Use of selenium in intensive care as adjunctive …...Use of selenium in intensive care as adjunctive therapy for sepsis, ischaemia/reperfusion and reanimation selenase® • improves

Use of selenium in intensive care as adjunctive therapy for sepsis, ischaemia/reperfusion and reanimation

selenase®

• improves selenium status

• eliminatesseleniumdeficiency

• reduces mortality

we are research

High dose for sepsis – so that selenium works

Day 1

Treatment ideally beginswithin 6 hours after admission to the ICU

as bolus 2,0001–3 µg Se

then as continuous infusion

1,6001–3 µg Se

at least 7 days

maintenance therapy

1,6001–3 µg Se / Day

Literature1 Manzanares W et al. 2012, Crit Care; 16:R662 Huang TS et al. 2013, PLoS One 8:e544313 Alhazzani W et al. 2013, Crit Care Med 41:1555–1564

selenase® for sepsis• Ahighdoseseleniumbolussignificantlyreducesthedeathrateforsepsispatients

by 27%. [1]

• Ahighdoseof≥1,000μgseleniumassodiumselenitepentahydrate(selenase®) perdaysignificantlyreducesthemortalityby23%.[1]

• Amaintenancetherapyof≥7dayssignificantlyimprovessurvival.[1]

[1]HuangTS,ShyuYC,ChenHY,LinLM,LoCY,YuanSS,ChenPJ.PLoSOne.2013;8(1):e54431.doi:10.1371/journal.pone.0054431 Effect of parenteral selenium supplementation in critically ill patients: a systematic review and meta-analy-sis. http://www.ncbi.nlm.nih.gov/pubmed/23372722

Summary2

http://www.ncbi.nlm.nih.gov/pubmed/22534505




selenase® for cardiac surgery

1 week before

Elective cardiac surgery 5001 µg Se / day oral

Day 1

Bolus ideally within 30 minutes after administration of anaesthesia; termination of the bolus before initiation of the cardiopulmonary bypass

Intraoperative as bolus (forabout30min.)

2,0001,2 µg Se

Bolus directly after admission to ICU

2,0001,2 µg Se

From day 2 of the

ICU staymaintenance therapy 1,0001,2 µg Se / day

Literature 1 Stoppe C et al 2013, Nutrition 29:1, 158–1652 Stoppe C et al 2014, Trials 15:339

selenase® for cardiac surgery• The selenium status correlates with the extent of cardiac damage [1]

• An intraoperative decrease of selenium is associated with the postoperative development of multi-organ failure [2]

• The postoperative decrease of selenium concentration is not attributed to the use of a heart-lung machine [3]

• Perioperative administration of selenase® prevents the strong postoperative decrease of selenium concentration [4]

[1]AltekinE,CokerC,SişmanAR,OnvuralB,KuralayF,KirimliO.JTraceElemMedBiol.2005;18(3):235-42.Therelation ship between trace elements and cardiac markers in acute coronary syndromes. http://www.ncbi.nlm.nih.gov/pubmed/15966572

[2]StoppeC,SchälteG,RossaintR,CoburnM,GrafB,SpillnerJ,MarxG,RexS.CritCareMed.2011Aug;39(8):1879-85. doi: 10.1097/CCM.0b013e3182190d48. The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients. http://www.ncbi.nlm.nih.gov/pubmed/21460705

[3]StevanovicA,CoburnM,MenonA,RossaintR,HeylandD,SchälteG,WerkerT,WonischW,KiehntopfM,Goetze-nichA,RexS,StoppeC.PLoSOne.2014Aug13;9(8):e104222.doi:10.1371/journal.pone.0104222.Theimportanceofintraoperative selenium blood levels on organ dysfunction in patients undergoing off-pump cardiac surgery: a randomised controlled trial. http://www.ncbi.nlm.nih.gov/pubmed/25118980

[4]StoppeC,SpillnerJ,RossaintR,CoburnM,SchälteG,WildenhuesA,MarxG,RexS.Nutrition.2013Jan;29(1):158-65. doi: 10.1016/j.nut.2012.05.013. Selenium blood concentrations in patients undergoing elective cardiac surgery and receiving perioperative sodium selenite. http://www.ncbi.nlm.nih.gov/pubmed/23010420

Summary 3







[1]ZimmermannC,WinnefeldK,StreckS,RoskosM,HaberlRL.EurNeurol.2004;51(3):157-61.Antioxidantstatusinacute stroke patients and patients at stroke risk. http://www.ncbi.nlm.nih.gov/pubmed/15073440

[2]KoyamaH,AbdulahR,OhkuboT,ImaiY,SatohH,NagaiK.NutrRes.2009Feb;29(2):94-9.doi:10.1016/j.nut-res.2009.01.002. Depressed serum selenoprotein P: possible new predicator of increased risk for cerebrovascular events. http://www.ncbi.nlm.nih.gov/pubmed/19285599

Sodium selenite for stroke

Day 1



1,0001 µg Se


5001 µg Se

From day 2 of the

ICU staymaintenance therapy 5001 µg Se / day

Literature 1 Reisinger J et al. 2009, Am J Emerg Med 27: 176–181

Sodium selenite for stroke• Strokepatientsshowsignificantlyreducedseleniumvalues[1]

• High glutathione peroxidase concentration correlates with low neurological deficiencyandapositiveoutcomeafterastroke[1]

• SignificantlyreducedSelenoproteinPconcentrationinpatientsafter an acute stroke [2]

• ReducedSelenoproteinPstatusisassociatedwithasignificantlyhigherrisk for stroke [2]

By now a randomized, double-blinded, placebo controlled trial with the title „Selenium and ische-micstrokeoutcome“(NCT02505295)isunderway, which investigates, if 2,000 µg selenium

in form of selenase® directly after patient admis-sionplus1,000µgseleniumperday(selenase®) forfivedaysreducesmortalityandneurologicaldamage.

Summary4




Sodium selenite for burnsSodium selenite: • reduces the number of infections [2]

• improves wound healing [3, 4]

• shortens the antibiotic treatment [2]

• shortens the hospital stay [1, 2]

[1]BergerMM,SpertiniF,ShenkinA,WardleC,WiesnerL,SchindlerC,ChioleroRL.AmJClinNutr.1998Aug;68(2):365-71. Trace element supplementation modulates pulmonary infection rates after major burns: a double-blind, placebo-cont-rolled trial. http://www.ncbi.nlm.nih.gov/pubmed/9701195

[2]BergerMM,EggimannP,HeylandDK,ChioléroRL,RevellyJP,DayA,RaffoulW,ShenkinA.CritCare.2006;10(6):R153.Reductionofnosocomialpneumoniaaftermajorburnsbytraceelementsupplementation:aggregationof two randomised trials. http://www.ncbi.nlm.nih.gov/pubmed/17081282

[3]BergerMM,BainesM,RaffoulW,BenathanM,ChioleroRL,ReevesC,RevellyJP,CayeuxMC,SénéchaudI,Shen-kinA.AmJClinNutr.2007May;85(5):1293-300.Traceelementsupplementationaftermajorburnsmodulatesantioxidantstatus and clinical course by way of increased tissue trace element concentrations. http://www.ncbi.nlm.nih.gov/pubmed/17490965

[4] Berger MM, Binnert C, Chiolero RL, Taylor W, Raffoul W, Cayeux MC, Benathan M, Shenkin A, Tappy L. Am J Clin Nutr. 2007May;85(5):1301-6.Traceelementsupplementationaftermajorburnsincreasesburnedskintraceelementconcentra-tions and modulates local protein metabolism but not whole-body substrate metabolism. http://www.ncbi.nlm.nih.gov/pubmed/17490966

Sodium selenite for burns

Day 1



5001–3 µg Se

14 days for burns < 60% of the body surface

21 days for burns ≥60%ofthe body surface

maintenance therapy 5001–3 µg Se / day

Literature1 Berger MM et al 2006, Crit Care 10:6, R1532 Berger MM et al 2007, Am J Clin Nutr 85:5, 1293–13003 Berger MM et al 2007, Am J Clin Nutr 85:5, 1301–1306

Summary 5








selenase® after reanimation• Low selenium status in the post-reanimation phase [1]

• Length of reanimation correlates negatively with the selenium level [2]

• Early administration of selenase® improves the neurological outcome of patients after cardiac arrest [3]

[1]FinkK,MoebesM,VetterC,BourgeoisN,SchmidB,BodeC,HelbingT,BuschHJ.CritCare.2015Feb26;19(1):58.Seleniumpreventsmicroparticle-inducedendothelialinflammationinpatientsaftercardiopulmonaryresuscitation. http://www.ncbi.nlm.nih.gov/pubmed/25886988

[2] Busch HJ: Neue klinische Daten bei reanimierten Patienten. Satelliten-Symposium „Selen - neue Therapieoption zur ReduktionvonReperfusionsschäden.20.SymposiumIntensivmedizin+Intensivpflege17.-19.Februar2010,Bremen.

[3]ReisingerJ,HöllingerK,LangW,SteinerC,WinterT,WinterA,MoriM,LindorferA,KiblböckD,SiostrzonekP.AmJEmergMed.2009Feb;27(2):176-81.doi:10.1016/j.ajem.2008.01.020.Doesearlyadministrationofseleniumimproveneurological outcome after cardiac arrest? http://www.ncbi.nlm.nih.gov/pubmed/19371525

selenase® after reanimation

Day 1The beginning of treatment directly after reanimation or ICU admission

as continuous infusion 1,0001 µg Se

Day 2 – 5 maintenance therapy 1,0001 µg Se / day

Literature 1 Reisinger J et al. 2009, Am J Emerg Med 27: 176–181

Summary6




Miscibility

Yes No

• 5% glucose solution

• Ringer solution

• Carbohydrate solutions (stability72hours(3days))

• Colloidal volume expander solutions (stability72hours(3days))

• Electrolyte solutions with increased potassiumconcentration(stability 48hours(2days))

• Crystalloid electrolyte solutions (stability48hours(2days))

• Amino acid solutions without cysteine (stability36hours(1.5days))

• Fat emulsions (stability24hours(1day))

• Vitaminsolutions(withoutvitaminC)

• Cytostatic agent solutions [1]

• Amino acid solutions that contain cysteine [2]

• Solutions thatcontainglutathione(GSH)[3]

• Vitaminsolutions that contain vitamin C [4]

[1] selenase® should generally be administered 1 hour before cytostatic agent application for timely incorporation in the endogenous protective systems.

[2,3] SH groups react with Na-selenite; Na-selenite can no longer satisfy its task as a radical scavenger

[4]Selenium(Se+IV) in sodium selenite is reduced by vitaminCtotheelementaryselenium(Se0) and is thereby ineffective.

Literature: RobinsonMF,ThomsonCD,HuemmerPK.NZMedJ.1985Aug14;98(784):627-9.Effectofamegadoseof ascorbic acid, a meal and orange juice on the absorption of selenium as sodium selenite. http://www.ncbi.nlm.nih.gov/pubmed/3861972

IpC.JNatlCancerInst.1986Jul;77(1):299-303.InteractionofvitaminCandseleniumsupplementationinthemodifica-tion of mammary carcinogenesis in rats. http://www.ncbi.nlm.nih.gov/pubmed/3088312

Summary 7



Products for injection therapy

Prescription only

selenase® 100 µg pro injectione

selenase® T pro injectione

100 µg Selenium / ampoule

500 µg Selenium / injection vial

10(N2)and50ampoules with 2 ml solution for injection

2,10(N2),30(3×10)and50 (5×10)glassvialswith10mlsolution for injection

selenase® 100 µg / T: Active substance: Sodium selenite pentahydrate, 50 µg selenium per ml. Indications: Clinically proven selenium deficiency that cannot be compensated by nutritional sour-ces. Selenium deficiencies may occur as a result of states of maldigestion and malabsorption, as well as in malnutrition (e.g. due to complete parenteral nutrition). Composition: selenase® 100 µg

pro injectione: 1 ampoule of 2 ml solution for injection contains: 0.333 mg sodium selenite pentahydrate, corresponding to 100 µg (micrograms) selenium. selenase® T pro injectione: 1 injection vial of 10 ml / 20 ml solution for injection contains: 1.67 mg / 3.33 mg sodium selenite pentahydrate, corresponding to 500 µg / 1000 µg selenium. selenase® 100 µg peroral: 1 drinking ampoule of 2 ml oral solution contains: 0.333 mg sodium selenite pentahydrate, corresponding to 100 µg selenium. selenase® T peroral: 1 ml oral solution contains: 0.167 mg sodium selenite pentahydrate, corresponding to 50 µg selenium. Excipients: Sodium chloride, hydrochloric acid, water for injections. Contra-indications: Selenium poisoning. Undesirable effects: None known to date if the medicinal product is administered according to prescription. selenase® 100 µg / T pro injectione: General disorders and administration site conditions: Frequency not known (cannot be estimated from the available data): After intramuscular administration local pain at the site of administration has been reported. Form of administration, size of packages: selenase® 100 µg pro

injectione: 10 or 50 ampoules of 2 ml solution for injection. selenase® T pro injectione: 2 or 10 injection vials of 10 ml solution for injection, hospital-size pack 30 (3 x 10) or 50 (5 x 10) injection vials of 10 ml solution for injection, 2 or 10 injection vials of 20 ml solution for injection, hospital-size pack 30 (3 x 10) or 50 (5 x 10) injection vials of 20 ml solution for injection. selenase® 100 µg

peroral: 20, 60, 90 or 100 ampoules of 2 ml oral solution. selenase® T peroral: 10 drinking bottles of 10 ml oral solution plus one measuring cup. 10/14 e

16 General facts about sepsis

16 Sepsis: Incidence

18 The problem: Diagnosis

18 The problem: Costs

20 Details on sepsis

20 Sepsis in Europe

22 MajorinfluenceoforganfailureonICUmortalityrates

24 ICUmortalityratesignificantlyhigherinsepsispatients

26 Postoperative sepsis

28 Selenium and sepsis

29 Selenium level declines in correlation to sepsis severity

30 Selenium concentration is inversely correlated with APACHE II and SAPS II scores

31 Minimum selenium concentration: independent predictor of ICU mortality

32 Where does selenium intervene in the process of sepsis?

34 Which effect does ROS production have on survival?

34 Why does the selenium status decline in patients with sepsis?

36 Whyisearlyadministrationofsodiumselenitecrucial(within≤6hours)?

38 Why inject sodium selenite as bolus?

40 selenase® for sepsis

42 Meta analysis of 9 sepsis trials

50 Pilot study

54 SICtrial(SeleniuminIntensiveCare)

60 Varioustrials

76 Overview of trials

80 General facts about ischaemia/reperfusion

80 Tissue damage with ischaemia/reperfusion

82 Important role of ROS with I/R

84 Challenges posed by complications in cardiac surgery

84 Increased severe complications in cardiac surgery

9Content

88 Selenium in the cardiovascular system

89 Selenoproteinsinfluencethecardiovascularsystem

90 Cardio-protective effect of selenium

91 Seleniumdeficitincreasestheriskofcardiovasculardiseases

92 ConnectionofseleniumwithKeshandiseaseandinfectiousmyocarditis

93 Selenium concentration: prognostic marker for acute coronary syndrome

94 Positive effect of a selenium supplementation for existing cardiovascular diseases

96 Selenium supplementation decreases cardiovascular mortality of elderly people

96 Selenium reduces cardiotoxicity of doxorubicin

98 selenase® for cardiac surgery

98 Selenium status correlates with the extent of cardiac damage

100 Sodium selenite protects from I/R damage

102Intraoperative decrease of selenium correlates with the postoperative development of multiorgan failure

103The postoperative decrease of selenium concentration is not attributed to the use of a heart-lung machine

104Perioperative administration of selenase® prevents postoperative decrease of selenium concentration

108 Selenium in the brain108 Selenium is essential for the brain

110 Glutathioneperoxidase1influencestheinfarctvolumes

112Glutathione peroxidase 4: essential for brain development and neuropathological diseases

114 Selenoprotein P knock-out causes severe neurological dysfunction

116 Sodium selenite for stroke

116 Sodium selenite acts neuroprotectively even hours after induction of the damage

120Seleniumdeficitmassivelyincreasessusceptibilitytoexcitotoxicity and increased neuronal cell loss

122 Principle of action of neuronal protection by sodium selenite

129 Impactofaseleniumdeficitonthebrainaffectedbystroke

10 Content

130 Selenium status and selenoprotein activity in the event of a stroke

130 Strokepatientsshowsiginficantlydecreasedseleniumvalues

132Correlationbetweenglutathionperoxidaseconcentration,neurologicaldeficit, and outcome

134 SignificantlyreducedSelenoproteinPconcentrationinpatientswithanacutestroke

136 Sodium selenite for burns

136 Significantlyreducedseleniumlevelsinburnvictims

136 No decline of selenium values with selenium supplementation

138 Significantlydecreasednumberofinfectionswithseleniumsupplementation

140 Improved wound healing with selenium supplementation

142 Selenium supplementation shortens hospital stay

144 selenase® after reanimation

144 Low selenium status in the post-reanimation phase

146 Significantlylowerseleniumlevelinnon-survivorsaftersuccessfulreanimation

147 Length of reanimation correlates negatively with the selenium level

148 Negative correlation between neurological damage and selenium concentration

150 Selenium protects the brain after cardiopulmonary reanimation

152 Additional information

152 Selenium in guidelines

154 biosyn Arzneimittel GmbH

11Content

Sepsis

General Germany registers over 175,000 sepsis patients each year

Despite medical progress in general, these numbers keep rising

Diagnosisisencumberedbynon-specificsymptomsandalackofgenerallyvalid biomarkers

Exorbitant costs for treating sepsis patients

Details on sepsis

Correlation between ICU mortality and sepsis incidence in Europe

Organ failure strongly affects ICU mortality rate

Thenumberoffailedorgansincreasessignificantlyinseveresepsis

Increasing number of postoperative sepsis cases

Selenium and sepsis

Selenium level declines in correlation with sepsis severity

Selenium concentration is inversely correlated with APACHE II and SAPS II scores

Minimum selenium concentration is an independent predictor of ICU mortality

Cut-off value of 36 µg/l selenium in serum for sepsis patients

Early(≤6hours)administrationofselenase® is crucial

Abolusadministrationreversesthepro-inflammatorystateviaanearly,transient, pro-oxidative effect of high-dose sodium selenite

Summary

Summary12

selenase® for sepsis

Meta analysis Parenteralsodiumselenitetreatmentsignificantlyreducestotalmortalityrateby17%(p=0.04)

Highersignificantreductionofmortalitywhenabolusisadministered (−27%;p=0.01),amaintenancetherapy≥7days(−23%;p=0.01) andadosingof≥1,000µgseleniumassodiumselenite-pentahydrate(selenase®)perday(−23%;p=0.04)

Pilot study Supplementation with selenase® increases the selenium level to values within the normal range

selenase®supplementationsignificantlyreducesmortality in patients with APACHE III score > 53

SIC trial Significantreductioninmortalityintheselenase®-supplemented groupby14.3%(p=0.049)

Significantreductioninmortalityinthesubgroups(septicshock,APACHEIII≥102,>3organfailure)intheselenase®-supplemented group by up to 26%

Varioustrials Possible correlation between selenium supplementation and procalcitonin

Supplementation with high-dose sodium selenite reduces the incidence of nosocomial pneumonia and improves sepsis severity

SIGNET trial: Fewer new infections in patients receiving selenase® supplementation for > 5 days

REDOXS trial: Compared to glutamine, selenium does not have any negati-veeffectonmortality,althoughthebeneficialeffectofseleniumsupplemen-tationisreducedbythelackofseleniumdeficiency

Significantlymorecriticallyillpatientsintheinterventiongroupimpacted the analysis of the retrospective trial on selenium supplementation in patients with severe sepsis

Summary 13

Ischaemia/reperfusion

General information

Ischaemiaandreperfusion(I/R)causetissuedamage

Reactive oxygen species play an important role in I/R

Challenges posed by complications in cardiac surgery

Severe complications in cardiac surgery despite great advancements present a major problem

Affect up to 16% of patients

Three pathophysiological mechanisms are responsible: ischaemia, reperfusionandperioperativeinflammation

Selenium supplementation intervenes at the same site of action as established pharmacological strategies

Selenium in the cardiovascular system

Selenoproteins play a large role in the cardiovascular system

50% increase in the selenium concentration is associated with a 24% risk reduction of coronary heart disease

Least risk of a cardiovascular disease by 150 – 160 µg/l selenium in serum

AseleniumdeficiencynegativelyinfluencesKeshandisease and infectious myocarditis

Positive effect of selenium supplementation on existing cardiovascular diseases

Selenium reduces the cardiotoxicity of doxorubicin


Selenium status correlates with the extent of cardiac damage

Sodium selenite protects from I/R damage

The intraoperative decline of selenium correlates with the postoperative development of a multiorgan failure

The postoperative decrease of selenium concentration is not attributed to the use of a heart-lung machine

Perioperative administration of selenase® prevents the strong postoperative decrease of the selenium concentration below the original value

Selenium in the brain

Selenium is essential for the brain

Glutathioneperoxidase-1influencestheinfarctvolume

Glutathione peroxidase 4 is essential in brain development and neuropathological diseases

The lack of the selenium transport proteins Selenoprotein P causes severe neurological dysfunction, which can be attenuated by sodium selenite supplementation

Summary14


Sodium selenite acts neuroprotectively even hours after induction of the damage

Seleniumdeficitresultsinamassiveincreaseinsusceptibility for excitotoxicity and increased neuronal cell loss

The neuroprotective effect of sodium selenite is based on:

• the reduction of the oxidative stress in neurons

• the preservation of the mitochondrial respiratory chain

• theinhibitionofNFκBandAF1activation

• the inhibition of ischaemia-induced DNA oxidation

• the normalization of ischaemia-activated autophagy

Selenium sta-tus and seleno-protein activity in the event of a stroke

Strokepatientsshowsignificantlyreducedseleniumvalues

High glutathione peroxidase concentration correlates with a low neurologicaldeficitandafavorableoutcomeforstrokes

SignificantlyreducedSelenoproteinPconcentration in patients with an acute stroke

A reduced Selenoprotein P level is accompanied byanassociatedsignificantlyhigherriskofstroke


Sodium selenite:

• reduces the number of infections

• improves wound healing

• shortens antibiotic therapy

• shortens the hospital stay


Low selenium status in the post-reanimation phase

Length of reanimation correlates negatively with the selenium level

Early administration of selenase® improves the neurological outcome of patients after cardiac arrest

Summary 15

General facts about sepsis

General information

• Germany registers over 175,000 sepsis patients each year

• Despite medical progress in general, these numbers keep rising

• Diagnosisisencumberedbynon-specificsymptomsandalackofgenerally valid biomarkers

• Exorbitant costs for treating sepsis patients

Sepsis: High incidence rateSepsis involves a complex systemic inflammatoryreactionaffectingtheentirebody and impairs tissue, organs and thereby all vital functions. If sepsis is not diagnosed and treated in a timely manner, it will invariably lead to septic shock, multiple organ failure and death. One third to one half of all patients do not survive sepsis.

Sepsis is the most common infection-re-latedcauseofdeath.Olderfiguresrepor-ted 1.5 million sepsis patients annually worldwide [1]. In Germany, the incidence is154,000peryear(Fig.1)[2]. New pub-lications even reported 175,000 cases [1]. However, the experts meanwhile assume that approx. 18 million people per year becomeafflictedgiventhatthemajority

ofdeathsascribedtoHIV/AIDS,malaria,pneumonia and other infectious diseases are most likely attributable to sepsis [3].

Despite general progress in medicine, these numbers are rising dramatically. The number of sepsis cases treated in hospital have doubled over the past 10 years [4] and meanwhile exceed the number of hospital admissions due to heartattacks(Fig.2)[5, 6]. Only 20 – 40% of sepsis patients acquired their sepsis outside of the hospital [7]. By contrast, for example, the incidence of postopera-tive sepsis in the USA tripled from 1997 to 2006.


Fig.

1Incidence and mortality of sepsis depending on age. [10]

45

40

35

30

25

20

15

10

5

0

30

25

20

15

10

5

0

60–6

465

–69

70–7

475

–79

80–8

4

< 1 1–4

5–9

10–1

415

–19

20–2

425

–29

30–3

435

–39

40–4

445

–49

50–5

455

–59

> 85

Incid

ence

per

100

,000

Mor

tality

%

Age

Incidence

Mortality

Fig.

2More hospital admissions due to sepsis than to myocardiac infarction. [5, 6]

0

100

200

300

400

2000/2001 2008

221

287

377

208

Rat

e pe

r 100

,000

inha

bita

nts

Sepsis

Myocardiacinfarction

17General facts about sepsis

Sepsis: problematic diagnosticsThediagnosisisfrequentlyconfirmed too late because the clinical symptoms andlaboratoryvalues(bodytemperature, heart rate, respiratory rate and white blood cell count) are relatively non-spe-cificandcanoccurinalargenumberof other diseases as well. Particularly in children, these symptoms are less meaningful because the onset of sepsis symptoms is usually very subtle, with the clinical picture suddenly worsening dramatically.

The high rate of misdiagnoses or cases diagnosed after it was too late is attribu-tabletodeficitsstillexistinginthedefi-nitionofthecondition,insufficientdiag-nosticcriteriaandfrequentlyinsufficientcompliance with clinical guidelines. An additional problem is, that for a diagnosis usingbloodparameters(“biomarkers”),there are still no generally approved biomarkers, in contrast to other acute di-seases. Some national and international guidelines recommend procalcitonin for guiding antibiotic therapy and verifying diagnosis of sepsis.

Sepsis: High costsBetween1997and2008,inflation-correc-ted costs of hospital treatment for sepsis patients rose annually by an average of 11.9% to approx. $14.6 billion in 2008 [6]. These numbers do not take into account the costs for long-term effects, because they are so far unknown. Sepsis survi-vors suffer from a large number of severe physical, cognitive and mental problems, which lead to a mortality risk twice as

high as that of a population control group even 5 years after surviving sepsis [8].

Over the past 10 years, the mean costs for hospital treatment per sepsis patient increased in the same magnitude to a current level of approx. € 55,000 in Ger-many as well [9].


Literature

1 Rangel-Frausto MS, Pittet D, Costigan M, Hwang T, Davis CS, Wenzel RP. JAMA.1995Jan11;273(2):117-23. The naturalhistoryofthesystemicinflammatoryresponsesyndrome(SIRS).Aprospectivestudy.

2

BrunkhorstFM,EngelC,ReinhartK,BoneH.-G,BrunkhorstR,BurchardiH,EckhardtK.-U,ForstH,GerlachH,Grond S, Gründling M, Huhle G, Oppert M, Olthoff D, Quintel M, Ragaller M, Rossaint R, Seeger W, Stüber F, WeilerN,WelteT,andLoefflerM.fortheGermanCompetenceNetworkSepsis(SepNet).Epidemiologyofseveresepsis and septic shock in Germany – results from the German „Prevalence“ Study CriticalCare2005;9(Suppl1):S83.

3International Organizations Declare Sepsis a Medical Emergency. Issued by an expert panel representing 20 adult and pediatric intensive care societies, October 4th 2010. 2010:Press release. Available from: http://www.prnewswi-re.com/news-releases/international-organizations-declare-sepsis-a-global-medical-emergency-104142073.html

4KumarG,KumarN,TanejaA,KaleekalT,TarimaS,McGinleyE,JimenezE,MohanA,KhanRA,WhittleJ,Ja-cobs E, Nanchal R; Milwaukee Initiative in Critical Care Outcomes Research Group of Investigators. Chest. 2011 Nov;140(5):1223-31.doi:10.1378/chest.11-0352.Nationwidetrendsofseveresepsisinthe21stcentury(2000-2007).

5YehRW,SidneyS,ChandraM,SorelM,SelbyJV,GoAS.NEnglJMed.2010Jun10;362(23):2155-65. doi: 10.1056/NEJMoa0908610. Population trends in the incidence and outcomes of acute myocardial infarction.

6 Hall MJ, Williams SN, DeFrances CJ, Golosinskiy A. NCHSDataBrief.2011Jun;(62):1-8. Inpatient care for sep-ticemia or sepsis: a challenge for patients and hospitals.

7BealeR,ReinhartK,BrunkhorstFM,DobbG,LevyM,MartinG,MartinC,RamseyG,SilvaE,ValletB,VincentJL,Janes JM, Sarwat S, Williams MD; PROGRESS Advisory Board. Infection.2009Jun;37(3):222-32. doi: 10.1007/s15010-008-8203-z.PromotingGlobalResearchExcellenceinSevereSepsis(PROGRESS):lessonsfromaninternational sepsis registry.

8 Angus DC. JAMA.2010Oct27;304(16):1833-4. doi: 10.1001/jama.2010.1546. The lingering consequences of sepsis: a hidden public health disaster?

9VincentJL,SakrY,SprungCL,RanieriVM,ReinhartK,GerlachH,MorenoR,CarletJ,LeGallJR,PayenD;Sepsis Occurrence in Acutely Ill Patients Investigators. CritCareMed.2006Feb;34(2):344-53. Sepsis in European intensive care units: results of the SOAP study.

10Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR; Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. CritCareMed.2001Jul;29(7):1303-10.

11 HeubleinS,HartmannM,HagelS,HutagalungR,BrunkhorstFM;EpidemiologiederSepsisindeutschenKranken-häusern-eineAnalyseadministrativerDaten.Intensiv-News2013(1)1-5.

19General facts about sepsis


http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098346/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098346/

http://www.prnewswire.com/news-releases/international-organizations-declare-sepsis-a-global-medical-emergency-104142073.html

http://www.prnewswire.com/news-releases/international-organizations-declare-sepsis-a-global-medical-emergency-104142073.html










Details on sepsis

General information

• Correlation between ICU mortality and sepsis incidence in Europe

• Organ failure strongly affects ICU mortality rate

• Thenumberoffailedorgansincreasessignificantlyinseveresepsis

• Increasing number of postoperative sepsis cases

Sepsis in EuropeMoreexactfiguresonthetopicofsepsisin Europe can be found in the SOPA trial 2006 [1].

Europe-wide, 37% of patients had sep-sis during their ICU stay. This number of patients illustrates the high prevalence of sepsis. This combined with the fact, that the sepsis mortality rate in europe is 27% during an ICU stay and increases to 50% in severe sepsis, shows clearly how important the topic of sepsis is, even in industrialized nations with very good medical care.

A large proportion of sepsis patients displayaseveresepsis(79%)and39%even suffer from septic shock. That me-ans that 15% of all patients admitted to an ICU suffered from septic shock.

ICU mortality in sepsis patients ranges between 10% in Switzerland and 35% in Italy; Germany has 16%, the second lowest ICU mortality rate. The hospital mortality in patients with sepsis in Ger-many and Switzerland was lowest at 20%, with the Netherlands registering the highest at 47%. A clear correlation between overall ICU mortality and the sepsis rate is evident across the different countries(Fig.1).Overall,ICUmortalityinpatientswithsepsiswassignificantlyhigher than in patients without sepsis (27%vs.14%;p<0.001).Inpatientswith severe sepsis and/or septic shock, ICU mortality increased on average to 32.2%and54.1%,respectively(Fig.2).In Germany, ICU mortality in severe sep-sis was 24%.


Fig.

1Correlation between ICU mortality of all patients and sepsis incidence in Europe. [1]

Switzerland

Germany

Countries licensed for selenase®

Countries not licensed for selenase®

Belgium

SpainAustria

ScandinaviaGreece

France

Eastern EuropeNetherlands

UK + Ireland

Portugal

Italy

0%0%

10%

20%

30%

Y = 0.51 x - 0.11R2 = 0.80

40%

10% 20% 30%

Sepsis

Mor

talit

y

40% 50% 60% 70% 80%

Fig.

2Comparison of sepsis incidence in ICU patients with ICU mortality in Europe. [1]

70%

63%

37%30%

15% 14%

27%32%

32%

60%

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0%

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No sepsis Sepsis Severe sepsis Septic shock

ICU mortality

21Details on sepsis

Fig.

3SignificantlyincreasingICUmortalityinpatients with organ failure and severe sepsis. [1]

35%

2%

21%

32%30%

25%

20%

15%

10%

5%

0%

ICU

mor

talit

y

No sepsis,no organ failure

No sepsis,with organ failure

Severe sepsis, with organ failure

Majorinfluenceoforganfailure on ICU mortality ratesAt ICU admission, 81% of patients dis-played organ failure [1]. 41% of these pa-tients had sepsis. In 38% of ICU patients without sepsis, no organ failure occurred. Also, ICU mortality in this group was barely 2%. In the remaining 62% of ICU patients without sepsis but with organ fai-lure, ICU mortality increased to 21%. In comparison, all ICU patients with severe sepsis had organ failure, and ICU morta-lityincreasedfurthersignificantlyto32%(p<0.01)(Fig.3).

Independent of an existing sepsis, there was a direct connection between the number of failed organs and ICU morta-lity(Fig.4).Inpatientswithnoorganfai-lure at ICU admission, the ICU mortality was 6%. In patients with 4 or more failed organs, ICU mortality increased to 65%.


Fig.

4Frequency of organ failure at ICU admission and the corresponding ICU mortality. [1]

50%

40%

30%

20%

10%

0%0 1 2 3 ≥4

0 1 2 3 ≥4

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Number of organ failures

% of patients

mortality rate

23Details on sepsis

Literature

1VincentJL,SakrY,SprungCL,RanieriVM,ReinhartK,GerlachH,MorenoR,CarletJ,LeGallJR,PayenD;Sepsis Occurrence in Acutely Ill Patients Investigators. CritCareMed.2006Feb;34(2):344-53. Sepsis in European intensive care units: results of the SOAP study.

2Bateman BT, Schmidt U, Berman MF, Bittner EA. Anesthesiology.2010Apr;112(4):917-25. doi: 10.1097/ALN.0b013e3181cea3d0. Temporal trends in the epidemiology of severe postoperative sepsis after elective surgery: a large, nationwide sample.

Fig.

5Thenumberoffailingorgansissignificantlyincreased in sepsis patients. [1]

70%

57%

25%28%

38%

12%

24%

4% 13%

60%

50%

40%

30%

20%

10%

0%

1 2 3 ≥4

70%

60%

50%

40%

30%

20%

10%

0%

No sepsis Severe sepsis

Number of organ failures

p < 0.001 p < 0.001 p < 0.001 p < 0.001

ICUmortalityratesignificantlyhigher in sepsis patientsSevere sepsis does not impact ICU mor-tality rate depending on the number of failing organs. But the number of organs thatfailinsepsispatientsissignificantlyincreased(Fig.5).Therefore,ICUmorta-lity in ICU patients with severe sepsis is stillsignificantlyhighercomparedtotho-

se without sepsis, but with organ failure. If the frequency of multiple organ failure (MOF)couldbeloweredinpatientswithsepsis, the high mortality rate in this group of patients would also be markedly reduced.




Diagnostic criteria for sepsis

Accordingto:ReinhartK,BrunkhorstFM,BoneHGetal.[Prevention,diagnosis,treatment,andfollow-upcareofsepsis.FirstrevisionoftheS2k.GuidelinesoftheGermanSepsisSociety(DSG)andtheGermanInterdisciplinaryAssociationforIntensiveandEmergencyCareMedicine(DIVI)].*Anaesthesist 2010; 59: 347–370.

Sepsis Severe sepsis Septic shock

Evidence of an infection



SIRS SIRS SIRS

Acute organ dysfunction

Cardiovascular instability

Evidence of an infection:Diagnosis of infection based on microbiological proof or clinical criteria

Systemicinflammatoryresponsesyndrome(SIRS)– at least 2 of the following criteria:Fever (≥38°C)orhypothermia (≤36°C),confirmedthroughrectal,intravascularorintravesicaldetermination

Tachycardia withaheartrate≥90/min

Tachypnea (respiratoryrate≥20/min)or hyperventilation(PaCO2≤4.3kPa/≤33mmHg)

Leukocytosis (≥12,000/mm3) or leukopenia (≤4,000/mm3)or≥10%immatureneutrophilsinthedifferentialbloodcount

Acute organ dysfunction – at least 1 of the following criteria:Acute encephalopathy: Reduced vigilance, disorientation, agitation, delirium.

Relative or absolute thrombocytopenia:Dropinplateletcount>30%within24hoursorplateletcount≤100,000/mm3. Thrombocytopenia due to acute bleeding or immunological causes must be ruled out.Arterial hypoxemia: PaO2≤10kPa(≤75mmHg)inroomairoraPaO2/FiO2ratio≤33kPa(≤250mmHg)onoxygen.Overt cardiac or pulmonary disease as the cause of the hypoxemia must be ruled out.Renal dysfunction: Diuresisof≤0.5ml/kg/hforatleast2hoursdespiteadequatevolumereplacementand/orariseinserum creatinine to more than twice the reference range.

Metabolic acidosis: Baseexcess≤5mmol/lorlactateconcentrationmorethan1.5timesthereferencerange.

Cardiovascular instability:

Systolicarterialbloodpressure≤90mmHgand/ormeanarterialbloodpressure≤65mmHglastingforatleast1houroruseofvasopressorrequiredtostabilizesystolicarterialbloodpressure≥90mmHgorarterialmeanpressure≥65mmHg.Hypotension despite adequate volume resuscitation not explained by other causes.

25Details on sepsis

http://link.springer.com/article/10.1007/s00101-010-1719-5

Fig.

6Significantincreaseinpostoperativesepsis from 1997 – 2006. [2]

19970

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1998 1999 2000 2001 2002 2003 2004 2005 2006

Per

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es

Sepsis

Severe sepsis

Postoperative sepsisSepsis is a major cause of postope-rative mortality. A trial conducted in 2010 investigated the development of postoperative sepsis from 1997 – 2006 using the largest patient database in the USA(morethan2millionpatients)[2]. During the analysis period, the incidence of postoperative sepsis increased from 0.7%to1.3%(p<0.001)andofseverepostoperative sepsis from 0.3% to 0.9% (p<0.001)(Fig.6).Thehigherincrea-sed rate of severe postoperative sepsis was found in all surgical intervention categories(Fig.7).Acountertrendwas

observed for hospital mortality rate. The mortality rate declined from 44.4% in 1997to34%in2006(p<0.001)(Fig.8).Even after accounting for potential confounders, a multivariate regression modelshowedadeclineinmortality(OR0.94; 95% CI, 0.93–0.95 per year increa-se in the trial period; p < 0.001). Overall, the decline in mortality cannot compen-sate the increase in postoperative sep-sis. Therefore the number of deaths from postoperative stress increases.


Fig.

7Increased number of severe postoperative sepsis is independent of the type of surgical intervention. [2]

0

0.5

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Cardiac Thorax Vascular Uppergastro-

intestinaltract

Lowergastro-

intestinaltract

Joint-replacement

Spine Gyneco-logical

Urological

Surgery

Per

100

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es

1997 – 1998

1999 – 2000

2001 – 2002

2003 – 2004

2005– 2006

Fig.

810% reduced mortality between 1997 – 2006 in severe postoperative sepsis. [2]

1998 1999 2000 2001 2002 2003 2004 2005 200619970

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27Details on sepsis

Selenium and sepsis

General information

• Selenium level declines in correlation with sepsis severity

• Selenium concentration is inversely correlated with APACHE II and SAPS II scores

• Minimum selenium concentration is an independent predictor of ICU mortality

• Cut-off value of 36 µg/l selenium in serum for sepsis patients

• Early(≤6hours)administrationofselenase® is crucial

• Abolusadministrationreversesthepro-inflammatorystateviaanearly, transient, pro-oxidative effect of high-dose sodium selenite


Selenium level declines in correlation with sepsis severityOne trial conducted in 2007 compared 45ICUpatientswithSIRS(systemicin-flammatoryresponsesyndrome),mainlyafter cardiac surgery, with a group of 15 ICU patients without SIRS [1]. The 45 patients were subdivided into the following groups SIRS, severe SIRS and severe sepsis or septic shock: SIRS (n=15),severeSIRS(n=15),severesepsisorsepticshock(n=15).Alreadyat ICU admission, 92% of all patients

had a serum selenium value below the German reference range. During their ICU stay, the selenium concentration continued to decline in all groups except for the control group without SIRS. The mean serum selenium levels at ICU ad-mission correlated negatively with sepsis severity(Fig.1).

Fig.

1Serum selenium levels in sepsis patients at ICU admission decline depending on sepsis severity. [1]

90

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Seru

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l µg/

l

SIRS* Severe sepsis/Septic shock

p < 0.05p < 0.05

p < 0.05

Reference value ≥ 80 µg/l

29Selenium and sepsis

Selenium concentration is inversely correlated with APACHE II and SAPS II scoresMinimum serum selenium concentra-tion is inversely correlated with maxi-mumnumberofleucocytes(R2=0.22;p < 0.01), maximum serum C reactive protein(CRP)(R2=0.28;p<0.01),maximumserumprocalcitonin(PCT)(R2=0.3;p<0.01)andmaximumseruminterleukin6(IL-6)(R2=0.42;p<0.01).

APACHE II and SAPS II scores, both in-dicatorsforinflammationandthedegreeof organ failure during an ICU stay, corre-lated inversely with the minimum serum seleniumvalue(APACHEII:R2=0.31;p < 0.01; SAPS II: R2=0.29;p<0.01)(Fig.2).Furthermoretheminimumserumselenium concentration is inversely cor-related with the maximum degree of org-an dysfunction respectively failure during anICUstay(R2=0.42;p<0.01).

Fig.

2Inverse correlation of serum selenium levels with APACHE II and SAPS II scores. [1]

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g/l]

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*SIRS=systemicinflammatoryresponsesyndrome


Minimum selenium concentration: independent predictor of ICU mortalityBoth the initial serum selenium value as well as the minimum serum selenium concentrationweresignificantlylowerin non-surviving compared to surviving patients(Fig.3).Areceiveroperatingcharacteristic(ROC)analysisforpredic-ting ICU mortality showed that the SAPS IIscore(AUC=0.903;95%CI:0.819–0.987, p < 0.01) and minimum serum seleniumconcentration(AUC=0.867;95% CI: 0.753–0.981, p < 0.01) were themostsignificantpredictivefactors.

A cut-off value for the minimum serum selenium concentration was set. A cut-off value of 36 µg/l selenium in serum has a sensitivityof89%,specificityof71%andpositive predictive value of 35%. Most importantly, however, it has a negative predictive value of 95%.

Therefore the probability to die increases below 36 µg/l selenium in serum.

Fig.

3The serum selenium level in surviving patients issignificantlyhigher.[1]

100

40

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20

0Non-survivors (9)

Serum selenium concentrationat ICU admission (µg/l)

Survivors (51)

p < 0.05

Non-survivors (9)Survivors (51)

p < 0.05

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Minimal serum selenium concentration (µg/l)


Cytokines:

TNFα IL-1 IL-6

Invasion of bacteria

and toxins

NF-κB activation

iNOSActivation of coagulation

NO

Tissue damage

Multiple organ dysfunction (MOD)

Multiple organ failure (MOF)

Neurological abnormalities

Fever Tachycardia

Leukocytosis

Purpura Petechia

Disseminated intravascular

coagulation (DIC)

Hypotension Cardiovascular hyporeactivity

Tissue hypoperfusion Hypoxia

Se [13]

Se [13]

Signaling processes


Invasion of bacteria

and toxins

NF-κB activation

COX-2 5-LO Adhesion molecules

Prostaglandins Leukotrienes

Thromboxanes

Neutrophil infiltration + activation

ROS

Endothelial injury

Tissue damage

Death

Capillary leakage

Se [13]

Se [16]

Se [17]

Se [16]

Selenium-Supplementatium

[References]

Effect of selenium

Fig.

4Where does selenium intervene in the process of sepsis?

Signaling processes


Which effect does ROS production have on survival?Huet et al. conducted a trial investigating the extent to which the production of re-activeoxygenspecies(ROS)correlateswith the severity of septic shock [2]. For this purpose, naive human umbilical vein endothelialcells(HUVEC)weretreatedwith plasma collected from 21 patients with septic shock and the induced ROS productionwasquantified.Comparedto controls, the plasma-induced ROS productionbyHUVECwassignificantly

higher in septic shock and ROS producti-onsignificantlycorrelatedwiththeSAPSIIscore(p=0.028)andtheSOFAscore(p=0.0012).Moreover,ROSproductioninnon-survivorswassignificantlyhig-hercomparedtosurvivors(p=0.0015)(Fig.5).Theseresultsdemonstratethatan early reduction of ROS production, as it can be achieved by application of selenase®, can increase the chance of survival of septic patients.

Why does the selenium status decline in patients with sepsis?Clinical sepsis is associated with a sig-nificantdecreaseinseleniumlevel[3, 4]. Lipopolysaccharides(LPS)arekeyplayers in the development of sepsis. These toxic compounds are produced when attacking bacteria divide, but also when antibiotics actively attack patho-gens. An injection of LPS in rats induces an acute-phase response and leads to significantlyreducedserumandliverselenium values [4]. Several recent trials have been able to elucidate some of the underlying mechanisms. It was demons-trated that an LPS-induced acute-phase response leads to a reduction in seleno-protein biosynthesis in the liver [5]. The liver is the main location of biosynthesis of selenoprotein P, which is released into the plasma and transports selenium to

other tissues. The human selenoprotein P promoter is negatively regulated by pro-inflammatorycytokinesinhumanhepatocytes [6].

In sepsis, a pathogenic cycle may be triggered in which selenoprotein P syn-thesis in the liver is diminished by sepsis andinflammatorycytokines.Thislowersselenium status in other tissues as well, increasing oxidative stress which further amplifiestheinflammatoryresponse (Fig.6).Fortheimmunesystem,thismeans that a low selenium status not only diminishes the transport capaci-ty of the lymphocytes and the cells of the innate immune system, but also leads to stress-induced lymphopenia [7].


Fig.

5SignificantdifferenceinROSproductioninsurviving andnon-survivingpatients(p=0.0015).[2]

ROS productionNon-survivors

ROS ProductionSurvivors

Course of illness

Fig.

6Cyclic reduction of selenium level in sepsis and intervention of selenium supplementation in this cycle. [8]

Sepsis or LPS-treatment

Decreased Selenium transport to tissues

Loss of circulating selenium-containing

proteins via leaky vessels

Liver downregulates Selenoprotein P

expression

Increased oxidative stress

Selenium supplementation

Pathogenic cykle of stressinduced immune suppression

Secretion of IL-6andTNFα

Se Se


Why is early administration of sodium selenite crucial(within≤6hours)?Levy et al. demonstrated that oxidation of cytochrome c by myocardiac cytochrome c oxidase is completely inhibited early in sepsis. Myocardiac cytochrome c oxida-se is the terminal oxidase in the electron transport chain [9]. This oxidative stress in mitochondria leads to mitochondrial dysfunction and is irreversible after 48 hours after the onset of tissue hypoxia (Fig.7).Irreversibleinhibitiondisruptsoxidative phosphorylation, which leads to sepsis-associated cardiac depressi-on. For an effective antioxidant strategy, selenium must be administered as soon as possible after onset of sepsis.

In a phase I dose-escalating clinical trial, it was shown that the glutathione concentration was not decreased by

increasing selenium dose in severely ill patients(p=0.03)[10]. Furthermore, an increasing selenium dose decreased the concentrations of thiobarbituric acid reactivesubstances(TBARS)significant-ly(p=0.03)andthusloweredoxidativestress. Motoyama et al. showed that in-creasing TBARS concentrations in sepsis patients correlated with a higher SOFA score(p<0.001)[11]. Plasma TBARS concentrationwassignificantlyhigherin sepsis patients with multi organ failu-re(MOF)thaninpatientswithoutMOF(57.1%vs.15.8%,p<0.001).Analysisof the ratio of mitochondrial DNA as an indirect marker of mitochondria function showed, that the function of mitochond-rias improved with increasing selenium dosage(p=0.001)(Fig.8)[10].


Fig.

8

Only a high selenium dosage improves mitochondrial function, reduces oxidative stress and increases antioxidative capacity in sepsis. [10]

GSH level stays stable

antioxidative capacity

TBARS (thiobarbituric acid

reactive substances)

oxidative stress

mitochondrial DNA

mitochondrial function

Selenium

Fig.

7Irreversible inhibition of the cytochrome c oxidase after 48 hours in severe sepsis. [9, 10, x]

0h

6h

24h

48h

competitive inhibition of cytochrome c oxidase

organ failure

antioxidant concentration

ROS

non-competitive inhibition of cytochrome c oxidase

irreversible mitochondrial damage

oxidation of mitochondrial DNA

[x]BrealeyD,KaryampudiS,JacquesTS,NovelliM,StidwillR,TaylorV,SmolenskiRT,SingerM.AmJPhysiolRegulIntegrCompPhysiol.2004Mar;286(3):R491-7. Mitochondrial dysfunction in a long-term rodent model of sepsis and organ failure.



Why inject sodium selenite as bolus?The effect of a bolus injection of 2,000 µg selenium as sodium selenite pentahydra-te was compared to a continous infusion of 4 µg/kg per hour in an experimental animal model for sepsis in sheep [12]. Only the bolus showed a positive effect on sepsis progression, although the overall dosis was comparable. The likely explanation for this is an early transient pro-oxidative effect of sodium selenite, that can be used as therapeutic strategy toreversethepro-inflammatorystateexisting in severe sepsis and septic shock.Thisexcessivepro-inflammatorystate is charakterized by high levels of

circulating cytokines and ROS, pha-gocytic hyperactivity of leucocytes due to delayed apoptosis, and a prolonged NFkB activation.

A bolus injection in the early phase of septicshockinhibitsNF-κBbindingtoDNAviastabilizationofdisulfidebonds.This regulates gene expression and synthesisofpro-inflammatorycytokines[13]. Additionally a bolus administration induces apoptosis and cytotoxicity in activated,pro-inflammatorycellsalongwith a direct virucidal or bactericidal effect [14, 15].

High dose for sepsis – so that selenium works

Day 1


as bolus 2,0001–3 µg Se


1,6001–3 µg Se

at least 7 days

maintenance therapy

1,6001–3 µg Se / Day

Literature1 Manzanares W et al. 2012, Crit Care; 16:R662 Huang TS et al. 2013, PLoS One 8:e544313 Alhazzani W et al. 2013, Crit Care Med 41:1555–1564





Literature

1SakrY,ReinhartK,BloosF,MarxG,RusswurmS,BauerM,BrunkhorstF.BrJAnaesth.2007Jun;98(6):775-84. Timecourseandrelationshipbetweenplasmaseleniumconcentrations,systemicinflammatoryresponse,sepsis,and multiorgan failure.

2HuetO,ObataR,AubronC,Spraul-DavitA,CharpentierJ,LaplaceC,Nguyen-KhoaT,ContiM,VicautE,MiraJP,Duranteau J. CritCareMed.2007Mar;35(3):821-6. Plasma-induced endothelial oxidative stress is related to the severity of septic shock.

3HollenbachB,MorgenthalerNG,StruckJ,AlonsoC,BergmannA,KöhrleJ,SchomburgL.J Trace Elem Med Biol. 2008;22(1):24-32. doi: 10.1016/j.jtemb.2007.11.003. New assay for the measurement of selenoprotein P as a sep-sis biomarker from serum.

4 MaehiraF,LuyoGA,MiyagiI,OshiroM,YamaneN,KubaM,NakazatoY.ClinChimActa.2002Feb;316(1-2):137-46. Alterations of serum selenium concentrations in the acute phase of pathological conditions.

5RenkoK,HofmannPJ,StoedterM,HollenbachB,BehrendsT,KöhrleJ,SchweizerU,SchomburgL.FASEB J. 2009Jun;23(6):1758-65. doi: 10.1096/fj.08-119370. Down-regulation of the hepatic selenoprotein biosynthesis machinery impairs selenium metabolism during the acute phase response in mice.

6 DreherI,JakobsTC,KöhrleJ.JBiolChem.1997Nov14;272(46):29364-71. Cloning and characterization of the human selenoprotein P promoter. Response of selenoprotein P expression to cytokines in liver cells.

7

CarcilloJA,DeanJM,HolubkovR,BergerJ,MeertKL,AnandKJ,ZimmermanJ,NewthCJ,HarrisonR,BurrJ,WillsonDF,NicholsonC;EuniceKennedyShriverNationalInstituteofChildHealthandHumanDevelop-ment(NICHD)CollaborativePediatricCriticalCareResearchNetwork(CPCCRN).Pediatr Crit Care Med. 2012 Mar;13(2):165-73. doi: 10.1097/PCC.0b013e31823896ae. The randomized comparative pediatric critical illness stress-inducedimmunesuppression(CRISIS)preventiontrial.

8 Huang Z, Rose AH, Hoffmann PR. AntioxidRedoxSignal.2012Apr1;16(7):705-43. doi: 10.1089/ars.2011.4145 Theroleofseleniumininflammationandimmunity:frommolecularmechanismstotherapeuticopportunities.

9 LevyRJ,VijayasarathyC,RajNR,AvadhaniNG,DeutschmanCS.Shock.2004Feb;21(2):110-4. Competitive and noncompetitive inhibition of myocardial cytochrome C oxidase in sepsis.

10HeylandDK,DhaliwalmR,DayA,DroverJ,CoteH,WischmeyerP.JPEN J Parenter Enteral Nutr. 2007 Mar-Apr;31(2):109-18. Optimizing the dose of glutamine dipeptides and antioxidants in critically ill patients: a phase I dose-findingstudy.

11 MotoyamaT,OkamotoK,KukitaI,HamaguchiM,KinoshitaY,OgawaH.CritCareMed.2003Apr;31(4):1048-52. Possibleroleofincreasedoxidantstressinmultipleorganfailureaftersystemicinflammatoryresponsesyndrome.

12WangZ,ForcevilleX,VanAntwerpenP,PiagnerelliM,AhishakiyeD,MacoursP,DeBackerD,NeveJ,VincentJL.Shock.2009Aug;32(2):140-6.doi:10.1097/SHK.0b013e318193c35d.Alarge-bolusinjection,butnotcontinuousinfusion of sodium selenite improves outcome in peritonitis.

13 MatthewsJR,WakasugiN,VirelizierJL,YodoiJ,HayRT.NucleicAcidsRes.1992Aug11;20(15):3821-30. Thiore-doxin regulates the DNA binding activity of NF-kappa B by reduction of a disulphide bond involving cysteine 62.

14 Spallholz JE. BiomedEnvironSci.1997Sep;10(2-3):260-70. Free radical generation by selenium compounds and their prooxidant toxicity.

15 StewartMS,SpallholzJE,NeldnerKH,PenceBC.FreeRadicBiolMed.1999Jan;26(1-2):42-8. Selenium com-pounds have disparate abilities to impose oxidative stress and induce apoptosis.

16 Mattmiller SA, Carlson BA, Sordillo LM. J Nutr Sci. 2013 Aug 29;2:e28. doi: 10.1017/jns.2013.17. eCollection 2013. Regulationofinflammationbyseleniumandselenoproteins:impactoneicosanoidbiosynthesis.

17 Rayman MP. Lancet.2012Mar31;379(9822):1256-68.doi:10.1016/S0140-6736(11)61452-9
























selenase® for sepsis

General information

• Supplementation with sodium selenite increases the selenium level to values within the normal range

• Significantreductioninmortalityintheselenium-supplementedgroup

• Possible correlation between selenium supplementation and procalcitonin [4]

• Supplementation with high-dose sodium selenite reduces the incidence of nosocomial pneumonia and improves sepsis severity


Meta analysis Parenteralsodiumselenitetreatmentsignificantlyreducestotalmortalityrateby17%(p=0.04)

Highersignificantreductionofmortalitywhenabolusisadministered (−27%;p=0.01),amaintenancetherapy≥7days(−23%;p=0.01) andadosingof≥1,000µgseleniumassodiumselenite-pentahydrate(selenase®)perday(−23%;p=0.04)

Pilot study Supplementation with selenase® increases the selenium level to values within the normal range

selenase®supplementationsignificantlyreducesmortalityinpatientswithAPACHE III score > 53

SIC trial Significantreductioninmortalityintheselenase®-supplemented group by14.3%(p=0.049)

Significantreductioninmortalityinthesubgroups(septicshock, APACHEIII≥102,>3organfailure)intheselenase®-supplemented group by up to 26%

Various trials

Possible correlation between selenase® supplementation and procalcitonin

Supplementation with high-dose sodium selenite reduces the incidence of nosocomial pneumonia and improves sepsis severity

SIGNET trial: Fewer new infections in patients receiving selenase® supple-mentation for > 5 days

REDOXS trial: Compared to glutamine, selenium does not have any negati-veeffectonmortality,althoughthebeneficialeffectofseleniumsupplemen-tationisreducedbythelackofseleniumdeficiency

Significantlymorecriticallyillpatientsintheinterventiongroupimpactedtheanalysis of the retrospective trial on selenium supplementation in patients with severe sepsis

41selenase® for sepsis

Parenteralsodiumselenitetreatmentsignificantly reducestotalmortalityby17%(p=0.04).

Twelve trials were included in the meta analysis, whereby the meta analysis wascarriedoutinnineofthese(Table1)[3]. In total, 965 patients took part in the nine studies; 482 participants received a sodium selenite supplementation and 483 a placebo. A total of 148 patients (30.7%)diedintheinterventiongroup,while180participants(37.3%)diedinthe placebo group. The mortality varied greatly between the studies, from 24% to 52%. Also the administration scheme differed considerably, both with respect to the duration and dose as well as the strategy. The use of sodium selenite was

uniform as the only approved selenium form for the drug product, whereby more than half of the trials were carried out with selenase®. All trials had a low risk of“detectionbias”,sincemortalitywasdefinedastheresult.Inaddition,mosttrialshadalowriskof“attritionbias”e.g.protocol noncompliance.

In total, the meta analysis shows that a parenteral sodium selenite supplementa-tionsignificantlyreducestotalmortality (RR0.83,95%CI0.70–0.99;p=0.04).

Meta analysis of 9 sepsis trials Withcorrectapplication,sodiumselenitesignificantly reduces mortality.

General information

• Alarge-bolusinjectionsignificantlyreducedmortality in sepsis patients by 27%

• Maintenancetherapylasting≥7dayssignificantlyimproved the probability of survival

• Ahighdoseof≥1,000µgseleniumintheformofsodiumselenitepentahydrate(selenase®)perdaysignificantlyreducedmortality by 23%

Sepsis42 selenase® for sepsis

Tab.

1 Included trials

Zimmermann et al.

selenase®

ZimmermannT,AlbrechtS,KuhneH,VogelsangU,GrutzmannR,etal.(1997)[Seleniumadministrationinpatientswithsepsissyndrome.Apros-pective randomized study]. MedKlin(Munich)92Suppl3:3–4.

Angstwurm et al.

selenase®

AngstwurmMW,SchottdorfJ,SchopohlJ,GaertnerR(1999)Seleniumreplacementinpatientswithseveresystemicinflammatoryresponsesyn-drome improves clinical outcome. Crit Care Med 27: 1807–1813.

Mishra et al. MishraV,BainesM,PerrySE,McLaughlinPJ,CarsonJ,etal.(2007) Effect of selenium supplementation on biochemical markers and outcome in critically ill patients. Clin Nutr 26: 41–50.

Angstwurm et al.

selenase®

Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, et al.(2007)SeleniuminIntensiveCare(SIC):resultsofaprospectiveran-domized, placebo-controlled, multiple-center study in patients with severe systemicinflammatoryresponsesyndrome,sepsis,andsepticshock.Crit Care Med 35:118–126.

Forceville et al. ForcevilleX,LaviolleB,AnnaneD,VitouxD,BleichnerG,etal.(2007)Effects of high doses of selenium, as sodium selenite, in septic shock: a placebocontrolled, randomized, double-blind, phase II study. Crit Care 11: R73.ForcevilleX(2007)Effectsofhighdosesofselenium,assodiumselenite, in septic shock patients a placebo-controlled, randomized, dou-ble-blind, multi-center phase II study–selenium and sepsis. J Trace Elem Med Biol 21 Suppl 1: 62–65.

Montoya et al. MontoyaGCHL,VillalobosSJA,OlveraGC,AguirreSJ,FrancoGJ(2009)Anti-inflammatoryeffectofseleniuminsepticpatients.RevAsocMexMedCrity Ter Int 23:199–205

Andrews et al.

selenase®

AndrewsPJ,AvenellA,NobleDW,CampbellMK,CroalBL,etal.(2011)Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients. BMJ 342: d1542.

Valentaetal.

selenase®

ValentaJ,BrodskaH,DrabekT,HendlJ,KazdaA(2011)High-doseseleni-um substitution in sepsis: a prospective randomized clinical trial. Intensive Care Med 37: 808–815.

Manzanares et al. ManzanaresW,BiestroA,TorreMH,GalussoF,FacchinG,etal.(2011)Highdose selenium reduces ventilator-associated pneumonia and illness severityincriticallyillpatientswithsystemicinflammation.Intensive Care Med 37: 1120–1127.

selenase®: Studies were carried out with selenase®

Sepsis 43selenase® for sepsis















Fig.

1Positivesignificantimpactofseleniumassodiumselenite on total mortality in the event of sepsis. [changed according to 1]

Day 16h Day 2 Day 3 Day 4

Nosocomial infections

Day 5 Day 6 Day 7 Day 10 – 14

Without sodium selenitesupplementation

Survival

Late Death

Early death

At ICU-admission (< 6 h):Bolus: 2,000 µg Se as sodium selenite

Mortality rate (RR 0.73; p = 0.01) [3] overwhelming immune response

Impaired immunity

Minimum 5 days Se as sodium selenite

New infections (RR 0.53; p = 0.03) [2]


Mortality rate (RR 0.77; p = 0.01) [3]

With sodium selenitesupplementation

Se = selenium

Immunosuppression

Immune response

Pro

-infla

mat

ory

Ant

i-inf

lam

ator

y

Hom

oeos

tasi

s

Viral reactivation

Bolus2,000 µg Seas sodium

selenite

1,600 µg Seas sodium selenite

per day

Meta analysis (9studies,n=965)[3] Asodiumselenitesupplementationsignificantly reducesmortalityforsepsispatients(RR(relativerisk)0.83CI(confidenceinterval)0.77–0.99;p=0.04)


Fig.

1Positivesignificantimpactofseleniumassodiumselenite on total mortality in the event of sepsis. [changed according to 1]

Day 16h Day 2 Day 3 Day 4

Nosocomial infections

Day 5 Day 6 Day 7 Day 10 – 14

Without sodium selenitesupplementation

Survival

Late Death

Early death

At ICU-admission (< 6 h):Bolus: 2,000 µg Se as sodium selenite

Mortality rate (RR 0.73; p = 0.01) [3] overwhelming immune response

Impaired immunity


New infections (RR 0.53; p = 0.03) [2]


Mortality rate (RR 0.77; p = 0.01) [3]

With sodium selenitesupplementation

Se = selenium

Immunosuppression

Immune response

Pro

-infla

mat

ory

Ant

i-inf

lam

ator

y

Hom

oeos

tasi

s

Viral reactivation

Bolus2,000 µg Seas sodium

selenite

1,600 µg Seas sodium selenite

per day

Meta analysis (9studies,n=965)[3] Asodiumselenitesupplementationsignificantly reducesmortalityforsepsispatients(RR(relativerisk)0.83CI(confidenceinterval)0.77–0.99;p=0.04)


Meta analysis of 9 sepsis trialsAhigh-dosebolussignificantlyreducesmortality in sepsis patients by 27%.

A bolus in the early phase of sepsis has several effects:

1. Down-regulation of the synthesis ofpro-inflammatorycytokines

2. Apoptosis and cytotoxicity in activated pro-inflammatorycells

3. Direct virucidal and bactericidal effectsThese effects prevent an unchecked immuneresponse(cytokinestorm)andthusanearlydeathfromsepsis(Fig.1).

In a comparison of the sodium selenite supplementation with a bolus to a so-dium selenitetherapy without a bolus, a lower mortality could be shown in the interventiongroupwithbolus(−7%; p=0.14).Aparenteralsodiumselenitesupplementation with bolus, however, reduced the total mortality with a higher significance(RR0.73,95%CI0.58–0.94;p=0.01).

Amaintenancetherapyof≥7dayssignificantly improves the probability of survival.

The impact of the duration of treatment on mortality was determined by means of uni-variant “random effects meta-re-gression”analysis.Astatisticallysignifi-cant association between the relative risk of mortality and duration of treatment

(Fig.2)wastherebydemonstrated. A sodium selenite supplementation of≥7daysreducedtotalmortality by23%(RR0.77,95%CI0.63–0.94; p=0.01).


Fig.

2Dependencyoftherelativerisk(RR) on the duration of treatment [3]

–1.00 5 10

6.5 days

15 20 25 30

–0.5

0.0

0.5

1.0

Treatment duration (days)

Log(

RR

)

Every circle represents one trial, whereby the size of the study correlates with the size of the circle. Anegativeeffect(circlebelowtheregressionplot)standsforthereductionofthemortalityrate.


Meta analysis of 9 sepsis trialsAhighdosingof≥1,000µgselenium as sodium selenite-pentahydrate per day significantlyreducesmortalityby23%.

In their meta analysis, Huang et al. dis-tinguished between sodium selenite sup-plementation with a high selenium dose (≥1,000µg/day)andalowdose(<1,000µg/day).Adosingof≥1,000µgseleniumperdaysignificantlyreducedthetotalmortality(RR0.77,95%CI0.61–0.99; p=0.04).Inacomparisonofseveralsepsis trials, Manzanares et al. could show that only a high sodium selenite supplementation(2,000µgbolus(day1)and1,600µg/dayselenium(day2–10))

sufficestoelevateserumseleniumcon-centration into the low reference range or to increase the activity of glutathione peroxidase 3 to a physiological level (Fig.3)[4]. A low sodium selenite therapy (1,200µgbolus(day1)and800µg/day(day2–10))isneitherinthepositiontosufficientlyincreasetheserumseleniumconcentrationnortosufficientlyinfluencethe activity of glutathione peroxidase 3 (Fig.4).

Fig.

3

Development of the serum selenium concentration for high and low-dosed sodium selenite supplementation [4]

10

0 2 4 6 8 10

3020

5040

807060

13012011010090

Days

Ser

um s

elen

ium

con

cent

ratio

n (µ

g/l)

low-dosed sodium selenitehigh-dosed sodium selenite


Fig.

4

Increase of glutathione peroxidase 3 activity to a physiological level takes place only with a high-dose sodium selenite supplementation [4]

0.00 2 4 6 8 10

0.4

0.2

0.8

0.6

1.4

1.2

1.0

2.0

1.8

1.6

Days

GP

x-3-

activ

ity (U

/ml)

low-dosed sodium selenitehigh-dosed sodium selenite

Sepsis StudienSepsis 49selenase® for sepsis

Pilot studySupplementation with selenase® increases the selenium level to values within the normal range

A controlled, randomized, prospective, open-label pilot trial analyzed the effects of selenase® supplementation in SIRS patients [1]. The selenase®-supplemented group(n=21)receiveddescendingdo-ses of selenase® of 535 µg selenium per day for 3 days, 285 µg selenium per day for 3 days, 155 µg selenium per day for 3 days, and 35 µg selenium per day the-reafter.Thecontrolgroup(n=21)recei-ved 35 µg/day selenium during the entire treatment period.

The serum selenium concentrations were belowthedefinedreferencevalueforseleniumingermany(80µg/lseleniuminserum) at admission to the ICU. Glutathi-oneperoxidaseactivitywasalsosignifi-cantly too low. While the serum selenium levels in the control group did not change over the observation period, the serum selenium concentration increased in the normal range from day 3 in the selena-se®-supplementedgroup(Fig.5). The data show that SIRS patients need a selenium dose > 500 µg to reach nor-mal range and that 155 µg selenium perdayisnotsufficienttomaintain a low normal level already achieved.


Fig.

5

Significantincreaseinserumseleniumconcentration in the selenase®-supplemented group in the reference range. [6]

100

90

30

40

50

60

70

80

20

10

03 7

Days

Seru

m s

elen

ium

con

cent

ratio

n in

[µg/

l]

0 14

p < 0.001

p < 0.001Reference rangep = 0.003

selenase®-supplemented group Control group


Pilot studySupplementation with selenase® improves clinical outcomes in SIRS patients

In both groups, the baseline APACHE III score was the same and decreased during their ICU stay. However, the APACHE III score in the selenase®-sup-plementedgroupimprovedsignifiantlymorepronounced(day7:p=0.019; day14:p=0.041).Moreover,only12%of the patients in the selenase®-supple-mented group but 42% in the control group had a higher APACHE III score on day 14 compared to ICU admission (p<0.05).

Mortality at discharge from the hospital was 33.4% in the selenase®-supplemen-ted group and 52.4% in the control group (p=0.135)(Fig.6).Acomparisonofpatients with an APACHE III score > 53 highlightsthebeneficialeffectofselena-se® on mortality rate. Although the pati-ent population in this subgroup analysis wasreducedto20(selenase®-supple-mentedgroup(n=11)andcontrolgroup(n=9)),therewasasignificantdecreasein mortality in the selenase®-supplemen-tedgroup(4of11patients(36%))versusthecontrolgroup(8of9patients(89%))(p=0.0053)(Fig.7).


Fig.

6

Intention-to-treat analysis of survival time in the selenase®-supplementedgroup(n=21) andcontrolgroup(n=21). [5]

100

40

60

80

2020 40 60 80 100

Sur

viva

l (%

)

0

Control

selenase®

p = 0.135

Survival time (days)

Fig.

7

Intention-to-treat analysis of survival time in patients with anAPACHEIIIscore>53(selenase®-supplemented group (n=11)andcontrolgroup(n=9)).[5]

100

40

60

80

2020 40 60 80 1000

p = 0.0053

Sur

viva

l (%

)

Survival time (days)

Control

selenase®


SIC trial (Selenium in Intensive Care)Phase III trial with selenase®

A prospective, randomized, double-blind, multicenter phase III trial conducted at 11 intensive care units in Germany, ana-lyzed whether the results obtained in the pilot study were reproducible in a pha-se III trial [2]. Overall, 249 patients with SIRS, sepsis, septic shock and an APA-CHE III score > 70 were randomized. The selenase® doses administered were increased to a 30-minute bolus infusion of 1,000 µg selenium, followed by 1,000 µg/day selenium as a continuous infusion for 14 days. In the placebo group, a dose of up to 100 µg/day sele-nium was allowed with the parenteral nutrition.

Eleven of the 249 randomized patients were excluded for various reasons. Thus, the intention-to-treat analysis included 238patients(Fig.8).Another49ofthese 238 patients had to be excluded further for the per-protocol analysis either because inclusion criteria were not met (n=14)orduetosevereviolations ofthetrialprotocol(n=35).Therefore, the per-protocol analysis only covered 189 patients, 92 in the selenase®-treated group and 97 in the placebo group.


Fig.

8 StudyprofileoftheSICtrial. [6]

Randomized patients

N=249

• 5 consent withdrawn• 1 suicide• 2 lost for follow up• 1 non-compliant• 2 termination of treatment

• 14 ex/inclusion criteria failure• 30 trial drug administration failure• 5 additional selenium substitutions

> 100 µg/day

Intention-to-treat analysis

N=238

Per-Protocol analysis

N=189

selenase®- supplemented

group

N=116

selenase®- supplemented

group

N=92

Placebo group

N=122

Placebo group

N=97


SIC trialSignificantlyincreasedseleniumvalue in the selenase®-supplemented group only.

The SIC trial also showed that seleni-um values at ICU admission were very low(Table2).Theseleniumconcen-trationincreasedsignificantlyintheselenase®-supplemented group only (p<0.001).Despitehigh-dosedailyselenase® supplementation, the medi-an selenium values only increased to 161.9 µg/l selenium in the serum and 144.5 µg/l selenium in whole blood onthelastday(day14)ofselenase® supplementation. After completing the intervention, the selenium level decrea-sedmarkedlywithinaweek(Fig.9).Inthetrial,nospecificadversereactionswere attributed to supplementation with high-dose selenase®. Overall, there was nosignificantdifferenceintheadver-se reactions in the intervention group (90.2%)andtheplacebogroup(96%).

The positive effect of selenase® supple-mentation showed in both the selenium concentration in blood and the glutathio-

ne peroxidase activity. Both parameters increased from suboptimal baseline values during intervention and decrea-sedagainsignficantlyafterendingtheselenase®supplementation(Fig.9).Thecurve characteristics reveals, that an optimal selenium supply during and after sepsisisnotsufficient,whenaseleniumdosage, as is currently used in parenteral nutrition respectively normal nutrition, is applied. Simultaneously the increase in glutathion peroxidase activity during intervention with 1,000 µg selenium as selenase® shows that a daily selenium intake of 100 µg in sepsis patients does not result in a plateau of selenopro-tein activity, but increases till ending of intervention. After selenase® supplemen-tation the glutathione peroxidase acitivty decreased again, though the patients still recieved up to 100 µg selenium with parenteral nutrition.

Tab.

2Comparison of selenium concentration in the selenase®- supplemented versus the placebo group p < 0.001. [2]

selenase®- supplemented group

Placebo group

Serum selenium concentration at ICU admission inallrandomizedpatients(n=249)

37.9 ± 18.2 µg/l 36.3 ± 12.6 µg/l

Selenium concentration in whole blood at ICU admissioninallrandomizedpatients(n=249)

58.4 ± 17.4 µg/l 58.4 ± 12.6 µg/l

Serum selenium concentration at ICU admission in patients included in the per-protocol analysis (n=189)

37.9 µg/l 35.5 µg/l

Serum selenium concentration after 14 days 161.9 µg/l 47.4 µg/l

Selenium concentration in whole blood after 14 days

144.5 µg/l 64.0 µg/l


Fig.

9

Development of selenium concentration and glutathione peroxidase activity during and after selenase® supplementation. [6]

selenase® Placebo group

selenase® Placebo group

End of selenase®

supplementation

Day 10

20406080

100120140160180200220240

Day 3 Day 7 Day 14 Day 21 Day 28

Day 1100120140160180200220240260280300320340

Day 3 Day 7 Day 14 Day 21 Day 28

Reference range

Glutathione peroxidase activity

in healthy europeans: 196 - 477 U/L[x]

Sel

eniu

m c

once

ntra

tion

in w

hole

blo

od [µ

g/l]

Glu

tath

ione

per

oxid

ase

activ

ity [U

/l]

End of selenase®

supplementation

[x]AlegríaA,BarberáR,ClementeG,FarréR,GarcíaMJ,LagardaMJ.JTraceElemMedBiol.1996Dec;10(4):223-8. Selenium and glutathione peroxidase reference values in whole blood and plasma of a reference population living in Valencia,Spain.



SIC trialSignificantreductioninmortality in the selenase®-supplemented group

In the intention-to-treat analysis (n=238),46of116patientsintheselenase®-supplemented group died and 61 of 122 in the placebo group. Thus, selenase® supplementation reduced mortalitynon-significantlyby10.3%(p=0.109;OR,0.66;95%CI,0.39–1.10)(Fig.10).Meanoverallsurvivalincrea-sed from 17.6 days in the placebo group to 20.3 days in the intervention group (p=0.098)(Fig.11).

As previously mentioned in the SIC trial description, 49 patients were excluded from the per-protocol analysis. Either the inclusioncriteriawerenotmet(n=14)

or severe violations of the trial protocol occurred(n=35).Therefore,theper-pro-tocol analysis only covered 189 patients, 92 in the selenase®-treated group and 97 in the placebo group.

In the per-protocol analysis, 28-days mortalitydecreasedsignificantlyfrom56.7% to 42.4% in the selenase®-sup-plementedgroup(p=0.049;OR,0,.56;CI,0.32–1.00)(Fig.12).Meanoverallsurvival increased from 16.4 days in the placebo group to 19.7 days in the inter-ventiongroup(p=0.048)(Fig.13).

Fig.

1028-days mortality in the intention- to-treatanalysis(n=238). [6]

70

20

30

10

40

60

50

0

Mor

talit

y %

p = 0.109

50 %

39.7 %

-10.3 %

Placebo selenase®

Fig.

1228-days mortality in the per-protocolanalysis(n=189).[6]

70

20

30

10

40

60

50

0Placebo selenase®

Mor

talit

y %

p = 0.049

-14.3 %56.7 %

42.4 %


Fig.

11 Survival time in the intention-to-treat analysis. [6]

100

25

50

75

021 28

Days

Sur

viva

l %

0 7 14

Placebo≤100µgSe/day

selenase®≥1,000µgSe/day

p = 0.098

n = 116

n = 122

Fig.

13 Survival time in the per-protocol analysis. [6]

100

25

50

75

021 28

Days

Sur

viva

l %

0 7 14

n = 92

n = 97

p = 0.048Placebo≤100µgSe/day

selenase®≥1,000µgSe/day


SIC trialSignificantreductioninmortalityinthesubgroups of the selenase®-supplemented group

The trial plan had already included a subgroup analysis. Patients with an APACHEIIIscore>102(n=27ineachgroup)benefitedevenmorefromaselenase®supplementation(Fig.14).28-days mortality decreased in this subgroup by 25.9% from 81.5% to 55.6% (p=0.04;OR,0.28;95%CI,0.08–0.97).In patients with septic shock, 28-days mortality decreased by 26.2% from 66.7%intheplacebogroup(30of45) to 40.5% in the selenase®-supplemented

group(15of37patients)(p=0.018; OR, 0.34; 95% CI, 0.14–0.84). In pati-ents with more than triple organ failure, 28-days mortality decreased by 22.6% in the comparison between the intervention group(42.5%;17of40patients)andtheplacebogroup(65.1%;28of43patients)(p=0.039;OR,0.40;95%CI0.16–0.96).The subgroup analysis highlights the fact,thatthebeneficialeffectbyselena-se® supplementation increases with sepsis severity.

SÉRÉNITÉ trialComparison of SIC and SÉRÉNITÉ trials

Like SIC, the SÉRÉNITÉ trial was a prospective, randomized, double-blind, multicenter trial conducted in France. However, this trial only included a total of 60 patients, i.e. a quarter of the number in the SIC trial [7]. The study included only patients with severe septic shock. While the SIC trial enrolled patients within 6

hours after ICU admission and adminis-tered a bolus infusion directly after trial enrollment, 90% of the patients in the SÉRÉNITÉ trial were enrolled within 48 hours of ICU admission. Furthermore, a bolus was not given. Instead, 4,000 µg selenium were administered as a contin-uousinfusion.Thesignificanceofabolus

Fig.

14Considerably reduced 28-days mortality in the selenase®-supplemented group acrossthepredefinedsubgroupsintheSICtrial.[6]

Reduction in mortality NNT (Numberneededtotreat)

SIC trial total - 14.3% (p=0.049) =7

definedsubgroups:

Septic shock - 26.2% (p=0.018) =4

APACHE III > 102 - 25.9% (p=0.040) =4

> 3 organ failure - 22.6% (p=0.039) =4-5


Fig.

15Mortality in the SÉRÉNITÉ trial in the sodium selenite-supplemented and placebo group. [7]

1

0.9

0.3

0.4

0.5

0.6

0.7

0.8

0.2

0.1

030 60 90 120 150 180

p = 0.691

240210 270 300 330 360

Days

Pro

babi

lity

of s

urvi

val

0

Sodium selenite

Placebo

consists of improving the selenium status of the sepsis patient as early and as rap-idly as possible. This enables the body to fightoxidativestress,andtohaveanan-ti-inflammatoryeffect.Theconsiderablylater and slower administration of sodium selenite was not able to compensate the resulting damage even though twice the amount of sodium selenite was used. In the SÉRÉNITÉ trial, the selenium value was not measured at ICU admission nor over the course of the study. Therefore, it is not possible to verify the patients’ selenium concentration at ICU admis-sion. Since many studies have shown that the selenium value at ICU admission is inversely correlated with mortality, the question arises as to whether the patient cohort in the SÉRÉNITÉ trial was more

severely ill than in the SIC trial. Another difference was the shorter daily seleni-um supplementation given for 9 versus 14 days. Here, as well, there is no way to verify which effect the shorter selenium supplementation had on the selenium value; whether the selenium concentra-tion decreased below reference range after the intervention ended, respectively to which degree. In view of these differ-ence, it is no surprise that a reduction in mortality was lacking in the seleni-um-supplementedgroup(Fig.15). In the SÉRÉNITÉ trial, no adverse reactions were attributed to selenium. This is particularly noteworthy be-cause 4,000 µg selenium were given on day 1, without any adverse effects on the patients.


Valenta et al., 2011Evidence of a correlation between selenase®supplementationandprocalcitonin(PCT)

ThetrialbyValentaetal.in2011,pro-duced another interesting result [8]. This prospective, randomized, open-label, single-centre clinical trial enrolled 150 patients with SIRS/sepsis and a SOFA score of >5. 75 patients were supple-mentedwith1,000µgselenium(selena-se®) on day 1 and 500 µg on days 2 – 14, administered as a 30-minute infu-sion in the morning. Patients in both, the intervention group and the control group received a standard dose of < 75 µg/day selenium with their parenteral nutrition.

This trial also revealed 3 effects of selenase® supplementation :

• In the intervention group, the selenium value and the glutathione peroxidase activity increased from a very low baseline value in the reference range as compared to the control group (Fig.16).

• Patients in both groups surviving 28 days showed a trend for a higher serum selenium level compared to non-survivors(59.2±45.7vs.56.1 ±44.2µg/l;p=0.068).

• Despite the high-dose selenase® supplementation,nospecificadversereactions or toxic effects occurred. Only 17 of the 799 serum selenium samples taken from 9 patients in the intervention group showed selenium values above the reference range (163.4±14.2µg/l,referencerange80 – 120 µg/l). All 9 patients survived.

This trial also showed a negative correla-tion between serum selenium level and severalinflammatorymarkersandsepsisseverityatICUadmission(Table3).


Fig.

16Development of serum selenium concentration during selenase® supplementation compared to the control group. [8]

120

60

80

100

40

20

0

Days

Seru

m s

elen

ium

con

cent

ratio

n [µ

g/l]

1 3

p < 0.001

p < 0.001

p < 0.001

p < 0.001p < 0.001

p < 0.001

5 70 1410

Reference range

selenase® Control

Tab.

3Negative correlation between the serum selenium level at ICU admission, inflammatorymarkersandsepsisseverity.[8]

r-value p-value

Procalcitonin(PCT) - 0.172 0.035

C-reactiveprotein(CRP) - 0.187 0.022

SOFA score - 0.277 0.001


Thetrialshowednosignificantdifferencein 28-days mortality between interven-tionvs.controlgroup(25.3%vs.32%;p=0.367).Asubgroupanalysispro-duced a trend to a lower mortality in the selenase®-supplemented group for pati-entswithAPACHEIIscore>28(32.6%vs.51.6%;p=0.100).

However,Valentaetal.madeaninteres-ting discovery in this trial. The compa-rison of PCT and CRP values between the intervention and the placebo group showed a decrease of both values inde-

pendently of selenase® supplementation over the course of the 14 days observati-on period. But the reduction in the inter-vention group was more pronounced. For PCT, the difference between the selenase®-supplemented group and the control group on day 7 was even signi-ficant(Fig.17).These data suggest a biological interaction between seleni-um and PCT.


Fig.

17

SignificantlygreaterdecreaseinPCTintheselenase®-supplemented group. Therewasnosignificantdifference,despitethedifferenceinPCTvaluesbetweenthetwogroupsonday0(p=0.108).[8]

1.8

0.6

0.8

1

1.2

1.4

1.6

0.4

0.2

07

p = 0.003

p = 0.009

p = 0.06p = 0.004

p < 0.05

Days

PC

T [µ

g/l]

0 14

Reference range

selenase®

Control


Manzanares et al., 2011Supplementation with high-dose sodium selenite reduces the incidence of nosocomial pneumonia and improves sepsis severity

This placebo-controlled, randomized pro-spective, single-blind phase II trial enrol-led 35 patients with SIRS and APACHE II scoresof≥15[9]. The intervention group received a bolus of 2,000 µg selenium and 1,600 µg/day for another 10 days. Both groups received an average of 77 respectively 73 µg/day selenium enterally.

In the sodium selenite-supplemented group, the incidence of early ventilator- associatedpneumoniawassignificantlyreducedby31%(p=0.04)(Fig.18).Theincidence of nosocomial pneumonia was also reduced in the intervention group by 19%(p=0.03).Theauthorsattributedthisbeneficialeffecttotheadministeredlarge bolus, because all three effects of abolusadministrationcaninfluencethedevelopment of early ventilator-associa-ted pneumonia.

• ReversibleinhibitionofNF-κBbindingto DNA

• Apoptosis and cytotoxicity in activated, pro-inflammatorycells

• Direct virucidal or bactericidal effect

Early ventilator-associated pneumonia in the ICU is a major cause of morbidity, mortality and costs. A reduction in the incidence of early ventilator-associated pneumonia via sodium selenite might make an important contribution.

Furthermore, the SOFA score was reduced in the sodium selenite-supple-mented group versus the placebo group onday10(p=0.0001).WhiletheSOFAscore in the intervention group continued tosignificantlydeclinefromday3today10, the SOFA score in the placebo group remainedvirtuallythesame(Fig.19).


Fig.

18Sodium selenite reduced the probability for a patient to acquire nosocomial pneumonia. [9]

1

0.4

0.2

0.6

0.8

08 124 16 20 24 28

Days

0

p = 0.024Prob

abilit

y of

rem

aini

ng fr

ee o

f ho

spita

l-acq

uire

d pn

eum

onia

with

in th

e fir

st 2

8 da

ys

Sodium selenite

Placebo

Fig.

19Sodiumselenitesignificantlyimprovedsepsisseverity basedontheSOFAvalue(p=0.0001).[9]

2 4 6 8 1000

3

6

9

12

1

4

7

10

2

5

8

11

13

SO

FA s

core

(mea

n va

lue

± S

D)

Days

Placebo

Sodium selenite


SIGNET trialFewer new infections in patients receiving selenase® supplementation for > 5 days

The SIGNET trial was a randomized, double-blinded, factorial, controlled multicenter trial with 502 participants [6]. Because of the factorial design, the pa-tients were randomized to the following studyarms:Placebogroup(n=125)parenteral nutrition containing standard formulation; selenase®group(n=127)standard formulation with addition of 500μgselenium;glutaminegroup(n=126)formulationincluding20.2gglutamine; selenase® + glutamine group (n=125)formulationwithadditionof500 µg selenium and 20.2 g glutamine.

Only 56% of the patients had sepsis. The selenase®-supplemented group showed a decreased rate of new in-fectionsby5%(p=0.24)incontrasttoglutamine supplementation. selenase® supplementationsignificantlyreducednew infections in patients who recei-vedinterventionfor≥5daysby13%(p=0.03)(Fig.20).


Fig.

20At least 5 days selenase® supplementation significantlyreducednewinfections.[10]

80

70

20

30

10

40

60

50

0Placebo selenase®≥5days

(n = 251)

Infe

ctio

ns %

p = 0.03

72.3 %

58.9 %

-13.4 %


REDOXS trialCompared to glutamine, selenium did not have any negativeeffectonmortality,althoughthebeneficial effect of selenium supplementation was reduced bythelackofseleniumdeficiency

The REDOXS trial was a randomized, controlled, double-blind, 2x2 factorial, multicenter trial with 1,223 severely ill patients with multiple organ failure [11]. Within 24 hours after ICU admission, the patients received either glutamine, anti-oxidants(including500µgseleniumasselenase®), both or placebo for a maxi-mumof28days(Table4).

Only in 31% of patients the primary diagnosis was sepsis at ICU admissi-on. Compared to other sepsis trials, the selenium value at ICU admission was not outside the normal range in any of the 66 analyzed trial patients. It is not known whether these patients were sepsis pati-ents. However, the median serum sele-nium level at 86 µg/l in the antioxidant group and 80 µg/l in the non-antioxidant group was far above the means in sepsis patients at 30 – 40 µg/l selenium in the serum. The aforementioned sepsis trials were exclusively conducted in Europe where the average selenium level in the population is clearly below the reference range of 80 µg/l selenium in the serum.

The REDOXS trial was conducted both in Canada, the USA and Europe. Both in Canada and the USA, the selenium status is markedly above the reference range of 80 µg/l.

In the antioxidant group, the selenium valueintheserumincreasedsignificantly(p<0.001),whereastheseleniumstatusin the non-antioxidant group only showed aslightincrease(Table5).Despitethesignificantincreaseinseleniumcon-centration, the authors reported that the median selenium level in both groups remained within the normal range at all measurement time points.

Supplementation with antioxidants had noeffecton28-daysmortality(30.8%vs.28.8%;p=0.48).Inadditiontotheabove-mentioned restrictions in the RE-DOXS trial, the positive effect of seleni-um might have been negated by the late initiation of supplementation with antio-xidants, the too low selenium dose and the interaction of vitamin C with selenium due to its concurrent administration.


Tab.

5 Increase in serum selenium value in the antioxidant group. [11]

Antioxidants No antioxidantsp-value

n median[Q1,Q3](µg/l) n median[Q1,Q3](µg/l)

ICU day 1 31 86(71–98) 30 80(65–85) 0.08

ICU day 4 28 142(137–164) 26 85(67–95) < 0.0001

ICU day 7 25 156(134–174) 19 89(82–107) < 0.0001

Tab.

4 Trial arms in the REDOXS trial. [11]

Trial arm Number Supplementation Administration

1 Glutamine(Gln) 3030.5 g Gln/kg body weight Parenteral

30 g Gln Enteral

2Antioxidants (AOX)

308

500 µg selenium as selenase® Parenteral

300 µg selenium, 20 mg zinc, 500 mg vitamin E, 10 mg beta-carotene, 1,500 mg vitamin C

Enteral

3 Gln + AOX 310 1 + 2

4 Placebo 302 −


Sakr et al., 2014Doctors give selenase® primarily severly ill patients

In a large retrospective study conducted in 2014, Sakr et al. analyzed the effect of a selenium supplementation in 1,047 pa-tients with severe sepsis treated over a period of more than 6 years in a surgical ICU [12]. Due to the retrospective nature of the study, the selenium-supplemented grouphadonly413(39%)patients.Thecontrol group received 100 µg/day sele-nium and selenium-supplemented group received a bolus of 1,000 µg selenium (selenase®) and 1,000 µg/day selenium (selenase®) for a maximum of 14 days.

The median duration of adjuvant seleni-umtherapywas8days(IQR=4–12).Thetwogroupspresentedwithsignifi-cantly different patient characteristics. Particularly, the higher SAPS II score (50.8vs.47.7,p=0.001)andthehigherproportionofpatientswithcancer(32.4%vs.24.6%;p=0.005)mayhaveaffectedthe study analysis. This is also evident in theparametersmeasuredtotestinflam-mationandorganfunction(C-reactiveprotein,PCT,bloodlactate)(Table6).

Dosurgicalsepsispatientsneedadifferent(higher) dosage than medical sepsis patients?

It is known that, among other things, a surgical intervention triggers oxidative stresswhichsignificantlyheightensthebody’s selenium consumption during and after surgery. It can therefore be assu-medthat,toachievethesamebeneficialeffect, surgical sepsis patients require higher selenium doses than medical sepsis patients. As trials on selenium supplementation in cardiac surgery have

shown, without selenium supplementati-on surgery causes the selenium concent-ration to decrease by around one quarter of the baseline value. In this study, the fact that no selenium levels were measured or stated makes it impossible to draw conclusions as to whether sele-nium concentration at ICU admission in surgical sepsis patients was lower than in medical sepsis patients.

Tab.

6Significantlydifferentpatientcharacteristics in the selenium and control group. [12]

Characteristics Control group Selenium group p-value

SAPS II 47.7 ± 17 50.8 ± 17.7 0.001

Cancer 24.6% 32.4% 0.005

C-reactive protein 78(13–193) 146(46–235) < 0.0001

Procalcitonin 2.3(0.7–7.2) 3.7(0.9–12.9) < 0.0001

Blood lactate 2.5(1.6–5.3) 2.9(1.7–5.6) 0.031


Literature

1Hotchkiss RS, Monneret G, Payen D. LancetInfectDis.2013Mar;13(3):260-8. doi: 10.1016/S1473-3099(13)70001-X.Immunosuppressioninsepsis:anovelunderstandingofthedisorderandanewtherapeuticapproach.

2AndrewsPJ,AvenellA,NobleDW,CampbellMK,CroalBL,SimpsonWG,ValeLD,BattisonCG,Jenkins-on DJ, Cook JA; Scottish Intensive care Glutamine or seleNium Evaluative Trial Trials Group. BMJ. 2011 Mar 17;342:d1542. doi: 10.1136/bmj.d1542. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients.

3Huang TS, Shyu YC, Chen HY, Lin LM, Lo CY, Yuan SS, Chen PJ. PLoSOne.2013;8(1):e54431. doi: 10.1371/jour-nal.pone.0054431 Effect of parenteral selenium supplementation in critically ill patients: a systematic review and meta-analysis.

4 Manzanares W, Hardy G. CurrOpinClinNutrMetabCare.2009May;12(3):273-80. doi: 10.1097/MCO.0b013e-32832a0cc2. Selenium supplementation in the critically ill: posology and pharmacokinetics.

5 Angstwurm MW, Schottdorf J, Schopohl J, Gaertner R. CritCareMed.1999Sep;27(9):1807-13. Selenium replace-mentinpatientswithseveresystemicinflammatoryresponsesyndromeimprovesclinicaloutcome.

6Angstwurm MW, Engelmann L, Zimmermann T, Lehmann C, Spes CH, Abel P, Strauss R, Meier-Hellmann A, Insel R, Radke J, Schüttler J, Gärtner R. CritCareMed.2007Jan;35(1):118-26.SeleniuminIntensiveCare(SIC):results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatoryresponsesyndrome,sepsis,andsepticshock.

7ForcevilleX,LaviolleB,AnnaneD,VitouxD,BleichnerG,KorachJM,CantaisE,GeorgesH,SoubirouJL,Com-bes A, Bellissant E. CritCare.2007;11(4):R73. Effects of high doses of selenium, as sodium selenite, in septic shock: a placebo-controlled, randomized, double-blind, phase II study.

8 ValentaJ,BrodskaH,DrabekT,HendlJ,KazdaA.IntensiveCareMed.2011May;37(5):808-15. doi: 10.1007/s00134-011-2153-0. High-dose selenium substitution in sepsis: a prospective randomized clinical trial.

9Manzanares W, Biestro A, Torre MH, Galusso F, Facchin G, Hardy G. IntensiveCareMed.2011Jul;37(7):1120-7. doi: 10.1007/s00134-011-2212-6. High-dose selenium reduces ventilator-associated pneumonia and illness severi-tyincriticallyillpatientswithsystemicinflammation.

10AndrewsPJ,AvenellA,NobleDW,CampbellMK,CroalBL,SimpsonWG,ValeLD,BattisonCG,Jenkins-on DJ, Cook JA; Scottish Intensive care Glutamine or seleNium Evaluative Trial Trials Group. BMJ. 2011 Mar 17;342:d1542. doi: 10.1136/bmj.d1542. Randomised trial of glutamine, selenium, or both, to supplement parenteral nutrition for critically ill patients.

11Heyland D, Muscedere J, Wischmeyer PE, Cook D, Jones G, Albert M, Elke G, Berger MM, Day AG; Canadian Critical Care Trials Group. NEnglJMed.2013Apr18;368(16):1489-97. doi: 10.1056/NEJMoa1212722. Erratum in:NEnglJMed.2013May9;368(19):1853.Arandomizedtrialofglutamineandantioxidantsincriticallyillpatients.

12SakrY,MaiaVP,SantosC,StrackeJ,ZeidanM,BayerO,ReinhartK.CritCare.2014Apr9;18(2):R68. doi: 10.1186/cc13825. Adjuvant selenium supplementation in the form of sodium selenite in postoperative critically ill patients with severe sepsis.
















Significantlymorecriticallyillpatientsintheinterventiongroup impacted the analysis of the retrospective trial on selenium supplementation in patients with severe sepsis

In this retrospective study, overall ICU mortality was 31.3% and hospital mortali-ty 41.8%. Whereas the ICU mortality didnotsignificantlydifferinthetwogroups(29.5%vs.33.9%;p=0.135), the selenium supplemented group dis-playedahigherhospitalmortality(39.15vs.46%;p=0.027).BoththeICUandhospitalstaysweresignificantlylongerintheinterventiongroup(p=0.01andp=0.001,respectively).However,amul-tivariate analysis showed, that adjuvant selenium therapy was not independently associated with worse hospital morta-lity(OR=1.19,95%CI=0.86–1.65;p=0.288).Themultivariateanalysis

included age, gender, SAPS II score, surgery type, co-morbidities, focus on sepsis, SOFA sub-scores and blood lactate levels.

The authors themselves point out, that the higher hospital mortality and the lon-ger ICU and hospital stays are attributab-letothesignificantlyhighernumber of severely ill patients in the selenium- supplemented group. Furthermore, the authors also point out that unlike early trials, in which the proportion of surgical patientsfluctuatedbetween13%and40%, their study contained 100% surgi-calcases(Fig.21).


Fig.

21Percentage of medical and surgical sepsis patients in different sepsis trials. [5–8, 10]

0%

20%

40%

60%

80%

10%

30%

50%

70%

90%

100%

Angstwurm(1999)

Angstwurm(2007)

Forceville(2007)

Valenta(2011)

Andrews(2011)

Heyland(2013)

Sakr(2014)

Medical sepsis Surgical sepsis


-

Trial design Number of patients Intervention Result LimitationsAngstwurm et al. (1999)

controlled, randomized, prospective, open-label pilot trial (single center)

N (selenase®) = 21N (control) = 21

Intervention group (selenase®):

535 µg/day selenium for 3 days, 285 µg/day selenium for 3 days, 155 µg/day selenium for 3 days and 35 µg/day selenium thereafter Placebo group:

35 µg/day selenium

Selenium level at ICU admission markedly below normalIntervention group (selenase®):

Selenium level ↑ (p = 0.003)APACHE III score↓ (p = 0.041)Mortality ↓ (-19%; p = 0.135)Patients with APACHE III > 53:

Mortality (at hospital discharge) ↓ (-53%; p = 0.0053)No adverse reactions from selenase®

No toxic symptoms

• trial size• no placebo group• low selenase® doses

Angstwurm et al. (2007)

Prospective, randomized, double-blind, multicenter phase III trial

N (selenase®) = 92N (placebo) = 97


Bolus: 1,000 µg1,000 µg/day selenium as selenase® for 14 days Placebo group:

< 100 µg/day selenium


Selenium level ↑ (p > 0.001)28-days mortality ↓ (-14%; p = 0.048)Pat. with septic shock:

28-days mortality ↓ (-26%; p = 0.018)Pat. with APACHE III > 102:

28-days mortality ↓ (-26%; p = 0.040)Pat. with > triple organ failure:

28-days mortality ↓ (-23%; p = 0.039)No adverse reactions from selenase®

No toxic symptoms

Forceville et al. (2007)

prospective, randomized, double-blind, multicenter trial

N (sodium selenite) = 31N (placebo) = 29

Intervention group:

Bolus: 4,000 µg selenium1,000 µg/day selenium for 9 days

Intervention group:

Duration of mechanical ventilation = no significant differenceMortality = no significant differenceNo adverse reactions from sodium seleniteNo toxic symptoms

• trial size• Patients enrolled too late (not until after 48h)• baseline selenium value unknown• selenium value not measured

Valenta et al. (2011)

Prospective, randomized, open-label trial (single center)


Intervention group:

1,000 µg selenium as selenase® on day 1500 µg/day selenium as selenase® for 14 days Control group:



Selenium level ↑ (p > 0.001)28-days mortality ↓ (-7%; p = 0.367)Pat. with APACHE II < 28:

28-days mortality ↓ (-19%; p = 0.100)Significant reduction in PCT vs. control group (p < 0.05)No adverse reactions from selenase®

No toxic symptoms

• no bolus

Manzanares et al. (2011)

placebo-controlled, randomized, prospective, single-blinded, phase II trial (single center)


Intervention group:

Bolus: 2,000 µg selenium1,600 µg/day selenium for 10 days Placebo group:

73 ± 16 µg/day selenium

Intervention group:

SOFA ↓ (p = 0.0001)Early ventilator-associated pneumonia ↓ (-31%; p = 0.04)Nosocomial pneumonia ↓ (-19%, p = 0.03)No adverse reactions from sodium seleniteNo toxic symptoms

• trial size• baseline selenium value unknown• selenium value not measured

Overview of trials








-

Trial design Number of patients Intervention Result LimitationsAngstwurm et al. (1999)

controlled, randomized, prospective, open-label pilot trial (single center)



535 µg/day selenium for 3 days, 285 µg/day selenium for 3 days, 155 µg/day selenium for 3 days and 35 µg/day selenium thereafter Placebo group:

35 µg/day selenium


Selenium level ↑ (p = 0.003)APACHE III score↓ (p = 0.041)Mortality ↓ (-19%; p = 0.135)Patients with APACHE III > 53:

Mortality (at hospital discharge) ↓ (-53%; p = 0.0053)No adverse reactions from selenase®

No toxic symptoms

• trial size• no placebo group• low selenase® doses

Angstwurm et al. (2007)

Prospective, randomized, double-blind, multicenter phase III trial

N (selenase®) = 92N (placebo) = 97


Bolus: 1,000 µg1,000 µg/day selenium as selenase® for 14 days Placebo group:



Selenium level ↑ (p > 0.001)28-days mortality ↓ (-14%; p = 0.048)Pat. with septic shock:

28-days mortality ↓ (-26%; p = 0.018)Pat. with APACHE III > 102:

28-days mortality ↓ (-26%; p = 0.040)Pat. with > triple organ failure:

28-days mortality ↓ (-23%; p = 0.039)No adverse reactions from selenase®

No toxic symptoms

Forceville et al. (2007)

prospective, randomized, double-blind, multicenter trial


Intervention group:

Bolus: 4,000 µg selenium1,000 µg/day selenium for 9 days

Intervention group:

Duration of mechanical ventilation = no significant differenceMortality = no significant differenceNo adverse reactions from sodium seleniteNo toxic symptoms

• trial size• Patients enrolled too late (not until after 48h)• baseline selenium value unknown• selenium value not measured

Valenta et al. (2011)

Prospective, randomized, open-label trial (single center)


Intervention group:

1,000 µg selenium as selenase® on day 1500 µg/day selenium as selenase® for 14 days Control group:



Selenium level ↑ (p > 0.001)28-days mortality ↓ (-7%; p = 0.367)Pat. with APACHE II < 28:

28-days mortality ↓ (-19%; p = 0.100)Significant reduction in PCT vs. control group (p < 0.05)No adverse reactions from selenase®

No toxic symptoms

• no bolus

Manzanares et al. (2011)

placebo-controlled, randomized, prospective, single-blinded, phase II trial (single center)


Intervention group:

Bolus: 2,000 µg selenium1,600 µg/day selenium for 10 days Placebo group:

73 ± 16 µg/day selenium

Intervention group:

SOFA ↓ (p = 0.0001)Early ventilator-associated pneumonia ↓ (-31%; p = 0.04)Nosocomial pneumonia ↓ (-19%, p = 0.03)No adverse reactions from sodium seleniteNo toxic symptoms

• trial size• baseline selenium value unknown• selenium value not measured








Trial design Number of patients Intervention Result Limitations

Andrews et al. (2011)

randomized, controlled, double-blind, factorial, multicenter trial

N (selenase®) = 127N (glutamine) = 126N (selenase® + glutamine) = 124N (placebo) = 125

Placebo group:

Standard parenteral nutritionGlutamine group:

+ 20.2 g glutamineselenase® group:

+ 500 µg seleniumselenase® + glutamine group:

+ 500 µg selenium + 20.2 g glutamine

selenase® group:

New infections ↓ (-5%, p= 0.24)New infections in patients with ≥ 5 days selenase® supplementation ↓ (-13%, p= 0.03)Mortality after 6 months = no significant difference

• Only 56% of participants were sepsis patients• baseline selenium value unknown• selenium value not measured

Heyland et al. (2013)

Randomized, controlled, blinded, 2-by-2 factorial, multicenter trial

N (antioxidants) = 308N (glutamine) = 303N (antioxidants + glutamine) = 310N (placebo) = 302

Antioxidant group:

500 µg/day selenium as selenase® parenteral + 300 µg selenium, 20 mg zinc, 500 mg vita-min E, 10 mg beta-carotene, 1500 mg vitamin C enteralGlutamine group:

0.5 g/kg body weight parenteral + 30 g enteral

Selenium level at ICU admission within reference rangeAntioxidant group:

Selenium level ↑ (p = < 0.001)28-days mortality = no significant difference

• only 31% of participants were sepsis patients• late initiation of selenium supplementation• low selenium dose• interaction through concomitant vitamin C

Sakr et al. (2014)

Retrospective trial N (selenase®) = 413N (control) = 634

Intervention group:

Bolus: 1,000 µg selenium1,000 µg/day selenium for 14 days Control group:

100 µg/day selenium

selenase® group:

ICU mortality = no significant differenceHospital mortality ↑ (+7%; p = 0.027)ICU stay ↑ (p = 0.01)Hospital stay ↑ (p = 0.001)Selenium supplementation not independently associated with worse out-come (OR = 1.19, p = 0.288)Selenium supplementation after a multivariate analysis not associated with hospital mortality

• retrospective trial• selenium group contains significantly more severely ill patients• no precise criteria for initiation of selenium supplementation• All patients were surgical patients with sepsis





Trial design Number of patients Intervention Result Limitations

Andrews et al. (2011)

randomized, controlled, double-blind, factorial, multicenter trial

N (selenase®) = 127N (glutamine) = 126N (selenase® + glutamine) = 124N (placebo) = 125

Placebo group:

Standard parenteral nutritionGlutamine group:

+ 20.2 g glutamineselenase® group:

+ 500 µg seleniumselenase® + glutamine group:

+ 500 µg selenium + 20.2 g glutamine

selenase® group:

New infections ↓ (-5%, p= 0.24)New infections in patients with ≥ 5 days selenase® supplementation ↓ (-13%, p= 0.03)Mortality after 6 months = no significant difference

• Only 56% of participants were sepsis patients• baseline selenium value unknown• selenium value not measured

Heyland et al. (2013)

Randomized, controlled, blinded, 2-by-2 factorial, multicenter trial

N (antioxidants) = 308N (glutamine) = 303N (antioxidants + glutamine) = 310N (placebo) = 302

Antioxidant group:

500 µg/day selenium as selenase® parenteral + 300 µg selenium, 20 mg zinc, 500 mg vita-min E, 10 mg beta-carotene, 1500 mg vitamin C enteralGlutamine group:

0.5 g/kg body weight parenteral + 30 g enteral

Selenium level at ICU admission within reference rangeAntioxidant group:

Selenium level ↑ (p = < 0.001)28-days mortality = no significant difference

• only 31% of participants were sepsis patients• late initiation of selenium supplementation• low selenium dose• interaction through concomitant vitamin C

Sakr et al. (2014)

Retrospective trial N (selenase®) = 413N (control) = 634

Intervention group:

Bolus: 1,000 µg selenium1,000 µg/day selenium for 14 days Control group:

100 µg/day selenium

selenase® group:

ICU mortality = no significant differenceHospital mortality ↑ (+7%; p = 0.027)ICU stay ↑ (p = 0.01)Hospital stay ↑ (p = 0.001)Selenium supplementation not independently associated with worse out-come (OR = 1.19, p = 0.288)Selenium supplementation after a multivariate analysis not associated with hospital mortality

• retrospective trial• selenium group contains significantly more severely ill patients• no precise criteria for initiation of selenium supplementation• All patients were surgical patients with sepsis





General facts about Ischaemia/reperfusion

General information

• Ischaemiaandreperfusion(I/R)causetissuedamage

• Reactive oxygen species play an important role in I/R

Tissue damage with ischaemia/reperfusionIschaemiaandreperfusion(I/R)arecharacterized by an initial restriction of thebloodflowtoanorganfollowedbythe re-establishment of the blood circula-tion and associated reoxygenation. This re-establishmentofthebloodflowand

the oxygen supply is often accompanied by a worsening of the tissue damage (“oxygenparadox”),acomprehensiveinflammatoryresponse,andcanlead toorganfailure(Tab.1).

Ischaemia/reperfusion80

Tab.

1 Examples of ischaemia and reperfusion injuries. [1]

Affected organ Example for clinical manifestation

Ischaemia and reperfusion in an individual organ

Heart Acute coronary syndrome

Kidney Acute kidney damage

Intestine Multiorgan failure

Brain Stroke

Ischaemia and reperfusion with several organs

Trauma and resuscitation Multiorgan failure; acute kidney damage; intestinal damage

Circulatory arrest Hypoxial brain damage; multiorgan failure; acute kidney damage

Sickle-cell anemia Acute breast syndrome

Sleep apnea High blood pressure; diabetes

Ischaemia and reperfusion during major surgery

Cardiac surgery Acute heart failure

Thorax surgery Acute lung damage

Peripheral vascular surgery Compartment syndrome of the extremities

Major vascular surgery Acute kidney damage

Organ transplantation Acute transplantation failure; early rejection of transplanted organs

Ischaemia/reperfusion 81

Important role of ROS with I/RMany factors are involved in the patho-genic mechanisms which contribute to I/R-induced damage and infarct. Thesignificanceoftheindividualfactorshasnotyetbeenfullyclarified.

However, there are increasingly indi-cations that Reactive Oxygen Species (ROS)playacriticalroleinthedamageto cellular components and the initiati-onoftheapoptosis(Fig.1).

Selenium and sepsisIschaemia/reperfusion82

Selenium and sepsis

Fig.

1 Impact of ischaemia/reperfusion at a cellular level. [2]

Hypoxia

ATP

CA2+ + Na+

Anaerobic glycolysis

NO/superoxide interactions + leucocyte and

platelet activation/infiltration

Lipid peroxidation +

DNA damage +

protein modification

ROS

Capillary No- Reflow effectInflammation

Necrosis, apoptosis

Cell change

ROS

Proliferation differentiation

migration

Remodeling angiogenesis

Ischaemia Reperfusion Reperfusion (repair)

Literature

1 EltzschigHK,EckleT.NatMed.2011Nov7;17(11):1391-401. doi: 10.1038/nm.2507. Ischemia and reperfusi-on--from mechanism to translation.

2 KalogerisT,BaoY,KorthuisRJ.Redox Biol. 2014 Jun 2;2:702-14. doi: 10.1016/j.redox.2014.05.006. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning.

Ischaemia/reperfusion 83



Challenge posed by complications in cardiac surgery

General information

• Severe complications with patients undergoing cardiac surgery despite great advancements is a major problem

• Affects up to 16% of the patients

• Three pathophysiological mechanisms are responsible: ischaemia,reperfusionandperioperativeinflammation

• Selenium supplementation intervenes at the same site of action as established pharmacological strategies

Increased severe complications in cardiac surgeryRoughly one million patients per year require cardiac surgery. This number will probably further increase in the next 10 years because of an aging society [1]. Despite great advancements in the stra-tegies for protecting the heart, cardiac surgery is still associated with serious complications. These include death, myocardiac infarction, cardiac arrest and failure, renal failure, stroke, gastrointes-tinal complications and respiratory arrest for up to 16% of the patients [2]. Most of these systemic complications are as-sociated with three patho-physiological mechanisms: ischaemia, reperfusion and perioperativeinflammation[3].

In the case of cardiac surgery using a heart-lung machine, the patient is expo-sed to numerous ischemic stimuli [3]:

1. Induction of a cardioplegic cardiac arrest

2. Micro-embolic events3. Reperfusion of the myocardium

through surgical revascularization4. Termination of the cardioplegic

cardiac arrest

Allthisleadstoaninflammatoryrespon-se associated with fever, leucocytosis, tachycardia,hypotension,fluidaccumu-lation in tissue, and organ failure [4]. Diverse procedures are applied in practice to reduce these causal mecha-nisms or effects, such as the reduction of oxidative stress and organ failure, to improve chances of the patient’s sur-vival. There are both pharmacological as well as non-pharmacological strategies that intervene at various points in the pathophysiological mechanisms. Seleni-um supplementation can advantageously intervene at every one of these points (Fig.1)[3].

The comparison of pharmacological strategies and selenium supplementation in the event of complications shows the immensesignificanceofseleniumforcardiacsurgery(Fig.2)[4].

Ischaemia/reperfusion84 Cardiac surgery

Fig.

1

Complications posed by cardiac surgery, treatment approachesandthepositiveinfluenceofseleniumsupplementation. [3]

Seleniumincluding

coated systems, surgery without

heart-lung machine

Seleniumincluding

N-acetylcystei-ne, methylthioni-

nium chloride

Coagulopathy, formation of

ROS, apoptosis

Multi-organ failure

Change of intracellular signal paths,

NF-κB activation, release of adhesion

molecules and integrins

Seleniumincluding

insulin, glyco-corticoide, sta-tins, aprotinin,

phospho-dieste-rase inhibitor

Death

Release of inflammatory

and anti- inflammatory

mediators

Cellular activation

Seleniumincluding

inhibitors of ad-hesion molecu-les or integrin

Seleniumincluding

monoclonal antibody,

receptor blocker

Stimuluse.g. Hypoxia, I/R

Ischaemia/reperfusion 85Cardiac surgery

Activation ofNF-κB

Phosphorylation ofIκBα

aprotininstatins

Insulinaprotininstatins

Antimediator therapy


Selenium [6]

Selenium [13]

Selenium [12]

Sildenafilinsulinstatins

Selenium [10]

Selenium [11] N-acetyl-cysteine

Selenium [5]

Inhibition or inactivation

Promotion or activation

Selenium [7]

Glucocorticoids

Selenium [8]

Selenium [9]

cell nucleus

Methylene bluestatins

Cell membrane

Phosphodiesterase inhibitor

Formation of NO

Cytokinesbacteriaviruses

IKK complex

ROS

Degradation of ROS

Tissue damage

Multiple organ failure

Cytokines adhesion moleculesother inflammatory

mediators

Surface activation leads to increased

leucocyte activation + release of inflammatory

mediators

Formation of protein kinase

Fig.

2

Site of action of pharmacological strategies and selenium supplementation to reduce complications of cardiac surgery. [3]

Ischaemia/reperfusion86 Cardiac surgery

Literature

1GroverA,GormanK,DallTM,JonasR,LytleB,SheminR,WoodD,KronI.Circulation.2009Aug11;120(6):488-94. doi:10.1161/CIRCULA-TIONAHA.108.776278. Shortage of cardiothoracic surgeons is likely by 2020.

2 Ghosh P, Schistek R, Unger F. Thorac Cardiovasc Surg. 2004 Dec;52(6):356-64. Coronary revascularization in DACH: 1991-2002.

3BenstoemC,GoetzenichA,KraemerS,BoroschS,ManzanaresW,Hardy G, Stoppe C. Nutrients.2015Apr27;7(5):3094-3118. Selenium andItsSupplementationinCardiovascularDisease-WhatdoWeKnow?

4Hall R. JCardiothoracVascAnesth.2013Oct;27(5):983-1033. doi: 10.1053/j.jvca.2012.09.013.Epub2012Dec29.Identificationofinflam-matory mediators and their modulation by strategies for the manage-mentofthesystemicinflammatoryresponseduringcardiacsurgery.

5 Spallholz JE. BiomedEnvironSci.1997Sep;10(2-3):260-70. Free radi-cal generation by selenium compounds and their prooxidant toxicity.

6YunCH,YangJS,KangSS,YangY,ChoJH,SonCG,HanSH.Int Im-munopharmacol.2007Sep;7(9):1192-8. NF-kappaB signaling pathway, not IFN-beta/STAT1, is responsible for the selenium suppression of LPS-induced nitric oxide production.

7ParkHS,ParkE,KimMS,AhnK,KimIY,ChoiEJ.J Biol Chem. 2000 Jan28;275(4):2527-31. Selenite inhibits the c-Jun N-terminal kinase/stress-activatedproteinkinase(JNK/SAPK)throughathiolredoxme-chanism.

8Kretz-RemyC,MehlenP,MiraultME,ArrigoAP.J Cell Biol. 1996 Jun;133(5):1083-93. Inhibition of I kappa B-alpha phosphorylation and degradation and subsequent NF-kappa B activation by glutathione pero-xidase overexpression.

9Kretz-RemyC,ArrigoAP.Biofactors.2001;14(1-4):117-25. Selenium: a key element that controls NF-kappa B activation and I kappa B alpha half life.

10Fu Y, Cheng WH, Porres JM, Ross DA, Lei XG. Free Radic Biol Med. 1999Sep;27(5-6):605-11.Knockoutofcellularglutathioneperoxidasegene renders mice susceptible to diquat-induced oxidative stress.

11

Schnabel R, Lubos E, Messow CM, Sinning CR, Zeller T, Wild PS, PeetzD,HandyDE,MunzelT,LoscalzoJ,LacknerKJ,Blanken-berg S. AmHeartJ.2008Dec;156(6):1201.e1-11. doi: 10.1016/j.ahj.2008.09.004. Selenium supplementation improves antioxidant capacity in vitro and in vivo in patients with coronary artery disease The SeleniumTherapyinCoronaryArterydiseasePatients(SETCAP)Study.

12Mattmiller SA, Carlson BA, Sordillo LM. J Nutr Sci. 2013 Aug 29;2:e28. doi:10.1017/jns.2013.17.Regulationofinflammationbyseleniumandselenoproteins: impact on eicosanoid biosynthesis.

13Huang Z, Rose AH, Hoffmann PR. Antioxid Redox Signal. 2012 Apr 1;16(7):705-43. doi: 10.1089/ars.2011.4145. The role of selenium in inflammationandimmunity:frommolecularmechanismstotherapeuticopportunities.

Activation ofNF-κB

Phosphorylation ofIκBα

aprotininstatins

Insulinaprotininstatins



Selenium [6]

Selenium [13]

Selenium [12]

Sildenafilinsulinstatins

Selenium [10]

Selenium [11] N-acetyl-cysteine

Selenium [5]

Inhibition or inactivation

Promotion or activation

Selenium [7]

Glucocorticoids

Selenium [8]

Selenium [9]

cell nucleus

Methylene bluestatins

Cell membrane

Phosphodiesterase inhibitor

Formation of NO

Cytokinesbacteriaviruses

IKK complex

ROS

Degradation of ROS

Tissue damage

Multiple organ failure

Cytokines adhesion moleculesother inflammatory

mediators

Surface activation leads to increased

leucocyte activation + release of inflammatory

mediators

Formation of protein kinase

Fig.

2

Site of action of pharmacological strategies and selenium supplementation to reduce complications of cardiac surgery. [3]

Ischaemia/reperfusion 87Cardiac surgery





















General information

• Selenoproteins play a major role in the cardiovascular system

• 50% increase in the selenium concentration is associated with a 24% reduction of risk of coronary heart disease

• Least risk of cardiovascular disease at 150 – 160 µg/l selenium in the serum

• AseleniumdeficiencynegativelyinfluencesKeshandisease and infectious myocarditis

• Positive effect of selenium supplementation on existing cardiovascular diseases

• Selenium reduces the cardiotoxicity of doxorubicin

Selenoprotein K

Overexpression reduces intracellular ROS and protects cardiomyocytes

Regulates CD36 expression in macrophages

Contributes to the formation of foam cells and atherogenesis

Selenoprotein R

Involved in dynamic actin reorganization during cardiac stress

Protects cardiomyocytes stressed by ROS

Regulates CD36 expression in macrophages

Glutathione peroxidase 1

Knock-out→ infarct size ↑

Overexpression protects the heart

Selenoprotein S

Involved in the development of subclinical cardiovascular dis-orders for patients with type 2 diabetes

Fig.

1 Functions of selenoproteins in the cardiovascular system. [1]

Ischaemia/reperfusion88 Cardiovascular system


General information

• Selenoproteins play a major role in the cardiovascular system

• 50% increase in the selenium concentration is associated with a 24% reduction of risk of coronary heart disease

• Least risk of cardiovascular disease at 150 – 160 µg/l selenium in the serum

• AseleniumdeficiencynegativelyinfluencesKeshandisease and infectious myocarditis

• Positive effect of selenium supplementation on existing cardiovascular diseases

• Selenium reduces the cardiotoxicity of doxorubicin

Selenoproteinsinfluence the cardiovascular systemOxidative stress is connected to several cardiovascular diseases. The seleno-protein glutathione peroxidase limits oxidative stress by the degradation of hydroperoxides(Fig.1).Thecellisthusprotected from lipoprotein and/or DNA damage. Thioredoxin reductases induce changes in the redox status and thereby regulate functions in the cardiovascular system. A subfamily of selenoproteins, SelW,SelV,SelTandSelHamongothers,formmixeddisulfideswithsub-

strate proteins and bind DNA in a re-dox-sensitive manner [1]. Selenoprotein T (SelT)isinvolvedincalciummobilizationand glucose metabolism [1]. However, the selenoproteins SelM and Sep15 are oxidoreductases in the lumen of the end-oplasmicreticulum.SelenoproteinK,anendoplasmic reticulum protein, is invol-ved in the antioxidant defense system of cardiomyocytes, while Selenoprotein R is overexpressed in the myocardium during a hypertrophy [2].

Thioredoxin reductase 1

Regulates remodeling by signal pathways

Trx-1 reduces hypertrophy and oxidative stress

TrxR1 overexpression during hypertrophy

Deiodinase 2

Involved in the regulation of the thyroid hormones

Principal isoform in the heart

Overexpression improves contractile functionality

Overexpression normalizes genes involved in pathological remodeling


Mitochondrial overexpression protects from I/R injuries

Protects cellular lipids from oxidative stress


Prevents LDL oxidation, vascularinflammation and atherogenesis

Up-regulated during hypertrophy

Ischaemia/reperfusion 89Cardiovascular system

Fig.

2Cardio-protective effect of high selenium status in the physiological range. [3]

Ischaemia/reperfusion

Oxidative stress

Infarct size

TNFα Connexin-43dephosphorylation

Loss of gap junction control

Cell-to-cell propagationof injury

Inflammatory response

Selenium status

Cardio-protective effect of seleniumAnimal experiments with rats that recei-ved either a selenium-poor or a seleni-um-rich diet furthermore showed that selenium reduces the cardiac content of TNFα[3].AlowerTNFαlevelindicatesreducedinflammation.Inaddition,theselenium-rich diet reduced the dephos-phorylation of Connexin-43. Connexin-43 is an important ventricular gap-junction protein that is a decisive factor both for the myocardiac infarct magnitude as well as for cardiac remodeling. The phos-phorylation of Connexin-43 inhibits the

intracellular communication of gap junc-tions. This shows that the cardio-protec-tive effect of selenium is at least partially attributed to the prevention of dephos-phorylation of Connexin-43. An additional effect of the selenium-enhanced diet was the increased activity of antioxidant selenoproteins, whereby oxidative stress wasreduced(Fig.2).Takentogether,this result shows that the quantity of seleniumconsumedinfluencesremode-ling after a cardiacl infarct.


Seleniumdeficitincreasestherisk of cardiovascular diseasesBoth animal experiments as well as stu-dies with humans have shown an inverse association between the selenium status and cardiovascular diseases. An obser-vation trial from 2009 moreover proposes a U-shaped association with a minimum at 150 – 160 µg/l selenium in the serum (Fig.3)[4].

A meta-analysis of 25 observational trials showed that a 50% increase in the sele-nium concentration is associated with a 24% reduction in the risk of coronary heart disease [5].

Fig.

3U-shaped association between the selenium status and cardiovascular diseases. [4]

120 140 160 180 2001000.25

0.5

1.0

Rel

ativ

e ris

k of

a p

erip

hera

l arte

rial d

isea

se

Selenium in serum [µg/l]

2.0Reference range in Germany80 – 120 µg/l


ConnectionofseleniumwithKeshandisease and infectious myocarditisKeshandiseaseisprobablythebest-in-vestigated human disease in connection withaseleniumdeficit.Thediseaseinvolves a dilated cardiomyopathy that primarilyoccursinchildreninKeshanprovince in China, and is characterized by multifocal myocardiac necrosis and calcification,whichisusuallyreversibleafter selenium supplementation [6]. Whileseleniumdeficiencyistheprimarypathogenic factor for the incidence of Keshandisease,mostprobablyaninfec-tious agent plays also a role. The Cox-sackie virus B4 was isolated in patients with this disease. Animal experiments withselenium-deficitmiceshowedthat a selenium supplementation reduced the cardiotoxicity of the Coxsackie virus B4. Furthermore, mice that by nature are resistant against viral-induced myocar-ditis are vulnerable to this disease with aselenium-deficitdiet.FinallyJunetal.

demonstratedthatmicewithadeficitselenium intake showed an increase in Coxsackie virus-induced myocarditis [7].

Selenium plays a major role not only for KeshandiseasebutalsoforChagasdi-sease. Chagas disease is a tropical car-diomyopathy caused by an infection with the parasite Trypanosoma cruzi. Clinical studies have shown that a lower seleni-um status worsens the heart dysfunction of these patients [8]. Moreover, animal experiments have demonstrated that a selenium supplementation reduces heart damage and improves survival rates. In the meantime, a randomized double- blind controlled trial is currently being conductedtoexaminetheinfluenceofselenium supplementation on the pro-gression of Chagas cardiomyopathy [9].

Literature

1 BenstoemC,GoetzenichA,KraemerS,BoroschS,ManzanaresW,HardyG,StoppeC.Nutrients. 2015 Apr 27;7(5):3094-3118.SeleniumandItsSupplementationinCardiovascularDisease-WhatdoWeKnow?

2 Tanguy S, Grauzam S, de Leiris J, Boucher F. MolNutrFoodRes.2012Jul;56(7):1106-21. doi: 10.1002/mnfr.201100766. Impact of dietary selenium intake on cardiac health: experimental approaches and human studies.

3Tanguy S, Rakotovao A, Jouan MG, Ghezzi C, de Leiris J, Boucher F. MolNutrFoodRes.2011Apr;55(4):522-9. doi:10.1002/mnfr.201000393.DietaryseleniumintakeinfluencesCx43dephosphorylation,TNF-αexpressionandcardiac remodeling after reperfused infarction.

4Bleys J, Navas-Acien A, Laclaustra M, Pastor-Barriuso R, Menke A, Ordovas J, Stranges S, Guallar E. Am J Epi-demiol.2009Apr15;169(8):996-1003. doi: 10.1093/aje/kwn414. Serum selenium and peripheral arterial disease: results from the national health and nutrition examination survey, 2003-2004.

5Flores-Mateo G, Navas-Acien A, Pastor-Barriuso R, Guallar E. AmJClinNutr.2006Oct;84(4):762-73. Selenium and coronary heart disease: a meta-analysis.

6Xu GL, Wang SC, Gu BQ, Yang YX, Song HB, Xue WL, Liang WS, Zhang PY. BiomedEnvironSci.1997Sep;10(2-3):316-26.FurtherinvestigationontheroleofseleniumdeficiencyintheaetiologyandpathogenesisofKeshandisease.

7 JunEJ,YeJS,HwangIS,KimYK,LeeH.ActaVirol.2011;55(1):23-9.Seleniumdeficiencycontributestothechro-nic myocarditis in coxsackievirus-infected mice.












Selenium concentration: prognostic marker for acute coronary syndromeThe so-called AtheroGene trial deter-mined the selenium concentration of 1,731 patients suffering from either aStableAnginapectoris(SAP)oran AcuteCoronarySyndrome(ACS)[10]. Within a median follow-up of 6.1 years, 190 patients died due to cardiovascu-lar-related causes. Of the ACS patients, the selenium level for the deceased was significantlylowerthanforthesurvivors (61.0µg/lvs.71.5µ/lseleniuminserum; p < 0.0001). A Cox regression model

showed that the probability of death from cardiovascular disease after adjustment for age and sex declines by 58% for a selenium concentration of more than 80 µg/l selenium in the serum compared to a selenium concentration of below 62µg/lselenium(HR0.42[95%CI0.24–0.72];p=0.002)(Fig.4).Forpatients with SAP, there was no associa-tion between the selenium level and the cardiovascular outcome.

Fig.

4Overall survival for patients with Acute Coronary Syndrome depends on the selenium level. [10]

0 2 4 6 80.00

0.80

0.90

Follow-up Time [Years]

1.00

0.95

0.85

p < 0.0001

Serum selenium concentration < 62 µg/lSerum selenium concentration 62 – 80 µg/lSerum selenium concentration > 80 µg/l

Pro

porti

onal

Sur

viva

l


Positive effect of a selenium supplementation for existing cardiovascular diseasesThis effect is clearest for patients who are fed parenterally. Several case stu-dies described pathological changes in parenterally fed patients who have symptomssimilartoKeshandisease. A selenium supplementation reverses this cardiomyopathic process [11]. A trial from 2012 evaluated the causes of cardiomyopathy in 18 obese patients who had both cardiomyopathy as well as an anamnesis with malabsorption after a stomach reduction [12]. None of the cardiac biopsies showed evidence of a viral infection. However, the cardiac selenium level and the glutathione per- oxidaseactivityweresignificantlyre-duced compared to idiopathic cardiomyo-pathy patients and controls. The 18 pati-ents were randomized and assigned to a group with selenium supplementation (n=10)andaplacebogroup(n=8).

After a six-month treatment, the myocar-diac selenium content and the glutathi-one peroxidase activity in the seleni-um-supplemented group had normalized. This was accompanied by an impro-vement in myocytic degeneration, auto-phagy as well as the cardiac function.

A similar trial, though not associated with malabsorption, of 30 patients showed a significantreductionoftheleftventricularvolume(p=0.03)after9monthsandthereby an improvement of the left vent-ricular function compared to the placebo group(Fig.5)[13]. Furthermore the quality of life of the patients in the selenium-sup-plemented group improved by 9.5 points (p=0.02)andworsenedslightlyintheplacebogroup(Fig.6).

Literature

8RiveraMT,deSouzaAP,MorenoAH,XavierSS,GomesJA,RochaMO,Correa-OliveiraR,NèveJ,VanderpasJ,Araújo-Jorge TC. AmJTropMedHyg.2002Jun;66(6):706-12. Progressive Chagas' cardiomyopathy is associated with low selenium levels.

9 Alvarenga Americano do Brasil PE et al. Trials. 2014 Oct 6;15:388. doi: 10.1186/1745-6215-15-388. Selenium Tre-atmentandChagasicCardiopathy(STCC):studyprotocolforadouble-blindrandomizedcontrolledtrial.

10LubosE,SinningCR,SchnabelRB,WildPS,ZellerT,RupprechtHJ,BickelC,LacknerKJ,PeetzD,LoscalzoJ,Münzel T, Blankenberg S. Atherosclerosis.2010Mar;209(1):271-7. doi: 10.1016/j.atherosclerosis.2009.09.008. Serum selenium and prognosis in cardiovascular disease: results from the AtheroGene study.

11 Joseph J, Loscalzo J. Nutrients.2013Jan31;5(2):340-58. doi: 10.3390/nu5020340. Selenistasis: epistatic effects of selenium on cardiovascular phenotype.

12Frustaci A, Sabbioni E, Fortaner S, Farina M, del Torchio R, Tafani M, Morgante E, Ciriolo MR, Russo MA, Chimen-ti C. EurJHeartFail.2012Feb;14(2):202-10.doi:10.1093/eurjhf/hfr167.Selenium-andzinc-deficientcardiomyo-pathy in human intestinal malabsorption: preliminary results of selenium/zinc infusion.

13WitteKK,NikitinNP,ParkerAC,vonHaehlingS,VolkHD,AnkerSD,ClarkAL,ClelandJG.Eur Heart J. 2005 Nov;26(21):2238-44. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure.









Fig.

5

Reduction of the left ventricular volume compared totheplacebogroup.LVEDV=LeftVentricularEnd-DiastolicVolume.[13]

140

220

180

p = 0.03

Baseline End of trial

260

LVE

DV

(Lef

t Ven

tricu

lar E

nd-D

iast

olic

Vol

ume)

[ml]

Selenium Supplementation Placebo

Fig.

6Improvement of the quality of life of the selenium-supplemented group with cardiomyopathy. [13]

60Baseline

Months

2 3 4 5 6 End of trial

80

70

Qua

lity

of li

fe [%

of t

he m

axim

um] Selenium Supplementation Placebo

p = 0.02


Selenium supplementation decreases cardiovascular mortality of elderly peopleInafive-yearcomprehensiveprospectiverandomized double-blind placebo-cont-rolled trial with Swedes between 70–80 years of age, the effect of a combined supplementation of selenium and coen-zyme Q10 or a placebo was examined for cardiovascular mortality [14]. In to-tal, 443 elderly Swedes participated who were examined every six months using echocardiography and the car-diac biomarkers N-terminal proBNP (NT-proBNP).Duringthefollow-upperiodof5.2years,asignificantreductionofthe cardiovascular mortality in the in-

tervention group compared to the pla-cebo-group(5.9%vs.12.6%;p=0.015)was demonstrated. The NT-proBNP level in the selenium/Q10-supplemented groupwassignificantlylower(214ng/lvs.302ng/lafter48months;p=0.014).Moreover the echocardiography showed significantlybettercardiacfunctionsintheinterventiongroup(p=0.03).Aninvariant proportional hazard regression analysis found a 55% reduction of car-diovascular mortality in the selenium/Q10-supplementedgroup(HR0.45[95%CI0.24–0.89];p=0.02)(Fig.7).

Selenium reduces cardiotoxicity of doxorubicinDoxorubicin is used to treat a large group of cancer diseases. The most serious side effect of doxorubicin is life-threa-tening damage to the heart. Numerous studies have demonstrated that oxidative stress plays a decisive role in the cardiotoxicity of doxorubicin. Several animal experiments showed that both a seleni-umdeficitaswellasreducedglutathioneperoxidase activity leads to an increase of the cardiotoxicity of Doxorubicin [15, 16].

In additional animal experiments, the effect of a co-administration of seleni-um and doxorubicin compared to a sole administration of doxorubicin was exa-mined. The results showed a attentuation of the left-ventricular dysfunction with a co-administration as well as prevention of oxidative stress by an increase of anti-oxidants and reduction of oxidants [15, 17].


Fig.

7Reduced cardiovascular mortality for the selenium/Q10-supplemented group compared to the placebo group. [14]

0.840 200 400 600 800 1,000

Days

1,200 1,400 1,600 1,800 2,000 2,200

0.86

0.88

0.90

0.92

0.94

0.96

0.98

1.00

Cum

ulat

ive

prop

ortio

n of

sur

vivo

rs

Selenium supplementation

Placebo

Literature

14AlehagenU,JohanssonP,BjörnstedtM,RosénA,DahlströmU.IntJCardiol.2013Sep1;167(5):1860-6. doi: 10.1016/j.ijcard.2012.04.156. Cardiovascular mortality and N-terminal-proBNP reduced after combined selenium and coenzyme Q10 supplementation: a 5-year prospective randomized double-blind placebo-controlled trial among elderly Swedish citizens.

15Gao J, Xiong Y, Ho YS, Liu X, Chua CC, Xu X, Wang H, Hamdy R, Chua BH. Biochim Biophys Acta. 2008 Oct;1783(10):2020-9.doi:10.1016/j.bbamcr.2008.05.027.Glutathioneperoxidase1-deficientmicearemoresu-sceptible to doxorubicin-induced cardiotoxicity.

16LiuZW,NiuXL,ChenKL,XingYJ,WangX,QiuC,GaoDF.BiolTraceElemRes.2013Jun;153(1-3):220-8. doi: 10.1007/s12011-013-9641-8. Selenium attenuates adriamycin-induced cardiac dysfunction via restoring expression of ATP-sensitive potassium channels in rats.

17DursunN,TaşkınE,YererAycanMB,SahinL.DrugChemToxicol.2011Apr;34(2):199-207. doi: 10.3109/01480545.2010.538693. Selenium-mediated cardioprotection against adriamycin-induced mitochondrial damage.








General information

• Selenium status correlates with the extent of the cardiac damage

• Sodium selenite protects from I/R damage

• Intraoperative decline of selenium correlates with the postoperative development of multiorgan failure

• The postoperative decrease of selenium concentration is not attributed to the use of a heart-lung machine

• Perioperative administration of selenase® prevents postoperative decrease of selenium concentration below the original value

Selenium status correlates with the extent of cardiac damageIn a trial from 2005, the examination of 70 patients with myocardiac infarct showed that the selenium concentration declinessignificantlywithincreasingda-mageofthecardiactissue(p=0.004)[1]. In order to determine the damage of the cardiac tissue, the following biological markers were determined: cardiac Tro-poninT(cTNT),cardiacTroponinI(cTNI)andcreatinekinase-MB-mass(CK-MBm)(Fig.1).Asaprognosticmarkerof myocardiac infarction, troponins were

used in connection with the C-reactive protein(CRP),amarkerforinflammation.Increased CRP levels correlate with a higher risk of a cardiological incident for patients with coronary disease. This trial alsoshowedasignificantpositivecor-relation of CRP with increasing cardiac damage. Simultaneously, the glutathione peroxidase correlated negatively with theseprognosticmarkers(Fig.2).

Ischaemia/reperfusion98 selenase® for cardiac surgery

Fig.

1Negative correlation of the selenium status with the extent of cardiac damage. [1]

0

40

20

80

60

100

120

140Se

Degree of Damage (cTnT, cTnl, CK-MBm)

moderate highlow

low vs. high: p = 0.004

Ser

um s

elen

ium

con

cent

ratio

n [µ

g/l]

Fig.

2

Positive correlation of CRP and negative correlation of glutathione peroxidase activity with the extent of cardiac damage. [1]

middle highlow

p=0.0001

0 0

5

10

15

20

25

2

4

6

8

10

12

14

CRPGlutathione peroxidase

p = 0,0001

Degree of Damage (cTnT, cTnl, CK-MBm)

p=0.0001

p=0.0001

p=0.032

Glu

tath

ione

per

oxid

ase

activ

ity [U

/ml]

CR

P c

once

ntra

tion

[mg/

l]

Ischaemia/reperfusion 99selenase® for cardiac surgery

Sodium selenite protects from I/R damageVenardosetal.analyzedtheeffectofso-dium selenite supplementation on I/R-in-duced damages in rats [2]. The animals were supplemented with either 0, 50, 240, or 1,000 µg sodium selenite/kg diet for 5 weeks. Then they were submitted to global ischaemia and reperfusion. The group treated with 240 µg sodium selenite/ kg diet served as a control group.The ischaemic contraction at the end of the ischaemic phase was deter-mined to identify the extent of ischemic damage.Thecontractionwassignifi-cantly greater in the selenite-free group (p<0.05vs.control)andreducedwithincreasing sodium selenite concentration (Fig.3).Thisdemonstratesthattheheart

shows a greater tolerance to ischaemia with higher selenium levels.

In order to determine the damage by reperfusion, the extent of the recreated cardiac function was compared. A sup-plementation with 1,000 µg sodium sele-nite/ kg diet improved the recovery of the cardiac function to 57% of the pre-ischa-miclevel(p<0.05).Incomparison,therecovery of cardiac function for the sodi-um selenite-free group or the group with 50 µg sodium selenite/ kg diet were significantlyreducedto38%and44% respectively(p<0.05).Thesedata indicate a cardio-protective effect of sodium selenite.

Fig.

3Reduction of the damage induced by ischaemia with increasing sodium selenite quantity. [2]

50 µg/kg 240 µg/kg 1,000 µg/kg Se-free0

25

50

75

Selenium in diet

100

Ischaemia

Decrease in damage

Max

imal

Con

tract

ion

[mm

Hg]


Literature

1 AltekinE,CokerC,SişmanAR,OnvuralB,KuralayF,KirimliO.JTraceElemMedBiol.2005;18(3):235-42. The relationship between trace elements and cardiac markers in acute coronary syndromes.

2 VenardosK,HarrisonG,HeadrickJ,PerkinsA.JTraceElemMedBiol.2004;18(1):81-8. Effects of dietary seleni-um on glutathione peroxidase and thioredoxin reductase activity and recovery from cardiac ischemia-reperfusion.

3Stoppe C, Schälte G, Rossaint R, Coburn M, Graf B, Spillner J, Marx G, Rex S. Crit Care Med. 2011 Aug;39(8):1879-85. doi: 10.1097/CCM.0b013e3182190d48. The intraoperative decrease of selenium is associated with the postoperative development of multiorgan dysfunction in cardiac surgical patients.

4StevanovicA,CoburnM,MenonA,RossaintR,HeylandD,SchälteG,WerkerT,WonischW,KiehntopfM,Goetze-nich A, Rex S, Stoppe C. PLoSOne.2014Aug13;9(8):e104222. doi: 10.1371/journal.pone.0104222. The import-ance of intraoperative selenium blood levels on organ dysfunction in patients undergoing off-pump cardiac surgery: a randomised controlled trial.

5Stoppe C, Spillner J, Rossaint R, Coburn M, Schälte G, Wildenhues A, Marx G, Rex S. Nutrition. 2013 Jan;29(1):158-65. doi: 10.1016/j.nut.2012.05.013. Selenium blood concentrations in patients undergoing elective cardiac surgery and receiving perioperative sodium selenite.

6

Stoppe C, McDonald B, Rex S, Manzanares W, Whitlock R, Fremes S, Fowler R, Lamarche Y, Meybohm P, Ha-berthürC,RossaintR,GoetzenichA,ElkeG,DayA,HeylandDK.Trials. 2014 Aug 28;15:339. doi: 10.1186/1745-6215-15-339.SodiUmSeleniTeAdminstrationINCardiacSurgery(SUSTAINCSX-trial):studydesignofaninterna-tional multicenter randomized double-blinded controlled trial of high dose sodium-selenite administration in high-risk cardiac surgical patients.

Fig.

4

Better recovery of cardiac function after I/R with increasing sodiumseleniteconcentration.*RPP(RatePressureProduct)=productfromheartrateandbloodpressure.[2]

50 µg/kg 240 µg/kg 1,000 µg/kg Se-free0

20

10

30

40

50

60

Selenium in diet

70

Percentage of recovered cardiac function*

37 %

57 %

Rec

over

y of

car

diac

func

tion

[%]










Intraoperative decrease of selenium correlates with the postoperative development of multiorgan failure Cardiac surgery using a cardiopulmonary bypass induces I/R mediated oxidative stress. A prospective observational trial with 60 patients undergoing cardiac surgery investigated whether the intraoperative decrease of circulatory trace elements is involved in this reaction [3]. Already before the operation, 50 patients (83%)showedasignificantseleniumdeficit,whilethecopperandzincconcen-trations were in the reference range. In all patients, the selenium concentration (89.05±12.65to70.84±10.46µg/lsele-nium in whole blood; p < 0.001) as well as the copper and zinc concentrations

after conclusion of the surgery had sig-nificantlydecreased(Fig.5).Duringtheirstay in the ICU, 12 patients developed multiorgan failure. A multi-logistic regres-sion analysis showed that the selenium concentration at the end of the surgery is an independent predictor with the postoperative appearance of multiorgan failure(HR0.85[95%CI0.76–0.94]; p=0.026).

Fig.

5Significantpostoperativereduction of selenium concentration. [3]

Sel

eniu

m c

once

ntra

tion

in w

hole

blo

od [µ

g/l]

pre-operative

p < 0.001

post-operative40

60

100

140

120

80

Reference range


The postoperative decrease of selenium concentration is not attributed to the use of a heart-lung machine These results were supported by an ad-ditional trial from 2014. In this prospecti-ve randomized interventional trial with 40 patients, it was examined whether the selenium level in connection with an “Off-Pump Coronary Artery Bypass“ procedure(OPCAB),wherenohe-art-lung machine is necessary, declines lessstronglycomparedtoan“On-Pump”procedure, since the oxidative stress for this procedure should be small [4]. More pronounced than in the trial by Stoppe et al., all patients displayed a selenium deficitalreadybeforethesurgery.Afterconclusion of the surgery, both groups

showedasignificantdeclineofseleni-umconcentration(p<0.001),wherebythe decrease in the on-pump group was moresignificant(31.2±13.6%vs.20.2±16.3%;p=0.04)(Fig.6).Ofthemeasu-redvalues(myocardiac-specificcreatinekinase, asymmetrical dimethylargini-ne, glutathione peroxidase), only the postoperative selenium concentration showed a correlation with the develop-ment of a postoperative organ dysfuncti-onbothforallpatients(p=0.037) as well as for the OPCAB group (p=0.023).

Fig.

6Significantlygreaterpostoperativedeclineoftheseleniumconcen-tration in the on-pump group. [4]

OPCAB On-Pump30

40

70

80

60

100

90

50

Sel

eniu

m c

once

ntra

tion

in w

hole

blo

od [µ

g/l]

postoperativepreoperative

p = 0.04

p < 0.001p < 0.001

Reference range



1 week before

Elective cardiac surgery 5001 µg Se / day oral

Day 1

Bolus ideally within 30 minutes after administration of anaesthesia; termination of the bolus before initiation of the cardiopulmonary bypass

Intraoperative as bolus (forabout30min.)

2,0001,2 µg Se


2,0001,2 µg Se

From day 2 of the

ICU staymaintenance therapy 1,0001,2 µg Se / day

Literature 1 Stoppe C et al 2013, Nutrition 29:1, 158-1652 Stoppe C et al 2014, Trials 15:339

Perioperative administration of selenase® prevents postoperative decrease of selenium concentrationIn a prospective observation trial, the effect of perioperative administration of selenase® was examined in 100 patients. Similar to the two other studies descri-bed, 75% of the patients already had aseleniumdeficitbeforesurgery.Theperioperative administration of 2,000 µg selenium as selenase® achieved a nor-malization of the selenium level at ICU admission(Fig.7).Moreover,thisbolusinjection prevented a post-operative decrease of the selenium concentration below the perioperative selenium value. The daily administration of 1,000 µg sele-nium as selenase® during the stay in the ICU stabilized the selenium level in the high reference range.

Both the selenium concentration at ICU admission as well as four hours later weresignificantlylowerinpatients,whodeveloped an organ dysfunction in the observation period, compared to patients withoutcomplications(Table1).AROCcurve analysis showed that the selenium concentrations at ICU admission and four hours after admission predicted an organ dysfunction, while the periopera-tive selenium value and the selenium concentrationonthefirstpostoperativeday had no predictive value.




Tab.

1

Significantlylowerseleniumconcentrationsforpatients with organ dysfunction. Selenium concentration in µg/l in whole blood. [5]

Patients with organ dysfunction

Patients without complications

P-value

Selenium concentration at ICU admission

118.47 ± 16.38 127.16 ± 17.69 0.030

Selenium concentration 4 hours after ICU admission

103.47 ± 13.45 110.84 ± 14.41 0.025

Fig.

7

A bolus injection of selenase® before surgery prevents the decrease in postoperative selenium concentration below the perioperative selenium level. [5]

80

60

140

Time (days)

200

180

160

100

120

Reference range

Pre-

oper

ative

Adm

issio

n4

hPO

D 1

POD

2PO

D 3

POD

4PO

D 5

POD

6PO

D 7

POD

8PO

D 9

POD

10PO

D 11

POD

12PO

D 13

POD

14PO

D 15

POD

16

Who

le b

lood

sel

eniu

m le

vels

(µg/

l)


For a matched-pair analysis of 42 pati-ents each, who showed no perioperative differences, the selenase®-supplemen-tedgrouprevealedasignificantlyhigherseleniumvalueatICUadmission(Fig.8).While the selenium level in the control group declined further during the stay in intensive care, the selenium concentrati-onincreasedfromthefirstpostoperativeday, whereby the difference from the second postoperative day was highly si-gnificant(p<0.001)(Fig.9).Onthefirstpostoperative day, the selenase®-supple-mentedgroupshowedasignificantlylo-werSAPSIIandSOFAvalue(p=0.005orp=0.007).Theselenase®-supple-mented group moreover revealed fewer respiratory organ dysfunctions

(p=0.040).Thecontrolgroupmorefrequently developed severe throm-bocytopenia(p=0.035)(Table2).

No side effects occurred during the trial which could be brought in connection with the selenase® application. The dosage regime proved to be safe. In ordertobetterconfirmtheseresults,a large-scale international multicentric randomized double-blind controlled trial (SUSTAIN-CSX)fortheuseofhigh-doseselenase® for patients undergoing cardi-ac surgery was initiated in 2015 [6].

Fig.

8

Significantlyincreasedseleniumconcentrationduring the ICU stay in the selenase®-supplementedgroup(n=42)compared toahistoricalcontrolgroup(n=42).[5]

Reference range

preoperative0

40

60

80

100

120

140

p < 0.05

postoperative

Sel

eniu

m c

once

ntra

tion

in s

erum

[µg/

l]

selenase® Control


Tab.

2

Significantdifferencesbetweentheselenase®-supplemented group and the control group onthefirstpostoperativeday.[5]

selenase®- sup-plemented group

Control group P-Value

SAPS II 23 ± 7 29 ± 8 0.005

SOFA 4 ± 2 7 ± 2 0.007

Respiratory organ dysfunction

0 4 0.040

Severe thrombocytopenia 3 10 0.035

Fig.

9

Significantlyhigherpostoperativeseleniumconcentrations in the selenase®-supplemented group(n=42)comparedtoahistoricalcontrolgroup(n=42).[5]

Reference range

pre-operative

0

40

60

80

100

120

140

p < 0.05

p < 0.05p < 0.05

1 2postoperative Day

3 4

Sel

eniu

m c

once

ntra

tion

in s

erum

[µg/

l]

selenase® Control


Selenium in the brain

General information

• Selenium plays an important role in the brain

• Glutathioneperoxidase-1influencestheinfarctvolume

• Glutathione peroxidase 4 is essential in brain development and in neuropathological diseases

• The lack of the selenium transport protein Selenoprotein P causes severe neurological dysfunction, which can be attenuated by sodium selenite supplementation

Selenium is essential for the brainThe total amount of selenium in the brain is comparatively low. In the brain, a concentration of 110 ± 21 ng sele-nium/g wet weight was determined in German adults. In contrast, there is 771 ± 169 ng selenium/g in the kidney and 291 ± 78 ng selenium/g in the liver. The brain thus contains only 2.3% of the entire selenium in a human body [1]. With a long-term low-selenium diet, the available selenium is preferably transpor-ted to the brain at the expense of other organs, such as the liver [2]. Approxima-tely 20% of the entire selenium amount in the brain is incorporated in glutathione peroxidase [2].Withasufficientseleniumsupply, the glutathione peroxidase activity in the liver is 13 times greater thaninthebrain.Afteraselenium-deficitdiet of about 6 months, the activity of

the glutathione peroxidase was reduced by 92%, while in the brain it only declined negligibly [3]. Selenium plays a decisive role for various diseases of the central nervoussystem(CNS),amongothersstroke, brain tumors, brain development and affective disorders. First indications delivered reports about neurological diseases in patients with low seleni-um status or restricted selenoprotein biosynthesis. Over a long time period, parenterally nourished patients with inadequate selenium content developed progressive encephalopathy [4]. Two rare mutations of the human SEPSECS gene that codes the selenocysteine synthase lead to progressive cerebellar and cereb-ral atrophy [5].

Ischaemia/reperfusion108 Selenium in the brain

Literature

1 Oster O, Schmiedel G, Prellwitz W. Biol Trace Elem Res. 1988 Jan-Apr;15:23-45. The organ distribution of seleni-um in German adults.

2 Steinbrenner H, Sies H. ArchBiochemBiophys.2013Aug15;536(2):152-7. doi: 10.1016/j.abb.2013.02.021. Seleni-um homeostasis and antioxidant selenoproteins in brain: implications for disorders in the central nervous system.

3 Buckman TD, Sutphin MS, Eckhert CD. BiochimBiophysActa.1993May13;1163(2):176-84. A comparison of the effects of dietary selenium on selenoprotein expression in rat brain and liver.

4HiratoJ,NakazatoY,KoyamaH,YamadaA,SuzukiN,KuroiwaM,TakahashiA,MatsuyamaS,AsayamaK.Acta Neuropathol.2003Sep;106(3):234-42. Encephalopathy in megacystis-microcolon-intestinal hypoperistalsis syndro-mepatientsonlong-termtotalparenteralnutritionpossiblyduetoseleniumdeficiency.

5AgamyO,BenZeevB,LevD,MarcusB,FineD,SuD,NarkisG,OfirR,HoffmannC,Leshinsky-SilverE,FlusserH, Sivan S, Söll D, Lerman-Sagie T, Birk OS. AmJHumGenet.2010Oct8;87(4):538-44. Mutations disrupting selenocysteine formation cause progressive cerebello-cerebral atrophy.

6CrackPJ,TaylorJM,FlentjarNJ,deHaanJ,HertzogP,IannelloRC,KolaI.JNeurochem.2001Sep;78(6):1389-99.Increasedinfarctsizeandexacerbatedapoptosisintheglutathioneperoxidase-1(Gpx-1)knockoutmousebrain in response to ischemia/reperfusion injury.

7 IshibashiN,ProkopenkoO,Weisbrot-LefkowitzM,ReuhlKR,MirochnitchenkoO.Brain Res Mol Brain Res. 2002 Dec30;109(1-2):34-44. Glutathione peroxidase inhibits cell death and glial activation following experimental stroke.

8YantLJ,RanQ,RaoL,VanRemmenH,ShibataniT,BelterJG,MottaL,RichardsonA,ProllaTA.Free Radic Biol Med.2003Feb15;34(4):496-502. The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults.

9 SavaskanNE,UferC,KühnH,BorchertA.BiolChem.2007Oct;388(10):1007-17. Molecular biology of glutathione peroxidase 4: from genomic structure to developmental expression and neural function.

10BellingerFP,BellingerMT,SealeLA,TakemotoAS,RamanAV,MikiT,Manning-BoğAB,BerryMJ,WhiteLR,Ross GW. MolNeurodegener.2011Jan21;6(1):8. doi: 10.1186/1750-1326-6-8. Glutathione Peroxidase 4 is associ-ated with Neuromelanin in Substantia Nigra and Dystrophic Axons in Putamen of Parkinson's brain.

11WirthEK,ConradM,WintererJ,WoznyC,CarlsonBA,RothS,SchmitzD,BornkammGW,CoppolaV,Tessa-rolloL,SchomburgL,KöhrleJ,HatfieldDL,SchweizerU.FASEBJ.2010Mar;24(3):844-52. doi: 10.1096/fj.09-143974. Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration.

12 Dringen R, Pawlowski PG, Hirrlinger J. JNeurosciRes.2005Jan1-15;79(1-2):157-65.Peroxidedetoxificationbybrain cells.

13BennerMJ,SettlesML,MurdochGK,HardyRW,RobisonBD.PhysiolGenomics.2013Aug1;45(15):653-66. doi: 10.1152/physiolgenomics.00030.2013.Sex-specifictranscriptionalresponsesofthezebrafish(Daniorerio)brainselenoproteome to acute sodium selenite supplementation.

14 JeeMK,JungJS,ChoiJI,JangJA,KangKS,ImYB,KangSK.Brain.2012Apr;135(Pt4):1237-52. doi: 10.1093/brain/aws047. MicroRNA 486 is a potentially novel target for the treatment of spinal cord injury.

15 BurkRF,HillKE,ReadR,BellewT.AmJPhysiol.1991Jul;261(1Pt1):E26-30. Response of rat selenoprotein P to selenium administration and fate of its selenium.

16 SchomburgL,SchweizerU,HoltmannB,FlohéL,SendtnerM,KöhrleJ.BiochemJ.2003Mar1;370(Pt2):397-402. Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues.

17 HillKE,ZhouJ,McMahanWJ,MotleyAK,AtkinsJF,GestelandRF,BurkRF.J Biol Chem. 2003 Apr 18;278(16):13640-6. Deletion of selenoprotein P alters distribution of selenium in the mouse.

18 HillKE,ZhouJ,McMahanWJ,MotleyAK,BurkRF.JNutr.2004Jan;134(1):157-61. Neurological dysfunction occurs in mice with targeted deletion of the selenoprotein P gene.

19RamanAV,PittsMW,SeyedaliA,HashimotoAC,SealeLA,BellingerFP,BerryMJ.Genes Brain Behav. 2012 Jul;11(5):601-13. doi: 10.1111/j.1601-183X.2012.00794.x. Absence of selenoprotein P but not selenocysteine lyase results in severe neurological dysfunction.

Ischaemia/reperfusion 109Selenium in the brain



























Fig.

13-fold increased infarct volume for glutathione peroxidase1(GPx1)knock-outmice.[6]

Infa

rct v

olum

e [m

m3 ]

GPx1 wildtype mice GPx1 knock-out mice

p < 0.01

0

50

100

150

Glutathioneperoxidase1influences the infarct volumeAs already long known, glutathione peroxidase1(GPx1)inknock-outmiceshow a 3-fold increase of infarct volume comparedwithwild-typemice(p<0.01)(Fig.1)[6].Thisisalsoreflectedintheincreased number of necrotic and apop-toticcells(Fig.2).Anearlieractivationof caspase 3 in GPx1 knock-out mice moreover indicates increased suscep-tibility compared to apoptosis in GPx1 knock-out mice.

Furthermore, an investigation with transgenic mice, which overexpressed glutathione peroxidase, revealed a signi-ficantreductionintheinfarctvolume

in consequence of I/R damage compared with non-transgenic mice [7]. An overex-pression of glutathione peroxidase signi-ficantlyreducedbothnecroticaswellasapoptotic cell death in endangered brain regions(p<0.05).Intheseanimals,theactivation of astrocytoma and microglia in the ischemic brain was reduced. In contrast to wild type-mice, glutathione peroxidase overexpressed mice showed asignificantlybetterpreservedtissuestructureandareducedinfiltrationofacuteinflammatorycells(p<0.05).


Fig.

2Significantlyincreasednumberofnecrotic and apoptotic cells in GPx1 knock-out mice. [6]

0

10

20

30

0

10

20

necr

otic

and

apo

ptot

ic c

ells

[%]

necr

otic

and

apo

ptot

ic c

ells

[%]

necr

otic

and

apo

ptot

ic c

ells

[%]

necr

otic

and

apo

ptot

ic c

ells

[%

]

0

5

10

15

0

10

20

30

Primary Motor Cortex Primary Somatosensory Cortex

Piriform Cortex

p < 0.05

p < 0.05

Caudate Putamen

GPx1-wildtype mice GPx1-knock-out mice

p < 0.05

p < 0.05


Glutathione peroxidase 4: essential for brain development and neuropathological diseasesGlutathioneperoxidase4(GPx4)isessential for survival. Homozygous GPx4 knock-out mice in the second trimester of pregnancy die in utero because of in-creased apoptosis and cell death, which result in the malformation of the embryo [8]. GPx4 is expressed in neurons, above all in the hippocampus [9]. Just recently it was demonstrated that the neuronal GPx4 expression plays an essential neu-roprotective role in Morbus Parkinson [10]. GPx4 moreover modulates the inter- neuronal function as well as the expres-sion of parvalbumin [11]. Furthermore, GPx4 prevents seizures and neurodegeneration [11].

GPx4 is a multifunctional antioxidative protein with anti-apoptotic characteristics [9]. This is particularly relevant because neurons, in contrast to glial cells, essentially depend on their GPx activity to detoxify free oxygen radicals (ROS)andlipidperoxides[12]. Increased ROS levels occur in neuropathological disorders such as trauma, seizure and ischaemia. Furthermore, it has been shown that the cytosolic variants of GPx4 are up-regulated after brain injuries [9].

However not in neurons, but rather in reactive astrocytes, a glial cell type that under normal conditions expresses no GPX4. After brain injuries, astrocytes change their cytoskeleton and migrate in the direction of the lesion, where they are involved in the repair of oligodendrocytes and myelination, as well as in the re-es-tablishment of the blood-brain barrier in ordertopreventneuroinflammation[9]. The expression of GPx4 in the astrocy-tes is therefore a response to stress that serves for neuro-protection to prevent additional damage. A sodium selenite supplementation in the physiological rangewithzebrafishsignificantlyincrea-sed the GPx4 expression in the brain comparedtoselenium-deficitzebrafish(p=0.048)(Fig.3)[13]. Apart from GPx4, the expression of GPx3 also increased, which also plays an active antioxidative role in the CNS [14]. Overall, these results suggest that a sodium selenite supple-mentation increases the antioxidative capacity of the brain [13].


Fig.

3

Sodium selenite supplementation inthephysiologicalrangesignificantlyincreases the GPx4 expression in the brain. [13]

0

p < 0.05

Rel

ativ

e ex

pres

sion

of

Glu

tath

ionp

erox

idas

e 4

in th

e br

ain

[log

2]

-0.05Sodium selenite supplemented groupControl group

0.05

0.1

0.15

0.2


Fig.

4

SignificantimprovementofbrainfunctiondisordersforSEPP1knock-out mice with a sodium selenite supplementation above the daily normal selenium requirement. [18]

Stri

de le

ngth

[cm

]

00 0.1 0.25

Sodium selenite supplementation [mg/kg]

2

4

6

SEPP1 wildtype mice

SEPP1 knock-out mice p < 0.05

p < 0.05

Selenoprotein P knock-out causes severe neurological dysfunctionAlmost all known selenoproteins occur in the brain, whereby the transport pro-tein for selenium, the selenoprotein P (SEPP1),makesseleniumavailableinthe form of selenocysteine for the ex-pression of selenoprotein. Under sele-niumdeficitconditionsseleniumfromSEPP1 is detected in the brain after two hours [15].The“knock-out”ofSEPP1leads to decreased selenium concen-tration and selenoprotein activities in the brain [16, 17]. SEPP1 knock-out mice developed brain function disorders and showed limited motor coordination with an adequate selenium diet with sodium selenite [16, 17]. However, the neurological disorders with an adequate selenium diet

with selenomethionine were so massive that half of the SEPP1 knock-out mice had to be euthanized. A sodium selenite supplementation above the daily normal selenium requirement could prevent brainfunctiondisorders(Fig.4)[18].

Moreover,significantlygreaterneuro-logical dysfunction occurred with male animals in SEPP1 knock-out mice (p<0.001)(Fig.5)[19]. A supplementation with sodium selenite attentuated the mo-toricdeficitsofmaleanimalstoagreaterdegree(p<0.001)(Fig.6).


Fig.

5Reduced motor coordination in SEPP1 knock-out mice is more pronounced in male animals. [19]

0

1

2

3

Turn

tim

e [s

econ

ds]

Pol

e Te

st [s

econ

ds]

0

4

8

12

p < 0.001Control group

Sodium selenite supplementation

SEPP1-wildtype mice SEPP1-knock-out mice

p < 0.01 p < 0.001

0

1

2

3

Turn

tim

e [s

econ

ds]

Pol

e Te

st [s

econ

ds]

0

4

8

12

p < 0.001

male female

male female

male female

male female

SEPP1-wildtype mice SEPP1-knock-out mice



General information

• Sodium selenite acts neuroprotectively even hours after induction of the damage

• Seleniumdeficitresultsinmassivelyincreasedsusceptibility to excitotoxicity and greater neuronal cell loss

• The neuroprotective effect of sodium selenite is based on:

• the reduction of oxidative stress in neurons

• the preservation of the mitochondrial respiratory chain

• theinhibitionofNFκB-andAF1activation

• the inhibition of the ischaemia-induced DNA oxidation

• the normalization of ischaemia-activated autophagy

Sodium selenite acts neuroprotectively even hours after induction of the damage Savaskan et al. investigated the role of selenium for stroke in vitro and in animal experiments. Glutamate was employed for the simulation of a stroke [1]. It is the predominant stimulating neurotrans-mitter in the brain. Under pathological conditions such as stroke, epilepsy and traumatic brain damage, glutamate can be toxic for neurons. Experiments have showed that simultaneous administrati-on of sodium selenite in a concentration dependent manner prevented glutamate inducedcelldeath(p<0.01)(Fig.1),wherebythegreatesteffect(98%protec-tion) was determined for a concentration of 100 nM sodium selenite, a concentra-

tion that lies in the human physiological range. Glutamate-induced cell death could not only be prevented with the simultaneous administration of sodium selenite, but also with a sodium sele-nite administration two hours after the glutamate-induceddamage(p<0.001)(Fig.2).Theseresultswereconfirmedin an additional study by Mehta et al. [2]. Bothasignificantneuroprotectiveeffectof sodium selenite with glutamate toxicity aswellaswithhypoxia(p<0.001or P<0.05)wasdemonstrated(Fig.3)

Ischaemia/reperfusion116 Sodium selenite for stroke

Fig.

1Concentration-dependent neuronal protection of sodium selenite. [1]

00

20

40

60

80

100

120* p < 0.01 p < 0.01

0

20

40

60

80

100

120

0.01 0.1 0.5 1 5 10 Control

Sodium selenite concentration [µM]

Neu

ropr

otec

tion

[%]

Cel

l via

bilit

y [%

]

Sodium selenite

Sodium selenite +Glutamate

Glutamate

*

* **

Fig.

2

A sodium selenite administration in the physiological range after two hours prevents neuron death. [1]

p < 0.01

p < 0.01

0

20

40

60

80

100

120

Control

Cel

l via

bilit

y [%

]

Sodium selenite

Sodiumselenite +Glutamate

Glutamate

Fig.

3

Neuroprotective effect of sodium selenite against glutamate toxicity and hypoxia. [2]

p < 0.001

p < 0.05

p < 0.001 p < 0.05

0

20

40

60

80

100

120

Control

Cel

l via

bilit

y [%

]

HypoxiaGlutamate

Sodium selenite supplementationControl group

Ischaemia/reperfusion 117Sodium selenite for stroke

Fig.

4Significantimprovementoftheneurologicaloutcome in sodium selenite supplemented ischaemia group. [3]

0

20

30

50

10

70

40

60

Beh

avio

ral S

core

p < 0.001

Flexion Spontaneous movement

p < 0.05 p < 0.001 p < 0.01

Control Ischaemia Ischaemia + Sodium selenite Sodium selenite

The comparison of neurological damage with ischaemia with and without sodium selenitesupplementsrevealedsignifi-cantlylessneurologicaldeficitswithaninterventionofsodiumselenite(p<0.05orp<0.01)(Fig.4)[3]. Also the death of brain cells with ischaemia was sig-nificantlyreducedby38%withsodiumselenitesupplementation(p<0.05) (Fig.5)[3].

A seven-day sodium selenite supplemen-tation before ischaemia in vivo resulted inasignificantreductionofbraindamage(p<0.01)(Fig.6)[2]. The infarct volume was thereby reduced from 36.4 ± 24.5% to 11.6 ± 5.0% compared to the control group 24 hours after re-establishment of the circulation. This in vivo result clearly shows the neuroprotective effect of sodi-um selenite for strokes.


Fig.

5Significantlylowerinductionofapoptosisinthesodiumselenite supplemented ischaemia group. [3]

0

20

30

50

10

70

80

40

60

Cas

pase

-3 a

ctiv

atio

n [%

cha

nge

of c

ontro

ll]

Control Ischaemia Ischaemia +Sodium selenite

Sodium selenite

p < 0.001 p < 0.05

+ 160 % - 38 %

Fig.

6

Sodium selenite supplementation significantlyreducesischaemiainduced brain damage. [2]

p < 0.05

0

20

40

60

80

Control

Infa

rct v

olum

e [%

]

Sodium selenite


Seleniumdeficitmassivelyincreases susceptibility to excitotoxicity and increased neuronal cell lossInordertoconfirmthisinvitroresult,ratswere administered a selenium adequate ordeficientdiet[1].Theresultconfirmedthe hierarchy of selenium distribution underselenium-deficitconditions. A selenium-poor diet in rats resulted in a dramatic reduction of the selenium concentrationintheliver(p<0.001),while in the brain, the selenium level wassignificantlyreducedby10% (p<0.01)(Fig.7)[1].

InaKainatmodelforexcitotoxicityitwashowever shown that this 10% reduction oftheseleniumlevelinthebrainsufficedtoproducesignificantlyhigherseizurerates(p<0.01)(Fig.8)[1]. Moreover, selenium-deficitratsshowedsignificantlymore apoptotic neurons and the neuronal celllossinthehippocampuswassignifi-cantly higher than in rats fed a selenium adequatediet(p<0.01)(Fig.9).

Fig.

7

Differentimpactofaseleniumdeficitontheseleniumconcentration in the liver and in the brain compared with an adequate selenium intake. [1]

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Sel

eniu

m c

once

ntra

tion

[mg/

kg]

Sel

eniu

m c

once

ntra

tion

[mg/

kg]

0

20

40

60

80

100

120

140

160

180

Adequate selenium diet

Liver Brain

Deficit selenium diet

Adequate selenium diet

Deficit selenium diet

p < 0.001 p < 0.01


Fig.

9

Aselenium-poordietleadstosignificantlygreaterneural cell loss in the hippocampus compared to a diet with adequate selenium. [1]

0-30 0 30 60 90 120 150 180

0.5

1

1.5

2

2.5

3

3.5

4

4.5

5

Sei

zure

act

ivity

Time after kainate injection [min]

Deficit selenium diet + kainate

Adequate selenium diet + kainate

Control

Fig.

8Seleniumdeficitleadstosignificanthigherseizurerates in the brain. [1]

0

50

75

125

25

100

num

ber o

f CA

1 ne

uron

s

Deficit selenium diet + control

Deficit selenium diet+ kainate

Adequate selenium diet+ kainate

p < 0.01

p < 0.001


Principle of action of neuronal protection by sodium selenite

Sodium selenite reduces oxidative stress in neurons

A surplus of glutamate induces high levelsofreactiveoxygenspecies(ROS)in neurons and thereby strongly increa-ses oxidative stress. Sodium selenite administration prevents the production ofROS(p<0.01)(Fig.10),whilehavingnoinfluenceontheglutathionelevel[1]. Also in the study by Mehta et al, sodium

selenitesignificantlyreducedtheproduc-tion of ROS induced by glutamate toxicity andhypoxia(p<0.001)orp<0.05) (Fig.11)[2]. One of the basic mechanisms of sodium selenite-mediated neuronal protectionliesinthesignificantattenuati-on of oxidative stress.

Fig.

10Sodium selenite reduces the number of ROS in stroke. [1]

0

20

40

60

80

100

120

140

160

180

200

Per

oxid

e le

vel (

RO

S)

Control Sodium selenite+ Glutamate

p < 0.01

Glutamate


Fig.

11SodiumselenitesignificantlyattenuatesROSformationinducedbyglutamate(A)andhypoxia(B).[2]

0

50

100

150

200

250

RO

S fo

rmat

ion

rela

tive

DH

E In

tens

ity (D

ihyd

roet

hidi

um) [

%]

ControlControl Glutamate Control Glutamate

Sodium selenite

0

50

100

150

200

250

RO

S fo

rmat

ion

rela

tive

DH

E In

tens

ity (D

ihyd

roet

hidi

um) [

%]

ControlControl Hypoxia Control Hypoxia

Sodium selenite

p < 0.001 p < 0.001

p < 0.01 p < 0.05

A

B


Sodium selenite preserves the mitochondrial respiratory chain after hypoxiaHypoxiasignificantlyreducestheactivityofthecomplexI–IVoftherespiratorychain(p<0.01)(Fig.12)[2]. A pretre-atment with sodium selenite increases the activity of the individual complexes onthebasallevelandalsosignificantlyreduces the inhibitory effect of hypoxia ontherespiratorychain(Table1).

Therefore, a sodium selenite supplemen-tation mitigates the negative effect of hypoxia on the mitochondrial respiratory chain, whereby the activity of the com-plex either remained at a normal level or significantlyimprovedcompared to no sodium selenite administration.

SodiumseleniteinhibitsNFκB- and AF-1 activationGlutamate treatment resulted in increa-sednuclearNFκBandAP-1level.Thisincrease was inhibited by sodium sele-nite [1].Thegel-shiftassaysignificantlyshowed that the glutamate-induced acti-vationandbondingofNFκBandAP-1ontheir“nuclearresponseelements”was

reduced by sodium selenite. The missing activationofNFκBandAP-1preventsneuronal cell death and reduces the activation of glial cells. The glial activa-tion raises stress signals and neuronal damage to a higher power, which leads tosecondarycelldeath(“secondhit”).

Tab.

1Sodiumselenitesignificantlypreventsorreducesthenegativeeffect of hypoxia on the complex of the respiratory chain. [2]

Hypoxia Hypoxia + sodium selenite

P-value

Complex I -37% -5% p < 0.01

Complex II + III -65% -45%

ComplexIV -24% -3% p < 0.001


Fig.

12Sodium selenite preserves the activity of the respiratory chain of mitochondria after hypoxia. [2]

0

50

100

150

Com

plex

I ac

tivity

[%]


Sodium selenite

0

50

100

150

Com

plex

II +

III a

ctiv

ity [%

]


Sodium selenite

0

50

100

150

Com

plex

IV a

ctiv

ity [%

]


Sodium selenite

p < 0.01

p < 0.001 p < 0.01

p < 0.01

p < 0.001 p < 0.001


Effect of sodium selenite is dependent on the biosynthesis of selenoproteinsIn contrast to sodium selenite, sodium selenate has no direct antioxidative characteristics, but rather is incorporated in selenoproteins. After sodium selenite was replaced by sodium selenate, most oftheneuroprotectiveprotection(70%)remained preserved [1]. This suggests

that the neuroprotective effect of sodium selenite depends on the biosynthesis of selenoprotein. The addition of cyclohe-ximide, which inhibits protein biosynthe-sis, cancels the neuroprotective effect of sodium selenite thereby supports the hypothesis(Fig.13).

Sodium selenite reduced ischaemia induced DNA oxidationIn addition, Mehta et al. investigated whether cerebral ischaemia induces oxidative DNA damage [2]. The evidence of8-OHdGrevealedasignificantincrea-se in the oxidative damage 24 hours after re-establishment of circulation. In comparison to this, a pre-treatment withsodiumselenitesignificantlyre-

duced the oxidative DNA damage (p<0.05)(Fig.14).Thus,theantioxida-tive impact of sodium selenite consists in avoiding the oxidation of DNA and thereby its being damaged.

Literature

1 SavaskanNE,BräuerAU,KühbacherM,EyüpogluIY,KyriakopoulosA,NinnemannO,BehneD,NitschR.FASEB J.2003Jan;17(1):112-4.Seleniumdeficiencyincreasessusceptibilitytoglutamate-inducedexcitotoxicity.

2MehtaSL,KumariS,MendelevN,LiPA.BMC Neurosci. 2012 Jul 9;13:79. doi: 10.1186/1471-2202-13-79. Seleni-um preserves mitochondrial function, stimulates mitochondrial biogenesis, and reduces infarct volume after focal cerebral ischemia.

3 YousufS,AtifF,AhmadM,HodaMN,KhanMB,IshratT,IslamF.Brain Res. 2007 May 25;1147:218-25. Selenium plays a modulatory role against cerebral ischemia-induced neuronal damage in rat hippocampus.






Fig.

13The addition of the protein synthesis inhibitor cycloheximide cancels the neuroprotective effect of sodium selenite. [1]

0

50

75

125

25

175

100

150

Cel

l via

bilit

y [%

]

Control Sodium selenite+ Glutamate

Sodium selenite+ Glutamate

+ Cycloheximid

Glutamate

p < 0.01 p < 0.001

Fig.

14Sodium selenite reduces DNA oxidation induced by ischaemia. [2]

0

20

30

50

60

10

40

8-O

HdG

pos

itive

cel

ls

Control Sodium selenite

p < 0.01


Sodium selenite normalizes ischaemia-activated autophagyIn order to remove damaged organelles and cell debris after a cerebral ischae-mia, autophagy is activated. LC3-II is a marker of autophagy. The measurement of LC3-II in vivo after an induced ischae-miarevealedasignificantincreaseafterfivehours(p<0.001)andadeclinetotheoriginallevelafter24hours(Fig.15)[2]. In rats, that received sodium selenite for seven days, the increase

ofLC3-IIafterfivehourswassignificantlylower(p<0.01).After24hoursthe LC3-IIlevelreductionwashighlysignifi-cant compared to the control group (p<0.001).Asodiumselenitepre-treat-ment prevents brain damage by ischae-mia. Therefore the activation of autopha-gy is reduced.

Fig.

15Sodium selenite inhibits the activation of autophagy after cerebral ischaemia. [2]

0

50

100

150

Cel

l via

bilit

y [%

]

Control

Control Sodium selenite Control Sodium selenite Control Sodium selenite

Glutamate Hypoxia

p < 0.05

p < 0.001 p < 0.001 p < 0.05


Fig.

16Effectofaseleniumdeficit(rightside)onthebrain affected by stroke, ischaemia and brain trauma. [1]

Glutamate release calcium influx

Glutamate-induced seizure

Glutamate release calcium influx

NF-κB NF-κB

Oxidative stress Oxidative stress

Neuron cell death

Neuron cell death

Glia activation

Glia activation

Tissue damage

Seizures

Tissue damage

Seizures

with sodium selenite pre-treatment Control group

Impactofaseleniumdeficit on the brain affected by stroke


Selenium status and selenoprotein activity in the event of a stroke

General information

• Strokepatientsshowsignificantlydecreasedseleniumvalues

• Correlation between glutathion peroxidase concentration, neurologicaldeficit,andoutcome

• SignificantlyreducedSelenoproteinPforpatientswithan acute stroke

• AreducedSelenoproteinPstatusissignificantlyassociated with a higher risk of a stroke

Strokepatientsshowsiginficantly decreased selenium values A trial by Zimmermann et al. has compa-red the antioxidant status of patients withacutestroke(n=11)withpatientswho suffered a stroke in the previous 12months(n=17)[1]. In patients with a stroke anamnesis, the average se-rum selenium concentration of 73.4 ± 11.1 µg/l was below the reference value

of80µg/lseleniuminserum.Valuesbe-low 80 µg/l selenium in serum are consi-deredasseleniumdeficit.Incomparison,the serum selenium level in patients with anacutestrokeshowedsignificantlylowerseleniumvalues(61.6±9.5µg/l; p<0.01)atadmission(Fig.1).


Fig.

1Significantlyreducedserumseleniumconcentration in patients with an acute stroke. [1]

p < 0.01 Reference range

Patients with stroke within

last 12 months

Patients with acute stroke

Admission to ICU


Day 1


Day 2


Day 7

0

10

20

30

40

50

60

70

80

90

Ser

um s

elen

ium

con

cent

ratio

n [µ

g/l]


Correlation between glutathion peroxidase concentration,neurologicaldeficit, and outcomeMeasurement of the selenium-depen-dent, antioxidant glutathione peroxidase displayedasignificantincreaseoftheglutathione peroxidase level in acute strokepatientsondayone(p<0.05)(Fig.2).Inhalfofthepatients,whosuf-fered a stroke in the previous 12 months, the glutathione levels were below the normal range. However, the glutathi-one concentration in patients with an acutestrokewassignificantlyincrea-sed(p<0.01)(Fig.3).Moreover,therewas a negative correlation between the glutathione peroxidase concentration and theNIHSS(NationalInstituteofHealth

StrokeScale)atadmission(r=−0.84;p<0.001)andaftersevendays(r=−0.63;p<0.05).Highglutathionepero-xidase concentrations correlated with alowneurologicaldeficit(lowerNIHSSvalue at admission) and with a favorab-leoutcome(lowerNIHSSvalueondayseven).Theseresultsconfirmedfindingsacquired in animal experiments, i.e. that glutathione peroxidase has a protective effect against brain damage and that a reduced glutathione peroxidase level is associated with increased stroke risk [2, 3].


Fig.

2Significantincreaseofglutathioneperoxidaseconcentration in patients with acute stroke. [1]


Day 1


Day 3

Patients with acute stroke,

admission to ICU


Day 7


last 12 months

0

100

50

150

200

Glu

tath

ione

per

oxid

ase

in s

erum

[U/l]

p < 0.05

Fig.

3Significantlyincreasedglutathioneconcentrationinpatientswith acute stroke. [1]


Day 1


Day 3

Patients with acute stroke,

admission to ICU


Day 7


last 12 months

0

40

20

60

80

100

120

Glu

tath

ione

con

cent

ratio

n in

blo

od [µ

mol

/l]

p < 0.01


SignificantlyreducedSelenoproteinP concentration in patients with an acute stroke In a population-based embedded case- controltrialwith1,632participants,Koya-ma et al. compared the serum selenium and Selenoprotein P concentrations of 30 stroke patients with 30 controls [2]. The serum selenium concentration was lower (105.2vs.116.5µg/l;p=0.054) in stroke patients. The result for the ser-um selenium values is comparable to the Zimmermann trial. A comparison of the two studies, however, also shows that localization plays a major role in a selenium trial. In studies from Europe, theseleniumlevelsaresignificantly lower in comparison with Japan, for instance,suchasthetrialbyKoyama.Apart from the serum selenium concent-

ration, the Selenoprotein P concentration withstrokepatientswassignificantlylower(54.5vs.63.9µg/l;p=0.006)(Ta-ble 1). A multivariate regression analysis showed, that a reduced Selenoprotein P level is associated with higher stroke risk (OR0.28;95%CI0.1–0.85).SincetheSelenoprotein P concentration depends on the selenium status, it can be con-cludedthatthesignificantlylowerserumselenium concentrations in Europe result in lower Selenoprotein P levels. Therefo-re the question must be posed whether aseleniumdeficientdietpresentsanadditional risk factor apart from hyperten-sion, smoking and hypercholesterolemia for stroke.

Literature

1 ZimmermannC,WinnefeldK,StreckS,RoskosM,HaberlRL.EurNeurol.2004;51(3):157-61. Antioxidant status in acute stroke patients and patients at stroke risk.

2KoyamaH,AbdulahR,OhkuboT,ImaiY,SatohH,NagaiK.NutrRes.2009Feb;29(2):94-9. doi: 10.1016/j.nut-res.2009.01.002. Depressed serum selenoprotein P: possible new predicator of increased risk for cerebrovascular events.




Tab.

1SignificantlylowerserumseleniumandSelenoproteinP concentrations in stroke patients. [2]

Stroke Control P-value

selenium in serum [µg/l] 105.2 ± 19.6 116.5 ± 16.6 0.054

Selenoprotein P [µg/l] 54.5 ± 8.69 63.0 ± 9.18 0.006


Day 1



1,0001 µg Se


5001 µg Se

From day 2 of the

ICU staymaintenance therapy 5001 µg Se / day

Literature 1 Reisinger J et al. 2009, Am J Emerg Med 27: 176-181




General information

Sodium selenite:

• reduces the number of infections

• improves wound healing

• shortens antibiotic therapy

• shortens the hospital stay

Significantlyreducedseleniumlevels in burn victimsInthefirstfivedaysaftertheinitialda-mage, extensive burns cause oxidative stress as shown by the simultaneous reduction of antioxidant vitamins and

trace elements, and show a major increase of thiobarbituric acid-reactive substances(TBARS)(Fig.1)[1].

No decline of selenium values with sodium selenite supplementationTheinfluenceofseleniumsupplementati-on on the selenium concentration in burn victims was examined in several studies. In every trial, with a selenium administra-tion of 229 – 379 µg daily, a normalizati-

on of the selenium value could be de-termined, while the selenium level of the placebogroupstayedinthehighlydeficitrange(Fig.2)[4].

Ischaemia/reperfusion136 Sodium selenite for burns

Fig.

1Oxidative stress in burn victims reduces the concentration of antioxidants and increases the concentration on TBARS. [1]

Control

Day1

Day 2

Day 3

0

Selenium

Con

cent

ratio

n in

[µm

ol/l]

or [

µg/l]

Vitamin C Vitamin E TBARS

10

20

30

40

50

60

70

80

Fig.

2Significantlyincreasedseleniumlevelintheselenium-supplemented group compared to the placebo group. [4]

10

20

40

60

80

100

120

2 3 6 11 16 21

Sele

nium

con

cent

ratio

n in

ser

um [µ

g/l]

Placebo Sodium selenite

Days post injury

Reference range

Ischaemia/reperfusion 137Sodium selenite for burns

Significantlydecreasednumberofinfectionswith sodium selenite supplementationA major problem for burn victims is in-fection. In two randomized double-blind placebo-controlled trials, Berger et al. investigatedtheinfluenceofsodiumselenitesupplementation(379µgseleni-um per day) on the infection rate of burn victims [3]. The infection rate was reduced from 3.5 episodes per patient intheplacebogroup(n=20)to2.0epi-sodes per patient in the sodium selenite group(n=21)(p<0.001).Thisreduction

was primarily attributed to the reduction of nosocomial pneumonias from 80% in the placebo group to 33% in the sodium selenitegroup(p<0.001),aswellas to the reduction of respiratory-associa-ted pneumonia from 13 to 6 episodes (p=0.023)(Fig.3).Inconsequence,thenumber of days for which antibiotic tre-atmentwasnecessary,wassignificantlyreducedfrom20to13days(p=0.021).


Fig.

3Lower incidence of nosocomial pneumonia in the sodium selenite-supplemented group of burn victims. [3]

3 8 13 18 23 280.0

0.2

0.6

Days post injury

1.0

0.8

0.4

0.1

0.3

0.7

0.9

0.5

Placebo

Sodium selenite

Pro

babi

lity

of p

reve

ntin

g no

soco

mia

l pne

umon

ia

p = 0.023


Fig.

4

Increase of the antioxidant selenium and the antioxidative acting glutathione peroxidase in burnt tissue in the selenium-supplemented group. [4, 5]

Day 3 Day 10 Day 20

0

Selenium

Con

cent

ratio

n [µ

g/l o

r mU

/mg

Pro

tein

]

GSH GSH Reductase GSH-Peroxidase

10

20

30

40

50

60

70

80

p < 0.05 p < 0.05 p < 0.05 p < 0.05

Improved wound healing with sodium selenite supplementationIn the trial Berger et al. investigated theinfluenceofsodiumselenitesupple-mentation(379µgseleniumperday)onwound healing [4, 5]. Eleven patients were assigned to the sodium selenite group and ten patients to the placebo group for this randomized double-blind pla-cebo-controlled trial. An examination of the burnt tissue after 3, 10 and 20 days revealed that the selenium concentration in burnt tissue of the selenium-supple-mentedgroupwassignificantlyincrea-sed. Simultaneously the concentration of glutathione, glutathione reductase andglutathioneperoxidasewassignifi-

cantly increased in the burnt tissue of theinterventiongroup(Fig.4).Thecom-parison of healthy and burnt tissue of the burn victims with healthy control tissue revealedasignificantreductionoftheselenium level in healthy as well as in burnt tissue. After 20 days, the sele-niumconcentrationrosesignificantlyinburnt tissue of the selenium-supplemen-tedgroupon(Fig.5).Thisresultismir-rored in the required skin grafts, which weresignificantlylessinthesodiumselenite-supplementedgroup(p=0.02)(Fig.6).


Fig.

5

Comparison of the selenium level in healthy and burnt tissue of the sodium selenite-supplemented and non-supplemented group as well as in a control group. [4, 5]

Burnt tissuePlacebo

Healthy tissuePlacebo

Healthy tissueSodium selenite

Burnt tissueSodium selenite

Healthy tissueControl

0

10

5

15

20

25

30

Sel

eniu

m c

once

ntra

tion

[nm

ol/g

dry

wei

ght]

Fig.

6

Sodiumselenite-supplementationsignificantlyreduced thenumberofrequiredskingraftsforburnvictims(p=0.02); BSA=BodySurfaceArea.[4]

0

20

40

60

80

100

120

140

160

180

200

Placebo Sodium selenite

Tota

l bur

ned

BS

A (in

%),

and

perc

enta

geof

bur

ns re

quiri

ng s

urge

ry


Sodium selenite supplementation shortens hospital stayA sodium selenite supplementation of 229 – 379 µg selenium per day reduced thehospitalstaysignificantlyafter normalization for the extent of burn (Tab.1)[2, 3].

For a burnt body surface of 40% the hospital stay was reduced from 40 days to 25 days on an average.


Day 1



5001–3 µg Se

14 days for burns < 60% of the body surface

21 days for burns ≥60%ofthe body surface

maintenance therapy 5001–3 µg Se / day

Literature1 Berger MM et al 2006, Crit Care 10:6, R1532 Berger MM et al 2007, Am J Clin Nutr 85:5, 1293-13003 Berger MM et al 2007, Am J Clin Nutr 85:5, 1301-1306





Literature

1 Bertin-Maghit M, Goudable J, Dalmas E, Steghens JP, Bouchard C, Gueugniaud PY, Petit P, Delafosse B. Intensive CareMed.2000Jun;26(6):800-3. Time course of oxidative stress after major burns.

2Berger MM, Spertini F, Shenkin A, Wardle C, Wiesner L, Schindler C, Chiolero RL. Am J Clin Nutr. 1998 Aug;68(2):365-71. Trace element supplementation modulates pulmonary infection rates after major burns: a doub-le-blind, placebo-controlled trial.

3BergerMM,EggimannP,HeylandDK,ChioléroRL,RevellyJP,DayA,RaffoulW,ShenkinA.Crit Care. 2006;10(6):R153. Reduction of nosocomial pneumonia after major burns by trace element supplementation: aggre-gation of two randomised trials.

4BergerMM,BainesM,RaffoulW,BenathanM,ChioleroRL,ReevesC,RevellyJP,CayeuxMC,SénéchaudI,Shenkin A. AmJClinNutr.2007May;85(5):1293-300. Trace element supplementation after major burns modulates antioxidant status and clinical course by way of increased tissue trace element concentrations.

5Berger MM, Binnert C, Chiolero RL, Taylor W, Raffoul W, Cayeux MC, Benathan M, Shenkin A, Tappy L. Am J Clin Nutr.2007May;85(5):1301-6. Trace element supplementation after major burns increases burned skin trace ele-ment concentrations and modulates local protein metabolism but not whole-body substrate metabolism.

6 DylewskiML,BenderJC,SmithAM,PrelackK,LydonM,WeberJM,SheridanRL.JTrauma.2010Sep;69(3):584-8; discussion 588. doi:10.1097/TA.0b013e3181e74c54. The selenium status of pediatric patients with burn injuries.

Tab.

1Comparison of sodium selenite supplemented patient group withaplacebogroup(n=41).[3]

Sodium selenite Placebo P-value

Bergeretal.(1998)N=20

ICUstay(days) 30(14–46) 39(18–58) n.s.

ICU stay dependent on the burnt body surface (days/%)

0.6 ± 0.2 0.9 ± 0.3 0.034

Bergeretal.(2006)N=41

ICUstay(days) 28(9–151) 39(16–145) 0.18

ICU stay dependent on the burnt body surface (days/%)

0.63(0.23–1.64) 0.99(0.43–2.48) 0.002

Selenoprotein P [µg/l] 54.5 ± 8.69 63.0 ± 9.18 0.006














General information

• Low selenium values in the post-reanimation phase

• Length of the reanimation correlates negatively with the selenium level

• Early administration of selenase® improves the neurological outcome of patients after cardiac arrest

Low selenium status in the post-reanimation phaseThe prognosis of pre-hospital cardiac arrest is still poor. Cardiopulmonary re-animation is only successful for about a third of all patients. Also in the post-rea-nimation phase, a fatal course or residual neurological damage is not precluded. Probable causes are on the one hand hypoxic organ damage due to the inter-rupted oxygen supply, and on the other hand reperfusion-caused damage. The suddenbackflowofbloodtode-oxyge-nated tissue causes an increase of free oxygen radicals and can furthermore trig-ger severe systemic immune responses.

The characteristic symptoms, which can be summarized under the term “post- reanimationsyndrome”,bearastrikingsimilarity to the clinical picture of sep-sis [1, 2]. Whether the post-reanimation syndrome is associated with a reduced selenium level, which is frequently observed with sepsis, was the object of a current trial by Fink et al. [3].

The serum selenium values of 77 pati-ents who were treated in the ICU after successful cardiopulmonary reanimation, were analyzed [3]. The serum selenium level was determined six hours after reanimation(dayone),after24hours(daytwo)andafter48hours(daythree).The serum selenium concentrations were compared with the serum values of 50 healthy study subjects without an anam-nesis of heart disease, and with those ofacontrolgroup(n=50)withastablecardiac disease. On average, the mea-sured serum values for the resuscitated patientsweresignificantlylowerbothincomparison to the healthy study subjects (86.0±2.9µg/lvs.109.1±1.3µg/l; p < 0.0001), as well as compared to the cardiaccontrolgroup(vs.94.2±2.2µg/l;p=0.04).Thelowserumseleniumvalues of the reanimated group also persistedondaytwo(84.8±2.9µg/l)anddaythree(82.1±3.1µg/l)afterthereanimation.

Ischaemia/reperfusion144 selenase® after reanimation

Fig.

1

Comparison of the serum selenium concentration in patients withcardio-pulmonaryreanimation(CPR),healthystudysubjects, and a control group with stable cardiac disease. [3]

CPRDay 2

Control group with cardiac disease

CPRDay 1

CPRDay 3

Healthy0

25

50

75

100

125

150

175

200

Ser

um s

elen

ium

con

cent

ratio

n [µ

g/l]

p < 0.0001(Healthy vs. CPR Day 1)

p = 0.04(Control group vs. CPR Day 1)

Ischaemia/reperfusion 145selenase® after reanimation

Significantlylowerseleniumstatus in non-survivors after reanimationIn the trial by Fink et al, the serum selenium values of patients who survived reanimation were compared [3]. The group was subdivided into survivors and non-survivors, whereby non-survi-vorsweredefinedasreanimatedpatientswho had not survived in the course of their stay in ICU. Successfully reanima-ted patients, who survived the period of ICU,showedsignificantlyhigherserumselenium values at admission to the ICU (98.1±4.5µg/lvs.75.6±3.4µg/l;p=

0.0007) and on day three after reanimati-on(89.9±4.9µg/lvs.74.1±3.4µg/l; p=0.048)(Fig.2).AROCcurveanalysisrevealed that the measurement of the se-rum selenium concentrations within the firsthoursafterICUadmissionpredictedICUmortality(AUC=0.665;p<0.05).Furthermore, the trial demonstrated that the minimum serum selenium concentra-tion correlates inversely with the maxi-mum damage to organs or with organ failure(R2=0.27;p<0.05).

Fig.

2

Comparison of the selenium concentration after successful reanimation for survivors and non-survivors. [4]

At ICU admission

0

20

40

60

80

100

120

Day 3 after reanimation

Ser

um s

elen

ium

con

cent

ratio

n (µ

g/l)

Non-survivorsSurvivors

p < 0.0007 p < 0.048Reference range


The length of reanimation correlates negatively with the selenium levelThe comparison of the serum seleni-um values six hours after successful resuscitation with the duration of reani-mation indicates a negative correlation

betweenthesetwoparameters(Fig.3).The longer the reanimation takes, the more rapidly the serum selenium level drops.

Fig.

3Negative correlation between the serum selenium concentration and the duration of reanimation. [4]

0 5 10 15 20 25 30 35

Duration of reanimation [min]

40 45 50 55 60 65 70 750

20

40

60

80

100

120

140

160

180

Ser

um s

elen

ium

con

cent

ratio

n [µ

g/l]


Negative correlation between neurological damage and selenium concentrationThe comparison of serum selenium levels of patients in good neurological condition after reanimation with patients with a hypoxic encephalopathy after reanimationshowedasignificantreduc-tion of the serum selenium concentration after 24 and 48 hours in the latter group (p=0.01)(Fig.4)

The results of Busch et al. indicate the important role of selenium for protection from reperfusion damage. After success-fulreanimation,patientscouldbenefitfrom early selenium therapy [5].

Literature

1 Adrie C, Adib-Conquy M, Laurent I et al. Successful cardiopulmonary resuscitation after cardiac arrest as a "sep-sis-like" syndrome. Circulation 2002; 106: 562–568.

2 Adrie C, Laurent I, Monchi M et al. Postresuscitation disease after cardiac arrest: a sepsis-like syndrome? Curr Opin Crit Care 2004; 10: 208–212.

3FinkK,MoebesM,VetterC,BourgeoisN,SchmidB,BodeC,HelbingT,BuschHJ.Crit Care. 2015 Feb 26;19(1):58.Seleniumpreventsmicroparticle-inducedendothelialinflammationinpatientsaftercardiopulmonaryresuscitation.

4Busch HJ: Neue klinische Daten bei reanimierten Patienten. Satelliten-Symposium „Selen – neue Therapieoption zurReduktionvonReperfusionsschäden“.20.SymposiumIntensivmedizin+Intensivpflege17.–19.Februar2010,Bremen.

5 Busch H-J. Welchen Nutzen hat die Selensubstitution in der Post-Reanimationsphase? Dtsch Med Wochenschr 2009; 134: 419–421.

6

Neumar RW, Nolan JP, Adrie C et al. Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication.AconsensusstatementfromtheInternationalLiaisonCommitteeonResuscitation(AmericanHe-art Association, Australian and New Zealand Council on Resuscitation, European Resuscitation Council, Heart and Stroke Foundation of Canada, InterAmerican Heart Foundation, Resuscitation Council of Asia, and the Resuscita-tion Council of Southern Africa); the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; and the Stroke Council. Circulation 2008; 118: 2452–2483.

7 Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002; 346: 549–556.

8 YamaguchiT,SanoK,TakakuraKetal.Ebseleninacuteischemicstroke:aplacebo-controlled,double-blindclini-cal trial. Ebselen Study Group. Stroke 1998; 29: 12–17.

9 Parnham M, Sies H. Ebselen: prospective therapy for cerebral ischaemia. Expert Opin Investig Drugs 2000; 9: 607–619.

10 ReisingerJ,HollingerK,LangWetal.Doesearlyadministrationofseleniumimproveneurologicaloutcomeaftercardiac arrest? Am J Emerg Med 2009; 27: 176–181.















Fig.

4Comparison of the selenium level in patients with and without neurological damage. [4]

0

10

In good neurological condition(n = 29)

Hypoxic encephalopathy(n = 15)

20

30

40

50

60

70

80

90

100

110

120p = 0.01

day 1 day 2 day 3 day 1 day 2 day 3

Ser

um s

elen

ium

con

cent

ratio

n [µ

g/l]

Reference range


Day 1The beginning of treatment directly after reanimation or ICU admission

as continuous infusion 1,0001 µg Se

Day 2 – 5 maintenance therapy 1,0001 µg Se / day

Literature 1 Reisinger J et al. 2009, Am J Emerg Med 27: 176-181



selenase® protects the brain after cardiopulmonary reanimationBrain damage is one of the most fre-quent causes of death and sequelae after successful cardiopulmonary rea-nimation [6]. Available treatment options for the attenuation of brain damage was so far primarily restricted to hypothermia treatment of the patient [7]. A currently di-scussed alternative is the administration of high-dose sodium selenite.

Selenium, which among other things is a component of the protein glutathione peroxidase, protects cells from oxidative stress. It is already successfully used in the prevention of neurological damage after an ischemic stroke [8, 9].

An austrian trial determined the effect of sodium selenite on the neurological course after cardiac arrest [10].

226 patients were included in this re-trospective analysis. 124 patients were administered selenase® intravenosuly forfivedaysdirectlyafterresuscitation.The daily dosage was 1,000 µg seleni-um for 106 patients, 400 µg selenium for two patients, and 200 µg selenium for 16 patients. The patients were evalua-ted according to the Glasgow-Pittsburgh Cerebral Performance Categories (CPC1-5).

50% of the patients treated with sodium selenite regained consciousness again and had no or only moderately impai-redbrainfunction(CPC1-2).17%hadseverebraindamage(CPC-3;needforlong-term care), 22% remained comato-se, and 11% died.

In the group of patients who had received no selenase®, only 39% of the patients achieved a CPC of 1-2, 9% were classi-fiedasCPC3,32%remainedcomatose,and20%died(Table1).

Thus, patients treated with selenase® compared to the control group had a 2.4-fold higher probability of regaining consciousness(p=0.014;95%-confi-denceinterval=1.19–4.76)(Table2).

On the basis of these results, the authors propose the hypothesis that the early administration of selenase® improves the patient’s neurological outcome after cardiac arrest.


Tab.

1Impact of a therapy with selenase® on the course of disease after cardiac arrest. [10]

selenase® (n=124)

Control (n=102)

Number of patients who regain consciousness with CPC 1-2

62(50%) 40(39%)

Number of patients who regain consciousness with CPC 3

21(17%) 9(9%)

Number of patients who remained comatose

27(22%) 33(32%)

Number of patients who died

14(11%) 20(20%)

Tab.

2Comparison of the predictors for regaining consciousness after reanimation. [10]

Variable Unit Adjusted OR (95%CI)

P-value

First monitored rhythm shockable vs nonshockable 3.73(1.87–7.52) < 0.001

Time until ROSC 1min(increase) 0.94(0.91–0.96) < 0.001

Selenium administration yes vs no 2.38(1.19–4.76) 0.014

SAPS II 1 point increase 0.96(0.93–0.99) 0.034

Cardiac arrest location in the hospital vs outside 1.76(0.79–3.92) 0.169

Therapeutic hypothermia yes vs no 1.73(0.49–6.10) 0.393

Bystander-initiated CPR yes vs no 1.31(0.66–2.62) 0.443

Statisticallysignificantp<0.05.ROSC=returnofspontaneouscirculation. OR=oddsratio.CI=confidenceinterval.


Selenium in guidelines

Adults Infants with low birth weight

Children (prematureand term infants)

Burn patients

Sepsis patients

ICU patients in general

Guideline Parenteral Nutrition of DGEM 2007

BiesalskiHKetal.:Wasser,Elektroly-te,VitamineundSpurenelemente.Akt Ern Med 2007; 32, Sup 1:S30–S34.

× × × × ×ESPEN Guidelines on Parenteral Nutrition

ClinicalNutrition(2009)28,387–400.× × × ×

Deutsche Sepsis-Leitlinien

Prävention, Diagnose, Therapie und Nachsorge der Sepsis

ReinhartK,BrunkhorstFM,AWMF online 2010.

×Canadian Clinical Practice Guide lines 2013

www.criticalcarenutrition.com× ×

Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically III Patient: SCCM and A.S.P.E.N.

McClave et al., Jpen33(2009)3,277–316.

× ×Guidelines on Pediatric Parenteral Nutrition

J of Pediatr Gastroenterol Nutr. 41:S39–S46, November 2005 ESPG-HAN

×Nutrition Support for Adults: Oral Nutrition Support, Enteral Tube Feeding and Parenteral Nutrition

National Institute for Clinical Excellen-ceFeb2006,UK

×

Summary152 Guidelines

http://www.dgem.de/material/pdfs/7%20Wasser,%20Elektrolyte,%20Vitamine,%20Spurenelementes-2006-951867.pdf

http://www.dgem.de/material/pdfs/7%20Wasser,%20Elektrolyte,%20Vitamine,%20Spurenelementes-2006-951867.pdf


http://www.awmf.org/leitlinien/detail/ll/079-001.html

http://www.awmf.org/leitlinien/detail/ll/079-001.html

http://www.criticalcarenutrition.com








153Guidelines

This hidden champion supplies its high-revenue blockbuster selenase® to 22 countries, primarily for oncology and intensive care medicine.

Founded in 1984, biosyn Arzneimittel GmbHwasoneofthefirstGermanbiotechnology companies. Now it has around 70 employees in Germany and subsidiaries in Liechtenstein, Austria and the USA.

Its portfolio encompasses some 30 pro-ducts ranging from biotechnologically engineered medicines through chemo-therapeutics to complementary drugs andfoodsupplementsforitsmainfields

of intensive care medicine and oncology. The company’s major concern is treating patients as a whole. biosyn, a rese-arch-focused pharmaceutical company, puts up to 25 percent of revenues back into its pipeline.

Its mission is to explore, evolve and mar-kethighlyefficaciousdrugswithlowsideeffects based on the most up-to-date evidence molecular biology has to offer.

High-qualityproductsfromtheworld’sfirst GMP-compliant production of sodium selenite

In 2009, biosyn Arzneimittel GmbH was, andpresumablystillis,thefirstandonlycompany in the world able to manufac-ture the active ingredient sodium selenite pentahydrate in internationally prescribed GMP quality – thanks to biosyn’s prop-rietary and patented production method. Itspurificationandcrystallizationtechno-logies allow microbe-free production of high-quality trace element compounds under cleanroom conditions.

This enables the production of injecta-ble liquid pharmaceuticals to meet the particularly stringent demands on quality.

biosyn currently manufactures anhyd-rous sodium selenite and sodium seleni-te pentahydrate for oral and parenteral formulations.

Thebiosynmotto“weareresearch”notonly symbolizes our dedication to me-dical and pharmaceutical progress but also for our drive to develop innovative manufacturing processes.

The company markets its selenium drugs under the brand name selenase® world-wide.

biosyn Arzneimittel GmbHbiosyn is the global market leader in high-dose selenium pharmaceuticals

GMP-compliant production of sodium selenite at biosyn: Vacuumdryingsystemfortargetedcrystallizationofmetallicsaltswithdefinedportionsofhydratedingredients

Summary154 Company

Summary 155Company

Contact and Informationwww.biosyn.de www.biosyncorp.com biosyn Arzneimittel GmbH Schorndorfer Straße 32 70734 Fellbach [email protected]

Managing Director:Dr.ThomasStiefelandOrtwinKottwitz Commercial Register: County Court Stuttgart HRB 262712 Place of performance: Fellbach, Legal venue Stuttgart

Use of selenium in intensive care as adjunctive therapy for sepsis, ischaemia/reperfusion and reanimation

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