | 77 | CS:56; PC:54 | CS: 39.5; PC: 35.9 | Septic shock | Hydrocortisone (50 mg) every 6 h for the first 7 d, 50 mg every 8 h for the next 3 d, then 50 mg every 12 h for 2 d and 50 mg once daily for 2 d | Time on norepinephrine and lactate clearance |
| Arabi et al,48 2010 | 1 | 75 | CS: 60.6; PC: 59.3 | CS: 44; PC: 44 | Cirrhosis and septic shock | Hydrocortisone bolus (50 mg) every 6 h until shock resolution | 28-d Mortality |
| Snijders et al,49 2010 | 1 | 213 | CS: 63.0; PC: 64.0 | CS: 47.1; PC: 36.7 | Community-acquired pneumonia and sepsis | Prednisolone (40 mg) intravenous once daily for 7 d | Rate of treatment failure at 7 d and 30 d |
| Meijvis et al,50 2011 | 2 | 304 | CS:64.5; PC:62.5 | CS:84; PC:87 | Community-acquired pneumonia and sepsis | Dexamethasone (5 mg) intravenously for 4 d | Length of hospital stay |
| Sabry,51 2011 | 3 | 80 | 63 | 56.1 | Community-acquired pneumonia and sepsis | Hydrocortisone bolus (200 mg) followed by intravenous dose of 300 mg daily for 7 d | Unclear |
| Yildiz et al,52 2011 | 1 | 55 | CS: 75; PC: 64 | CS: 22.2; PC: 45.5 | Sepsis or septic shock | Prednisolone intravenous boluses 3 times daily at 6 am (10 mg), 2 pm (5 mg), and 10 pm (5 mg) for 10 d | 28-d Mortality |
| Liu et al,53 2012 | 1 | 26 | CS: 69.8; PC: 55.9 | CS: 25.0; PC: 28.6 | ARDS and sepsis | Hydrocortisone bolus (100 mg) followed by 100 mg every 8 h for 3 d | 28-d Mortality |
| Rezk and Ibrahim,54 2013 | 1 | 27 | NR | NR | ARDS and sepsis | Methylprednisolone loading dose of 1 mg/kg, followed by continuous infusion of 1 mg/kg per day from days 1-14, 0.5 mg/kg per day from days 15-21, 0.25 mg/kg per day from days 22-25, and 0.125 mg/kg per day from days 26-28 | Unclear |
| Gordon et al,55 2014 | 4 | 61 | CS: 61; PC: 60 | CS: 42; PC: 40 | Septic shock | Hydrocortisone (50 mg) every 6 h for the first 5 d, 50 mg every 12 h for the next 3 d, 50 mg every 24 h for the last 3 d | Difference in plasma vasopressin concentration between treatment groups |
| Huang et al,56 2014 | 1 | 40 | CS: 53.9; PC: 55.7 | CS: 50.0; PC: 40.0 | Sepsis | Hydrocortisone (300 mg) daily as a continuous infusion for 7 d | 28-d Mortality |
| Torres et al,57 2015 | 3 | 120 | CS: 64.5; PC: 66.1 | CS: 43; PC: 34 | Community-acquired pneumonia and sepsis | Methylprednisolone intravenous bolus of 0.5 mg/kg/12 h for 5 d started within 36 h of hospital admission | Rate of treatment failure |
| Gordon et al,58 2016 | 18 | 421 | 66 | 42 | Septic shock | Hydrocortisone (50 mg) every 6 h for the first 5 d, 50 mg every 12 h for the next 3 d, 50 mg every 24 h for the last 3 d | Kidney failure–free days to 28 d |
| Keh et al,59 2016 | 34 | 380 | CS: 65.5; PC: 64.6 | CS: 33.3; PC: 36.9 | Severe sepsis | Hydrocortisone bolus (50 mg) followed by a continuous infusion of 200 mg daily for 3 d | 14-d Septic shock |
| Tongyoo,60 2016 | 1 | 206 | CS: 64.5; PC: 64.3 | CS: 49.0; PC: 48.5 | Severe sepsis or septic shock and ARDS | Hydrocortisone (50 mg) every 6 h for 7 d | 28-d Mortality |
| Lv et al,61 2017 | 1 | 118 | CS: 68.8; PC: 64.8 | CS: 43.1; PC: 38.3 | Septic shock | Hydrocortisone (200 mg) daily as a continuous infusion for 6 d | 28-d Mortality |
| Annane et al,14 2018 | 34 | 1241 | CS:66; PC: 66 | CS: 34.5; PC: 32.3 | Septic shock | Hydrocortisone bolus (50 mg) every 6 h and oral fludrocortisone (50 μg) every 24 h for 7 d | 90-d Mortality |
| Venkatesh et al,15 2018 | 69 | 3800 | CS: 62.3; PC: 62.7 | CS: 39.6; PC: 38.7 | Septic shock | Hydrocortisone (200 mg) intravenously every day for a maximum of 7 d or until ICU discharge or death | 90-d Mortality |
Abbreviations: ARDS, acute respiratory distress syndrome; CS, corticosteroids; ICU, intensive care unit; NR, not reported; Pao2:FIo2, ratio of partial pressure of arterial oxygen to fraction of inspired oxygen; PC, placebo or control.