Selenium supplementation for critically ill adults

  • Review
  • Intervention

Authors


Abstract

Background

Selenium is a trace mineral essential to health and has an important role in immunity, defence against tissue damage and thyroid function. Improving selenium status could help protect against overwhelming tissue damage and infection in critically ill adults. This Cochrane review was originally published in 2004 updated in 2007 and again 2015.

Objectives

The primary objective was to examine the effect of nutrition supplemented with selenium or ebselen on mortality in critically ill patients.

The secondary objective was to examine the relationship between selenium or ebselen supplementation and number of infections, duration of mechanical ventilation, length of intensive care unit stay and length of hospital stay.

Search methods

In this update, we searched the current issue of the Cochrane Central Register of Controlled Trials, the Cochrane Library (2014, Issue 5); MEDLINE (Ovid SP, to May 20, 2014), EMBASE (Ovid SP, to May 20, 2014), CAB, BIOSIS and CINAHL. We handsearched the reference lists of the newest reviews and cross-checked with our search in MEDLINE. We contacted the main authors of included studies to request any missed, unreported or ongoing studies. The latest search was performed up to 21 May 2014. The search is now from inception until 21 May 2014.

Selection criteria

We included randomized controlled trials (RCTs) irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted the trial investigators and authors in order to retrieve relevant and missing data.

Data collection and analysis

Two review authors independently extracted data and we resolved any disagreements by discussion. Our primary outcome measure was all-cause mortality. We performed several subgroup and sensitivity analyses to assess the effects of selenium in critically ill patients. We presented pooled estimates of the effects of intervention as risk ratios (RRs) with 95% confidence intervals (CIs). We assessed the risk of bias through assessment of trial methodological components and the risk of random error through trial sequential analysis.

Main results

We included six new RCTs in this review update. In total we included 16 RCTs (2084 participants) in this review. Most trials were at high risk of bias. The availability of outcome data was limited and trials involving selenium supplementation were, with the exception of one trial, small regarding sample size. Thus the results must be interpreted with caution.

Thirteen trials of intravenous sodium selenite showed a statistically significant reduction in overall mortality (RR 0.82, 95% CI 0.72 to 0.93, 1391 participants, very low quality of evidence). However, the overall point estimate on mortality is primarily influenced by trials of high risk of bias. Meta-analysis of three trials of ebselen had a RR of 0.83 (95% CI 0.52 to 1.34, 693 participants, very low quality of evidence).

Nine trials of intravenous sodium selenite were analysed for 28 days mortality with no statistically significant difference (RR 0.84, 95% CI 0.69 to 1.02, 1180 participants, very low quality of evidence) while three trials were analysed for 90 days mortality with similar findings (RR 0.96, 95% Cl 0.78 to 1.18, 614 participants, very low quality of evidence).

Two trials of ebselen were analysed for 90 days mortality and were not found to yield any benefit (RR 0.72, 95% Cl 0.42 to 1.22, 588 participants, very low quality of evidence).

For mortality among intensive care patients selenium supplementation failed to indicate any statistically significant advantage (RR 0.88, 95% CI 0.77 to 1.01, nine trials, 1168 participants, very low quality of evidence).

Six trials of intravenous sodium selenite found no statistically significant difference for participants developing infection (RR 0.96, 95% CI 0.75 to 1.23, 934 patients, very low quality of evidence). Similarly, three trials of ebselen provided data for participants developing infections (pyrexia, respiratory infections or meningitis) with no obvious benefit (RR 0.60, 95% CI 0.36 to 1.02, 685 participants, very low quality of evidence).

Our analyses showed no effect of selenium or ebselen on adverse events (Selenium: RR 1.03, 95% Cl 0.85 to 1.24; six trials, 925 participants ; Ebselen: RR 1.16, 95% CI 0.40 to 3.36; two trials, 588 participants, very low quality of evidence).

No clear evidence emerged in favour of selenium supplementation for outcomes such as number of days on a ventilator (mean difference (MD) -0.86, 95% CI -4.39 to 2.67, four trials, 191 participants, very low quality of evidence), length of intensive care unit stay (MD 0.54, 95% CI -2.27 to 3.34, seven trials, 934 participants, very low quality of evidence) or length of hospital stay (MD -3.33, 95% Cl -5.22 to -1.44, five trials, 693 participants, very low quality of evidence).

The quality of trial methodology was low. Due to high risk of bias in the included trials, results must be interpreted with caution.

Authors' conclusions

Despite publication of a number of trials, the current evidence to recommend supplementation of critically ill patients with selenium or ebselen remains disputed. Trials are required which overcome the methodological inadequacies of the reviewed studies, particularly in relation to sample size, design and outcomes.

アブストラクト

重症の成人患者に対するセレン補充

背景

セレンは健康に不可欠な微量ミネラルで、免疫、組織障害に対する防御、甲状腺機能に重要な役割を果たす。重症の成人患者では、セレンの状態を改善することが、高度の組織障害や感染を防ぐことにつながる可能性がある。本コクラン・レビューは2004年に初版が発表され、2007年、2015年に更新された。

目的

主要目的は、重症患者の死亡率に対するセレンまたはエブセレン補充の効果を調べることである。

副次目的は、セレンやエブセレンの補充と、感染数、人工呼吸器の使用期間、集中治療室の滞在期間、および入院期間との関連性を調べることである。

検索戦略

今回の更新にあたり以下を検索した。Cochrane Central Register of Controlled Trialsの最新号、コクラン・ライブラリ(2014年、第5号)、MEDLINE(Ovid SP、2014年5月20日まで)、EMBASE(Ovid SP、2014年5月20日まで)、CAB、BIOSIS、CINAHL。最新の総説の文献リストを手作業で検索し、MEDLINEの検索結果と照合した。選択した研究の主な著者に、欠測や未報告、継続中の研究について問い合わせた。最新の検索は2014年5月21日まで実施した。現在、開始から2014年5月21日までについて検索した。

選択基準

発表の有無、発表日、ブラインド化(盲検化)の有無、発表されたアウトカム、および言語を問わず、ランダム化比較試験(RCT)を選択した。治験責任医師や著者に連絡し、関連性のあるデータや欠測データを得た。

データ収集と分析

2名のレビュー著者が独自にデータを抽出し、相違について協議のうえ解決した。主要アウトカム指標は全死因死亡率とした。複数のサブグループ解析および感度解析を実施し、重症患者に対するセレンの効果を評価した。介入効果に関する統合推定値として、95% 信頼区間(CI)を付したリスク比(RR)を提示した。試験の方法論に関する評価によりバイアスのリスクを、逐次解析により偶然誤差のリスクを評価した。

主な結果

本レビューの更新に際し、6件の新規RCTを選択した。本レビューでは合計16件のRCT(2084例)を選択した。ほとんどの試験でバイアスのリスクが高かった。利用可能なアウトカムデータが限定的で、セレン補充に関する試験は、1件を除き、サンプル・サイズが小規模であった。したがって、結果の解釈には注意を要する。

亜セレン酸ナトリウムを静脈内投与した13件の試験では、総死亡率が統計学的に有意に低下した(RR 0.82、95% CI 0.72 ~ 0.93、1391例、エビデンスの質は極めて低い)。しかし、試験のバイアスのリスクが高いことが、死亡率の全般的な点推定値に影響を与えた。エブセレンに関する3件の試験のメタアナリシスでは、RRが0.83であった(95% CI 0.52 ~ 1.34、693例、エビデンスの質は極めて低い)。

亜セレン酸ナトリウムを静脈内投与した9件の試験では28日間の死亡率を解析し、統計学的な有意差はみられなかった(RR 0.84、95% CI 0.69 ~ 1.02、1180例、エビデンスの質は極めて低い)。一方、3件の試験では90日間の死亡率を解析し、同様の知見が得られた(RR 0.96、95% Cl 0.78 ~ 1.18、614例、エビデンスの質は極めて低い)。

エブセレンに関する2件の試験では90日間の死亡率を解析し、いかなる利益も認められなかった(RR 0.72、95% Cl 0.42 ~ 1.22、588例、エビデンスの質は極めて低い)。

集中治療患者の死亡率について、セレン補充による統計学的に有意な利益はみられなかった(RR 0.88、95% CI 0.77 ~ 1.01、9件の試験、1168例、エビデンスの質は極めて低い)。

亜セレン酸ナトリウムを静脈内投与した6件の試験では、感染症の発症について統計学的な有意差はみられなかった(RR 0.96、95% CI 0.75 ~ 1.23、934例、エビデンスの質は極めて低い)。同様に、エブセレンに関する3件の試験で、感染症の発症に関するデータが得られたが(発熱、呼吸器感染症、髄膜炎)、明白な利益はなかった(RR 0.60、95% CI 0.36 ~ 1.02、685例、エビデンスの質は極めて低い)。

我々の解析では、有害事象に対するセレンやエブセレンの影響はみられなかった(セレン:RR 1.03、95% Cl 0.85 ~ 1.24、6件の試験、925例。エブセレン:RR 1.16、95% CI 0.40 ~ 3.36、2件の試験、588例、エビデンスの質は極めて低い)。

以下のアウトカムについて、セレン補充を支持する明白なエビデンスはなかった。人工呼吸器の使用期間:平均差(MD) -0.86、95% CI -4.39 ~ 2.67、4件の試験、191例、エビデンスの質は極めて低い。集中治療室の滞在期間:MD 0.54、95% CI -2.27 ~ 3.34、7件の試験、934例、エビデンスの質は極めて低い。入院期間:MD -3.33、95% Cl -5.22 ~ -1.44、5件の試験、693例、エビデンスの質は極めて低い。

試験の方法論的な質は低かった。選択した試験ではバイアスのリスクが高いため、結果の解釈には注意を要する。

著者の結論

多くの試験が発表されているが、重症患者にセレンやエブセレンの補充を推奨する最新のエビデンスについては、議論が続いている。本レビューで選択した試験の方法論的な不備(特にサンプル・サイズ、デザイン、アウトカム)を克服する試験が必要である。

Plain language summary

Selenium supplements for adults who are critically ill

Selenium is a mineral that is essential to health. It has an important role in defence against tissue damage and disease. Improving selenium status could help protect adults with serious illness.

In this updated review, Cochrane researchers assessed the effects of additional selenium supplementation for adults recovering from critical illness. We investigated whether the number of people who died changed by giving a selenium supplement during their treatment. Also we checked the impact of such a strategy on the rate of infections and other diseases for these patients while in hospital. We also examined whether selenium affected the duration of respiratory assistance for patients on ventilators and the length of their stay in the intensive care unit and the hospital.

We included 16 trials with 2084 participants. Thirteen trials carried out tests with selenium while three trials examined selenium-containing compound ebselen. Overall quality of the included trials was poor, with little information on quality indicators. The results were limited and these trials involving selenium supplementation were mostly small. In most trials, there was a high risk of poor or even incorrect information. Thus the results must be interpreted with caution. The evidence is current to 21 May 2014.

Thirteen trials of intravenous sodium selenite showed a statistically significant effect on death. Three trials of the selenium-containing compound ebselen showed no effect on death. No effects on infections or secondary diseases were observed.

No clear evidence emerged for the benefits of selenium or ebselen supplementation for days on a respirator, length of intensive care unit stay, length of hospital stay or quality of life. Due to the quality of included trials, one must be cautious when interpreting the strength of the evidence in favour of selenium supplementation despite a statistically significant finding.

Overall, there was low quality evidence from the studies for the all results. Trials are required which overcome the statistical uncertainty of the reviewed studies, particularly in relation to sample size, design and outcomes.

Laienverständliche Zusammenfassung

Zusätzliche Selengaben bei Erwachsenen mit einer lebensbedrohlichen Erkrankung

Selen ist ein Mineralstoff, der von großer Bedeutung für die Gesundheit ist. Er spielt eine wichtige Rolle beim Schutz gegen Gewebeschäden und Erkrankungen. Die Verbesserung des Selenstatus könnte dabei helfen, schwer erkrankte Erwachsene zu schützen.

In diesem aktualisierten Review beurteilten Wissenschaftler des Cochrane-Netzwerks die Wirkung zusätzlicher Selengaben auf Erwachsene, die sich von einer lebensbedrohlichen Erkrankung erholten. Wir untersuchten, ob die Anzahl der Todesfälle sich veränderte, wenn während der Behandlung ein Selenpräparat verabreicht wurde. Außerdem prüften wir den Einfluss einer solchen Strategie auf die Häufigkeit von Infektionen und anderen Erkrankungen bei diesen Patienten während ihres Krankenhausaufenthalts. Wir untersuchten auch, ob Selen die Dauer der Atemunterstützung bei Patienten an Beatmungsgeräten und die Länge ihres Aufenthalts auf der Intensivstation und im Krankenhaus beeinflusste.

Wir schlossen 16 Studien mit 2084 Teilnehmern ein. 13 Studien untersuchten Selen, die drei übrigen die selenhaltige Verbindung Ebselen. Insgesamt war die Qualität der eingeschlossenen Studien niedrig und es gab kaum Informationen zu Qualitätsindikatoren. Die Ergebnisse unterlagen Einschränkungen und die Studien zur zusätzlichen Versorgung mit Selen waren überwiegend klein. In den meisten Studien bestand ein hohes Risiko für unzureichende oder sogar falsche Daten. Die Ergebnisse müssen daher mit Vorsicht interpretiert werden. Die Evidenz ist auf dem Stand vom 21. Mai 2014.

13 Studien zu intravenös verabreichtem Natriumselenit zeigten einen statistisch signifikanten Effekt auf Todesfälle. Drei Studien mit der selenhaltigen Verbindung Ebselen zeigten keine Wirkung auf Todesfälle. Es wurden keine Wirkungen auf Infektionen oder Sekundärerkrankungen beobachtet.

Es bestand keine eindeutige Evidenz für den Nutzen einer Selen- oder Ebselengabe im Hinblick auf die Tage am Beatmungsgerät, die Länge des Aufenthalts auf der Intensivstation, die Länge des Krankenhausaufenthalts oder die Lebensqualität. Aufgrund der Qualität der eingeschlossenen Studien muss trotz eines statistisch signifikanten Ergebnisses die Stärke der Evidenz für eine Selen-Supplementierung mit Vorsicht interpretiert werden.

Insgesamt lieferten die Studien für alle Ergebnisse Evidenz von niedriger Qualität. Es werden Studien benötigt, die die statistische Unsicherheit der untersuchten Studien überwinden, insbesondere in Bezug auf Stichprobengröße, Aufbau und Endpunkte.

Anmerkungen zur Übersetzung

S. Schmidt-Wussow, freigegeben durch Cochrane Schweiz.

Laički sažetak

Selen kao dodatak prehrani za odrasle osobe koje su životno ugrožene

Selen je mineral koji je bitan za zdravlje. Ima važnu ulogu u u obrani od oštećenja tkiva i bolesti. Poboljšanje statusa selena moglo bi možda pomoći u zaštiti odraslih osoba koje pate od teške bolesti.

U ovom obnovljenom Cochrane sustavnom pregledu literature znanstvenici su analizirali učinke davanja selena kao dodatka prehrani odraslim osobama koje se oporavljaju od teških bolesti koje ugrožavaju život. Istraženo je da li se broj ljudi koji su umrli promijenio ako su dobili dodatak selena za vrijeme liječenja. Također smo provjeravali utjecaj davanja selena na stopu infekcija i drugih bolesti za te pacijente dok se liječe u bolnici. Također smo ispitivali da li je selen djelovao na trajanje potpore disanju za pacijente koji dišu uz pomoć stroja i dužinu njihovog boravka u jedinici intenzivne njege i bolnici.

U sustavni pregled je uključeno 16 istraživanja u kojima je sudjelovalo ukupno 2084 sudionika. U 13 pokusa istražen je selen, dok su tri studije ispitivale spoj ebselen koji sadrži selen. Ukupna kvaliteta uključenih studija je bila niska, s malo informacija o pokazateljima kvalitete. Rezultati su bili ograničeni i ta ispitivanja koja uključuju dodatak selena su bila većinom malena (uključila su malen broj ispitanika). U većini ispitivanja, bio je velik rizik od slabih ili čak netočnih informacija. Stoga se ti rezultati trebaju tumačiti s oprezom. Dokazi se temelje na literaturi objavljenoj do 21. svibnja 2014. 

Trinaest studija intravenskog natrijevog selenita je pokazalo statistički značajan utjecaj na smrt. Tri studije spoja ebselena nisu pokazale nikakav učinak na smrt. Nisu uočeni nikakvi učinci na infekcije ili sekundarne bolesti.

Nisu zabilježeni jasni dokazi o korisnom učinku selena ili ebselena na dane provedene na respiratoru, duljinu boravka u jedinici intenzivne skrbi, duljinu boravka u bolnici ili kvalitetu života. S obzirom na lošu kvalitetu uključenih studija, nužan je oprez pri tumačenju snage dokaza koji idu u prilog uzimanju dodataka selena unatoč statistički značajnim rezultatima.

Zaključno, pronađeni su dokazi niske kvalitete iz uključenih istraživanja za sve rezultate. Potrebno je provesti nova istraživanja koja će razriješiti statističku nesigurnost analiziranih postojećih studija, posebno u odnosu na veličinu uzorka (broj ispitanika), ustroj istraživanja i ishode.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Ivana Sruk
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

Streszczenie prostym językiem

Suplementy selenu dla dorosłych, którzy są krytycznie chorzy

Selen jest minerałem niezbędnym dla zdrowia. Odgrywa ważną rolę w ochronie przed uszkodzeniami tkanek i chorobami. Zwiększenie poziomu selenu w organizmie może zatem wykazywać działanie ochronne u osób dorosłych z poważnymi chorobami.

W niniejszej aktualizacji przeglądu autorzy Cochrane podjęli sie oszacowania wpływu dodatkowej suplementacji selenu u dorosłych chorych w trakcie rekonwalescencji w przebiegu stanów krytycznych. Analizowaliśmy, czy doszło do zmiany liczba zgonów u chorych przyjmujących selen w trakcie ich leczenia. Sprawdziliśmy następnie wpływ takiej interwencji na częstość zakażeń i innych chorób u tych pacjentów podczas hospitalizacji. Zbadaliśmy też, czy selen wpływa na czas wspomagania oddechu u osób podłączonych do respiratora (urządzenie mechaniczne wspomagające pracę układu oddechowego; przyp.tłum.) oraz na długość pobytu pacjenta w oddziale intensywnej opieki i w szpitalu.

Włączyliśmy 16 badań obejmujących łącznie 2084 uczestników. W 13 badaniach analizowano stosowanie selenu, a w kolejnych trzech oceniano ebselen, związek w którego skład wchodzi selen. Ogólna jakość włączonych badań była słaba i przedstawiano w nich niewiele informacji na temat wskaźników jakości. Wyniki były ograniczone, a badania dotyczące suplementacji selenu obejmowały niewielką liczbę uczestników. W większości badań stwierdzono duże ryzyko podawania niekompletnych lub nawet błędnych informacji. Z tego powodu wyniki należy interpretować z ostrożnością. Dane są aktualne do 21 maja 2014 r.

W trzynastu badaniach z dożylną podażą selenianu sodu wykazano statystycznie istotny wpływ na częstość zgonów u pacjentów. Trzy badania analizujące ebselen nie wykazały żadnego wpływu na odsetek zgonów. Nie zaobserwowano wpływu na zakażenia lub choroby wtórne.

Nie stwierdzono jednoznacznych danych naukowych wskazujących na korzyści z suplementacji selenu lub ebselenu na liczbę dni, które wymagały zastosowania respiratora, długość pobytu w oddziale intensywnej terapii, długość hospitalizacji lub jakość życia. Ze względu na jakość włączonych badań, wnioski odnośnie suplementacji selenem należy interpretować z ostrożnością, pomimo stwierdzenia statystycznej istotności wyników.

Ogólnie, dane naukowe charakteryzowały się niską jakością dla wszystkich wyników. Konieczne są badania, które jakością przewyższą badania włączone do przeglądu, szczególnie w odniesieniu do wielkości próby (liczby uczestników; przyp.tłum.), zaprojektowania badania oraz wyników.

Uwagi do tłumaczenia

Tłumaczenie: Joanna Zając Redakcja: Magdalena Koperny, Małgorzata Kołcz

平易な要約

重症の成人患者に対するセレン補充

セレンは健康に不可欠なミネラルである。組織障害や疾患に対する防御に重要な役割を果たす。重症の成人患者では、セレンの状態を改善することが、患者を守ることにつながる可能性がある。

今回更新したレビューでは、重症疾患から回復中の成人に対するセレン補充の効果について、コクランの研究者が評価した。治療中にセレンを補充することで死亡者数が変化するのかを調べた。また、入院中のこれらの患者について、セレン補充が感染率や他の疾患に与える影響をチェックした。セレンが人工呼吸器の使用期間、集中治療室の滞在期間、および入院期間に影響を与えるかについても調べた。

参加者2084名を対象とした16件の試験を選択した。13件の試験ではセレンについて調べ、3件の試験ではセレン含有化合物のエブセレンについて調べていた。選択した試験の質は全般的に低く、質の指標に関する情報がほとんどなかった。結果は限定的で、セレン補充に関するこれらの試験の多くが小規模なものであった。大部分の試験では、情報の不足や不正確性に関するリスクが高かった。したがって、結果の解釈には注意を要する。エビデンスは2014年5月21日までのものである。

亜セレン酸ナトリウムを静脈内投与した13件の試験では、死亡に対し統計学的に有意な効果がみられた。セレン含有化合物のエブセレンに関する3件の試験では、死亡に対する効果はみられなかった。感染症や続発性疾患に対する影響はみられなかった。

人工呼吸器の使用期間、集中治療室の滞在期間、入院期間、および生活の質について、セレンやエブセレンの補充による利益を示す明らかなエビデンスはなかった。統計学的に有意な所見であっても、セレン補充を支持するエビデンスの確実性の解釈には注意を要する。

研究結果について、全般的にエビデンスの質が低かった。本レビューで選択した試験の統計的不確実性(特にサンプル・サイズ、デザイン、アウトカム)を克服する試験が必要である。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2018.1.28]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。 
CD003703 Pub3

Summary of findings(Explanation)

Summary of findings for the main comparison. Summary of findings table 1
  1. Abbreviations: CI: confidence interval; RR: risk ratio; MD: mean difference; ICU: intensive care unit.
    1With the exception of SIGNET 2011, all included trials were at high risk of bias. Most studies were small and poorly described.
    2The entry refers to: Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Janka 2013; Kuklinski 1991; Lindner 2004; Manzanares 2011; Mishra 2007; Montoya 2009; SIGNET 2011; Valenta 2011; and Zimmermann 1997.
    3The entry refers to: Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Manzanares 2011; Mishra 2007; and SIGNET 2011.
    4The entry refers to: Angstwurm 1999; Berger 2001; Forceville 2007; and Montoya 2009.
    5The entry refers to: Angstwurm 1999; Berger 2001; Forceville 2007; Montoya 2009; and SIGNET 2011.

Selenium supplementation compared with control for critically ill adults

Patient or population: Patients with critical illnesses

Settings: ICU setting

Intervention: Selenium or ebselen

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No. of participants
(studies)
Quality of the evidence
(GRADE)
Assumed riskCorresponding risk
ControlSelenium
Overall mortality (regardless of the follow-up period) All patients are high risk population RR 0.82, 95% CI 0.72 to 0.93)1391
(13)
⊕⊝⊝⊝
very low 1,2
ICU length of stay (selenium)The mean length of stay in an ICU ranged across control groups from
9 days to 26.5 days
The mean length of stay in an ICU ranged across intervention groups from
7.5 days to 22.8 days
MD 0.54, 95% CI -2.27 to 3.34934
(7)
⊕⊝⊝⊝
very low 1,3
Days on ventilator (selenium)

The mean days on ventilator ranged across control groups from

6 days to 16 days

The mean days on ventilator ranged across intervention groups from
6 days to 19.8 days
MD -0.86, 95% CI -4.39 to 2.67191
(4)
⊕⊝⊝⊝
very low 1,4
Length of hospital stay (selenium)The mean length of hospital stay ranged across control groups from
17 days to 62.8 days
The mean length of hospital stay ranged across intervention groups from
12.5 days to 83 days
MD -3.33. 95% CI -5.22 to -1.44693
(5)
⊕⊝⊝⊝
very low 1,5
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Critical illness is characterized by hyperinflammation, cellular immune dysfunction, oxidative stress and mitochondrial dysfunction. Oxidative stress reflects an imbalance between highly reactive oxygen molecules, known as free radicals, and the ability of the body to counteract their harmful effects through neutralization by antioxidants. Selenium is a trace mineral that is essential to this neutralization. Selenium-containing proteins include glutathione peroxidases and thioredoxin reductases (Angstwurm 2006), which are antioxidant enzymes essential for the removal of damaging reactive oxygen species (ROS). 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 people appears to enhance the immune response (Rayman 2012). The iodothyronine deiodinase enzymes, which control the production of the hormone triiodothyronine from thyroxine, also require selenium.

Description of the intervention

Selenium intake from plants (and thus animals) generally reflects the levels present in soils. There is particular concern that intake in people living in most parts of Europe is insufficient (Rayman 2012); intakes are generally higher in people living in North America. Selenium status is further impaired in people with poor quality diets, such as alcoholics, and when dietary intake is reduced, for example during a chronic illness and gastrointestinal malfunction.

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).

How the intervention might work

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). Selenium appears to be pivotal in this role (Manzanares 2009). Berger 2007 reported fewer infections after major burns compared with placebo when providing an antioxidant trace element supplement containing selenium, zinc and copper. Giladi 2011 similarly reported that antioxidant supplementation with vitamin C, vitamin E and selenium in people with severe trauma was associated with fewer infections and less organ dysfunction compared to placebo.

Why it is important to do this review

In the last two decades, several clinical trials have evaluated the role of antioxidant micronutrients either as a monotherapy or in combined therapy, as part of an antioxidant strategy for critically ill patients.

Several systematic reviews have reported reduced risk of mortality as a result of selenium supplementation (Heyland 2005; Huang 2013; Landucci 2014; Manzanares 2012).

The organic selenium-containing compound ebselen has also been investigated for its antioxidant properties in critical illness (Parnham 2000).

We aimed to systematically review randomized controlled trials (RCTs) of either selenium or ebselen supplementation in adults with critical illness. More compelling evidence is needed on this subject and on its potential benefits.

Objectives

The primary objective was to examine the effect of nutrition supplemented with selenium or ebselen on mortality in critically ill patients.

The secondary objective was to examine the relationship between selenium or ebselen supplementation and number of infections, duration of mechanical ventilation, length of intensive care unit stay and length of hospital stay.

Methods

Criteria for considering studies for this review

Types of studies

We included RCTs irrespective of publication status, date of publication, blinding status, outcomes published or language. We contacted the trial investigators and authors for relevant data. We included unpublished trials only if trial data and methodological descriptions were provided either in written form or could be retrieved from the trial authors. We excluded cross-over trials. No cluster-RCTs were identified but we plan to include these, if found, in future updates.

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.

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.

We excluded trials including neonates and participants aged under 18 years.

Types of interventions

We included trials on 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 undertook separate subgroup analyses of trials in which we calculated risk ratio (RR) for selenium/ebselen versus no selenium. If selenium was one of several components in an antioxidant supplement protocol, the trial was excluded based on our inability to assess the direct and isolated benefit of selenium.

Types of outcome measures

Primary outcomes
  1. Overall mortality (longest follow-up, regardless of the period of follow-up).

  2. Mortality by duration (studies reporting mortality for 28 and 90 days).

Secondary outcomes
  1. Number of infectious complications (as defined in each of the included studies).

  2. Adverse events.

  3. Length of stay in an intensive care unit (ICU).

  4. Number of days on a ventilator.

  5. Length of hospital stay.

  6. Quality of life after discharge (as defined in the included studies).

  7. Economic outcomes.

Search methods for identification of studies

Electronic searches

In this review update, we performed a search update up to 20 May 2014. Thus, we searched the Cochrane Central Register of Controlled Trials (the Cochrane Library 2014, Issue 5; see Appendix 1). We updated our search of MEDLINE (Ovid SP, to May 20, 2014, see Appendix 2) and EMBASE (Ovid SP, to May 20, 2014, see Appendix 3). The search is now from inception until 21 May 2014

Searching other resources

We handsearched the reference lists of reviews (Huang 2013; Landucci 2014; Manzanares 2012), randomized and non-randomized studies, and editorials for additional studies. We searched the ASPEN and ESPEN databases without finding references to selenium or ebselen. References were crosschecked with our search in MEDLINE. We contacted the main authors of included studies to ask for any missed, unreported or ongoing studies.

We searched for ongoing clinical trials and unpublished studies on the following Internet sites:

  1. http://www.controlled-trials.com

  2. http://clinicaltrials.gov

  3. http://www.centerwatch.com

No language restriction was applied to eligible reports. The latest search was performed 22 October 2014.

Data collection and analysis

Two review authors (MA, AA) independently screened and classified all citations as potential primary studies, review articles or other. Also, the two review authors independently examined all potential primary studies and decided on their inclusion in the review. Data on methodology and outcomes from each trial were independently extracted and evaluated in accordance with the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved any disagreements by consensus among the review authors.

Selection of studies

We assessed the articles identified from the described searches and excluded obviously irrelevant reports. Two review authors (MA, AA) independently examined articles for eligibility and screened the titles and abstracts in order to identify studies for eligibility (see: Characteristics of included studies; Characteristics of excluded studies). This process was performed without blinding of authors, institution, journal of publication or results. We resolved any disagreements by consensus among the review authors. We provide a detailed description of the search and assessment.

Data extraction and management

We independently extracted and collected the data without being blinded to the author, source institution or the publication source of trials. We resolved disagreements by discussion and approached all first authors of the included trials for additional information on risks of bias. For more detailed information please see the 'Contributions of authors' section.

Assessment of risk of bias in included studies

We evaluated the validity and design characteristics of each trial. Trials were evaluated for major potential sources of bias (random sequence generation, allocation concealment, blinding, intention-to-treat (ITT) analysis and completeness of follow-up). We assessed each trial quality factor separately and defined the trials as having low risk of bias only if they adequately fulfilled all of the below described criteria.

1. Random sequence generation

Assessment of randomization: sufficiency of the method in producing two comparable groups before intervention.

Grade: ’low risk’: a truly random process (e.g. random computer number generator, coin tossing, throwing dice); ’high risk’: any non-random process (e.g. date of birth, date of admission by hospital or clinic record number or by availability of the intervention); or ’unclear risk’: insufficient information.

2. Allocation concealment

Allocation method prevented investigators or participants from foreseeing assignment.

Grade: ’low risk’: central allocation or sealed opaque envelopes; ’high risk’: using open allocation schedule or other unconcealed procedure; or ’unclear risk’: insufficient information.

3. Blinding

Assessment of appropriate blinding of the team of investigators and participants: person responsible for participant care, participants and outcome assessors.

Grade: ’low risk’: blinding considered adequate if participants and personnel were kept unaware of intervention allocations after inclusion of participants into the study, and if the method of blinding involved a placebo indistinguishable from the intervention, as mortality is an objective outcome; ’high risk’: not double-blinded, categorized as an open label study, or without use of a placebo indistinguishable from the intervention; ’unclear risk’: blinding not described.

4. Incomplete outcome data

Completeness of outcome data, including attritions and exclusions.

Grade: ’low risk’: numbers and reasons for drop-outs and withdrawals in the intervention groups described, or no drop-outs or withdrawals was specified; ’high risk’: no description of drop-outs and withdrawals provided; ’unclear risk’: report gave the impression of no drop-outs or withdrawals, but this was not specifically stated.

5. Selective reporting

The possibility of selective outcome reporting.

Grade: ’low risk’: reported outcomes prespecified in an available study protocol, or, if this is not available, published report includes all expected outcomes; ’high risk’: not all prespecified outcomes reported, reported using non-prespecified subscales, reported incompletely or report fails to include a key outcome that would have been expected for such a study; ’unclear risk’: insufficient information.

6. Funding bias

Assessment of any possible funding bias:

Grade: ’low risk’: reported no funding, funding from universities or public institutions; ’high risk’: funding from private investors, pharmaceutical companies or trial investigator employed by the pharmaceutical company; ’unclear risk’: insufficient information.

7. Other bias

Assessment of any possible sources of bias not addressed in domains 1 to 6.

Grade: ’low risk’: report appears to be free of such biases; ’high risk’: at least one important bias is present that is related to study design, early stopping because of some data-dependent process, extreme baseline imbalance, academic bias, claimed fraudulence or other problems; or ’unclear risk’: insufficient information, or evidence that an identified problem will introduce bias.

Measures of treatment effect

Dichotomous data

We calculated RRs with 95% confidence intervals (CIs) for dichotomous data (binary outcomes). These included:

Primary outcomes:

  1. Mortality by duration and overall mortality.

Secondary outcomes:

  1. Number of infectious complications.

  2. Adverse events.

Continuous data

We used the mean difference (MD) or RR if data were continuous and measured in the same way between trials. These included:

  1. Length of stay in an ICU.

  2. Number of days on a ventilator.

  3. Length of hospital stay.

Unit of analysis issues

Cross-over trials

We excluded cross-over trials from our meta-analyses because of the potential risk of "carry-over" of treatment effect.

Studies with multiple intervention groups

In studies designed with multiple intervention groups we combined groups to create a single pair wise comparison in accordance with Higgins 2011. In trials with two or more groups receiving different doses, we combined data for the primary and secondary outcomes.

Dealing with missing data

We contacted the authors of trials with missing data in order to retrieve the relevant information. For all included studies we noted levels of attrition and any exclusion of participants. In case of missing data, we chose 'complete-case analysis' for our primary outcomes, which excludes from the analysis all participants with the outcome missing. Selective outcome reporting occurs when non-significant results are selectively withheld from publication (Chan 2004), and is defined as the selection, on the basis of the results, of a subset of the original variables recorded for inclusion in publication of trials (Hutton 2000). The most important types of selective outcome reporting are: selective omission of outcomes from reports; selective choice of data for an outcome; selective reporting of different analyses using the same data; selective reporting of subsets of the data; and selective under-reporting of data (Higgins 2011).

Assessment of heterogeneity

We explored heterogeneity using the I² statistic and Chi² test. An I² statistic above 50% represents substantial heterogeneity (Higgins 2003). In case of an I² statistic value > 0 (mortality outcome), we tried to determine the cause of heterogeneity by performing relevant subgroup analyses. We used the Chi² test to provide an indication of heterogeneity between studies, with P ≤ 0.1 considered significant.

Assessment of reporting biases

Funding bias is related to the possible publication delay or discouragement of undesired results in trials sponsored by the industry (Higgins 2011). To explore the role of funding, we planned to conduct a sensitivity analysis based on our primary endpoint.

Data synthesis

Using RevMan 5.3, we calculated RR with 95% CIs for dichotomous variables and MD with 95% CIs for continuous outcomes. We used the Chi² test to provide an indication of heterogeneity between studies, with P < 0.1 considered significant. The degree of heterogeneity observed in the results was quantified using the I² statistic, which can be interpreted as the proportion of the total variation observed between the studies that is attributable to differences between studies rather than sampling error (Higgins 2002). An I² statistic value > 75% is considered very heterogeneous. We used both a random-effects model and a fixed-effect model. If the I² statistic value was 0 we only reported the results from the fixed-effect model; and in the case of the I² statistic value being > 0 we reported only the results from the random-effects model.

Trial sequential analysis

Trial sequential analysis (TSA) is a methodology that combines an information size calculation for meta-analysis with a threshold of statistical significance. TSA is a tool for quantifying the statistical reliability of data in a cumulative meta-analysis, adjusting significance levels for sparse data and repetitive testing on accumulating data. We conducted TSA (Brok 2009; Pogue 1997; Thorlund 2009; Wetterslev 2008) at least on the primary outcomes and on the secondary outcomes if the accrued information size was an acceptable fraction of the estimated required information size to allow meaningful analyses (> 20). If the actual accrued information size was too low, we provided the required information size given the actual diversity in case of low risk of bias (Wetterslev 2009) or adjusted with a possible diversity of 25% in case of high risk of bias and absence of actual diversity.

Meta-analysis may result in type I errors due to random errors arising from sparse data or repeated significance testing when updating the meta-analysis with new trials (Brok 2009; Wetterslev 2008). Bias (systematic error) from trials with low methodological quality, outcome measure bias, publication bias, early stopping for benefit and small trial bias may also result in spurious P values (Brok 2009; Higgins 2011; Wetterslev 2008).

In a single trial, interim analysis increases the risk of type I errors. To avoid these, group sequential monitoring boundaries are applied to decide whether a trial could be terminated early because of a sufficiently small P value, i.e. the cumulative Z-curve crosses the monitoring boundaries (Lan 1983). Sequential monitoring boundaries can also be applied to meta-analysis, and are called trial sequential monitoring boundaries. In TSA, the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and helps to clarify whether additional trials are needed.

The idea in TSA is that if the cumulative Z-curve crosses the boundary, a sufficient level of evidence is reached and no further trials may be needed (firm evidence). If the Z-curve does not cross the boundary, then there is insufficient evidence to reach a conclusion. To construct the trial sequential monitoring boundaries the required information size is needed and is calculated as the least number of participants needed in a well-powered single trial (Brok 2009; Pogue 1997; Thorlund 2011; Trial Sequential Analysis (TSA); Wetterslev 2008). We aimed to apply TSA as it prevents an increase in the risk of type I error with sparse data or multiple updating in a cumulative meta-analysis. Hence, TSA provides us with important information in order to estimate the level of evidence of the experimental intervention, the need for additional trials and their sample size.

Subgroup analysis and investigation of heterogeneity

We conducted the following subgroup analyses:

  1. Mortality by duration. We planned to use 28, 90 days and the longest follow-up period. If data were provided in 30 days we included them in the same analysis as 28 days.

  2. Mortality among patients admitted in a general ICU.

  3. Mortality among patients admitted under the diagnosis of acute pancreatitis.

  4. Number of infected participants.

  5. Number of participants with adverse event.

  6. Length of stay in the ICU.

  7. Number of days on a ventilator.

  8. Length of hospital stay.

We considered P values < 0.05 as indicating significant interaction between the subgroup category.

Sensitivity analysis

We decided to carry out a sensitivity analysis on the results by applying fixed-effect and random-effects models to assess the impact of heterogeneity on our results.

Summary of findings

We used the principles of the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach to provide an overall assessment of the evidence relating to the following outcomes: Overall mortality (regardless of the follow-up period), ICU length of stay (selenium), Days on ventilator (selenium), Length of hospital stay (selenium) (Summary of findings for the main comparison).

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification; Characteristics of ongoing studies sections.

Results of the search

In this updated review, 11 trials was identified via the search strategy, 6 were included, 5 were excluded, two were classified as ongoing and two are awaiting assessment. We have listed the reasons for excluding the 5 studies in the 'Characteristics of excluded studies' table. Three included studies and three excluded studies were published in German only, and one included trial was in Spanish. Translations to English were performed for these studies. Some trials had multiple full text publications (Angstwurm 1999; Berger 2001; Saito 1998; SIGNET 2011; Zimmermann 1997). A total of 2084 patients were included in this review update.

Of the six new included studies, we found one by handsearching (Montoya 2009) and five using our search string (Forceville 2007; Janka 2013; Manzanares 2011; SIGNET 2011; Valenta 2011). We sought further details and obtained them for four studies (Angstwurm 2007; Angstwurm 1999; Manzanares 2011; Valenta 2011). The flow chart for this updated review is given in Figure 1.

Figure 1.

Study flow diagram for the updated review. (In the original article, Avenell 2004, 10 studies were included and 11 studies were excluded with reasons. Three were awaiting classification, of which one has now been excluded (Kiessling 2006). Two studies are still ongoing).

Included studies

The included trials were all published between 1997 and 2013 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 of selenium was a multicentre trial in Germany (Angstwurm 2007), one was a multicentre trial in the UK (SIGNET 2011) and one was a multicentre trial in France (Forceville 2007). The remaining Selenium trials were single centre trials in the Czech Republic, Germany, Switzerland, the UK and Uruguay (Angstwurm 1999; Berger 2001; Janka 2013; Kuklinski 1991; Lindner 2004; Manzanares 2011; Mishra 2007; Valenta 2011; Zimmermann 1997). One trial did not state the location (Montoya 2009).

The 16 included studies involved a total of 2084 participants. We have provided the details of the included studies in the 'Characteristics of included studies' section. Eleven trials recruited more male than female participants (Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Janka 2013; Lindner 2004; Montoya 2009; Ogawa 1999; SIGNET 2011; Valenta 2011; Yamaguchi 1998). One trial recruited only men (Kuklinski 1991), one did not report the sex of the participants (Zimmermann 1997) and three studies had more women than men (Manzanares 2011; Mishra 2007; Saito 1998). Where reported, the mean age of participants was greater 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; Forceville 2007; Janka 2013; Manzanares 2011; Mishra 2007; Montoya 2009; Valenta 2011; Zimmermann 1997), severe multiple injury (Berger 2001), more serious cases of acute pancreatitis (Kuklinski 1991; Lindner 2004) and gastrointestinal failure requiring parenteral nutrition (56% with sepsis; SIGNET 2011). 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 and thus, we chose not to consider them as identical interventions. 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. The trials of selenium used intravenous selenium, usually given as a sodium selenite, as a continuous infusion over 24 hours, with doses of selenium ranging from 155 mcg to 4000 mcg (often decreasing the dose as time went on). Four studies gave loading bolus doses on the first day (Angstwurm 2007; Manzanares 2011; Montoya 2009; Zimmermann 1997) and a fifth (Valenta 2011) gave daily boluses. Only Zimmermann 1997 had no comparison infusion. No trial examined the impact of selenium or ebselen supplementation for more than 28 days.

Berger 2001 included three trial groups: selenium only, selenium combined with alpha-tocopherol and zinc, and placebo control. We have presented only the comparison between selenium and placebo. The SIGNET 2011 trial included four study groups: glutamine only, selenium only, selenium combined with glutamine, and a placebo group. We pooled data for selenium only and selenium combined with glutamine as the treatment group, and glutamine only and placebo as the control group.

Excluded studies

We excluded 16 studies (Berger 1998; Berger 2004a; Berger 2004b; Berger 2005a; Berger 2005b; Berger 2008; Börner 1997; Collier 2008; Kiessling 2006; Porter 1999; REDOXS 2011; Stoppe 2010; Thiele 1997; Uden 1990; Watters 2002; Wollschläger 1997) for the reasons detailed in the 'Characteristics of excluded studies' section.

Ongoing studies

Two studies are ongoing (Geoghegan 2009; Yamaguchi 2003; see the 'Characteristics of ongoing studies' section.

Awaiting classification

Two studies are awaiting classification (SEREAL 2012; SISPCT; see the 'Characteristics of studies awaiting classification' section.

Risk of bias in included studies

The risk of bias of the included studies was high. The trials often failed to report trial methodology in sufficient detail. One trial had improved methodology after further details were obtained from one trial author (Angstwurm 1999). See Description of studies, Figure 2 and Figure 3

Figure 2.

'Risk of bias' graph: review authors' judgements about each 'Risk of bias' item presented as percentages across all included studies.

Figure 3.

'Risk of bias' summary: review authors' judgements about each 'Risk of bias' item for each included study.

All but one of the included studies were RCTs; Valenta 2011 was a quasi-RCT.

In eight trials groups were clearly comparable at baseline (Angstwurm 1999; Kuklinski 1991; Lindner 2004; Janka 2013; Montoya 2009; Ogawa 1999; SIGNET 2011; Yamaguchi 1998). Four trials did not clearly report following up all participants to the end of the trial (Lindner 2004; Mishra 2007; Montoya 2009; Zimmermann 1997). 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. Six trials gave objectively described definitions of trial outcomes (Angstwurm 1999; Berger 2001; Manzanares 2011; Ogawa 1999; SIGNET 2011; Yamaguchi 1998).

Allocation

Concealment of allocation was confirmed in only three trials (Berger 2001; Montoya 2009; SIGNET 2011). The other trials did not clearly report the method of concealment of allocation. Although not always explicitly stated, ITT analysis was undertaken in seven of the 16 trials (Angstwurm 1999; Forceville 2007; Kuklinski 1991; Ogawa 1999; Saito 1998; SIGNET 2011; Zimmermann 1997). The risk of selection bias is high.

Blinding

Ten trials were reported to be blinded or double blinded (Angstwurm 2007; Berger 2001, Lindner 2004; Manzanares 2011; Mishra 2007; Montoya 2009; Ogawa 1999; Saito 1998; SIGNET 2011; Yamaguchi 1998). For the outcomes assessed in this review, it was often unclear to whom the blinding referred. Only Angstwurm 2007 and Angstwurm 1999 recruited consecutive eligible patients. Due to the poorly described level of blinding in most trials, the risk of bias remains unclear.

Incomplete outcome data

One trial, Montoya 2009, had a follow-up period of 10 days. The average (median) length of mechanical ventilation in the control group was 13 days compared to nine days in the intervention group. The median length of stay in hospital was 17 days for the control group and 12 days for the intervention group. It remains unclear how long the patients indeed were followed-up. Most trials poorly described or failed to describe the follow-up period (Angstwurm 1999; Lindner 2004; Mishra 2007; Montoya 2009; SIGNET 2011; Valenta 2011; Zimmermann 1997). The risk of attrition bias is thus high.

Selective reporting

Only two trials had published a protocol or registered the trial in an available database (Forceville 2007; SIGNET 2011). Thus, for most trials we are unable to assess the degree of reporting bias. The overall risk of bias is high for selective reporting.

Other potential sources of bias

Funding bias

Four studies provided a conflict of interest statement (Forceville 2007; Manzanares 2011; SIGNET 2011; Valenta 2011). Five trials reported receiving pharmaceutical company funding (Angstwurm 2007; Ogawa 1999; Saito 1998; SIGNET 2011; Yamaguchi 1998), and in one trial a study was acknowledged for providing the study drug (Forceville 2007).

Effects of interventions

See: Summary of findings for the main comparison Summary of findings table 1

The outcomes reported in the included studies are listed in the 'Characteristics of included studies' table. Where available, we have presented mortality results using denominators based on the numbers of participants at randomization. Generally, we have presented the results for other outcomes using denominators based on the numbers of participants available at follow-up.

Primary outcomes

Mortality

All 16 included studies provided mortality data, 13 trials used selenium as intravenous sodium selenite (Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Kuklinski 1991; Janka 2013; Lindner 2004; Manzanares 2011; Mishra 2007; Montoya 2009; SIGNET 2011; Valenta 2011; Zimmermann 1997) and three trials used ebselen (Ogawa 1999; Saito 1998; Yamaguchi 1998).

In trials of selenium, overall mortality was reduced in the intervention group (RR 0.82, 95% Cl 0.72 to 0.93, I² statistic = 0%, fixed-effect model) while for ebselen the RR in favour of intervention among trials was 0.83 (95% Cl 0.52 to 1.34, I² statistic = 0%, fixed-effect model). Combined data for mortality showed a RR of 0.82 (95% Cl 0.72 to 0.93; I² statistic = 0%, test for subgroup differences: I² statistic = 0%; Analysis 1.1; Figure 4).

Figure 4.

Funnel plot of comparison: 1.2 Overall mortality (regardless of the follow-up period).

Twenty-eight days mortality among selenium studies yielded a RR of 0.84 (Cl 95% 0.69 to 1.02, I² statistic = 21%, random-effects model) while at 90 days RR was 0.96 (95% CI 0.78 to 1.18, I² statistic = 0% random-effects model) (Analysis 2.1).

Inclusion of the data from the three trials of ebselen showed no statistically significant difference in mortality (RR 0.83, 95% CI 0.52 to 1.34; I² statistic = 0%). Only Ogawa 1999 reported mortality at 30 days (RR 1.78, 95% CI 0.53 to 5.95) while Saito 1998 and Yamaguchi 1998 reported mortality data at three months follow-up (RR 0.72, 95% CI 0.42 to 1.22) (Analysis 2.2).

Mortality in trials of selenium in intensive care patients (Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Janka 2013; Manzanares 2011; Mishra 2007; SIGNET 2011; Valenta 2011; Zimmermann 1997) compared with trials in patients with acute pancreatitis (Kuklinski 1991; Lindner 2004) yielded a RR of 0.88 (95% CI 0.77 to 1.01, I² statistic = 0%, random-effects model). In patients with acute pancreatitis the RR was 0.40 (95% CI 0.01 to 12.30, I² statistic = 81% random-effects model) (Analysis 2.3).

Secondary outcomes

Number of infectious complications

Six trials of intravenous sodium selenite provided data on this outcome (Angstwurm 2007; Berger 2001; Forceville 2007; Lindner 2004; Manzanares 2011; SIGNET 2011).

Berger 2001 provided data for participants developing infections based on the number of participants requiring antibiotics. Angstwurm 2007 reported no significant difference in the incidence of new infections (for example the development of hospital acquired pneumonia, as well as the incidence of acute respiratory distress syndrome). Forceville 2007 reported participants with at least one episode of nosocomial pneumonia and one participant on selenium developing a superinfection. Similarly, Manzanares 2011 reported participants with ventilator-associated pneumonia. Lindner 2004 provided data on patients developing sepsis or peritonitis. SIGNET 2011 reported new infections at 14 days post-randomization (both clinically suspected infections (used in our meta-analysis)) and infections confirmed and based on Centers for Disease Control and Prevention criteria (reported odds ratio 0.75, 95% CI 0.52 to 1.08, P = 0.12). Based on data from these six trials, there was no statistically significant difference (RR 0.96, 95% CI 0.75 to 1.23, I² statistic = 16%, random-effects model; Analysis 3.1). Mishra 2007 reported an infection rate instead of number of infections; consequently the data could not be included but no significant difference between groups was found.

All three trials of ebselen (Ogawa 1999; Saito 1998; Yamaguchi 1998) provided data for participants developing infections (pyrexia, respiratory infections or meningitis) with no statistically significant difference (RR 0.60, 95% CI 0.36 to 1.02, I² statistic = 33%, random-effects model; Analysis 3.1).

Adverse events

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. Three trials reported numbers of participants developing any serious adverse event (Forceville 2007; Manzanares 2011; SIGNET 2011). Mishra 2007 reported that five of the 18 selenium supplemented participants required renal replacement compared with seven of the 22 controls. The RR for an adverse event from these six trials was 1.03 (95% CI 0.85 to 1.24, I² statistic = 41%; Analysis 4.1).

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 significantly different (Ogawa 1999). Combining the results for Saito 1998 and Yamaguchi 1998 (no available data for Ogawa 1999) yielded a RR of 1.16 (95% CI 0.40 to 3.36, I² statistic = 68%; Analysis 4.1).

Length of stay in ICU

Seven trials of intravenous sodium selenite provided data on the length of stay in intensive care (Angstwurm 1999; Angstwurm 2007; Berger 2001; Forceville 2007; Manzanares 2011; Mishra 2007; SIGNET 2011; Table 1). Three trials provided data directly suitable for meta-analysis (Angstwurm 2007; Manzanares 2011; Mishra 2007). Four trials (Angstwurm 1999; Berger 2001; Forceville 2007; SIGNET 2011) provided data which had to be processed. The overall MD was 0.54 (95% CI -2.27 to 3.34, I² statistic = 72%, random-effects model; Analysis 4.2).

Table 1. Length of stay in ICU
  1. Analysis 4.2

    All findings given as mean (SD). If the original figures were provided in median (range) or interquartile range, we converted them to mean (SD) (Hozo 2005).

TrialSeleniumControl
Angstwurm 199922.8 days (20.8)26.5 days (22)
Angstwurm 200715.1 days (10)12.7 days (9)
Berger 20017,5 days (3.5)9 days (7.1)
Forceville 200722.3 days (9.6)17 days (8.7)
Manzanares 201114 days (11)13days (6)
Mishra 200721.3 days (16.2)20.8 days (21.8)
SIGNET 201114.5 days (4.6)16.7 days (5.9)
MD 0.54 (95% CI -2.27 to 3.34, I² statistic = 72%, random-effects model)
Number of days on a ventilator

Five trials of intravenous sodium selenite provided data for the number of days on a ventilator (Table 2). Four trials provided data suitable for meta-analysis (Angstwurm 1999; Berger 2001; Forceville 2007; Montoya 2009; Table 2). One trial, Angstwurm 2007, reported the incidence and hours of mechanical ventilation as not significantly different between groups (mean of 13 days with selenium for 84 participants and 11 days with placebo for 95 participants), but stated no range of days. The overall MD was -0.86 (95% CI -4.39 to 2.67, I² statistic = 89%, random-effects model; Analysis 4.3).

Table 2. Number of days on a ventilator
  1. Analysis 4.3)

    All findings given as mean (SD). If the original figures were provided in median (range), we converted them to mean (SD) (Hozo 2005).

TrialSeleniumControl
Angstwurm 199911 days (5.9)16 (12.6)
Berger 20016 days (2.9)6 days (5.7)
Forceville 200719.8 days (7.8)14.8 days (4.4)
Montoya 20099.3 days (1.5)12 days (1.8)
MD -0.86 (95% CI -4.39 to 2.67, I² statistic = 89%, random-effects model)
Length of hospital stay

Five trials, all of intravenous sodium selenite, provided data on the length of hospital stay (Angstwurm 1999; Berger 2001; Forceville 2007; Montoya 2009; SIGNET 2011; Table 3). The overall MD was -3.33 (95% CI -5.22 to -1.44, I² statistic = 42%, random-effects model; Analysis 4.4).

Table 3. Length of hospital stay
  1. Analysis 4.4

    All findings given as mean (SD). If the original figures were provided in median (range) or interquartile range, we converted them to mean (SD) (Hozo 2005).

TrialSeleniumControl
Angstwurm 199938.5 days (24.4)39.5 days (15.7)
Berger 200183 days (73.5)62.8 days (30.2)
Forceville 200731.3 days (18)32 days (11.6)
Montoya 200912.5 days (0.6)17 days (1.7)
SIGNET 201131.7 days (10.9)33.8 days (12.4)
MD -3.33 (95% CI -5.22 to -1.44, I² statistic = 42%, random-effects model)
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, Yamaguchi 1998 reported that the Modified Barthel Index Score (Shah 1989), an assessment of functional status, was significantly improved by ebselen at a final follow-up time of three months.

Only one trial, Ogawa 1999, stated the results in values. The other two trials, Saito 1998 and Yamaguchi 1998, showed only a graphical representation. Consequently, we were unable to make an analysis for this subgroup.

No trials of selenium have provided quality of life data.

Economic outcomes

No trials provided details of costs or economic outcomes.

Other findings

Six trials found significantly increased activity of the antioxidant selenoenzyme glutathione peroxidase, demonstrating the potential for intravenous selenium to improve antioxidant capacity in participants (Angstwurm 2007; Angstwurm 1999; Berger 2001; Manzanares 2011; Mishra 2007; Valenta 2011). 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).

Trials sequential analysis (TSA):

Since TSA was not part of the previous version of this review, Avenell 2004, we used the calculated relative risk and event rates of Analysis 1.1 to calculate the required information size. In our TSA of the impact of selenium supplementation on mortality among critically ill patients using a control event proportion of 32% found in the included trials, with a type 1 error of 5% and a 18% relative risk reduction (80% power), the trial sequential monitoring boundary for benefit is not crossed by the z-curve (Figure 5). However, these lines are very close to crossing each other. This may suggest a probability of lack of random error for the conclusion of an effect of 18% relative risk reduction even though the required information size (N = 2605) has not yet been reached. Nevertheless, one must exert caution when interpreting the results of our TSA on mortality since all included studies are at high risk of bias and the intervention effect is likely to have been overestimated in the traditional meta-analysis. This will inevitably influence the TSA result. As a general rule TSA is unable to adjust for risk of bias and is ideally designed for studies with low risk of bias. Thus, we anticipate a higher degree of heterogeneity and diversity, and consequently a different TSA output once the results of the ongoing large RCTs are published.

Figure 5.

Trial sequential analysis (TSA) of all trials examining the effect of Selenium supplementation on mortality among critically ill. Using a control event proportion of 32% found in the included trials, with a type 1 error of 5% and a 18% relative risk reduction (80% power), the trial sequential monitoring boundary for benefit is not crossed by the z-curve. However, these lines are very close to crossing each other which may indicate a probability of lack of random error for the conclusion of an effect of 18% relative risk reduction even though the required information size (N = 2605) has not yet been reached. However, caution must be exerted when interpreting the results of this TSA since all included studies are at high risk of bias and the intervention effect is likely to have been overestimated in the traditional meta-analysis.

Discussion

Summary of main results

In this review update we found no clear evidence that selenium supplementation reduces mortality in critically ill adults despite a statistically significant finding. This is mainly due to the high risk of bias, most likely overestimating the overall intervention effect. Even though we are unable to rule out a beneficial effect, the evidence remains dubious as a result of the poor methodological quality of the trials. For instance, only three trials clearly reported concealment of allocation (Berger 2001; Montoya 2009; SIGNET 2011). Few trials reported on outcomes other than mortality or clearly defined the reported outcomes. Periods of follow-up were often short and did not allow for the prolonged recovery from critical illness. There was insufficient data to examine the effect of methodological superiority or dose of selenium on the outcomes.

Selenium supplementation in the general ICU population with severe sepsis or septic shock has been investigated by SISPCT, which with a sample size of 1180 and rigorous methodology may help clarifying a potential benefit or harm of selenium. The lead author of SISPCT expects to publish the results within the next year. Additionally, based on data from current published trials it remains at best uncertain as to whether loading bolus or continuous doses are preferred (Manzanares 2011).

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, Yamaguchi 2003, are still awaited.

Furthermore, we found no evidence to suggest that these interventions are harmful.

Overall completeness and applicability of evidence

We are confident that we identified all available studies from our search strategy. Several authors have been contacted but have not identified any additional trials for inclusion.

In contrast to Avenell 2004, in this update we revised the primary endpoints, adding overall mortality regardless of the period of follow-up, and carried out TSA in order to reduce the risk of random error. Yet, the review conclusions remain the same.

The applicability of our results only refers to critically ill adult patients and as such there is insufficient evidence to support the routine use of this intervention.

Quality of the evidence

The RCT is considered the most rigorous method for determining whether a cause-effect relationship exists between an intervention and outcome. The strength of the RCT lies in the process of randomization.

No trials were reported as at overall low-risk of bias (Figure 2; Figure 3). Fifteen of the 16 included trials were at high risk of bias regarding random sequence generation (selection bias). Only one trial has published the protocol (SIGNET 2011) and only two trials had been registered in a database (Forceville 2007; SIGNET 2011), which is why we deemed 14 of the 16 included trials at high risk of reporting bias. All trials of ebselen were at high risk of funding bias. Thus, due to the overall high risk of bias in these included trials, the results should be interpreted with caution.

Application of the GRADE approach enables us to incorporate risk of bias, directness of evidence, heterogeneity, precision of effect estimate, and risk of publication bias. Based on the above mentioned criteria, the quality of evidence in this review was very low and there was a high risk of bias

Potential biases in the review process

In this update we remained loyal to the original protocol, Avenell 2002, with only minor changes in order to avoid bias. Two review authors (MA, AA) independently performed data extraction and 'Risk of bias' assessment. We consulted the Managing Editor and Trials Search Coordinator of the Cochrane Anaesthesia, Critical and Emergency Care Group throughout the entire process of the review update.

Despite our prior knowledge to the conclusions of other recently published systematic reviews (Huang 2013; Landucci 2014; Manzanares 2012), we have adhered to Cochrane methodology and applied additional statistical methods, such as TSA, to strengthen our conclusions and reduce the risk of random error.

Agreements and disagreements with other studies or reviews

The overall conclusions of this Cochrane review do not agree with the statements and findings of the most recently published systematic reviews and meta-analysis (Huang 2013; Landucci 2014; Manzanares 2012). All three meta-analyses reported a significantly decreased mortality in the selenium group. However, two papers did not address the quality of studies included (Huang 2013; Manzanares 2012). Landucci 2014 reported the quality of evidence of the meta-analysis as low due to unclear quality of randomization in many studies. These papers did not adhere to PRISMA guidelines.

Authors' conclusions

Implications for practice

Despite a statistically significant finding on longest follow-up mortality (RR 0.82, 95% CI 0.72 to 0.93), one must be cautious when interpreting the strength of the evidence for the routine use of selenium or ebselen supplementation in critically ill patients. Serious methodological shortcomings of the included studies are likely to have influenced the overall intervention effect (Summary of findings for the main comparison). Additionally, we failed to show a reduced time on mechanical ventilation, length of stay in ICU or length of stay in hospital. Our review did not indicate any harmful effect of the intervention among critically ill patients.

The GRADE approach only reaffirmed our interpretation of the level of evidence and we are confident that at this stage the quality of evidence is very low and risk of bias very high.

Implications for research

We await the publication of the large multicentre RCT, SISPCT, as it will provide important information essential to calculate the required information size in order to reject or accept a beneficial effect of selenium supplementation. Based on our current TSA, the required information size of 2605 patients is not far from the 2084 patients included in this paper. However, large, well-designed, adequately powered trials of selenium supplementation, at low risk of bias and conforming to the CONSORT statement (Moher 2010), will most likely increase the required information size. Future research should examine functional status, patient-perceived quality of life and include economic evaluation. Independent observers should assess outcomes and the period of follow-up should extended and preferably exceed current arbitrary defined short limits (i.e. 28 days up to six months).

Acknowledgements

We thank the review authors of the first edition of this review, Alison Avenell, David Noble, John Barr and Tom Engelhardt, for their hard work (Avenell 2004).

Furthermore we thank Mette Berger, Helena Brodska, Xavier Forceville, Roland Gärtner, Frank Bloos, Arndt Kiessling, William Manzanares and Tomoko Motohashifor for providing further information about their trials. We are grateful to Matilde Jo Allingstrup, Tim Søvæld Nielsen, Jesper Røjskjær and Anders Perner for their help and editorial advice during this review update. We acknowledge Dr Karen Hovhannisyan (Trials Search Co-ordinator, Cochrane Anaesthesia, Critical and Emergency Care Group (ACE) ) for his assistance in providing our different search strategies. We thank Jane Cracknell (Managing Editor, ACE) for her valuable assistance during the entire process.

Data and analyses

Download statistical data

Comparison 1. Selenium versus no selenium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Overall mortality (regardless of the period of follow-up)162084Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.93]
1.1 Overall mortality (Selenium)131391Risk Ratio (M-H, Fixed, 95% CI)0.82 [0.72, 0.93]
1.2 Overall mortality (Ebselen)3693Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.52, 1.34]
Analysis 1.1.

Analysis 1.1.

Comparison 1 Selenium versus no selenium, Outcome 1 Overall mortality (regardless of the period of follow-up).

Comparison 2. Selenium versus no selenium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Mortality by duration (Selenium)11 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Selenium 28 day91180Risk Ratio (M-H, Random, 95% CI)0.84 [0.69, 1.02]
1.2 Selenium 90 day3614Risk Ratio (M-H, Random, 95% CI)0.96 [0.78, 1.18]
2 Mortality by duration (Ebselen)3 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2.1 Ebselen 30 day1105Risk Ratio (M-H, Random, 95% CI)1.78 [0.53, 5.95]
2.2 Ebselen 3 month2588Risk Ratio (M-H, Random, 95% CI)0.72 [0.42, 1.22]
3 Mortality: ICU and pancreatitis (Selenium)111255Risk Ratio (M-H, Random, 95% CI)0.87 [0.74, 1.02]
3.1 General intensive care patients91168Risk Ratio (M-H, Random, 95% CI)0.88 [0.77, 1.01]
3.2 Acute pancreatitis287Risk Ratio (M-H, Random, 95% CI)0.40 [0.01, 12.30]
Analysis 2.1.

Analysis 2.1.

Comparison 2 Selenium versus no selenium, Outcome 1 Mortality by duration (Selenium).

Analysis 2.2.

Analysis 2.2.

Comparison 2 Selenium versus no selenium, Outcome 2 Mortality by duration (Ebselen).

Analysis 2.3.

Analysis 2.3.

Comparison 2 Selenium versus no selenium, Outcome 3 Mortality: ICU and pancreatitis (Selenium).

Comparison 3. Selenium versus no selenium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Number of infected participants9 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Selenium6934Risk Ratio (M-H, Random, 95% CI)0.96 [0.75, 1.23]
1.2 Ebselen3685Risk Ratio (M-H, Random, 95% CI)0.60 [0.36, 1.02]
Analysis 3.1.

Analysis 3.1.

Comparison 3 Selenium versus no selenium, Outcome 1 Number of infected participants.

Comparison 4. Selenium versus no selenium
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Number of participants with adverse event8 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Selenium6925Risk Ratio (M-H, Random, 95% CI)1.03 [0.85, 1.24]
1.2 Ebselen2588Risk Ratio (M-H, Random, 95% CI)1.16 [0.40, 3.36]
2 Length of stay in ICU (Selenium)7934Mean Difference (IV, Random, 95% CI)0.54 [-2.27, 3.34]
3 Number of days on a ventilator (Selenium)4191Mean Difference (IV, Random, 95% CI)-0.86 [-4.39, 2.67]
4 Length of hospital stay (Selenium)5693Mean Difference (IV, Random, 95% CI)-3.33 [-5.22, -1.44]
Analysis 4.1.

Analysis 4.1.

Comparison 4 Selenium versus no selenium, Outcome 1 Number of participants with adverse event.

Analysis 4.2.

Analysis 4.2.

Comparison 4 Selenium versus no selenium, Outcome 2 Length of stay in ICU (Selenium).

Analysis 4.3.

Analysis 4.3.

Comparison 4 Selenium versus no selenium, Outcome 3 Number of days on a ventilator (Selenium).

Analysis 4.4.

Analysis 4.4.

Comparison 4 Selenium versus no selenium, Outcome 4 Length of hospital stay (Selenium).

Appendices

Appendix 1. Cochrane Central Register of Controlled Trials search strategy

#1 MeSH descriptor: [Selenium] explode all trees
#2 MeSH descriptor: [Selenium Compounds] explode all trees
#3 selen*
#4 ebselen
#5 #1 or #2 or #3 or #4
#6 #5

Appendix 2. MEDLINE (Ovid SP) and Healthstar search strategy

1. exp Selenium Compounds/ or exp Selenium/ or (selen* or ebselen*).mp.2. (randomized controlled trial.pt. or controlled clinical trial.pt.or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (animals.sh not (humans.sh and animals.sh))
3. 1 and 2

Appendix 3. EMBASE (Ovid SP) search strategy

1. exp selenium derivative/ or exp selenium/ or (selen* or ebselen*).ti,ab.
2. (placebo.sh. or controlled study.ab. or random*.ti,ab. or trial*.ti,ab. or ((singl* or doubl* or trebl* or tripl*) adj3 (blind* or mask*)).ti,ab.) not (animals not (humans and animals)).sh.
3. 1 and 2

Appendix 4. CAB abstracts search strategy

1. random$.tw
2. trials$.tw
3. placebo$.tw
4. 1 or 2 or 3
5. selen$.tw
6. ebselen.tw
7. 5 or 6
8. 4 and 7

Appendix 5. BIOSIS search strategy

#1 TI=selen* or TI=ebselen*
#2 TS=(random* or trial* or placebo*)
#3 #1 and #2

Appendix 6. CINAHL (EBSCOhost) search strategy

S1 ((MM "Selenium") OR (MM "Selenium Compounds")) or selen* or ebselen*
S2 random* or ((clinical or controlled) N3 trials) or placebo* or multicenter or prospective or ((blind* or mask*) N3 (single or double or triple or treble))
S3 S1 and S2

What's new

DateEventDescription
22 April 2016AmendedTypo corrected. The word significant was missing from one sentence in the plain language summary. The sentence has beedn corrected to read: ' Thirteen trials of intravenous sodium selenite showed a statistically significant effect on death.'

History

DateEventDescription
25 June 2015New citation required but conclusions have not changed

The previous review authors (Avenell A, Noble DW, Barr J, Engelhardt T) decided not to update this Cochrane review. Two new review authors have updated this review (Allingstrup M, Afshari A).

The conclusions have not changed in this updated Cochrane review.

25 June 2015New search has been performed

We searched the databases up to 21 May 2014. We included six new trials of selenium (2084 participants) in this review update (Forceville 2007; Janka 2013; Manzanares 2011; Montoya 2009; SIGNET 2011; Valenta 2011). This review now includes 16 studies in total.

We updated the Methods, included full 'Risk of bias' tables and 'Summary of findings' tables. We used trial sequential analysis.

17 August 2007New search has been performedThree new trials are included. Two of these were previously classified as ongoing trials (Mishra 2005, Angstwurm 2006). The conclusions of the review are unchanged.
16 August 2007New search has been performedSearch reran
16 August 2007New search has been performedSearch strategies reran until 17th August 2007

Contributions of authors

Updated review

Mikkel Allingstrup (MA), Arash Afshari (AA).

MA and AA searched the literature, performed quality assessment and extraction of data from trials, and wrote the review update.

Original published review and first update

All four authors (Alison Avenell, David W Noble, John Barr, Thomas Engelhardt) were involved in protocol development, searched the literature, performed quality assessment and data abstraction of trials, and wrote the review (Avenell 2004).

Declarations of interest

Mikkel Allingstrup declares no conflicts of interest.

Arash Afshari declares no conflicts of interest.

Sources of support

Internal sources

  • Herlev Hospital, University of Copenhagen, Denmark.

    Department of Anaesthesia and Intensive Care

  • Rigshospitalet, University of Copenhagen, Denmark.

    Anaesthesia and Surgical Clinic Department 4013

External sources

  • No sources of support supplied

Differences between protocol and review

In this review update we have revised the first primary endpoint to overall mortality, which is the longest time of follow-up. Mortality by duration (28 and 90 days) is preserved as our second primary endpoint. We performed a TSA and included it in this review update.

Notes

2015 update: we updated the methods, included full 'Risk of bias' tables and 'Summary of findings' tables. We used TSA.

This review was also updated in 2007 (Avenell 2004). At that time Cochrane updates did not earn a new citation unless they had new authors or a change to conclusions. The 2007 version of this review included three new trials; two of these were previously classified as ongoing trials (Angstwurm 2006; Lindner 2004; Mishra 2007). The conclusions of the 2007 review were unchanged. Therefore the 2007 update did not earn a new citation

We 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 the original review (Avenell 2004).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Angstwurm 1999

MethodsMethod of randomization: states stratified randomization only
Assessor blinding: states open label
Intention to treat (ITT): carried out
Lost to follow-up: none
ParticipantsLocation: ICU, Klinikum Innenstadt, University of Munich, Germany
Period of trial: recruitment March 1995 to August 1996
42 patients
Inclusion criteria: APACHE score ≥ 15, and clinical and laboratory signs of new systemic inflammatory response syndrome (SIRS) according to sepsis criteria (American College of Chest Physicians/Society of Critical Care Medicine), first 24 hours after admission
Exclusion criteria: age < 18 years, pregnancy, after cardiopulmonary resuscitation, severe gastrointestinal bleeding, trauma, surgery, chronic renal failure, refusal to participate
Sex: 29 males, 13 females
Age: mean age 56 years (range 18 to 83 years)
Interventions

Timing of intervention: from day of admission to intensive care for additional supplementation for nine days

  1. Continuous intravenous sodium selenite (535 mcg selenium for 3 days, 285 mcg selenium for 3 days, 155 mcg selenium for 3 days, 35 mcg selenium for remainder of total treatment time; and standard parenteral nutrition including glutamine 20 g/L

  2. Continuous placebo of saline and intravenous 35 mcg selenium as sodium selenite, and standard parenteral nutrition including glutamine 20 g/L

Allocated: 21/21
Assessed: 21/21

Outcomes

Length of follow-up: until discharge

Main outcomes:

  • Mortality

Other outcomes:

  • Number of days on a ventilator

  • Length of hospital stay

NotesRequest for further details of interventions sent 24 October 2003, reply received 17 November 2003.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskPatients were stratified randomly into two groups. No further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen label trial
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNone stated
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Unclear riskNone stated
Other biasUnclear riskNone

Angstwurm 2007

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: performed
ITT: not performed
Lost to follow-up: reported
ParticipantsLocation: 11 independent German ICUs
Period of trial: enrolment December 1999 to October 2004
249 patients
Inclusion criteria: men and women > 18 years with APACHE III score (22) > 70 and at least two of the following criteria: rectal body temperature > 38°C or hypothermia < 36°C, heart rate > 90 per minute, respiratory frequency > 20 per minute and PaCO2 < 32 mmHg (< 4.3 kPa), leucocytes > 12 000/µL or < 4 000/µL or > 10% immature leucocytes, decrease of platelet count > 50 % within the first 24 hrs or platelets < 150,000/µL at admission; admission into the trial after diagnosis within 24 hours; beginning of treatment within 1 hour after inclusion.
Exclusion criteria: pregnancy; missing informed consent of patient or relative/intimate friend; withdrawal of informed consent after inclusion into trial; participation in any clinical trial within last 30 days; prior participation in this clinical trial; cerebral injury due to hypoxia after cardiopulmonary resuscitation; primary concomitant disease with expected high mortality within 2 months; not for resuscitation; malignant primary disease as cause of systemic inflammatory response syndrome or sepsis, e.g. agranulocytosis as result of chemotherapy or idiopathic bone marrow aplasia; haemorrhagic - necrotising pancreatitis without infectious complications.
Sex: 162 males, 76 females
Age: 64.6 years (SD 14.0)
Interventions

Timing of intervention: admission into trial after diagnosis within 24 hours, trial treatment beginning within 1 hour after inclusion

  1. 48 mL vial as bolus intravenous injection over 30 minutes providing 1000 mcg sodium selenite, followed by continuous infusion of 2 mL/hour over 24 hours for 14 days, total dose 15,000 mcg selenium. Allowed selenium from other preparations of up to 100 mcg/day.

  2. Matching placebo of 0.9% sodium chloride give as same regimen. Allowed selenium from other preparations of up to 100 mcg/day.

Allocated: unclear
Assessed: 116/122

Outcomes

Length of follow-up: 28 days

Main outcomes:

  • 28 day mortality

  • Participants with new infections

Other outcomes:

  • Number of days on a ventilator

  • Length of ICU stay

  • Participants with adverse events

NotesEmail From Professor Gärtner on 8 August 2006 provided further details on participants with infections, length of ventilation, numbers randomized to each group, and details of the randomization process.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low risk249 randomized patients, 238 underwent ITT analysis. 14 patients failed exclusion/inclusion criteria after ITT analysis, 30 drug administration failure. 189 underwent per protocol analyse.
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
High riskSponsored by biosyn Arzneimittel GmbH, Fellbach, Germany
Other biasHigh riskThe trial had two exclusion criteria which could lead to bias: primary concomitant disease with an expected high mortality within 2 months and patients with a "do-not-resuscitate code"

Berger 2001

MethodsMethod of randomization: concealed
Assessor blinding: states double-blinded but no further details
ITT: performed
Lost to follow-up: none
ParticipantsLocation: surgicalICU of the Central Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Period of trial: before 2000
21 patients
Inclusion criteria: severe multiple injury (injury Severity Score, ISS, > 15) involving at least two body systems, pathophysiological changes requiring ICU support, age 18 to 75 years, admission within 24 hours of injury
Exclusion criteria: pre-existing renal or hepatic failure, foreseeable imminent death, no informed consent, documented hypothyroidism prior to accident
Sex: 15 males, 6 females
Age: age range 18 to 74 years
Interventions

Timing of intervention: from day of admission for five days

  1. Slow intravenous infusion over 24 hours of 500 mcg selenium as sodium selenite/day

  2. Infusion vehicle over 24 hours

  3. Slow intravenous infusion over 24 hours of 500 mcg selenium/day and 13 mg zinc/day, 150 mg alpha-tocopherol in 5 ml 10% lipid emulsion (Lipovenös, Fresenius, Stans, Switzerland) as slow injection once daily upon initiation of intravenous infusion (data for this group not used in this review)

Allocated: 9/12/11
Assessed: 9/12/11

Outcomes

Length of follow-up: appears followed up until died or left hospital, maximum length of stay 249 days

Main outcomes:

  • Mortality

  • Numbers of patients with infection (defined as requiring antibiotics)

Other outcomes:

  • Number of days on a ventilator

  • Length of ICU stay

  • Length of hospital stay

NotesITT data taken from paper in Nutrition Research
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Low riskConcealed
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. The trace element solutions were transparent, colourless, and clinically undetectable, identified with a number code known to the pharmacist only
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low riskNone lost to follow-up
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Unclear riskNot stated
Other biasUnclear riskNone

Forceville 2007

Methods

Method of randomization: stratified in each centre by blocks of four, sequentially numbered identical boxes provided to the investigator by the pharmacist, following the order of the randomization list

Assessor blinding: states double-blind

ITT: performed

Lost to follow-up: none

Participants

Location: 7 ICUs in France

Period of trial: randomization from 8 February 2002 to 12 March 2004

Inclusion criteria: severe documented infection (one or more of positive culture or Gram stain of normally sterile fluid, clinical focus of infection, nosocomial infection; need for mechanical ventilation; severe septic shock (circulatory failure requiring at least 1 L in previous 24 hours and treated for at least one hour with >15 mcg/kg/min dopamine or > 0.2 mcg/kg/min epinephrine or norepinephrine corresponding to class 4 of cardiovascular failure of Sequential Organ Failure Assessment score; Simplified Acute Physiologic Score II of 25 or more; consent from patients or representatives

Exclusion criteria: pregnancy, end-stage chronic disease, limitation of care in place, preliminary circulatory failure, shock due to urinary infection without bacteraemia, peritonitis due to peritoneal dialysis or trauma, participant in another trial

Sex: 38 males, 22 females

Age: selenium 66 years (SD 14), placebo 69 years (SD 12)

Interventions

Timing of intervention: unclear when started, given for 10 days

  1. 4000 mcg selenium as intravenous sodium selenite (in 192 mL saline) over 24 hrs, then 1000 mcg selenium as sodium selenite (in 48 mL saline) over 24 hrs for 9 days

  2. Matching saline placebo for 10 days

Allocated: 31/29

Assessed: 31/29

Outcomes

Length of follow-up: one year after randomization

Main outcomes:

  • Mortality

  • Participants with infection

  • Length of stay in an ICU

  • Length of stay in hospital

  • Adverse events

NotesThe trial is registered at ClinicalTrials.gov. There is complete agreement between the information registered in the database and the results in the article.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. All patients, pharmacists, medical- and nursing staff remained blinded throughout the trial period. In each centre, sequentially identical numbered boxes containing the whole treatment for each patient were delivered to the investigator by the pharmacist following the order of the randomizations list.
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomized patients were analysed according to the treatment group in which they were assigned
Selective reporting (reporting bias)Low riskNone. trial details available on ClinicalTrials.gov (Forceville 2007)
Funding bias
All outcomes
Low riskFunding by grant from the Ministry of Health, France
Other biasHigh riskThe principal Investigator, Xavier Forceville, is shareholder in a company named SÉRÉNITÉ-Forceville

Janka 2013

Methods

Method of randomization: Odd or even date of admission to ICU

Assessor blinding: no details, prospective observational trial

ITT: no details.
Lost to follow-up: none

Participants

Location: The 1st Clinic of Anaesthesiology and Intensive Care Medicine, University Hospital of Louis Pasteur in Košice, Slovak Republic.

Period of trial: January 2008. No end date stated.

72 patients
Inclusion criteria: patients who developed sepsis, severe sepsis or septic shock during hospitalisation, APACHE 19-40 after admission.

Exclusion criteria: APACHE < 19

Sex: 49 males, 23 females
Age: mean age 53 years, 23 to 79

Interventions

Timing of intervention: immediately after admission to ICU department, no details.

Trial intervention was for a maximum of six days.

Case: continuous infusion, sodium selenite pentahydrate at 750 mg/day for 6 days

Control: continuous infusion, NaCl 50 mL/day for 6 days

Outcomes

Length of follow-up: 28 days

Main outcomes:

  • 28-day mortality

Other outcomes:

  • APACHE II score

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskOdd or even date of admission to ICU
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low risk95 patients included. 15 lost to follow-up, 8 died within the first day after admission (lost to follow-up). 72 patients underwent per protocol analyse.
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Low riskFinancially supported by Slovak grant agency for Science
Other biasUnclear riskNone

Kuklinski 1991

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: not reported
ITT: carried out
Lost to follow-up: none
ParticipantsLocation: hospital, Rostock, Germany
Period of trial: before 1991
17 patients
Inclusion criteria: contrast CT scan showed pancreatic necrosis, < 72 hours since onset of pancreatitis
Exclusion criteria: mild pancreatitis
Sex: all male
Age: range 28 to 65 years
Interventions

Timing of intervention: 28 days

  1. Intravenous 500 mcg sodium selenite daily duration unclear (Selenase pro injectione, GN PHARM, Arzneimittel GmbH, Stuttgart)

  2. No treatment

Allocated: 8/9
Assessed: 8/9

Outcomes

Length of follow-up:

Main outcome:

  • Mortality

NotesRequest for further details on dose of selenium given sent 20 October 2003. Letter returned as author no longer at address in publication.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo patients lost to follow-up
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Unclear riskNot stated
Other biasHigh riskOnly men were included in the trial

Lindner 2004

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: not reported
ITT: not reported
Lost to follow-up: details provided
ParticipantsLocation: medical centre, Chemnitz, Germany
Period of trial: enrolment January 1997 to November 1998
70 patients
Inclusion criteria: severe acute pancreatitis managed on medical wards, severe abdominal pain, 3-fold increase of amylase and lipase, onset within 72 hours
Exclusion criteria: none given
Sex: 39 males, 28 females (completers)
Age: median 50 to 52 years
Interventions

Timing of intervention: start unclear, given until discharged

  1. Day 1 2000 mcg selenium as sodium selenite, days 2 to 5 1000 mcg/d, day 6 until discharged 300 mcg/d

  2. 0.9% sodium chloride placebo

Allocated: 35/35
Assessed: 32/35

Outcomes

Length of follow-up: until discharge

Main outcomes:

  • Mortality

  • Number of patients with infectious complications (sepsis)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskState blinded, no further details
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High riskNo details on follow-up
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Unclear riskNot stated
Other biasUnclear riskNone

Manzanares 2011

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: states participants blinded
ITT: not carried out
Lost to follow-up: not complete, four patients excluded
ParticipantsLocation: single centre, university hospital ICU, Montevideo, Uruguay
Period of trial: randomization Decmber 2006 to January 2008
35 patients
Inclusion criteria: patients with systemic inflammatory response and APACHE II score ≥ 15 and predicted mechanical ventilation > 48 hours.
Exclusion criteria: age < 18 years, pregnancy, brain injury after cardiopulmonary arrest, malignant disease, immune deficiency, chronic renal failure, participation in another trial, limitation of care, refused consent.
Sex: 15 males, 16 females
Age: mean age 58 (17 SD) years for 15 in selenite group, 54 (SD 17) for 16 in placebo group
Interventions

Timing of intervention: randomized within first 24 hours of ICU admission

  1. Intravenous selenium 2000 mcg (as selenious acid) bolus loading dose over 2 hours within 2 hours of enrolment; thereafter 1600 mcg/d in 240 mL 0.9% NaCl for 10 days

  2. Matching placebo 0.9% NaCl only for 10 days

Allocated: 16/19
Assessed: 15/16

Outcomes

Length of follow-up: duration of hospital stay

Main outcomes:

  • Mortality at in intensive care and hospital

  • Infections

Other outcomes:

  • Days on ventilator

  • Length of ICU stay

NotesWe emailed Dr Manzanares 27 April 2011 for details of adverse events and deaths, who provided information on 28 April 2011
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskSingle-blinded. Only patients were blinded to the intervention
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients were followed up for the entire trial
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Low riskSupported in part by grant from the Comisión Sectorial para la Investigación Cientııfica and the Fondo Clemente Estable 2004 and Ministerio de Educación y Cultura, Uruguay.
Other biasUnclear riskNone

Mishra 2007

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: states double-blind
ITT: not reported
Lost to follow-up: no details provided
ParticipantsLocation: ICU, Liverpool, UK
Period of trial: before 2002 to 2004
40 patients
Inclusion criteria: APACHE II score > 15, clinical suspicion of infection and > 1 organ dysfunction
Exclusion criteria: chronic renal failure, alcoholic liver disease, immunodeficiency
Sex: 19 males, 21 females
Age: mean age 66 years
Interventions

Timing of intervention: within 24 hours of admission to intensive care and within 72 hours since diagnosis of sepsis, given until discharged

  1. Intravenous selenium 470 mcg/day for 3 days, then 320 mcg/day for 3 days, then 160 mcg/day for 3 days, and 30 mcg/day thereafter

  2. 30 mcg/day

Allocated: 18/22
Assessed: 18/22 for mortality

Outcomes

Length of follow-up: 28 days

Main outcomes:

  • Mortality at 28 days

  • Infections

Other outcomes:

  • Length of ICU stay

  • Renal replacement therapy

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blind. The investigators were blinded to the study treatment
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High riskNo data on follow-up
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Low riskSupported by National Health Service trust with a Research and Development grant
Other biasHigh riskTrial designed to recruit 80 patients to provide adequate power to analyse clinical endpoints, but ended the trial after recruiting only 40 patients due to an unexpectedly low consent rate

Montoya 2009

Methods

Method of randomization: states randomized in sealed envelopes

Assessor blinding: states double-blind in but no further details
ITT: no details
Lost to follow-up: None

Participants

Location: a single ICU, no further details

Period of trial: October 2007 to February 2008

68 patients
Inclusion criteria: diagnosis of sepsis, age over 18 years

Exclusion criteria: chronic pro-inflammatory state, pregnant patients and patients receiving total parenteral nutrition.

Sex: 38 males, 30 females
Age: mean age 66 years

Interventions

Timing of intervention: no details

Trial intervention was for 10 days

Case: 1000 μg selenium the first day, 500 μg the second day and 200 μg/day until the end of the trial.

Control: 100 μg/day selenium up to the end of the trial

Outcomes

Length of follow-up: no details

Main outcomes:

  • SOFA score

Other outcomes:

  • APACHE score and mortality

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)Low riskSealed envelopes
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High riskStates nothing on follow-up
Selective reporting (reporting bias)High riskReports to have a follow-up period of 10 days. The average length of mechanical ventilation in the control group is set to 13 days (median) compared to 9 days (median) in the intervention group. The length of stay in hospital is stated as 17 days (median) for the control group and 12 days (median), longest range 20 days for the intervention group. It is unclear how long the patients have been followed-up
Funding bias
All outcomes
Unclear riskNone stated
Other biasHigh risk

Does not describe the time from randomization to treatment initiation.

Does not describe how many patients randomized (error in flow-chart)

Ogawa 1999

MethodsMethod of randomization: states randomized list but no further details
Assessor blinding: states double-blind but no further details
ITT: ITT for mortality only
Lost to follow-up: none
ParticipantsLocation: 28 Japanese neurosurgical and neurological units
Period of trial: recruitment June 1994 to November 1996
105 patients
Inclusion criteria: acute stroke with complete occlusion of the M1 (M2) portion of the middle cerebral artery (MCA) on cerebral angiography and no low-density area (LDA) in the MCA territory on computed tomography (CT), could start drug treatment within 12 hours of stroke
Exclusion criteria: distinct fresh LDA in the MCA territory on CT scans; stenosis or occlusion of trunk arteries, other than MCA; haemorrhagic stroke including subarachnoid haemorrhage; pregnancy; severe hepatorenal or metabolic disease
Sex: 67 males, 32 females
Age: mean age 66 years
Interventions

Timing of intervention: started within 12 hours of middle cerebral artery occlusion, given for 14 days

  1. Oral ebselen 150 mg twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness

  2. Oral placebo granules twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness

Allocated: 48/57
Assessed: 48/57 for mortality

Outcomes

Length of follow-up: 14 days

Main outcomes:

  • Mortality

  • Numbers of patients with infection

Other outcomes:

  • Quality of life - Glasgow Outcome Scale

NotesRequest for further details of denominators and infections sent 22 October 2003, but no reply received
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskPatients were randomized with the use of separate randomization lists balanced for each participating centre. No further details
Allocation concealment (selection bias)Unclear risk State, before code opening patients were assessed whether they fulfilled ex/inclusion criteria
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low risk105 patients were enrolled. Six patients were excluded from ITT analysis. Another 16 patients were excluded before protocol analysis. 83 patients were subjected to analysis
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
High riskSupported by Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan
Other biasUnclear riskNone

Saito 1998

MethodsMethod of randomization: states randomized lists but no further details
Assessor blinding: states double-blind and blinded outcome assessment
ITT: performed
Lost to follow-up: none
ParticipantsLocation: 84 Japanese neurosurgical units
Period of trial: enrolled November 1992 to April 1994
286 patients
Inclusion criteria: subarachnoid haemorrhage (SAH) from aneurysmal rupture within previous 96 hours, and SAH Hunt and Kosnik grade II to IV or World Federation of Neurosurgical Surgeons grade I to IV at admission
Exclusion criteria: pregnancy; age < 20 years or > 71 years; major cardiopulmonary, hepatorenal or metabolic disease; large intracerebral or intraventricular clots
Sex: 112 males, 174 females
Age: mean age 56 years
Interventions

Timing of intervention: started within 96 hours of subarachnoid haemorrhage, given for 14 days

  1. Oral ebselen 150 mg twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness

  2. Oral placebo granules twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness

Allocated: 145/141
Assessed: 145/141

Outcomes

Length of follow-up: 3 months

Main outcomes:

  • Mortality

  • Numbers of patients with meningitis, respiratory infection

Other outcomes:

  • Quality of life - Glasgow Outcome Scale

NotesRequest for further details of unpublished trial mentioned in main trial report, and numbers of patients with infections sent 21 October 2003, but no reply received
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates, separate balanced randomized lists for each participating centre, but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDouble-blinded
Blinding of outcome assessment (detection bias)
All outcomes
Low riskBlinded outcome assessment
Incomplete outcome data (attrition bias)
All outcomes
Low risk286 patients enrolled, all subjected to ITT analysis. 42 patients were excluded. 244 were subjected to protocol-compatible analysis
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
High riskSupported by Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Other biasUnclear riskNone

SIGNET 2011

Methods

Method of randomization: remote telephone computer system generated random allocation

Assessor blinding: states double-blinded

ITT: performed

Lost to follow-up: none for mortality and infections

ParticipantsLocation: 10 ICUs in Scotland (and associated high dependency units if also under the care of the same intensivists)
Period of trial: recruitment June 2004 to November 2008
502 patients
Inclusion criteria: expected to be on intensive care and high dependency units (levels 2 and 3 care) under the care of the ICU consultants for at least 48 hours, aged ≥ 16 years or over, require parenteral nutrition and expected to have at least half of daily nutritional requirements given by that route
Exclusion criteria: pregnant women, people whose expected stay in the UK is < six months, severe renal failure (creatinine clearance < 10 mL/min and not on renal replacement therapy)
Sex: 304 males, 198 females
Age: mean age 63.8 (SD 14.9) years
Interventions

Timing of intervention: from as soon as practicable by pharmacy, when decision made to commence parenteral nutrition for a maximum of 7 days, or until parenteral nutrition ceased

  1. 20.2 g glutamine in standard parenteral nutrition

  2. 500 mcg selenium as sodium selenite added to standard parenteral nutrition

  3. Glutamine and in standard parenteral nutrition with 500mcg selenium as sodium selenite

  4. Standard parenteral nutrition only

Volume of feed could be reduced for men < 60 kg and women < 70 kg
Allocated: 126/127/124/125
Assessed: 126/127/124/125

Outcomes

Length of follow-up: 6 months after randomization

Main outcomes:

  • Mortality

  • Number of participants with infection in first 14 days (all clinically suspected, and all Centers for Disease Control and Prevention criteria confirmed infections)

Other outcomes:

  • Length of stay in an ICU

  • Length of hospital stay

  • Quality of life after discharge

  • Adverse events

  • Economic outcomes

NotesAlison Avenell and David Noble were SIGNET trial investigators. Data was extracted by their trial co-investigators John Barr and Tom Engelhardt. Funding was provided by Fresenius-Kabi and Oxford Nutrition. The trial is registered at The ISRCTN registry and the protocol is published. Except for minor changes regard to the number of primary endpoints, there is full agreement between registrars, protocol and the results in the article.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA remote telephone computer system generated random allocation
Allocation concealment (selection bias)Low riskAdequate
Blinding of participants and personnel (performance bias)
All outcomes
Low riskPatients, clinicians and investigators were blinded to treatment allocation
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High risk1134 patients were screened for participation. 506 did not meet inclusion criteria. For 53 patients, trial parenteral nutrition was not immediately available, leaving 575 patients from whom consent was sought. 502 patients were randomized. No data on follow-up.
Selective reporting (reporting bias)Low riskNone. Full protocol and trial registration available (SIGNET 2011)
Funding bias
All outcomes
High riskFunding was provided by Fresenius-Kabi and Oxford Nutrition as unrestricted grants for the trial nutrition components
Other biasUnclear riskNone

Valenta 2011

Methods

Method of randomization: randomized according to date of birth

Assessor blinding: open label

ITT: not carried out

Lost to follow-up: none

Participants

Location: single centre, university hospital mixed ICU

Period of trial: March 2004 to April 2009

Inclusion criteria: over 18 years, admitted with systemic inflammatory response syndrome, sepsis, septic shock, SOFS score over 5

Exclusion criteria: expected hospital stay < 5 days, persistent vegetative state after hypoxic brain injury or traumatic brain injury, pregnancy, participation in another clinical trial, failure to gain consent, patient with limited care (e.g. do not resuscitate advance directive on file)

Sex: 97 males, 53 females (of 150 assessed)

Age: mean 60 years (SD 16) selenium, 60 years (SD 15) control

Interventions

Timing of intervention: day one for 5 to 14 days

  1. 1000 mcg selenium as sodium selenite in 100 mL 0.9% NaCl over 30 minutes through central venous catheter at 9am on first day, thereafter 500 mcg/day over 30 minutes

  2. No placebo

Allocated: 93/89

Assessed: 75/75

Outcomes

Length of follow-up: 28 days

Main outcome:

Mortality

NotesDr Helena Brodska gave details of randomization and control group intervention on 27 April 2011
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskRandomized according to date of birth
Allocation concealment (selection bias)High riskQuasi-randomized by hospital number
Blinding of participants and personnel (performance bias)
All outcomes
High riskOpen-label trial
Blinding of outcome assessment (detection bias)
All outcomes
High riskData on inclusion and follow-up not specified
Incomplete outcome data (attrition bias)
All outcomes
High riskNone lost to follow-up
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Unclear riskNot stated
Other biasUnclear riskNone

Yamaguchi 1998

MethodsMethod of randomization: states randomized lists but no further details
Assessor blinding: states double-blinded but no further details
ITT: not carried out
Lost to follow-up: incomplete, two patients excluded
ParticipantsLocation: 68 Japanese neurological and neurosurgical units
Period of trial: recruitment June 1994 to December 1996
302 patients
Inclusion criteria: acute ischemics stroke, including thrombosis and embolism, by symptoms and CT scan; could receive drug treatment within 48 hours of onset
Exclusion criteria: transient ischaemic attacks; pregnancy; surgery interfering with the assessment of neurological function; previous stroke with residual neurological impairment; major cardiopulmonary, hepatic, renal or metabolic disease; haemorrhagic stroke
Sex: 189 males, 111 females
Age: mean age 65 years, range 22 to 85 years
Interventions

Timing of intervention: started within 48 hours of stroke, given for 14 days

  1. Oral ebselen 150 mg twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness

  2. Oral placebo granules twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness

Allocated: 152/150
Assessed: 151/149

Outcomes

Length of follow-up: 3 months

Main outcomes:

  • Mortality

  • Numbers of patients with respiratory infection

Other outcomes:

  • Quality of life - Glasgow Outcome Scale, modified Barthel Index

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates separate randomization lists balanced for each participating centre, but no further details
Allocation concealment (selection bias)Unclear riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
Low risk302 patients were enrolled in the trial, 2 patients were excluded before ITT-analysis. 300 patients were subjected to ITT analysis, 58 more patients were excluded from PC analysis. 242 patients were subjected to protocol-compatible analysis.
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Unclear riskNot stated
Other biasUnclear riskNone

Zimmermann 1997

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: not reported
ITT: not reported
Lost to follow-up: not reported
ParticipantsLocation: university hospital, Dresden, Germany
Period of trial: before 1997
40 patients
Inclusion criteria: systemic inflammatory response syndrome and organ failure
Exclusion criteria: none given
Sex: not given
Age: not given
Interventions

Timing of intervention: start unclear, given for 28 days

  1. 1000 mcg bolus of sodium selenite, thereafter 1000 mcg/24 hours as continuous intravenous infusion, for 28 days

  2. No treatment

Allocated: 20/20
Assessed: ?20/?20

OutcomesLength of follow-up: 28 days
Main outcome:
Mortality
NotesRequest for details of denominators and infections sent 21 October 2003, but no reply received
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High riskStates randomized but no further details
Allocation concealment (selection bias)High riskNot stated
Blinding of participants and personnel (performance bias)
All outcomes
High riskNot stated
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNot stated
Incomplete outcome data (attrition bias)
All outcomes
High riskNo data on follow-up.
Selective reporting (reporting bias)High riskProtocol or trial registration not available. Protocol not registered on www.clinicaltrials.gov
Funding bias
All outcomes
Unclear riskNot stated
Other biasUnclear riskNone

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Berger 1998RCT in adults with burns; selenium part of trace element supplement evaluated, which also contained copper and zinc
Berger 2004aRCT in adults with burns; selenium part of trace element supplement evaluated, which also contained copper and zinc
Berger 2004bRCT in adults with cardiac surgery; selenium part of antioxidant supplement evaluated.
Berger 2005aCombined results of Berger 2004a and Berger 1998
Berger 2005bRCT in adults with cardiac surgery, myocardial infarction, trauma or subarachnoid haemorrhage; selenium part of antioxidant supplement evaluated.
Berger 2008Selenium part of trace element supplement evaluated
Börner 1997Not a RCT, not adults
Collier 2008Selenium part of trace element supplement evaluated
Kiessling 2006Trial terminated without publishing data
Porter 1999RCT of antioxidant therapy (including selenium) versus placebo in trauma patients
REDOXS 2011Factorial RCT of parenteral and enteral glutamine, and antioxidants (parenterally as selenium 500 µg, and enteral selenium 300 µg, beta carotene 10 mg, vitamin E 500 mg, and vitamin C 1500 mg)
Stoppe 2010Not a RCT, no outcomes relevant
Thiele 1997Not a RCT, not critical care
Uden 1990Randomized, crossover trial of antioxidant therapy (including selenium) versus placebo in the prevention of recurrence of pancreatitis
Watters 2002RCT of micronutrients (including selenium) versus placebo in patients undergoing elective aneurysmectomy
Wollschläger 1997Not a RCT, selenium supplementation in acute pancreatitis

Characteristics of studies awaiting assessment [ordered by study ID]

Geoghegan 2009

MethodsRCT
ParticipantsPatients with subarachnoid haemorrhage (grade 2 to 5)
Interventions1000 mcg/d versus 500 mcg/d versus no sodium selenite intravenously, on ICU to maximum of 14 days
Outcomes28 day mortality, APACHE II and SOFA scores
NotesWe emailed author (m.geoghegan@qmul.ac.uk and pgsmd@qmul.ac.uk) on 21 October 2014 but received no answer

Yamaguchi 2003

MethodsRandomized, placebo-controlled trial
Participants394 patients with acute non-lacunar stroke (cardio-embolic or atherothrombotic infarction < 24 hours)
InterventionsEbselen 150 mg twice daily or placebo started within 24 hours of onset for 14 days
OutcomesGlasgow Outcome Scale three months post stroke, National Institute of Health Stroke Scale and Barthel Index scores at one and three months
NotesWe emailed the author (tyamaguchi-rtec@umin.ac.jp) on 21 October 2014 but did not receive an answer.

Characteristics of ongoing studies [ordered by study ID]

SEREAL 2012

Trial name or titleSelenium Replacement and Serum Selenium Level in Severe Sepsis and Septic Shock Patients
MethodsRCT
ParticipantsNot yet recruiting
Interventions

Selenium: 500 mcg (10 mL) mixed to 230 mL of normal saline will be infused continuously per day (10 mL/hour). Study drugs will be infused for 7 days.

Placebo: 10 mL mixed with 230 mL of normal saline will be infused continuously per day (10 mL/hour). Study drugs will be infused for 7 days.

Outcomes

Primary outcomes:

  • 28-day mortality

Secondary outcomes:

  • ICU length of stay

  • Mortality at hospital discharge,

  • Development of the new infection

  • Ventilator days

  • Renal replacement therapy days

  • Oxidative stress marker

  • Changes in severity scores

  • 3-month mortality

  • Vasopressor days

Starting dateSeptember 2012
Contact informationProfessor Gil Joon Suh, suhgil@snu.ac.kr
NotesStatus of the trial has not been verified in more than two years after the expected end date on clinicaltrials.gov. We emailed author (suhgil@snu.ac.kr) on 21 October 2014 but received no answer.

SISPCT

Trial name or title SISPCT
MethodsRCT
Participants1180 adult participants with severe sepsis or septic shock
InterventionsFactorial designed, randomized trial of placebo-controlled selenium (bolus 2000 mcg, then 1000 mcg daily as 24-hour infusion for up to 21 days) and procalcitonin guided antibiotic therapy
Outcomes

Primary outcome:

  • 28 days all-cause mortality

Secondary outcomes:

  • Mean total SOFA ( Sequential Organ Failure Assessment)-score, and SOFA subscores

  • 90 days all-cause mortality

  • Frequency and duration of mechanical ventilation until day 90

  • Frequency and duration of renal replacement therapy until day 90

  • Frequency and duration of vasopressor support until day 90

  • Frequencies of adverse and severe adverse events

  • Clinical cure and microbiological cure on day 4, 7, 10, and 14 (*)

  • Duration of antibiotic therapy (*)

  • Costs of antibiotic therapy (*)

  • Duration until change of antibiotic therapy (*)

  • Antibiotic exposure days (*)

  • Days alive without antibiotics (*)

  • Frequency of antibiotic resistance (*)

  • ICU length of stay until day 90

  • Hospital length of stay until day 90

  • Number of surgical procedures for source control (*)

  • Number of diagnostic procedures for searching the focus of infection (*)

(*) Endpoints are for the procalcitonin intervention only

Starting date2009
Contact informationWe obtained information from Frank Bloos via Frank.Bloos@med.uni-jena.de on21 October 2014, the same day we emailed him. The trial group is currently writing the manuscript for publication and does not want to reveal data at this time. Publication is estimated to in 2015.
Notes 

Ancillary