Selenium is a trace mineral that is essential to human health. Selenium-containing proteins include glutathione peroxidases and thioredoxin reductases (Angstwurm 2006a), which are antioxidant enzymes essential for the removal of damaging reactive oxygen species (ROS) also known as free radicals. ROS damage proteins, polysaccharides, nucleic acids and polyunsaturated fatty acids, which may lead to cell death (Geoghegan 2006). Selenium deficiency impairs the immune response; and supplementation in replete individuals appears to enhance the immune response (Rayman 2000). The iodothyronine deiodinase enzymes that control the production of the hormone triiodothyronine from thyroxine also require selenium.
Selenium intake from plants (and thus animals) generally reflects the levels present in soils. There is particular concern that intake in most parts of Europe is insufficient (Rayman 2000); intakes are generally higher in North America. Selenium status will be further impaired in those people with poor quality diets, such as alcoholics, and when dietary intake is reduced, for example during a chronic illness and postoperatively.
Ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) is an organic selenium-containing compound which appears to act as a mimic of glutathione peroxidase; it may thus also have anti-oxidant properties (Parnham 2000).
Evidence suggests that excessive oxidative stress plays an important role in the development of complications of critical illness, such as the systemic inflammatory response which leads to acute respiratory distress syndrome (ARDS) and multiple organ failure (Bulger 2001). Berger 1998a found that providing an antioxidant trace element supplement containing selenium, zinc and copper was associated with fewer infections after major burns compared with placebo. Porter 1999a also found that antioxidant supplementation with selenium, vitamin C, vitamin E and N-acetylcysteine for patients after severe trauma was associated with fewer infectious complications and less organ dysfunction compared to placebo.
A systematic review of randomized controlled trials of antioxidant nutrients in critical illness found a statistically significant reduction in mortality but not infections (Heyland 2005). There was a trend for lower mortality for antioxidants containing selenium (relative risk 0.59, 95% confidence intervals 0.32 to 1.08, P = 0.09).
The organic selenium-containing compound ebselen has also been investigated for its antioxidant properties in critical illness (Parnham 2000). We wished to systematically review randomized controlled trials of either selenium or ebselen supplementation in adults with critical illness.
The primary objective was to examine the effect of nutrition supplemented with selenium or ebselen on mortality and number of infections in critically ill patients.
The secondary objective was to examine the relationship between selenium or ebselen supplementation and duration of mechanical ventilation, length of intensive care unit stay and length of hospital stay.
Criteria for considering studies for this review
Types of studies
We included all randomized controlled trials of selenium supplementation or ebselen supplementation in critically ill patients, given in addition to their routine care.
Trials were included despite lack of blinding or placebo treatment.
We included unpublished studies and abstracts.
Types of participants
We included studies on adults with critical illness (including patients with burns, head injury, brain haemorrhage, cerebrovascular accident) and those undergoing elective major surgery.
We did not include studies on neonates and paediatric patients (that is aged less than 18 years).
Studies reporting mixed groups of participants (for example combined data of critically ill and medical patients) were included only if data could be provided separately for patients with critical illness.
Types of interventions
We examined nutritional interventions by the enteral or parenteral route, or both routes, supplemented with additional selenium versus nutritional care by the same route without additional selenium. We examined all types of selenium compounds including ebselen. We did not include immunonutritional interventions where selenium was one of several nutrients given together (for example with arginine and omega-3 fatty acids).
Types of outcome measures
We sought information on the following primary outcomes:
1. mortality (including early and late mortality, in the first month or later);
2. number of infectious complications (as defined in each of the included studies).
We also sought information on:
3. number of days on a ventilator;
4. length of stay in an intensive care unit (ICU);
5. length of hospital stay;
6. quality of life after discharge (as defined in the included studies);
7. adverse events;
8. economic outcomes.
Search methods for identification of studies
In our original review we searched databases from inception until 2003. In this updated review we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 3). We updated our search of MEDLINE (to July Week 2 2007), EMBASE (to Week 30 2007), CAB abstracts (to June 2007), BIOSIS (to 2 August 2007), CINAHL (to July Week 3 2007) and HEALTHSTAR (to September 2002). In MEDLINE and HEALTHSTAR the first two levels of the standard Cochrane search strategy for the identification of randomized controlled trials (Higgins 2005) were used with specific search terms (Appendix 1). Similar strategies were used for EMBASE and CINAHL. Search terms for CAB abstracts are given in Appendix 2, BIOSIS in Appendix 3and CENTRAL in Appendix 4.
Searching other resources
We also updated our search of reference lists of previous trials and review articles; books related to critical care, selenium and nutrition support; intensive care and nutrition journals (Clinical Nutrition to volume 26(3) June 2007, Journal of Parenteral and Enteral Nutrition to 31(1) Jan/February 2007, Critical Care Medicine to volume 35(8) August 2007, Intensive Care Medicine to volume 33(8) August 2007); database of ongoing research (Current Controlled Trials July 2007). We communicated with colleagues, particularly published trialists, in order to identify new trials. No language restriction was applied to eligible reports.
Data collection and analysis
Two authors independently screened and classified all citations as potential primary studies, review articles or other. Also independently, two authors examined all potential primary studies and decided on their inclusion in the review. Authors independently abstracted data on methodology and outcomes from each study, in duplicate, utilizing the components of a previously published system (Heyland 1998) to assess methodological quality (see below). Disagreements were resolved within pairs by consensus.
Methodological quality assessment criteria
- Allocation concealment:
- concealed allocation, e.g. computer generated allocation by phone from a site remote from recruitment;
- allocation not concealed or not sure (i.e. small but possible chance of disclosure of assignment or author states random but without description);
- quasi-randomized (allocated alternately or by a predictable method, e.g. date of birth).
- intention to treat (participants analysed according to the arm they were originally allocated whether or not they received or completed the intervention);
- Blinding as reported by the investigators:
- double blinded;
- single blinded;
- not blinded.
- Patient selection:
- consecutive eligible patients enrolled in the trial;
- selected patients enrolled in the trial or unable to tell.
- Comparability of groups at baseline:
- no or not sure.
- Extent of follow up:
- 100% of participants;
- < 100% of participants.
- Treatment protocol:
- described so that it could be replicated by others;
- poorly described.
- Co-interventions (the extent to which non-trial interventions such as antibiotics, nutritional support, ventilation, oxygen and transfusions were applied equally across groups):
- well described and all equal;
- described but not equal or not sure;
- not described.
- objectively defined so that others could use this definition (e.g. pneumonia using invasive diagnostic technique criteria);
- partially described;
- not described.
Prior hypotheses regarding sources of heterogeneity
The planned subgroup analyses to explore possible sources of heterogeneity were as follows.
- Studies of surgical patients or patients with acute pancreatitis compared to studies of other critically ill patients.
- Since there might be a dose-related response to selenium supplementation, we planned to group together studies evaluating higher selenium content formulae (greater than or equal to the cut-off point) and compare them to studies with lower selenium content formulae (using the median dose of selenium from the studies as the cut off).
- Studies of ebselen compared with studies of other selenium compounds.
- Study quality based on concealment of allocation, intention-to-treat analysis or level of blinding.
The primary outcomes were early (within the first month) and late mortality and the incidence of infectious complications. We defined the infectious complication rate as the number of patients who developed infectious complications. The secondary outcomes were length of stay in ICU and hospital stay, in days. We combined data to estimate the common relative risk of death and infectious complications and we also calculated the associated 95% confidence intervals (CI). We used relative risk (RR) to summarize the treatment effect. We used the more conservative random-effects model to estimate overall relative risk and effect size due to the presence of study heterogeneity. Heterogeneity was expressed as the I
Description of studies
Of the 24 studies identified via the search strategy, 10 were included, 11 were excluded, two are ongoing and two are awaiting assessment. The reasons for excluding the 11 studies are given in the table 'Characteristics of excluded studies'. Three included studies and three excluded studies were published in German only. Translations from German to English were performed for these studies. Unpublished studies were sought but not found. Some trials had multiple full text publications (Angstwurm 1999; Berger 2001; Saito 1998; Zimmermann 1997).
Of the three new included studies, one was found by handsearching, one was found by contact with the author after finding the trial in a conference proceeding and one was found in both MEDLINE and EMBASE. All seven of the previously included studies were identified via the MEDLINE search strategy. We sought further details from trial investigators for all seven studies and obtained them for two (Angstwurm 2007; Angstwurm 1999).
The included trials were all published between 1997 and 2007 except for one trial which was published in 1991 (Kuklinski 1991). Three trials of ebselen were Japanese multicentre trials (Ogawa 1999; Saito 1998; Yamaguchi 1998). One trial was a multicentre trial in German (Angstwurm 2007). The remaining trials were single centre trials in Germany, Switzerland and the UK. All selenium trials were of selenium given as sodium selenite (Angstwurm 2007; Angstwurm 1999; Berger 2001; Kuklinski 1991; Lindner 2004; Mishra 2007; Zimmermann 1997).
The 10 included studies involved a total of 1172 participants. The details of the included studies are provided in the table 'Characteristics of included studies'. Six trials recruited more male than female participants ( Angstwurm 1999; Berger 2001; Ogawa 1999; Yamaguchi 1998). One trial recruited only men (Kuklinski 1991), one did not report the sex of the participants (Zimmermann 1997) and two studies had more women than men (Mishra 2007; Saito 1998). Where reported, the mean age of participants was more than 50 years. Two trials excluded participants older than 75 and 71 years, respectively (Berger 2001; Saito 1998).
Trials of selenium recruited participants with the following conditions: sepsis or systemic inflammatory response syndrome (Angstwurm 2007; Angstwurm 1999; Mishra 2007; Zimmermann 1997), severe multiple injury (Berger 2001) and more serious cases of acute pancreatitis (Kuklinski 1991; Lindner 2004). The three trials of ebselen were conducted in participants with acute neurological conditions: acute middle cerebral artery occlusion (Ogawa 1999), aneurysmal subarachnoid haemorrhage (Saito 1998) and acute ischaemic stroke (Yamaguchi 1998). It is unclear whether ebselen and selenium have similar mechanisms of action so all trials were not combined. For the ebselen trials no details were provided concerning the need for ventilation or the level of critical illness care required.
The three neurological trials of ebselen (Ogawa 1999; Saito 1998; Yamaguchi 1998) all used an enteral dose of 300 mg daily for 14 days that was compared to a matching placebo. Seven trials of selenium used intravenous sodium selenite, usually given as a continuous infusion over 24 hours, with doses of selenium ranging from 155 mcg to 2000 mcg (Angstwurm 2007; Angstwurm 1999, Berger 2001; Kuklinski 1991; Lindner 2004; Mishra 2007; Zimmermann 1997). Only Zimmermann 1997 had no comparison infusion. No study examined selenium or ebselen supplementation for more than 28 days.
The study by Berger 2001 included three study groups: selenium only, selenium combined with alpha-tocopherol and zinc, and placebo control. Only the comparison between selenium and placebo was presented here.
There were insufficient data to explore studies with better methodology compared to those with lesser methodology and studies evaluating higher selenium doses compared to those with lower selenium doses.
Risk of bias in included studies
The quality of trial methodology, as reported, was disappointing. The trials often failed to report trial methodology in sufficient detail. One trial had improved methodology after further details were obtained from one author (Angstwurm 1999).
All included studies were randomized controlled trials; no quasi-randomized clinical trials were included. Concealment of allocation was confirmed in only one of the seven trials: Cochrane allocation concealment score A (Berger 2001). The other trials did not clearly report the method of concealment of allocation: Cochrane allocation concealment score of B. Although not always explicitly stated, intention-to-treat analysis was undertaken in five of the 10 trials (Angstwurm 1999; Kuklinski 1991; Ogawa 1999; Saito 1998; Zimmermann 1997). Seven trials were reported to be blinded or double blinded (Angstwurm 2007; Berger 2001, Lindner 2004; Mishra 2007; Ogawa 1999; Saito 1998; Yamaguchi 1998). For the outcomes assessed in this review, it was unclear to whom the blinding referred. Only Angstwurm 2007 and Angstwurm 1999 recruited consecutive eligible patients.
In five trials (Angstwurm 1999; Kuklinski 1991; Lindner 2004; Ogawa 1999; Yamaguchi 1998) groups were clearly comparable at baseline. All but four trials (Angstwurm 2007; Lindner 2004; Yamaguchi 1998; Zimmermann 1997) clearly reported following up all participants for all outcomes until the end of the study. All trials clearly reported the treatments given for the trial but no trial clearly described the co-interventions as being equally provided to all groups. Four trials (Angstwurm 1999; Berger 2001; Ogawa 1999; Yamaguchi 1998) gave objectively described definitions of trial outcomes.
Effects of interventions
The outcomes reported in the included studies are listed in the table of 'Characteristics of included studies'. Where available, mortality results have been presented using denominators based on the numbers of participants at randomization. Generally, the results for other outcomes have been presented using denominators based on the numbers of participants available at follow up.
All 10 included studies provided mortality data, seven trials using selenium as intravenous sodium selenite (Angstwurm 2007; Angstwurm 1999; Berger 2001; Kuklinski 1991; Lindner 2004; Mishra 2007; Zimmermann 1997) and three trials of ebselen (Ogawa 1999; Saito 1998; Yamaguchi 1998).
Overall mortality (table 'comparison and data' 01.01) from trials of selenium showed a relative risk of 0.75 (95% CI 0.53 to 1.06, I
Mortality (table 'comparison and data' 01.02) in trials of selenium in general intensive care patients (Angstwurm 1999; Angstwurm 2007; Berger 2001; Mishra 2007; Zimmermann 1997) was compared with trials in patients with acute pancreatitis (Kuklinski 1991; Lindner 2004). The relative risk in general intensive care patients was 0.75 (95% CI 0.59 to 0.96, I
Pooling of the data (table 'comparison and data' 01.02) from the three trials of ebselen showed no statistically significant difference in mortality (RR 0.83, 95% CI 0.51 to 1.35) and no evidence of statistical heterogeneity (I
Four trials of intravenous sodium selenite provided data. Berger 2001 provided data for participants developing infections based on the number of participants requiring antibiotics. Angstwurm 2007 reported that the incidence of new infections, for example the development of hospital acquired pneumonia, as well as the incidence of acute respiratory distress syndrome was not significantly different between the groups. Lindner 2004 provided data on the participants developing sepsis or peritonitis. Pooling (table 'comparison and data' 02.01) these three trials gave a relative risk of 1.22 (95% CI 0.67 to 2.23, I
All three trials of ebselen (Ogawa 1999; Saito 1998; Yamaguchi 1998) provided data for participants developing infections (pyrexia, respiratory infections or meningitis) (table 'comparison and data' 02.01), with no statistically significant difference (RR 0.60, 95% CI 0.36 to 1.02).
Days on a ventilator
Two trials of intravenous sodium selenite provided data for the number of days on a ventilator. In the trial by Angstwurm 1999 days of ventilation were not statistically different between the supplemented and unsupplemented groups (median of 9 days with a range of 3 to 23 days compared with 10 days and range of 1 to 43 days, respectively). In the trial by Berger 2001 the supplemented group was ventilated for a median of 5 days (range 2 to 12 days) and the control group a median of 2 days (range 1 to 19 days), which was also reported as not statistically significant. Angstwurm 2007 reported that the incidence and hours of mechanical ventilation were not statistically significantly different between groups.
Length of stay in intensive care unit
Three trials of intravenous sodium selenite provided data on the length of stay in intensive care (Angstwurm 2007; Berger 2001; Mishra 2007). Angstwurm 2007 reported no significant difference for intensive care length of stay between the two groups. In Berger 2001 the supplemented group stayed for a median of 7 days (range 2 to 14 days) while the control group stayed a median of 4.5 days (range 2 to 25 days). This was reported as not significantly different. Mishra 2007 reported a length of stay of 21.3 (SD 16.2) days in the supplemented group and 20.8 (SD 21.8) days in the control group (reported P = 0.94)
Length of hospital stay
Two trials, both of intravenous sodium selenite, provided data for the length of hospital stay (Angstwurm 1999; Berger 2001). Angstwurm 1999 reported no significant difference between groups for survivors: median stay of 28 days (range 8 to 90 days) for the selenium group and a median of 36 days (range 16 to 70 days) for the control group. Berger 2001 also reported no significant difference between groups: median stay 35 days (range 13 to 249 days) for the selenium group and a median of 57.5 days (range 16 to 120 days) for the control group.
Quality of life after discharge
Trials of ebselen (Ogawa 1999; Saito 1998; Yamaguchi 1998) reported no statistically significant difference in Glasgow Outcome Scales (Jennett 1975) at final follow up. However the Modified Barthel Index Score (Shah 1989), an assessment of functional status, was reported as significantly improved by ebselen at a final follow-up time of three months in the trial by Yamaguchi 1998. No trials of selenium provided quality of life data.
Trial investigators reported a wide variety of individual adverse events, including: organ failure, shock, requirement for inotropic support, requirement for fluids or transfusion, gastrointestinal bleeding, cerebral infarction and haemorrhage, nausea and vomiting, acute myocardial infarction, pulmonary embolism, enterocolitis, pancreatitis and skin rash. Angstwurm 1999 reported that renal failure requiring continuous veno-venous haemodialysis was required for three of the 21 participants receiving intravenous sodium selenite and nine of the 21 participants in the control group. Angstwurm 2007 reported that the need for haemodialysis or vasopressor therapy was identical in the two groups and that adverse events occurred in 110/122 of the intravenous sodium selenite group and 119/124 of the placebo group. Mishra 2007 reported that five of the 18 selenium supplemented participants required renal replacement compared with seven of the 22 controls. The relative risk of adverse event from these three trials was 0.75 (95% CI 0.40 to 1.43, I
In the three trials of ebselen, the overall incidence of adverse events in the ebselen and placebo groups were reported as 7.3% and 3.3%, respectively (Yamaguchi 1998); 10% and 14%, respectively (Saito 1998); and as not significant different (Ogawa 1999). Combining the results for Saito 1998 and Yamaguchi 1998 (no meta-analysis data were available for Ogawa 1999) yielded a relative risk of 1.16 (95% CI 0.40 to 3.36, I
No trials provided details of costs or economic outcomes.
This review found weak evidence that selenium supplementation, as intravenous sodium selenite, improves mortality in critically ill adults. The evidence was more suggestive of a benefit on mortality in the first month for general intensive care unit patients rather than patients with severe pancreatitis. The evidence is weak as a result of the poor methodological quality of the trials, for example only one trial clearly reported concealment of allocation. Few trials reported on outcomes other than mortality or clearly defined the reported outcomes. Periods of follow up were short and did not allow for the prolonged recovery from critical illness. There were insufficient data to examine the effect of methodological superiority or dose of selenium on the outcomes.
There was no clear evidence of benefit from the use of ebselen in patients with stroke or subarachnoid haemorrhage. The results of one large trial are still awaited (Yamaguchi 2003).
There was also no evidence to suggest that these interventions were harmful.
Four trials (Angstwurm 2007; Angstwurm 1999; Berger 2001; Mishra 2007) found significantly increased activity of the antioxidant selenoenzyme glutathione peroxidase, demonstrating the potential for intravenous sodium selenite to improve antioxidant capacity in participants. The measurement of selenium levels in the blood may be an unreliable marker of selenium status because levels fall with an acute phase response provoked by injury or infection (Sattar 1997).
Implications for practice
There is insufficient evidence to recommend the supplementation of critically ill patients with selenium or ebselen except as interventions being investigated in the setting of a randomized clinical trial.
Implications for research
Large, well-designed, adequately powered trials of selenium and ebselen supplementation are required. The design and reporting of any future trial should conform to the CONSORT statement (Moher 2001) or any future development of it. Future research should examine functional status, patient perceived quality of life and include an economic evaluation. Independent observers should assess outcomes and the period of follow up should be for at least one year.
We thank Mette Berger, Roland Gärtner, Tomoko Motohashi and Takenori Yamaguchi for providing further information about their trials. We would like to thank Mathew Zacharias, Nathan Pace, Naji Abumrad, Daren Heyland, Saúl Rugeles, Ann Moller, Iveta Simera, Kathie Godfrey and Amy Godfrey Arkle for their help and editorial advice during the preparation of this review.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. Medline and Healthstar search strategy
1. selenium compounds.mp
5. 1 or 2 or 3 or 4
Appendix 2. CAB abstracts search strategy
4. 1 or 2 or 3
7. 5 or 6
8. 4 and 7
Appendix 3. BIOSIS search strategy
4. 1 or 2 or 3
7. 5 or 6
8. 4 and 7
Appendix 4. Cochrane Central Register of Controlled Trials
1. selen* (all fields)
2. ebselen (all fields)
3. 1 or 2
Last assessed as up-to-date: 16 August 2007.
Protocol first published: Issue 3, 2002
Review first published: Issue 4, 2004
Contributions of authors
All four reviewers were involved in protocol development, literature searching, quality assessment and data abstraction of trials, and production of the review.
Declarations of interest
Alison Avenell and David Noble are grantholders in the ongoing SIGNET trial.
Sources of support
- University of Aberdeen, UK.
- Grampian University Hospitals NHS Trust, UK.
- Chief Scientist Office of the Scottish Executive Health Department, UK.
Medical Subject Headings (MeSH)
*Dietary Supplements; Antioxidants [adverse effects; *therapeutic use]; Azoles [adverse effects; *therapeutic use]; Critical Illness [mortality; *therapy]; Organoselenium Compounds [adverse effects; *therapeutic use]; Randomized Controlled Trials as Topic; Selenium [adverse effects; *therapeutic use]
MeSH check words
* Indicates the major publication for the study