Web site designed and maintained by
Chris Cairns
© SICS EBM Group 2004
|
|
|
|
Selenium in severe sepsis
Citation/s: Angstwurm, M.W.A, et al. Selenium in Intensive Care (SIC): Results of a prospective randomized, placebo-controlled, multiple-centre study in patients with severe systemic inflammatory response syndrome, sepsis and septic shock. Crit Care Med (2007) 35: 118 – 126
Three-part Clinical Question: Patients: SIRS, an APACHE III score > 70 and a decrease of platelet count >50% within 24 hours or < 150000/µL on admission. Intervention: Selenium in addition to standard therapy Outcome: 28 day mortality
Search Terms: Selenium, Septic Shock, Sepsis, Randomized Controlled Trial, Outcome
The Study: Double-blinded, concealed randomised controlled trial with intention-to-treat (ITT). Setting: 11 intensive care units in Germany. The Study Patients: Adult Intensive Care Patients with SIRS, an APACHE III score > 70 and a decrease of platelet count > 50% within the first 24 hours or < 150.000/µL at admission. Exclusions: pregnancy, hypoxic brain injury after CPR, primary concomitant disease with an expected high mortality within 2 months, DNR-decision, malignant primary disease, haemorrhagic-necrotizing pancreatitis. Initially 249 patients were randomized. 11 patients were excluded before intention-to-treat-analysis because of withdrawal of consent, loss of follow-up, suicide, DNR-decision, primary malignant disease or non-compliance. 238 patients were analysed as “intention-to-treat”. Before breaking the code further 49 patients had to be excluded because of not fulfilling the inclusion criteria (n=14) or severe violation of the study protocol (n=35). That left only 189 patients for final per-protocol analysis.
Control group (N = 97; 97 analysed): Standard therapy. 29 patients received intensive insulin therapy. 67 patients received hydrocortisone (200mg/day). No patient received activated Protein C.
Experimental group (N = 92; 92 analysed): Intravenous bolus-injection of 1mg Sodium Selenite over 30min followed by continuous intravenous infusion (2ml/hour) for 14 days in addition to standard therapy. 25 patients received intensive insulin therapy. 56 patients received hydrocortisone (200mg/day). No patient received activated Protein C.
The Evidence: Protocol compliant patients
The Evidence: “Intention-to-treat” analysis#
Strictly speaking “intention-to-treat” analysis should have included all 249 patients randomized. Data on the 11 patients not included in the authors ITT numbers are not supplied in the manuscript to allow independent analysis.
Particular subgroups who seem to be more likely to benefit are patients with septic shock and DIC (p = 0.018), patients with more than 3 organ failures (p = 0.039) and patients with an APACHE III Score > 102 (p = 0.04). There were no specific adverse effects associated with high-dose-selenium supplementation.
EBM Comments: 1. Do the methods allow accurate testing of the hypothesis? No. See below.
2. Do the statistical tests correctly test the results to allow differentiation of statistically significant results? No. In the ITT analysis the reduction of mortality does not reach statistical significance (p = 0.109). The conclusions seem to be based on the final per-protocol-analysis. The ITT quoted in the paper is not the true ITT figure. The power analysis predicted that 198 patients would be required.
3. Are conclusions valid in light of the results? (That high-dose sodium-selenite reduces mortality in patients with severe sepsis or septic shock.)No, as they are based on the underpowered per-protocol analysis.
4. Did results get omitted, and why? Yes See above. 49 Patients excluded from final analysis because of not fulfilling the inclusion criteria (n=14) or “severe” violation of the study protocol (n=35): study medication delayed or interrupted for > 6hours (n=13), no bolus administration (n=6), number of vial administration lower than defined (n=11) and administration of additional sodium-selenite >100 µg/day (n=5).
5. Did they suggest areas of further research? Yes. A larger trial is suggested to confirm the results of this trial. The currently underway SIGNET trail could fulfil this role.
6. Did they make any recommendations based on the results and were they appropriate? Yes, they recommend the use of adjuvant, high-dose selenium in patients with severe sepsis and septic shock. Due to the statistical flaw this seems inappropriate at present.
7. Is the study relevant to my clinical practice? Yes.
8. What level of evidence does this study present? 1-.
9. What grade of recommendation can I make on this result alone? None.
10. What grade of recommendation can I make when this study is considered along with other available evidence? None. A Cochrane review in 2004[1], that included mortality data from four trials of selenium, showed after use of a random effects model to account for moderate statistical heterogeneity no statistically significant difference (RR 0.52, 95% CI 0.20 – 1.34). Pooling of data from three trials of ebselen (selenium related compound) showed no statistically significant difference in mortality (RR 0.83, 95% CI 0.52 to 1.34). Updated statistics including Angstwurm’s 2006 data with a weight of 45.3% result in a RR of 0.76, 95% CI 0.54 – 1.08).
11. Should I change my practice because of these results? No. As there is no apparent harm; current users and non-users could continue until larger trial results are available.
12. Should I audit my current practice because of these results? No.
Appraised by: Stephan Dalchow, SpR Anaesthetics, Anaesthetic Department, Gartnavel General Hospital, 1053 Great Western Road, Glasgow G12 04N; 06 January 2007
Citation: EBM Critical Appraisals. Scottish Intensive Care Society EBM Group. 2007 & JICS 2007 Vol8(1). Dalchow S. Angstwurm, M.W.A, et al. Selenium in Intensive Care (SIC): Results of a prospective randomized, placebo-controlled, multiple-centre study in patients with severe systemic inflammatory response syndrome, sepsis and septic shock. Crit Care Med (2007) 35: 118 – 126 ©SICS EBM 2007 Reviewed and edited by Chris Cairns & Peter Andrews
[1] Avenell A, Noble DW, Barr J, Engelhardt T. Selenium supplementation for critically ill adults. Cochrane Database of Systematic Reviews 2004, Issue 4. Art.No.: CD003703.DOI:10.1002/14651858. CD003703.pub2.
| ||||||||||||||||||||||||||||||||||||||||||
