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Selenium supplementation for critically ill adults

  1. Alison Avenell1,*,
  2. David W Noble2,
  3. John Barr3,
  4. Thomas Engelhardt3

Editorial Group: Cochrane Anaesthesia Group

Published Online: 18 OCT 2004

Assessed as up-to-date: 16 AUG 2007

DOI: 10.1002/14651858.CD003703.pub2


How to Cite

Avenell A, Noble DW, Barr J, Engelhardt T. Selenium supplementation for critically ill adults. Cochrane Database of Systematic Reviews 2004, Issue 4. Art. No.: CD003703. DOI: 10.1002/14651858.CD003703.pub2.

Author Information

  1. 1

    University of Aberdeen, Health Services Research Unit, Aberdeen, UK

  2. 2

    Aberdeen Royal Infirmary, Intensive Care Unit and Department of Anaesthesia, Aberdeen, Scotland, UK

  3. 3

    Aberdeen Royal Infirmary, Department of Anaesthesia and Intensive Care, Aberdeen, Scotland, UK

*Alison Avenell, Health Services Research Unit, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK. a.avenell@abdn.ac.uk.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 18 OCT 2004

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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: carried out
Lost to follow up: none


ParticipantsLocation: intensive care unit, Klinikum Innenstadt, University of Munich, Germany
Period of study: recruitment March 1995 to August 1996
42 patients
Inclusion criteria: APACHE score greater or equal to 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)


InterventionsTiming of intervention: from day of admission to intensive care for additional supplementation for nine days
a: 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
b: 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


OutcomesLength 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 24th October 2003, reply received 17th November 2003.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Angstwurm 2007

MethodsMethod of randomisation: states randomised but no further details
Assessor blinding: carried out
Intention to treat: not carried out
Lost to follow up: reported


ParticipantsLocation: 11 independent German intensive care units
Period of study: 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 h or platelets < 150 000/µl at admission; admission into the study after diagnosis within 24 h; beginning of treatment within 1h after inclusion.
Exclusion criteria: pregnancy; missing informed consent of patient or relative/intimate friend; withdrawal of informed consent after inclusion into study; 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)


InterventionsTiming of intervention: admission into study after diagnosis within 24 hours, study treatment beginning within 1 hour after inclusion
a: 48 ml vial as bolus intravenous injection over 30 minutes of sodium selenite providing 1000 mcg selenium, 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.
b: Matching placebo of 0.9% sodium chloride give as same regimen. Allowed selenium from other preparations of up to 100 mcg/day.
Allocated: ???/???
Assessed: 116/122


OutcomesLength of follow up: 28 days
Main outcomes:
28 day mortality
Participants with new infections
Other outcomes:
Number of hours on a ventilator
Length of ICU stay
Participants with adverse events


NotesEmailed 8th August 2006 asking for further details on participants with all infections, length of ventilation, total numbers randomised to each group, and further details of the randomisation process.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Berger 2001

MethodsMethod of randomization: concealed
Assessor blinding: states double-blind but no further details
Intention to treat: carried out
Lost to follow up: none


ParticipantsLocation: surgical intensive care unit (ICU) of the Central Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Period of study: 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


InterventionsTiming of intervention: from day of admission for five days
a: slow intravenous infusion over 24 hours of 500 mcg selenium as sodium selenite/day
b: infusion vehicle over 24 hours
c: 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


OutcomesLength 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 intensive care unit stay
Length of hospital stay


NotesIntention to treat data taken from paper in Nutrition Research.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?YesA - Adequate

Kuklinski 1991

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: not reported
Intention to treat: carried out
Lost to follow up: none


ParticipantsLocation: hospital, Rostock, Germany
Period of study: before 1991
17 patients
Inclusion criteria: contrast CT scan showed pancreatic necrosis, less than 72 hours since onset of pancreatitis
Exclusion criteria: mild pancreatitis
Sex: all male
Age: range 28 - 65 years


InterventionsTiming of intervention: unclear ?8 days
a: intravenous 500 mcg sodium selenite daily duration unclear (Selenase pro injectione, GN PHARM, Arzneimittel GmbH, Stuttgart)
b: no treatment
Allocated: 8/9
Assessed: 8/9


OutcomesLength of follow up:
Main outcome:
Mortality


NotesRequest for further details on dose of selenium given sent 20th October 2003. Letter returned as author no longer at address in publication.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Lindner 2004

MethodsMethod of randomisation: states randomised but no further details
Assessor blinding: not reported
Intention to treat: not reported
Lost to follow up: details provided


ParticipantsLocation: medical centre, Chemnitz, Germany
Period of study: 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 50-52 years


InterventionsTiming of intervention: start unclear, given until discharged
a: day 1 2000 mcg selenium as sodium selenite, days 2-5 1000 mcg/d, day 6 until discharged 300 mcg/d
b: 0.9% sodium chloride placebo,
Allocated: 35/35
Assessed: 32/35


OutcomesLength of follow up: until discharge
Main outcomes:
Mortality
Number of patients with infectious complications (sepsis)


Notes


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Mishra 2007

MethodsMethod of randomisation: states randomised but no further details
Assessor blinding: states double-blind
Intention to treat: not reported
Lost to follow up: no details provided


ParticipantsLocation: intensive care unit, Liverpool, UK
Period of study: before 2005
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


InterventionsTiming of intervention: within 24 hours of admission to intensive care and within 72 hours since diagnosis of sepsis, given until discharged
a: intravenous selenium 470 mcg/d for 3 days, then 320 mcg/d for 3 days, then 160 mcg/d for 3 days, and 30 mcg/d thereafter
b: 30 mcg/d
Allocated: 18/22
Assessed: 18/22 for mortality


OutcomesLength of follow up: 28 days
Main outcomes:
Mortality at 28 days
Infections
Other outcomes:
Length of intensive care unit stay
Renal replacement therapy


Notes


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Ogawa 1999

MethodsMethod of randomization: states randomized list but no further details
Assessor blinding: states double-blind but no further details
Intention to treat: ITT for mortality only
Lost to follow up: none


ParticipantsLocation: 28 Japanese neurosurgical and neurological units
Period of study: 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


InterventionsTiming of intervention: started within 12 hours of middle cerebral artery occlusion, given for 14 days
a: oral ebselen 150 mg twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness
b: 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


OutcomesLength of follow up:
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 October 22nd 2003, no reply received.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Saito 1998

MethodsMethod of randomization: states randomized lists but no further details
Assessor blinding: states double-blind and blinded outcome assessment
Intention to treat: carried out
Lost to follow up: none


ParticipantsLocation: 84 Japanese neurosurgical units
Period of study: 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


InterventionsTiming of intervention: started within 96 hours of subarachnoid haemorrhage, given for 14 days
a: oral ebselen 150 mg twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness
b: oral placebo granules twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness
Allocated: 145/141
Assessed: 145/141


OutcomesLength 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 21st October 2003, no reply received.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Yamaguchi 1998

MethodsMethod of randomization: states randomized lists but no further details
Assessor blinding: states double-blind but no further details
Intention to treat: not carried out
Lost to follow up: not complete, two patients excluded


ParticipantsLocation: 68 Japanese neurological and neurosurgical units
Period of study: recruitment June 1994 to December 1996
302 patients
Inclusion criteria: acute ischaemic 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


InterventionsTiming of intervention: started within 48 hours of stroke, given for 14 days
a: oral ebselen 150 mg twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness
b: oral placebo granules twice daily given enterally as fine granules dispersed in water, gastric tube if disturbed consciousness
Allocated: 152/150
Assessed: 151/149


OutcomesLength 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

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

Zimmermann 1997

MethodsMethod of randomization: states randomized but no further details
Assessor blinding: not reported
Intention to treat: not reported
Lost to follow up: not reported


ParticipantsLocation: university hospital, Dresden, Germany
Period of study: before 1997
40 patients
Inclusion criteria: systemic inflammatory response syndrome and organ failure
Exclusion criteria: none given
Sex: not given
Age: not given


InterventionsTiming of intervention: start unclear, given for 28 days
a: 1000 mcg bolus of sodium selenite, thereafter 1000 mcg/24 hours as continuous intravenous infusion, for 28 days
b: 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 21st October 2003, no reply received.


Risk of bias

ItemAuthors' judgementDescription

Allocation concealment?UnclearB - Unclear

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Berger 1998Randomized trial in adults with burns; selenium part of trace element supplement evaluated, which also contained copper and zinc

Berger 2004aRandomized trial in adults with burns; selenium part of trace element supplement evaluated, which also contained copper and zinc

Berger 2004bRandomized trial in adults with cardiac surgery; selenium part of antioxidant supplement evaluated.

Berger 2005aCombined results of Berger 2004 and Berger 1998

Berger 2005bRandomized trial in adults with cardiac surgery, myocardial infarction, trauma or subarachnoid haemorrhage; selenium part of antioxidant supplement evaluated.

Börner 1997Not randomized trial, not adults

Porter 1999Randomized trial of antioxidant therapy (including selenium) versus placebo in trauma patients

Thiele 1997Not randomized trial, not critical care

Uden 1990Randomized, crossover trial of antioxidant therapy (including selenium) versus placebo in the prevention of recurrence of pancreatitis

Watters 2002Randomized trial of micronutrients (including selenium) versus placebo in patients undergoing elective aneurysmectomy

Wollschläger 1997Not randomized trial, selenium supplementation in acute pancreatitis

 
Characteristics of ongoing studies [ordered by study ID]
Andrews 2004

Trial name or titleSIGNET trial (Scottish multicentre trial of glutamine and selenium supplemented parenteral nutrition for critically ill patients)

Methods

Participants500 patients, on intensive care units, requiring at least half nutritional requirements by parenteral route, aged 16 years and over

InterventionsFactorial design with glutamine containing versus non-glutamine containing parenteral nutrition for 7 days, with or without 500 mcg/d selenium as sodium selenite for 7 days

OutcomesParticipants with new infections, length of stay in intensive care, mortality, infections, days of antibiotic use, duration of parenteral nutrition, alive ventilator-free days, acute hospital length of stay, quality of life, economic evaluation

Starting dateJune 2004, recruitment due to finish August 2008

Contact informationDr Peter Andrews; Anaesthetics, Intensive Care and Pain Medicine; University of Edinburgh, Western General Hospital, Crewe Road, Edinburgh, EH24 2XU, UK

Notes

Yamaguchi 2003

Trial name or titleForty centre, double-blind, placebo-controlled trial

Methods

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

Starting dateMarch 2000, recruitment finished September 2002

Contact informationTakanori Yamaguchi, for the Ebselen Study Group, National Cardiovascular Center, Osaka, Japan

NotesLetter requesting further details sent 20th October 2003. Reply received 3rd November 2003, giving further details of inclusion criteria and trial intervention from Dr T Motohashi, Daiichi Pharmaceutical Co Ltd. Email sent to Dr Motohashi requesting results of trial 12th June 2006, reply received 19th June 2006 stating that publication is still planned.

 
Comparison 1. Selenium versus no selenium

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Mortality by duration (sodium selenite)7476Risk Ratio (M-H, Random, 95% CI)0.75 [0.53, 1.06]

    1.1 Selenium 28 day
5364Risk Ratio (M-H, Random, 95% CI)0.71 [0.43, 1.17]

    1.2 Selenium 90 day
2112Risk Ratio (M-H, Random, 95% CI)0.87 [0.35, 2.14]

 2 Selenium mortality ICU and pancreatitis (sodium selenite)7476Risk Ratio (M-H, Random, 95% CI)0.75 [0.53, 1.06]

    2.1 General intensive care patients
5389Risk Ratio (M-H, Random, 95% CI)0.75 [0.59, 0.96]

    2.2 Acute pancreatitis
287Risk Ratio (M-H, Random, 95% CI)0.40 [0.01, 12.30]

 3 Mortality by duration (ebselen)3693Risk Ratio (M-H, Random, 95% CI)0.83 [0.51, 1.35]

    3.1 Ebselen 30 day
1105Risk Ratio (M-H, Random, 95% CI)1.78 [0.53, 5.95]

    3.2 Ebselen 3 month
2588Risk Ratio (M-H, Random, 95% CI)0.72 [0.42, 1.22]

 
Comparison 2. Selenium versus no selenium

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of infected participants6Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Selenium
3337Risk Ratio (M-H, Random, 95% CI)1.22 [0.67, 2.23]

    1.2 Ebselen
3685Risk Ratio (M-H, Random, 95% CI)0.60 [0.36, 1.02]

 
Comparison 3. Selenium versus no selenium

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Number of participants with adverse event5Risk Ratio (M-H, Random, 95% CI)Subtotals only

    1.1 Selenium
3328Risk Ratio (M-H, Random, 95% CI)0.75 [0.40, 1.43]

    1.2 Ebselen
2588Risk Ratio (M-H, Random, 95% CI)1.16 [0.40, 3.36]