Introduction
Methods
Registration and reporting format
Search strategy
Eligibility criteria
Data extraction
Assessment of methodological quality
Data synthesis and analysis
Grading of the evidence
Results
Study selection
Study characteristics of RCTs from the systematic reviews and meta-analyses
First author, year, country (ref) | Study design | Sample size, intervention/placebo, Mean age, critical illness types | Intervention (s): first and following dose | Comparison (s) | APACHE or SAPS or SOFA score, intervention/placebo | Follow-up duration | Outcomes |
---|---|---|---|---|---|---|---|
Andrew, 2011, UK [45] | A double-blinded randomized parallel trial | 127/125, 64.5 years, GI bleeding | Intravenous sodium selenite 500 μg/day for 7 day | Selenium ≤ 50 μg /day | APACHE II: 20/20 | 14 day | Infection, adverse events, LOS hospital, LOS ICU, mortality by duration (28 days), mortality |
Angstwurm, 2007, Germany [46] | Prospective randomized, placebo-controlled, multiple-center trial | 122/124, 64.6 years, SIRS, sepsis, and septic shock | Bolus and continuous intravenous sodium selenite bolus 1000 μg/day, followed by a continuous dose of 1000 μg/day | Placebo | APACHE III: 92.2/91.2 | 28 days | Mortality, mortality by duration (28 days), infection, adverse events, pneumonia, LOS ICU |
Angstwurm, 1999, Germany [47] | Prospective open-label pilot RCT | 21/21, 56 years, SIRS | Continuous intravenous sodium selenite, 535 μg/day for 3 days then 285 μg/day for 3 days then 155 μg/day for 3 days then 35 μg/day for the remainder of the total treatment time | Placebo | APACHE II: ≥ 15/≥ 15 | Until discharge | Adverse event, LOS hospital, LOS ICU, renal failure length of ventilation, mortality by duration (28 days), mortality |
Bloos, 2016, Germany [48] | Placebo-controlled trial, multi-center | 543/546, 65.7 years, mixed ICU patients with severe sepsis or septic shock in last 24 h | Sodium selenite, IV loading dose of 1000 μg/day followed by a continuous 1000 μg/day | Placebo | APACHE II: 24.7/24.4 | 90 days | Infection, adverse events, LOS ICU, mortality by duration (28 days), mortality |
Brodska, 2015, Czech Republic [60] | Prospective, randomized, open-label single center | 75/75, 60 years, SIRS/sepsis | Intravenous sodium selenite, 1000 μg/day on the first day, 500 μg/day on subsequent days in the form of Na selenite pentahydrate | Standard selenium dose (< 75 μg/day) | APACHE II: 30/28 | Until discharge | Mortality by duration (28 days) |
Berger, 2001, Switzerland [7] | Prospective couple blind RCT | 9/12, 42 years trauma patients | Slow intravenous selenium 500 μg/day | Placebo | APACHE II: 13/11 | 20 days | Infection, LOS ICU, days on ventilation, mortality by duration (28 days), mortality |
Chelkeba, 2017, Iran [49] | Prospective RCT | 29/25, 38 years, septic patients | Intravenous selenium selenite, high‑dose parenteral sodium selenite (2 μg/day intravenous bolus, followed by 1.5 μg/day IV continuous infusion plus standard therapy | Standard therapy | APACHE II: 17/16.4 | 90 days | LOS ICU, LOS hospital, days on ventilation, renal failure, mortality, mortality by duration (28 days) |
Forcevill, 2007, France [50] | Double-blind, phase II RCT | 31/29, 67.5 years, severe septic shock patients with documented infection and mechanically ventilated | Intravenous sodium selenite, 400 μg/day (in 192 mL saline) over 24 h, then 1000 μg/da (in 48 mL saline) over 24 h for 9 days | Placebo | NR | 208 days | Infection, pneumonia, adverse event, LOS ICU, LOS hospital, days of ventilation, renal failure, mortality by duration (28 days), mortality |
Gartner, 1983, Germany [61] | Double-blind parallel RCT | 21/21, SIRS/sepsis | Intravenous sodium selenite, 500 μg/day, 250 μg/day, and 125 μg/day, each amount for 3 days | 35 μg/day sodium selenite during the whole treatment period | APACHE II: 17/19 | 48 days | Renal failure, mortality by duration (28 days) |
Janka, 2013, Slovak Republic [51] | Prospective observational trial | 35/37, 53 years, septic patients | Continuous intravenous sodium selenite pentahydrate at 750 μg/day | Placebo | APACHE II: 24/34 | 28 days | Mortality by duration (28 days), mortality |
Khalili, 2017, Iran [62] | Clinical trial | 125/182, 35.5 years, traumatic brain injury | Sodium selenate pentahydrate intravenously, 1000 μg/day for the first 5 days, followed by 500 μg/day for an additional 5 days | No treatment | NR | 96 days | Mortality by duration (28 days), LOS hospital, LOS ICU |
Kuklinski, 1991, Germany [52] | RCT | 8/9, 46.5 years, acute pancreatic necrosis | Intravenous 500 μg/day sodium selenite | No treatment | NR | NR | Mortality, mortality by duration (28 days) |
Lindner, 2004, Germany [53] | Prospective randomized trial | 35/35, 51 years, severe acute pancreatitis | Intravenous sodium selenite day 1, 2000 μg/day, days 2–5, 1000 μg/day, day 6 until discharged 300 μg/day | Placebo | NR | 90 days | Mortality, infection |
Mahmoodpoor, 2018, Iran [63] | clinical trial | 20/20, 54.7 years, acute respiratory distress syndrome | Intravenous sodium selenite, 3000 μg/day in as an initial bolus during the first 3 h of first day followed by 1500 μg/day at the same hourly interval on days 2–10 | Normal saline | APACHE II: 21/23 | NR | Mortality by duration (28 days), infection, LOS hospital, days on ventilation |
Moghaddam, 2017, Iran [65] | Double-blinded controlled trial | 57/56, 41.5 years, traumatic brain injury | Intravenous sodium selenite, 500 μg/day for 30 min and then 500 μg/day se during 24 h continuously | Standard care | APACHE III: 49.91/49.34 | 32 days | Days of ventilation, LOS ICU, LOS hospital, Mortality by duration (28 days) |
Manzanares, 2011, Uruguay [54] | Prospective, placebo-controlled, randomized, single-blinded phase II study | 15/16, 58 years, SIRS | Intravenous selenium bolus loading 2000 μg/day then 1600 μg/day for10 days | 0.9% NaCl only for 10 days | APACHE II: 21/23 | 28 days | Mortality, renal failure, days of ventilation, LOS ICU, infection, pneumonia, adverse events |
Manzanares, 2010, Uruguay [64] | Prospective, placebo-controlled, randomized, single-blinded phase II study | 10/10, 42.5 years, SIRS/sepsis | Intravenous selenium, 2000 μg/day (as selenious acid) bolus loading dose over 2 h thereafter 1600 μg/day for 10 days | Loading dose of selenium selenite 1200 μg over 2 h and thereafter 800 μg as a continuous intravenous infusion | APACHE II: 21/23 | NR | Mortality by duration (28 days), infection, renal failure, LOS ICU |
Montoya, 2009, Mexico {56] | Prospective, randomized, double-blind trial | 34/34, 66 years, sepsis | Selenium 1000 μg/day IV on day 1 then 500 μg/day on day 2 then 200 μg/day for 7 day | 100 μg/day selenium up to the end of the trial | APACHE II: 17.6/19.8 | NR | Mortality, LOS hospital, days of ventilation |
Mishra, 2007, UK [55] | Double-blind controlled trial | 18/22, 66 years, sepsis | Intravenous selenium, 470 μg/day for 3 days, then 320 μg/day for 3 days, then 160 μg/day for 3 days, and 30 μg/day thereafter | 30 μg/day selenium | APACHE II: 17.6/19.8 | 28 days | Mortality, mortality by duration (28 days), adverse events, renal failure, LOS ICU |
Reisinger, 2009, Austria [66] | Double-blind, placebo-controlled, randomized trial | 124/102, 65 years, cardiac arrest after CPR | Intravenous sodium selenite, infusion of 200 to 1000 μg/day over 30 min | Placebo | SAPSIII:59/59 | 96 days | Mortality by duration (28 days) |
Schmidt, 2018, Switzerland [67] | Randomized,placebo-controlled, double-blinded clinical trial | 206/205, 67 years, elective cardiac surgery | Intravenous bolus of 4000 μg/day sodium selenite and then 1000 μg/day | Placebo | SAPSII: 28/29 | NR | LOS ICU, LOS hospital, renal failure, mortality by duration (28 days) |
Valenta, 2011, Czech Republic [57] | Prospective randomized, open-label, single-center clinical trial | 93/89, 28 years, SIRS/sepsis | Na selenite, 1000 μg/day on the first day, 500 μg/day on days 2–14 via a central venous catheter | Standard Selenium dose (< 75 μg/day) | APACHE II: 30/28 | 28 days | Mortality, mortality by duration (28 days) |
Woth, 2014, Hungary [58] | RCT | 23/17, 20 years, severe septic | Intravenous sodium selenite, bolus for 30 min on the first day, the treatment group received 1000 µg/day continuous infusion for 14 days | NR | SOFA score > 2 | 7 days | Mortality, mortality by duration (28 days) |
Zimmerman, 1997, Germany [59] | A prospective randomized study | 20/20, SIRS | Intravenous Na-Selenite, 1000 μg/day bolus then 1000 μg/day as a continuous infusion | Standard therapy | APACHE II: 15/15 | 28 days | Mortality, mortality by duration (28 days) |
Methodological quality of the systematic reviews and meta-analyses
Findings from the meta-analysis
Primary outcomes
Mortality (regardless of the period of time)
Outcomes | Comparison (s) | Number of trials | Number of participants (intervention/control) | Follow-up (range), wk | Dose (range) µg/day | Effect size (95%CI) | Absolute effect (95% CI) | P-value | I2 (%) | Pheterogeneity | Egger’s test | Certainty of evidence (GRADE) |
---|---|---|---|---|---|---|---|---|---|---|---|---|
Mortality (regardless of period of time) | Placebo, no treatment, standard care and low dose of selenium | 16 | 2324 (1161/1163) | 1–52 | 30–4000 | RR, 0.83 (0.71, 0.98) | 14 lower (24 lower to 3 lower) | 0.024 | 31.6 | 0.110 | 0.036 | Low |
Mortality by duration (28 days) | Placebo, no treatment, standard care, normal saline and low dose of selenium | 21 | 3714 (1839/1875) | 1–52 | 30–4000 | RR, 0.95 (0.82, 1.09) | 10 lower (16 lower to 4 lower) | 0.478 | 21.1 | 0.189 | 0.476 | Moderate |
Risk of acute renal failure | Placebo, standard care, low dose of selenium | 8 | 700 (359/341) | 1.5–2 | 30–4000 | RR, 0.67 (0.46, 0.98) | 5 lower (10 lower to 0) | 0.038 | 0.0 | 0.659 | 0.180 | Low |
Adverse events | Placebo and low dose of selenium | 7 | 2014 (1002/ 1012) | 1–3 | 30–4000 | RR, 0.98 (0.88, 1.10) | 51 lower (79 lower to 23 lower) | 0.788 | 26.4 | 0.227 | 0.761 | Moderate |
Risk of infection | Placebo, normal saline and low dose of selenium | 9 | 2083 (1037/1046) | 2–52 | 300–4000 | RR, 0.92 (0.80, 1.05) | 0.0 (3 lower to 4 upper) | 0.207 | 0.0 | 0.620 | 0.673 | Moderate |
Risk of pneumonia | Placebo | 3 | 280 (138/142) | 4–52 | 1000–4000 | RR, 1.11 (0.72, 1.72) | 3 lower (17 lower to 11 uppers) | 0.625 | 5.1 | 0.349 | 0.117 | Low |
Length of ICU stay | Placebo, no treatment, standard care, low dose of selenium | 13 | 2928 (1431/1497) | 2–52 | 30–4000 | MD, 0.15 (− 1.75, 2.05) | – | 0.876 | 95.8 | < 0.001 | 0.850 | Very low |
Length of hospital stay | Placebo, no treatment, normal saline standard care, low dose of selenium | 9 | 1597 (774/823) | 2–52 | 35–3000 | MD, − 0.51 (− 3.74, 2.72) | – | 0.757 | 96.0 | < 0.001 | 0.428 | Very low |
Days on ventilation | Placebo, normal saline standard care, low dose of selenium | 8 | 429 (216/213) | 3–52 | 35–4000 | MD, − 0.98 (− 2.93, 0.98) | – | 0.329 | 76.4 | < 0.001 | 0.186 | Very low |