Table 1.
Characteristics of the included studies in the in adult patients with sepsis.
| Study | Study Type | S/M Center | Study Period | Total Patients/Patients in CS No. | Mean Age, Years | Female/Male of Patient No. | Type of Patient Population | Sepsis or Septic Shock Definition | The time of CS Administration | Experimental Intervention | Reported Outcomes | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Annane et al. (21) | RCT | M | NA | 1241/614 | CS: 66 PC: 66 | 415/826 | Septic shock | Sepsis-3 | NA | 50 mg/6 h hydrocortisone intravenously + fludrocortisone 50 µg for 7 days | 28, 90, and 180 days, ICU and hospital discharge, etc. | |||
| Venkatesh et al. (64) | RCT | M | 03/2013 −04/2017 |
3,658/1,832 | CS: 62.3 PC: 62.7 | 1,399/2,259 | Septic shock | Sepsis-3 | NA | 200 mg/day hydrocortisone intravenous infusion for 7 days | 90- and 28-day mortality; ICU/hospital stay time, etc. | |||
| Annane et al. (22) | RCT | M | 10/1995 −02/1999 |
300/151 | CS: 62 PC: 60 |
200/100 | Septic shock | Sepsis-2 | NA | 50 mg/6 h hydrocortisone bolus and 50 μg fludrocortisone orally/24 h for 7 days |
28-day mortality | |||
| Lv et al. (45) | RCT | S | 09/2015–09/2016 | 118/58 | CS: 68.8 PC: 64.8 |
70/68 | Septic shock | NA | With vasoactive drugs initiating | 200 mg/day hydrocortisone for 6 days | 28-day mortality; reversal of shock; hospital mortality; ICU/hospital stay |
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| Klastersky et al. (42) | RCT | S | NA | 85/46 | NA | 47/38 | Severe sepsis | NA | With antibacterial agents | Betamethasone 0.5 mg/kg every 12 h for 3 days | 30-day mortality | |||
| Bone et al. (26) | RCT | M | 11/1982–12/1985 | 382/191 | CS:53.0 PC: 53.6 |
147/235 | Septic shock | NA | 2 h from entry | Methylprednisolone bolus (30 mg/kg) repeated every 6 h for 24 h |
Shock incidence; shock reversal; overall mortality; 14-day mortality |
|||
| Schumer et al. (54) | RCT | S | 1967–1975 | 172/86 | 50 | 5/167 | Septic shock | NA | At the time of diagnosis | Methylprednisolone (30 mg/kg) dose was repeated once in both groups after 4 h | Mortality; shock associated mortality; organ injury associated mortality |
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| Sprung et al. (57) | RCT | M | 08/1979–02/1982 | 59/43 | CS: 58 PC: 55 |
13/46 | Septic shock | NA | After the onset of shock | Methylprednisolone (30 mg/kg); |
Shock reversal; hospital mortality; blood cultures; adverse events |
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| Yildiz et al. (65) | RCT | S | 05/1997–04/1999 | 40/20 | CS: 57.8 PC: 56.5 |
16/24 | Sepsis | Sepsis-1 | Within 2 h after randomization | Prednisolone intravenous blouses 2 times/day at 6:00 a.m. (5 mg) and at 6:00 p.m. (2.5 mg) for 10 days | 28-day mortality; sepsis-related organ dysfunction | |||
| Vasscsg et al. (36) | RCT | M | 10/1983–04/1986 | 223/112 | CS: 60.9 PC: 60.6 |
NA | Sepsis | NA | Within 2 h of diagnosis | Methylprednisolone bolus (30 mg/kg) repeated every 6 h for 24 h | 14-day mortality; adverse occurrences |
|||
| Luce et al. (44) | RCT | S | 09/1983–08/1986 | 75/38 | NA | NA | Sepsis and ARDS | NA | After patients inclusion | Methylprednisolone (30 mg/kg) every 6 h, 4 times | ARDS incidence; all-cause mortality; adverse events |
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| Bollaert et al. (25) | RCT | M | NA | 41/22 | CS: 66 PC: 56 |
14/27 | Septic shock | Sepsis-1 | NA | Hydrocortisone bolus (100 mg) every 8 h for 5 days, then tapered over 6 days | 7 days reversal of shock; 28 days reversal of shock; 28-day mortality; adverse events |
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| Tilouch et al. (60) | RCT | S | 04/2013–06/2016 | 70/33 | CS (continuous infusion): 69 CS (bolus): 70 |
43/27 | Septic shock | NA | NA | Hydrocortisone 200 mg/days by continuous infusion for 7 days; Hydrocortisone 50 mg intravenously every 6 h for 7 days | Shock reversal at day 7; 28-day mortality; vasopressor-free days; ICU and hospital length of stay; occurrence of superinfection |
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| Huang et al. (38) | RCT | S | 12/2010–12/2012 | 60/20 | CS: 53.9 PC: 55.7 |
25/35 | Sepsis | Sepsis-2 | NA | Hydrocortisone (300 mg) daily as a continuous infusion for 7 days | 28-day mortality; 3 days shock reversal |
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| Briegel et al. (27) | RCT | S | NA | 40/20 | CS: 47 PC: 51 |
19/21 | Septic shock | Sepsis-1 | Within 30 min | Hydrocortisone bolus (100 mg), followed by a continuous infusion of 0.18 mg/kg per hour until shock reversal, then tapered off | Shock reversal; hemodynamic variables; MOSD |
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| Chawla et al. (28) | RCT | S | NA | 44/23 | NA | NA | Septic shock | NA | NA | Hydrocortisone (100 mg)/8 h for 3 days | Shock reversal | |||
| Loisa et al. (43) | RCT | S | 07/2005–04/2006 | 48/NA | NA | NA | Septic shock | Sepsis-2 | NA | Hydrocortisone intravenous bolus of 50 mg/6 h for 5 days | Reversal of shock | |||
| Confalonieri et al. (30) | RCT | M | 07/2000–03/2003 | 46/23 | CS: 60.4 PC: 66.6 |
14/32 | Sepsis and CAP | NA | NA | Hydrocortisone bolus (200 mg), followed by a continuous infusion of 10 mg/h for 7 days, then tapered off over 4 days |
MODS score by Study Day 8 and development of delayed septic shock; duration of mechanical ventilation; length of ICU/RIU hospital stay; survival to hospital discharge and to 60 days |
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| Sprung et al. (56) | RCT | M | 03/2002–11/2005 | 499/251 | CS: 63 PC: 63 |
167/332 | Septic shock | Sepsis-1 | NA | Hydrocortisone (50 mg)/6 h for 5 days, then 50 mg/12 h for 3 days, then 50 mg/day for 3 days | 28-day mortality | |||
| Keh et al. (40) | RCT | S | 03/1997–09/2000 | 40/20 | 52 | 26/14 | Septic shock | Sepsis-1 | NA | Hydrocortisone bolus (100 mg) followed by a continuous infusion of 10 mg/h for 3 days | Plasma cortisol | |||
| Arabi et al. (23) | RCT | S | 04/2004–10/2007 | 75/39 | CS: 44 PC: 44 |
33/42 | Cirrhosis and septic shock | Sepsis-2 | NA | Hydrocortisone bolus (50 mg)/6 h until shock resolution | 28-day mortality;shock reversal; ventilation-free days; length of stay in ICU; length of stay in hospital | |||
| Fernandez-Serrano et al. (33) | RCT | S | NA | 56/28 | CS: 61 PC: 66 |
NA | Severe CAP | NA | 30 min before starting the antibiotic treatment | Methylprednisolone as an intravenous bolus of 200 mg administered 30 min followed by 29 mg/6 h for 3 days, then 20 mg/12 h for 3 days, and finally 20 mg/days for another 3 days | Need for mechanical ventilation; time to resolution of morbidity score ICU length of stay; hospital length of stay | |||
| Rinaldi et al. (52) | RCT | S | NA | 40/20 | CS: 68 PC: 66 |
NA | Severe sepsis | Sepsis-1 | NA | Hydrocortisone (300 mg/day) continuous infusion for 6 days | Mortality; SOFA score |
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| Cicarelli et al. (29) | RCT | S | 11/2004–12/2005 | 29/14 | CS: 69 PC: 61 |
16/13 | Septic shock | NA | NA | Dexamethasone (0.2 mg/kg) given 3 times at 36 h | SOFA score 7-day mortality; 28-day mortality lactate evolution |
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| Aboab et al. (18) | RCT | S | NA | 23/10 | CS: 55 PC: 56 |
9/14 | Septic shock | Sepsis-1 | NA | Hydrocortisone bolus (50 mg) 6 h and fludrocortisone (50 μg) for 7 days | Blood pressure, etc. | |||
| Annane et al. (20) | RCT | M | 01/2006–01/2009 | 518/264 | CS: 63.9 PC: 64.3 |
195/323 | Septic shock | NA | NA | Hydrocortisone 50 mg/6 h; fludrocortisone orally in 50 µg tablets/day, each for 7 days | In-hospital mortality mechanical ventilation-free within 28 days; length of stay in ICU |
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| Yildiz et al. (66) | RCT | S | 04/2005–05/2008 | 55/27 | CS: 75 PC: 64 |
36/19 | Sepsis | Sepsis-1 | Within 24 h after admission | Prednisolone intravenous boluses 3 times daily at 6 a.m. (10 mg), 2 p.m. (5 mg), and 10 p.m. (5 mg) for 10 days | 28-day mortality; hospital stay |
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| Meduri et al. (46) | RCT | M | 04/1997–04/2002 | 91/63 | CS: 59.1 PC: 54.5 |
44/47 | ARDS and sepsis | NA | NA | Methylprednisolone loading dose of 1 mg/kg, followed by continuous infusion of 1 mg/kg per day then 0.5 mg/kg per day from 15–21 days | Length of ICU stay; hospital stay; ICU mortality; hospital mortality |
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| Snijders et al. (55) | RCT | S | 08/2005–07/2008 | 213/104 | CS: 63.0 PC: 64.0 |
89/124 | Sepsis and CAP | NA | After randomization | Prednisolone (40 mg) intravenous once daily for 7 days | Treatment failure at 7 and 30 days; treatment cure at 7 and 30 days | |||
| Meijvis et al. (48) | RCT | M | 11/2007–09/2010 | 304/151 | CS: 64.5 PC: 62.5 |
133/171 | Sepsis and CAP | NA | Within a maximum of 12 h from admission | Dexamethasone (5 mg) intravenously for 4 days | Length of hospital stay; hospital mortality; adverse events |
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| Mirea et al. (49) | RCT | S | NA | 112/54 | CS (200): 64.3 CS(300): 65.1 |
NA | Septic shock | NA | NA | Hydrocortisone 50 mg intravenous bolus per 6 h or 200 mg per day as a continuous infusion for a maximum of 7 days | Mean serum sodium values over 7 days; short-term mortality, etc. |
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| Rezk et al. (17) | RCT | S | 10/2011–10/2012 | 27/18 | NA | 4/23 | Sepsis and ARDS | NA | NA | 1 mg/kg methylprednisolone, followed by continuous infusion of 1 mg/kg per day from day 1 to 14, 0.5 mg/kg per day from day 15 to 21, 0.25 mg/kg per day from day 22–25, and 0.125 mg/kg per day from day 26 to 28 | Mortality; extubation from mechanical ventilation |
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| Gordon et al. (34) | RCT | M | 10/2010–03/2012 | 61/31 | CS: 61 PC: 60 |
25/36 | Septic shock | Sepsis-1 | NA | Hydrocortisone (50 mg) every 6 h for the first 5 days, 50 mg every 12 h for the next 3 days | Mortality; organ failure-free days |
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| Tongyoo et al. (62) | RCT | S | 12/2010–12/2014 | 197/98 | CS: 64.5 PC: 64.3 |
96/101 | Sepsis and ARDS | Sepsis-1 | Within 12 h | Hydrocortisone (50 mg) every 6 h for 7 days | 28-day mortality; mechanical ventilation-free days; 60-day mortality; adverse events |
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| Blum et al. (24) | RCT | M | 12/2009–05/2014 | 800/400 | CS: 74 PC: 73 | NA | CAP | NA | NA | Prednisone 50 mg per day for 7 days | All-cause mortality 30 and 180 days | |||
| Oppert et al. (51) | RCT | S | NA | 41/18 | CS: 59 PC: 47 |
9/32 | Septic shock | Sepsis-1 | After inclusion | Hydrocortisone bolus (50 mg), followed by continuous infusion of 0.18 mg/kg per hour up to cessation of vasopressor for ≥1 h | Vasopressor-free time; 28 days survival; SOFA score; adrenal reserve |
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| Angus et al. (19) | RCT | M | 03/2020–06/2020 | 379/278 | CS: 60.4 PC: 65.9 |
111/273 | Severe COVID-19 | NA | NA | Intravenous hydrocortisone (50 mg or 100 mg every 6 h) for 7 days | Organ support-free and mortality within 21 days | |||
| Torres et al. (63) | RCT | M | 06/2004–02/2012 | 120/61 | CS: 64.5 PC: 66.1 |
46/74 | CAP and sepsis | NA | Within 36 h of hospital admission | Methylprednisolone intravenous bolus of 0.5 mg/kg/12 h for 5 days started within 36 h of hospital admission |
Length of ICU and hospital; in-hospital mortality |
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| Gordon et al. (35) | RCT | M | 02/2013–05/2015 | 409/202 | 66 | 171/238 | Septic shock | Sepsis-1 | After inclusion | Hydrocortisone (50 mg) every 6 h for the first 5 days | Mortality; serious adverse events |
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| Edalatifard et al. (32) | RCT | S | 04/2020–06/2020 | 62/34 | CS: 55.8 PC: 61.7 |
23/39 | Severe COVID-19 | NA | After inclusion | Methylprednisolone intravenous injection, 250 mg/day for 3 days | Time of clinical improvement or death | |||
| Keh et al. (41) | RCT | M | 01/2009–08/2013 | 353/177 | CS: 65.5 PC: 64.6 |
124/229 | Severe sepsis | Sepsi-2 | NA | Hydrocortisone bolus (50 mg) followed by a continuous infusion of 200 mg daily for 3 days | Mortality in ICU or hospital; adverse events |
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| Doluee et al. (58) | RCT | S | 08/2014–04/2015 | 160/NA | NA | NA | Septic shock | NA | NA | Hydrocortisone (50 mg intravenous bolus every 6 h for 7 days) | 28-day mortality shock termination |
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| Nafae et al. (50) | RCT | S | NA | 80/NA | NA | NA | Severe CAP | NA | NA | Hydrocortisone 200 mg as intravenous bolus followed by infusion at 10 mg/h for 7 days | In-hospital mortality; serious adverse events | |||
| Dequin et al. (31) | RCT | M | 03/2020–06/2020 | 149/76 | CS: 63.1 PC: 66.3 |
45/104 | Severe COVID-19 | NA | NA | Hydrocortisone at aninitial dose of 200 mg/day continued at 200 mg/day until day 7 | Duration of mechanical ventilation; hospital length of stay | |||
| Meduri et al. (47) | RCT | S | NA | 80/NA | NA | NA | Sepsis | NA | Severe sepsis <48 h ICU entry | Hydrocortisone as a bolus of 300 mg | Mortality at 7 days and at 28 days, etc. | |||
| Tandan et al. (59) | RCT | S | NA | 51 | 51 | NA | Septic shock and adrenal insufficiency | NA | NA | Hydrocortisone (stated low dose but actual dose and duration NR) | 28-day mortality; the survival of hospital discharge | |||
| Hyvernat et al. (39) | RCT | M | 11/2008–07/2010 | 122/63 | CS(200): 64.3 CS(300): 65.1 |
80/42 | Septic shock | Sepsis-2 | When patients presenting septic shock | Hydrocortisone 50 mg/6 h for 5 days |
28 days all-cause mortality; free of vasopressor; free of mechanical ventilation | |||
| Tomazini et al. (61) | RCT | M | 04/2020–07/2020 | 299/151 | CS: 60.1 PC: 62.7 |
112/187 | COVID-19-associated ARDS | NA | NA | 20 mg dexamethasone for 5 days, 10 mg dexamethasone for 5 days or until ICU discharge | Ventilator-free and 28 days all-cause mortality; ICU-free days | |||
| Hu et al. (37) | RCT | S | 02/2007–01/2009 | 77/34 | CS: 56 PC: 54 |
48/29 | Septic shock | Sepsis-2 | After randomization | Hydrocortisone 50 mg/6 h for the first 7 days, 50 mg every 8 h for the next 3 days | Mortality; length of ICU stay |
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| Sabry et al. (53) | RCT | M | 07/2010–01/2011 | 80/40 | 63 | 22/58 | Sepsis and CAP | NA | NA | Hydrocortisone bolus (200 mg) followed by intravenous dose of 300 mg daily for 7 days | Duration of the mechanical ventilation | |||
RCT, randomized controlled trial; M, multicenter; S, single-center; ARDS, acute respiratory distress syndrome; CS, corticosteroids; PC, placebo or control; ICU, intensive care unit; NA, not acquired; MODS, multiple organ dysfunction syndrome; SOFA, sepsis-related organ failure assessment; IL, interleukin; COVID-19, coronavirus disease 2019; CAP, community-acquired pneumonia.