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
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
Treatment ideally beginswithin 6 hours after admission to the ICU
Bolus directly after admission to ICU
1,0001 µg Se
then as continuous infusion
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
Treatment ideally beginswithin 12 hours after admission to the ICU
then as continuous infusion
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
selenase® for cardiac surgery
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 post- operative 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 for stroke
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 for burns
Sodium selenite:
• reduces the number of infections
• improves wound healing
• shortens antibiotic therapy
• shortens the hospital stay
selenase® after reanimation
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.
16 General facts about sepsis
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].
18 General facts about sepsis
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
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%.
20 Details on sepsis
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%
50%
40%
30%
20%
10%
0%
70%
60%
50%
40%
30%
20%
10%
0%Incidence
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%.
22 Details on sepsis
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
50%
40%
30%
20%
10%
0%
70%
60%
50%
40%
30%
20%
10%
0%
70%
60%
50%
40%
30%
20%
10%
0%
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.
24 Details on sepsis
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
Evidence of an infection
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
Fig.
6Significantincreaseinpostoperativesepsis from 1997 – 2006. [2]
19970
0.2
0.4
0.6
0.8
1
1.2
1.4
1998 1999 2000 2001 2002 2003 2004 2005 2006
Per
100
cas
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.
26 Details on sepsis
Fig.
7Increased number of severe postoperative sepsis is independent of the type of surgical intervention. [2]
0
0.5
1
1.5
2
2.5
Cardiac Thorax Vascular Uppergastro-
intestinaltract
Lowergastro-
intestinaltract
Joint-replacement
Spine Gyneco-logical
Urological
Surgery
Per
100
cas
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
10
20
30
40
50
Per
100
cas
es
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
28 Selenium and sepsis
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
30
40
50
60
70
80
20
10
0Severe SIRS*
Seru
m s
elen
ium
leve
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]
50
30
40
20
10
0
60
40
50
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0Severe SIRS*
Sco
re p
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s
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Min
imal
ser
um s
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cent
ratio
n [µ
g/l]
SAPS II-Score
Minimalserum selenium concentration
APACHE II-Score
*SIRS=systemicinflammatoryresponsesyndrome
30 Selenium and sepsis
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
60
80
20
0Non-survivors (9)
Serum selenium concentrationat ICU admission (µg/l)
Survivors (51)
p < 0.05
Non-survivors (9)Survivors (51)
p < 0.05
100
40
60
80
20
0
Minimal serum selenium concentration (µg/l)
31Selenium and sepsis
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
32 Selenium and sepsis
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
33Selenium and sepsis
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].
34 Selenium and sepsis
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
35Selenium and sepsis
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].
36 Selenium and sepsis
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.
37Selenium and sepsis
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
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
38 Selenium and sepsis
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
39Selenium and sepsis
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
40 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®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]
Minimum 7 days Se as sodium selenite
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)
Sepsis44 selenase® 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]
Minimum 7 days Se as sodium selenite
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)
Sepsis 45selenase® for sepsis
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).
Sepsis46 selenase® for sepsis
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.
Sepsis 47selenase® for sepsis
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
Sepsis48 selenase® for sepsis
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.
50 selenase® for sepsis
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
51selenase® for sepsis
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).
52 selenase® for sepsis
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®
53selenase® for sepsis
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.
54 selenase® for sepsis
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
55selenase® for sepsis
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
56 selenase® for sepsis
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.
57selenase® for sepsis
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 %
58 selenase® for sepsis
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
59selenase® for sepsis
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
60 selenase® for sepsis
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.
61selenase® for sepsis
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).
62 selenase® for sepsis
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
63selenase® for sepsis
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.
64 selenase® for sepsis
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
65selenase® for sepsis
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).
66 selenase® for sepsis
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
67selenase® for sepsis
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).
68 selenase® for sepsis
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 %
69selenase® for sepsis
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.
70 selenase® for sepsis
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 −
71selenase® for sepsis
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
72 selenase® for sepsis
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.
73selenase® for 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).
74 selenase® for sepsis
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
75selenase® for 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
Intervention group (selenase®):
Bolus: 1,000 µg1,000 µg/day selenium as selenase® for 14 days Placebo group:
< 100 µg/day selenium
Selenium level at ICU admission markedly below normalIntervention group (selenase®):
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)
N (selenase®) = 75N (control) = 75
Intervention group:
1,000 µg selenium as selenase® on day 1500 µg/day selenium as selenase® for 14 days Control group:
< 75 µg/day selenium
Selenium level at ICU admission markedly below normalIntervention group (selenase®):
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)
N (sodium selenite) = 15N (placebo) = 16
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
76 selenase® for 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
Intervention group (selenase®):
Bolus: 1,000 µg1,000 µg/day selenium as selenase® for 14 days Placebo group:
< 100 µg/day selenium
Selenium level at ICU admission markedly below normalIntervention group (selenase®):
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)
N (selenase®) = 75N (control) = 75
Intervention group:
1,000 µg selenium as selenase® on day 1500 µg/day selenium as selenase® for 14 days Control group:
< 75 µg/day selenium
Selenium level at ICU admission markedly below normalIntervention group (selenase®):
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)
N (sodium selenite) = 15N (placebo) = 16
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
77selenase® for 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
78 selenase® for 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
79selenase® for 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
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
Antimediator therapy
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/reperfusion 87Cardiac surgery
Selenium in the 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
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
Selenium in the 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
Glutathione peroxidase 4
Mitochondrial overexpression protects from I/R injuries
Protects cellular lipids from oxidative stress
Glutathione peroxidase 3
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.
Ischaemia/reperfusion90 Cardiovascular system
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
Ischaemia/reperfusion 91Cardiovascular system
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.
Ischaemia/reperfusion92 Cardiovascular system
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
Ischaemia/reperfusion 93Cardiovascular system
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.
Ischaemia/reperfusion94 Cardiovascular system
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
Ischaemia/reperfusion 95Cardiovascular system
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 cardio- toxicity 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].
Ischaemia/reperfusion96 Cardiovascular system
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.
Ischaemia/reperfusion 97Cardiovascular system
selenase® for cardiac surgery
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]
Ischaemia/reperfusion100 selenase® for cardiac surgery
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
[%]
Ischaemia/reperfusion 101selenase® for cardiac surgery
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 intra- operative 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
Ischaemia/reperfusion102 selenase® for cardiac surgery
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
Ischaemia/reperfusion 103selenase® for cardiac surgery
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
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.
Ischaemia/reperfusion104 selenase® for cardiac surgery
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)
Ischaemia/reperfusion 105selenase® for cardiac surgery
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
Ischaemia/reperfusion106 selenase® for cardiac surgery
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
Ischaemia/reperfusion 107selenase® for cardiac surgery
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).
Ischaemia/reperfusion110 Selenium in the brain
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
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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
Ischaemia/reperfusion 111Selenium in the brain
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 neuro- degeneration [11].
GPx4 is a multifunctional antioxidative protein with anti-apoptotic character- istics [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].
Ischaemia/reperfusion112 Selenium in the brain
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
Ischaemia/reperfusion 113Selenium in the brain
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).
Ischaemia/reperfusion114 Selenium in the brain
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
Ischaemia/reperfusion 115Selenium in the brain
Sodium selenite for stroke
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.
Ischaemia/reperfusion118 Sodium selenite for stroke
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
Ischaemia/reperfusion 119Sodium selenite for stroke
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
Ischaemia/reperfusion120 Sodium selenite for stroke
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
Ischaemia/reperfusion 121Sodium selenite for stroke
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
Ischaemia/reperfusion122 Sodium selenite for stroke
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
Ischaemia/reperfusion 123Sodium selenite for stroke
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
Ischaemia/reperfusion124 Sodium selenite for stroke
Fig.
12Sodium selenite preserves the activity of the respiratory chain of mitochondria after hypoxia. [2]
0
50
100
150
Com
plex
I ac
tivity
[%]
ControlControl Hypoxia Control Hypoxia
Sodium selenite
0
50
100
150
Com
plex
II +
III a
ctiv
ity [%
]
ControlControl Hypoxia Control Hypoxia
Sodium selenite
0
50
100
150
Com
plex
IV a
ctiv
ity [%
]
ControlControl Hypoxia Control Hypoxia
Sodium selenite
p < 0.01
p < 0.001 p < 0.01
p < 0.01
p < 0.001 p < 0.001
Ischaemia/reperfusion 125Sodium selenite for stroke
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.
Ischaemia/reperfusion126 Sodium selenite for stroke
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
Ischaemia/reperfusion 127Sodium selenite for stroke
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
Ischaemia/reperfusion128 Sodium selenite for stroke
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
Ischaemia/reperfusion 129Sodium selenite for 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).
Ischaemia/reperfusion130 Sodium selenite for stroke
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
Patients with acute stroke
Day 1
Patients with acute stroke
Day 2
Patients with acute stroke
Day 7
0
10
20
30
40
50
60
70
80
90
Ser
um s
elen
ium
con
cent
ratio
n [µ
g/l]
Ischaemia/reperfusion 131Sodium selenite for stroke
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].
Ischaemia/reperfusion132 Sodium selenite for stroke
Fig.
2Significantincreaseofglutathioneperoxidaseconcentration in patients with acute stroke. [1]
Patients with acute stroke
Day 1
Patients with acute stroke
Day 3
Patients with acute stroke,
admission to ICU
Patients with acute stroke
Day 7
Patients with stroke within
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]
Patients with acute stroke
Day 1
Patients with acute stroke
Day 3
Patients with acute stroke,
admission to ICU
Patients with acute stroke
Day 7
Patients with stroke within
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
Ischaemia/reperfusion 133Sodium selenite for stroke
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.
Ischaemia/reperfusion134 Sodium selenite for stroke
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
Sodium selenite for stroke
Day 1
Treatment ideally beginswithin 6 hours after admission to the ICU
Bolus directly after admission to ICU
1,0001 µg Se
then as continuous infusion
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
Ischaemia/reperfusion 135Sodium selenite for stroke
Sodium selenite for burns
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).
Ischaemia/reperfusion138 Sodium selenite for burns
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
Ischaemia/reperfusion 139Sodium selenite for burns
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).
Ischaemia/reperfusion140 Sodium selenite for burns
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
Ischaemia/reperfusion 141Sodium selenite for burns
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.
Sodium selenite for burns
Day 1
Treatment ideally beginswithin 12 hours after admission to the ICU
then as continuous infusion
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
Ischaemia/reperfusion142 Sodium selenite for burns
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
Ischaemia/reperfusion 143Sodium selenite for burns
selenase® after reanimation
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
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200
Ser
um s
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ium
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cent
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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 sur- vived 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
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ium
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cent
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n (µ
g/l)
Non-survivorsSurvivors
p < 0.0007 p < 0.048Reference range
Ischaemia/reperfusion146 selenase® after reanimation
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
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um s
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Ischaemia/reperfusion 147selenase® after reanimation
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.
Ischaemia/reperfusion148 selenase® after reanimation
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
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cent
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n [µ
g/l]
Reference range
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
Ischaemia/reperfusion 149selenase® after reanimation
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.
Ischaemia/reperfusion150 selenase® after reanimation
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.
Ischaemia/reperfusion 151selenase® after reanimation
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
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
we are research
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