With the development of open heart surgery in the last decades the life expectance and the quality of life of patients with congenital or aquired heart diseases improved substantially. However, all patients are still at risk for a post perfusion syndrome (PPS), due to a whole body inflammatory reaction induced by the blood surface interaction of the extracorporeal circuit. By the blood surface interaction the contact and complement system are activated. Contact system activation is related with the impaired hemostasis during and after cardiopulmonary bypass (CPB), whereas the activation of the complement system correlates with the organ dysfunction following CPB. 

This thesis evaluates the material independent blood activation during CPB and the role of this activation process on the development of the post perfusion syndrome. We especially investigated the release of endotoxin, its effect on the whole body inflammatory reaction and the protective effect of corticosteroids on this reaction. ...

Zie: Summary.

Jansen, Nicolaas Johannes Georgius,

Jansen, Nicolaas Johannes Georgius

Dissertations of the University of Groningen

   University of GroningenBlood activation by cardiopulmonary bypass and endotoxinJansen, Nicolaas Johannes GeorgiusIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1991Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Jansen, N. J. G. (1991). Blood activation by cardiopulmonary bypass and endotoxin. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-10-2022Sulttu.tnvWith the development of open heart surgery in the last decades the lifeexpectance and the quality of life of patients with congenital or aquired heart diseasesimproved substantially. However, all patients are still at risk for a post perfusionsyndrome (PPS), due to a whole body inflammatory reaction induced by the bloodsurface interaction of the extracorporeal circuit. By the blood surface interaction thecontact and complement system are activated. Contact system activation is relatedwith the impaired hemostasis during and after cardiopulmonary bypass (CPB),whereas the activ ation of the complement sy stem correlates with the organ dysfunctionfollowing CPB. Although the recent use of protease inhibitors reduced the activationof the contact system and consequently preserved hemostasis, no reduction ofcomplement activation nor in organ dysfunction has been observed.Since complement activation is particularly seen after reperfusion of the heartand lungs at the completion of the cardiac correction, we considered blood activationby a process independent of the blood surface interaction. This thesis evaluates thematerial independent blood activation during CPB and the role of this activationprocess on the development ofthe post perfusion syndrome. We especially investigatedthe release of endotoxin, its effect on the whole body inflammatory reaction and theprotective effect of corticosteroids on this reaction.Chapter l is a general introduction to this thesis, describing and specifying thetargets of the problems. In addenda I,II and III a more detailed description is givenof the post perfusion syndrome, the complement system and endotoxin in relation toopen heart surgery.To clarify if endotoxin could contribute to the development of the whole bodyinflammatory reaction the time relation of release of endotoxin into the systemiccirculation and its activation process during CPB was investigated in a prospectivestudy on patients undergoing CPB (chapter 2). We found significant increases ofendotoxin concentration after start of bypass and after release of the aortic cross-clamp, accompagnied by an immediate increase in complement activation (C3a) andthe formation of tumor necrosis factor (TNF) later on. Since TNF is a more potentmediator of organ dysfunction and endothelial injury than the complement factorC3a by itself, we concluded that endotoxin may play a pivotal role in the generationof the whole body inflammatory reaction.In a placebo controlled double blind study on patients undergoing CPB, thetreatment of dexamethasone on the material irrdependent blood activation and on thedevelopment of the post perfusion syndrome following CPB was investigated(chapter 3). We showed a strong leukocyte inflammatory reaction upon release ofthe aortic cross-clamp of which particulary the TNF formation correlated with thehemodynamic instabil ity seen in the post operative period. Prophylacticdexamethasone treatnlent ( I mglkgbw) inhibited the leukocyte inflammatory reactionof this material independent blood activation effectively and prevented the postl l lperfusion phenomena, while no inhibition of complement activation during CPBwas observed. Therefore it could be concluded that the material independent bloodactivation, seen after release of the aortic cross-clamp, is the main mediator in thedevelopment of the post perfusion syndrome and not the material dependentactivation induced by the surface of the extracorporeal circuit.To determine if other corticosteroid regimens could also have an inhibitoryeffect on the material independent blood activation process during CPB, weinvestigated the effects of three - most frequently used - corticosteroid regimensduring CPB, in a placebo controlled double blind clinical study (chapter 4). A highdose corticosteroid treatment was the most effective in inhibiting the materialindependent activation, especially dexamethasone in a dose of I mg/kgbw, morethan methylprednisolone (30 mg&gbw). A low dose corticosteroid treatment(prednisolone 1 mg/kgbw) was less effective because of a short duration of action.None of the corticosteroid regimens had any effect on the material dependent bloodactivation.To determine the effects of endotoxin on the activation of blood cells andplasmatic systems in more detail and to investigate the protective effects ofcorticosteroids on this process, studies were performed in rabbits.Inchapter5we showedthattheactivationof bloodcells, complement, arachidonicacid and fibrinolytic systems, seen after a short endotoxin infusion, correspondedwith the activation seen afterrelease of the aortic cross-clamp in patients undergoingCPB. All rabbits died upon the endotoxin infusion after about 48 hours. This studyshowed that endotoxin is indeed a strong activator of blood cells and plasmaticsystems with deleterious effects and therefore can contribute to a whole bodyinflammatory reaction.In chapter 6 we investigated if corticosteroids could prevent the activationprocess and deleterious effects of endotoxin in rabbits. The effects of a prophylacticlow and high dose methylprednisolone treatment were evaluated, to determine if alow dose corticosteroid treatment with less side effects could be as effective as a highdose. Both corticosteroid treatments were not able to inhibit the complementactivation, but both effectively inhibited the activation of leukocytes, platelets andtheir release products and prevented death of all animals. So prophylactic corticosteroidtreatment, both alow andahighdose, prevents thedeleterious effects of endotoxemiaand supports the beneficial effects of corticosteroid treatment on the materialindependent activation observed in patients undergoing CPB.We evaluated in chapter 7 the effect of corticosteroid treatment on complernentinduced white blood cell and platelet aggregation, as is known to occur bycomplement activation during CPB. Complement activated plasma and serum wereinfused in rabbits, prophylacticaly treated with a high dose methylprednisolone ora placebo. We showed that high dose methylprednisolone treatment was able toinhibit in serum the complement induced blood cell aggregation, but not in plasma.We concluded therefore that corticosteroids are not able in vivo to inhibit comple-t t2ment IplasmaI n ion thereleaseTNF, Cfocus cdescribendotoCtWtcausin6reactiohemodcouldirso prevanimalof cort:vation,We themediatdependand/orespecia19 cPBtt bloodrr in therendenthibitoryPB, we:gimens. A highnaterialv, moreeatmentI action.nt bloodells andfects of:hidonicipondedlergoingris studylasmatic,le body:tivationhylacticnine if aas a highplement:lets and:osteroidtoxemiamaterialplernentccur bylm wereolone ori able toplasma.comple-ment induced blood cell aggregation and that other simultaneously activatedplasmatic components, such as fibrin monomers, play arole in blood cell aggregation.In an epilogue (chapter 8) the role of the material independent blood activationon the development of the whole body inflammatory reaction is described. Therelease of endotoxin into the systemic circulation, especially by the formation ofTNF, can be responsible for the adverse effects in CPB. Therefore it is important tofocus on the endotoxin release to improve the clinical course following CPB. Wedescribe the possibilities of preventing systemic endotoxemia and treatment ofendotoxemia in patients undergoing CPB.CoNcr,usloNWe demonstrated a significant increase in endotoxin concentration during CPB,causing a material lndependent blood activation with a strong leukocyte inflammatoryreaction. Especially the formation of TNF by endotoxin correlated with thehemodynamic instabillity seen in the post operative period. Corticosteroid treatmentcould inhibitthe leukocyte inflammatory reaction, including theTNFformation, andso prevented the hemodynamic instability after CPB in a dose dependent way. In theanimal studies we could mimic these effects of endotoxin and the protective effectsof corticosteroid treatment. Furthermore we demonstrated that complement acti-vation, induced by blood surface interaction, couldnotbe inhibited by corticosteroids.We therefore postulate that the material independent blood activation is the mainmediator in the development of the post pedusion syndrome instead of the materialdependent blood activation. Therefore attention has to be focussed on the inhibitionand/or prevention of the material independent blood activation during CPB, andespecially on the endotoxin release.1 1 3

English

Blood activation by cardiopulmonary bypass and endotoxin

Proceedings - University of Groningen

University of Groningen

   University of GroningenBlood activation by cardiopulmonary bypass and endotoxinJansen, Nicolaas Johannes GeorgiusIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1991Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Jansen, N. J. G. (1991). Blood activation by cardiopulmonary bypass and endotoxin. Groningen: s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Sulttu.tnvWith the development of open heart surgery in the last decades the lifeexpectance and the quality of life of patients with congenital or aquired heart diseasesimproved substantially. However, all patients are still at risk for a post perfusionsyndrome (PPS), due to a whole body inflammatory reaction induced by the bloodsurface interaction of the extracorporeal circuit. By the blood surface interaction thecontact and complement system are activated. Contact system activation is relatedwith the impaired hemostasis during and after cardiopulmonary bypass (CPB),whereas the activ ation of the complement sy stem correlates with the organ dysfunctionfollowing CPB. Although the recent use of protease inhibitors reduced the activationof the contact system and consequently preserved hemostasis, no reduction ofcomplement activation nor in organ dysfunction has been observed.Since complement activation is particularly seen after reperfusion of the heartand lungs at the completion of the cardiac correction, we considered blood activationby a process independent of the blood surface interaction. This thesis evaluates thematerial independent blood activation during CPB and the role of this activationprocess on the development ofthe post perfusion syndrome. We especially investigatedthe release of endotoxin, its effect on the whole body inflammatory reaction and theprotective effect of corticosteroids on this reaction.Chapter l is a general introduction to this thesis, describing and specifying thetargets of the problems. In addenda I,II and III a more detailed description is givenof the post perfusion syndrome, the complement system and endotoxin in relation toopen heart surgery.To clarify if endotoxin could contribute to the development of the whole bodyinflammatory reaction the time relation of release of endotoxin into the systemiccirculation and its activation process during CPB was investigated in a prospectivestudy on patients undergoing CPB (chapter 2). We found significant increases ofendotoxin concentration after start of bypass and after release of the aortic cross-clamp, accompagnied by an immediate increase in complement activation (C3a) andthe formation of tumor necrosis factor (TNF) later on. Since TNF is a more potentmediator of organ dysfunction and endothelial injury than the complement factorC3a by itself, we concluded that endotoxin may play a pivotal role in the generationof the whole body inflammatory reaction.In a placebo controlled double blind study on patients undergoing CPB, thetreatment of dexamethasone on the material irrdependent blood activation and on thedevelopment of the post perfusion syndrome following CPB was investigated(chapter 3). We showed a strong leukocyte inflammatory reaction upon release ofthe aortic cross-clamp of which particulary the TNF formation correlated with thehemodynamic instabil ity seen in the post operative period. Prophylacticdexamethasone treatnlent ( I mglkgbw) inhibited the leukocyte inflammatory reactionof this material independent blood activation effectively and prevented the postl l lperfusion phenomena, while no inhibition of complement activation during CPBwas observed. Therefore it could be concluded that the material independent bloodactivation, seen after release of the aortic cross-clamp, is the main mediator in thedevelopment of the post perfusion syndrome and not the material dependentactivation induced by the surface of the extracorporeal circuit.To determine if other corticosteroid regimens could also have an inhibitoryeffect on the material independent blood activation process during CPB, weinvestigated the effects of three - most frequently used - corticosteroid regimensduring CPB, in a placebo controlled double blind clinical study (chapter 4). A highdose corticosteroid treatment was the most effective in inhibiting the materialindependent activation, especially dexamethasone in a dose of I mg/kgbw, morethan methylprednisolone (30 mg&gbw). A low dose corticosteroid treatment(prednisolone 1 mg/kgbw) was less effective because of a short duration of action.None of the corticosteroid regimens had any effect on the material dependent bloodactivation.To determine the effects of endotoxin on the activation of blood cells andplasmatic systems in more detail and to investigate the protective effects ofcorticosteroids on this process, studies were performed in rabbits.Inchapter5we showedthattheactivationof bloodcells, complement, arachidonicacid and fibrinolytic systems, seen after a short endotoxin infusion, correspondedwith the activation seen afterrelease of the aortic cross-clamp in patients undergoingCPB. All rabbits died upon the endotoxin infusion after about 48 hours. This studyshowed that endotoxin is indeed a strong activator of blood cells and plasmaticsystems with deleterious effects and therefore can contribute to a whole bodyinflammatory reaction.In chapter 6 we investigated if corticosteroids could prevent the activationprocess and deleterious effects of endotoxin in rabbits. The effects of a prophylacticlow and high dose methylprednisolone treatment were evaluated, to determine if alow dose corticosteroid treatment with less side effects could be as effective as a highdose. Both corticosteroid treatments were not able to inhibit the complementactivation, but both effectively inhibited the activation of leukocytes, platelets andtheir release products and prevented death of all animals. So prophylactic corticosteroidtreatment, both alow andahighdose, prevents thedeleterious effects of endotoxemiaand supports the beneficial effects of corticosteroid treatment on the materialindependent activation observed in patients undergoing CPB.We evaluated in chapter 7 the effect of corticosteroid treatment on complernentinduced white blood cell and platelet aggregation, as is known to occur bycomplement activation during CPB. Complement activated plasma and serum wereinfused in rabbits, prophylacticaly treated with a high dose methylprednisolone ora placebo. We showed that high dose methylprednisolone treatment was able toinhibit in serum the complement induced blood cell aggregation, but not in plasma.We concluded therefore that corticosteroids are not able in vivo to inhibit comple-t t2ment IplasmaI n ion thereleaseTNF, Cfocus cdescribendotoCtWtcausin6reactiohemodcouldirso prevanimalof cort:vation,We themediatdependand/orespecia19 cPBtt bloodrr in therendenthibitoryPB, we:gimens. A highnaterialv, moreeatmentI action.nt bloodells andfects of:hidonicipondedlergoingris studylasmatic,le body:tivationhylacticnine if aas a highplement:lets and:osteroidtoxemiamaterialplernentccur bylm wereolone ori able toplasma.comple-ment induced blood cell aggregation and that other simultaneously activatedplasmatic components, such as fibrin monomers, play arole in blood cell aggregation.In an epilogue (chapter 8) the role of the material independent blood activationon the development of the whole body inflammatory reaction is described. Therelease of endotoxin into the systemic circulation, especially by the formation ofTNF, can be responsible for the adverse effects in CPB. Therefore it is important tofocus on the endotoxin release to improve the clinical course following CPB. Wedescribe the possibilities of preventing systemic endotoxemia and treatment ofendotoxemia in patients undergoing CPB.CoNcr,usloNWe demonstrated a significant increase in endotoxin concentration during CPB,causing a material lndependent blood activation with a strong leukocyte inflammatoryreaction. Especially the formation of TNF by endotoxin correlated with thehemodynamic instabillity seen in the post operative period. Corticosteroid treatmentcould inhibitthe leukocyte inflammatory reaction, including theTNFformation, andso prevented the hemodynamic instability after CPB in a dose dependent way. In theanimal studies we could mimic these effects of endotoxin and the protective effectsof corticosteroid treatment. Furthermore we demonstrated that complement acti-vation, induced by blood surface interaction, couldnotbe inhibited by corticosteroids.We therefore postulate that the material independent blood activation is the mainmediator in the development of the post pedusion syndrome instead of the materialdependent blood activation. Therefore attention has to be focussed on the inhibitionand/or prevention of the material independent blood activation during CPB, andespecially on the endotoxin release.1 1 3

   University of GroningenBlood activation by cardiopulmonary bypass and endotoxinJansen, Nicolaas Johannes GeorgiusIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1991Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Jansen, N. J. G. (1991). Blood activation by cardiopulmonary bypass and endotoxin. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 03-06-2022Sulttu.tnvWith the development of open heart surgery in the last decades the lifeexpectance and the quality of life of patients with congenital or aquired heart diseasesimproved substantially. However, all patients are still at risk for a post perfusionsyndrome (PPS), due to a whole body inflammatory reaction induced by the bloodsurface interaction of the extracorporeal circuit. By the blood surface interaction thecontact and complement system are activated. Contact system activation is relatedwith the impaired hemostasis during and after cardiopulmonary bypass (CPB),whereas the activ ation of the complement sy stem correlates with the organ dysfunctionfollowing CPB. Although the recent use of protease inhibitors reduced the activationof the contact system and consequently preserved hemostasis, no reduction ofcomplement activation nor in organ dysfunction has been observed.Since complement activation is particularly seen after reperfusion of the heartand lungs at the completion of the cardiac correction, we considered blood activationby a process independent of the blood surface interaction. This thesis evaluates thematerial independent blood activation during CPB and the role of this activationprocess on the development ofthe post perfusion syndrome. We especially investigatedthe release of endotoxin, its effect on the whole body inflammatory reaction and theprotective effect of corticosteroids on this reaction.Chapter l is a general introduction to this thesis, describing and specifying thetargets of the problems. In addenda I,II and III a more detailed description is givenof the post perfusion syndrome, the complement system and endotoxin in relation toopen heart surgery.To clarify if endotoxin could contribute to the development of the whole bodyinflammatory reaction the time relation of release of endotoxin into the systemiccirculation and its activation process during CPB was investigated in a prospectivestudy on patients undergoing CPB (chapter 2). We found significant increases ofendotoxin concentration after start of bypass and after release of the aortic cross-clamp, accompagnied by an immediate increase in complement activation (C3a) andthe formation of tumor necrosis factor (TNF) later on. Since TNF is a more potentmediator of organ dysfunction and endothelial injury than the complement factorC3a by itself, we concluded that endotoxin may play a pivotal role in the generationof the whole body inflammatory reaction.In a placebo controlled double blind study on patients undergoing CPB, thetreatment of dexamethasone on the material irrdependent blood activation and on thedevelopment of the post perfusion syndrome following CPB was investigated(chapter 3). We showed a strong leukocyte inflammatory reaction upon release ofthe aortic cross-clamp of which particulary the TNF formation correlated with thehemodynamic instabil ity seen in the post operative period. Prophylacticdexamethasone treatnlent ( I mglkgbw) inhibited the leukocyte inflammatory reactionof this material independent blood activation effectively and prevented the postl l lperfusion phenomena, while no inhibition of complement activation during CPBwas observed. Therefore it could be concluded that the material independent bloodactivation, seen after release of the aortic cross-clamp, is the main mediator in thedevelopment of the post perfusion syndrome and not the material dependentactivation induced by the surface of the extracorporeal circuit.To determine if other corticosteroid regimens could also have an inhibitoryeffect on the material independent blood activation process during CPB, weinvestigated the effects of three - most frequently used - corticosteroid regimensduring CPB, in a placebo controlled double blind clinical study (chapter 4). A highdose corticosteroid treatment was the most effective in inhibiting the materialindependent activation, especially dexamethasone in a dose of I mg/kgbw, morethan methylprednisolone (30 mg&gbw). A low dose corticosteroid treatment(prednisolone 1 mg/kgbw) was less effective because of a short duration of action.None of the corticosteroid regimens had any effect on the material dependent bloodactivation.To determine the effects of endotoxin on the activation of blood cells andplasmatic systems in more detail and to investigate the protective effects ofcorticosteroids on this process, studies were performed in rabbits.Inchapter5we showedthattheactivationof bloodcells, complement, arachidonicacid and fibrinolytic systems, seen after a short endotoxin infusion, correspondedwith the activation seen afterrelease of the aortic cross-clamp in patients undergoingCPB. All rabbits died upon the endotoxin infusion after about 48 hours. This studyshowed that endotoxin is indeed a strong activator of blood cells and plasmaticsystems with deleterious effects and therefore can contribute to a whole bodyinflammatory reaction.In chapter 6 we investigated if corticosteroids could prevent the activationprocess and deleterious effects of endotoxin in rabbits. The effects of a prophylacticlow and high dose methylprednisolone treatment were evaluated, to determine if alow dose corticosteroid treatment with less side effects could be as effective as a highdose. Both corticosteroid treatments were not able to inhibit the complementactivation, but both effectively inhibited the activation of leukocytes, platelets andtheir release products and prevented death of all animals. So prophylactic corticosteroidtreatment, both alow andahighdose, prevents thedeleterious effects of endotoxemiaand supports the beneficial effects of corticosteroid treatment on the materialindependent activation observed in patients undergoing CPB.We evaluated in chapter 7 the effect of corticosteroid treatment on complernentinduced white blood cell and platelet aggregation, as is known to occur bycomplement activation during CPB. Complement activated plasma and serum wereinfused in rabbits, prophylacticaly treated with a high dose methylprednisolone ora placebo. We showed that high dose methylprednisolone treatment was able toinhibit in serum the complement induced blood cell aggregation, but not in plasma.We concluded therefore that corticosteroids are not able in vivo to inhibit comple-t t2ment IplasmaI n ion thereleaseTNF, Cfocus cdescribendotoCtWtcausin6reactiohemodcouldirso prevanimalof cort:vation,We themediatdependand/orespecia19 cPBtt bloodrr in therendenthibitoryPB, we:gimens. A highnaterialv, moreeatmentI action.nt bloodells andfects of:hidonicipondedlergoingris studylasmatic,le body:tivationhylacticnine if aas a highplement:lets and:osteroidtoxemiamaterialplernentccur bylm wereolone ori able toplasma.comple-ment induced blood cell aggregation and that other simultaneously activatedplasmatic components, such as fibrin monomers, play arole in blood cell aggregation.In an epilogue (chapter 8) the role of the material independent blood activationon the development of the whole body inflammatory reaction is described. Therelease of endotoxin into the systemic circulation, especially by the formation ofTNF, can be responsible for the adverse effects in CPB. Therefore it is important tofocus on the endotoxin release to improve the clinical course following CPB. Wedescribe the possibilities of preventing systemic endotoxemia and treatment ofendotoxemia in patients undergoing CPB.CoNcr,usloNWe demonstrated a significant increase in endotoxin concentration during CPB,causing a material lndependent blood activation with a strong leukocyte inflammatoryreaction. Especially the formation of TNF by endotoxin correlated with thehemodynamic instabillity seen in the post operative period. Corticosteroid treatmentcould inhibitthe leukocyte inflammatory reaction, including theTNFformation, andso prevented the hemodynamic instability after CPB in a dose dependent way. In theanimal studies we could mimic these effects of endotoxin and the protective effectsof corticosteroid treatment. Furthermore we demonstrated that complement acti-vation, induced by blood surface interaction, couldnotbe inhibited by corticosteroids.We therefore postulate that the material independent blood activation is the mainmediator in the development of the post pedusion syndrome instead of the materialdependent blood activation. Therefore attention has to be focussed on the inhibitionand/or prevention of the material independent blood activation during CPB, andespecially on the endotoxin release.1 1 3

ARTS repository - University of Groningen

NARCIS 

   University of GroningenBlood activation by cardiopulmonary bypass and endotoxinJansen, Nicolaas Johannes GeorgiusIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1991Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Jansen, N. J. G. (1991). Blood activation by cardiopulmonary bypass and endotoxin. s.n.CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 07-06-2022Sulttu.tnvWith the development of open heart surgery in the last decades the lifeexpectance and the quality of life of patients with congenital or aquired heart diseasesimproved substantially. However, all patients are still at risk for a post perfusionsyndrome (PPS), due to a whole body inflammatory reaction induced by the bloodsurface interaction of the extracorporeal circuit. By the blood surface interaction thecontact and complement system are activated. Contact system activation is relatedwith the impaired hemostasis during and after cardiopulmonary bypass (CPB),whereas the activ ation of the complement sy stem correlates with the organ dysfunctionfollowing CPB. Although the recent use of protease inhibitors reduced the activationof the contact system and consequently preserved hemostasis, no reduction ofcomplement activation nor in organ dysfunction has been observed.Since complement activation is particularly seen after reperfusion of the heartand lungs at the completion of the cardiac correction, we considered blood activationby a process independent of the blood surface interaction. This thesis evaluates thematerial independent blood activation during CPB and the role of this activationprocess on the development ofthe post perfusion syndrome. We especially investigatedthe release of endotoxin, its effect on the whole body inflammatory reaction and theprotective effect of corticosteroids on this reaction.Chapter l is a general introduction to this thesis, describing and specifying thetargets of the problems. In addenda I,II and III a more detailed description is givenof the post perfusion syndrome, the complement system and endotoxin in relation toopen heart surgery.To clarify if endotoxin could contribute to the development of the whole bodyinflammatory reaction the time relation of release of endotoxin into the systemiccirculation and its activation process during CPB was investigated in a prospectivestudy on patients undergoing CPB (chapter 2). We found significant increases ofendotoxin concentration after start of bypass and after release of the aortic cross-clamp, accompagnied by an immediate increase in complement activation (C3a) andthe formation of tumor necrosis factor (TNF) later on. Since TNF is a more potentmediator of organ dysfunction and endothelial injury than the complement factorC3a by itself, we concluded that endotoxin may play a pivotal role in the generationof the whole body inflammatory reaction.In a placebo controlled double blind study on patients undergoing CPB, thetreatment of dexamethasone on the material irrdependent blood activation and on thedevelopment of the post perfusion syndrome following CPB was investigated(chapter 3). We showed a strong leukocyte inflammatory reaction upon release ofthe aortic cross-clamp of which particulary the TNF formation correlated with thehemodynamic instabil ity seen in the post operative period. Prophylacticdexamethasone treatnlent ( I mglkgbw) inhibited the leukocyte inflammatory reactionof this material independent blood activation effectively and prevented the postl l lperfusion phenomena, while no inhibition of complement activation during CPBwas observed. Therefore it could be concluded that the material independent bloodactivation, seen after release of the aortic cross-clamp, is the main mediator in thedevelopment of the post perfusion syndrome and not the material dependentactivation induced by the surface of the extracorporeal circuit.To determine if other corticosteroid regimens could also have an inhibitoryeffect on the material independent blood activation process during CPB, weinvestigated the effects of three - most frequently used - corticosteroid regimensduring CPB, in a placebo controlled double blind clinical study (chapter 4). A highdose corticosteroid treatment was the most effective in inhibiting the materialindependent activation, especially dexamethasone in a dose of I mg/kgbw, morethan methylprednisolone (30 mg&gbw). A low dose corticosteroid treatment(prednisolone 1 mg/kgbw) was less effective because of a short duration of action.None of the corticosteroid regimens had any effect on the material dependent bloodactivation.To determine the effects of endotoxin on the activation of blood cells andplasmatic systems in more detail and to investigate the protective effects ofcorticosteroids on this process, studies were performed in rabbits.Inchapter5we showedthattheactivationof bloodcells, complement, arachidonicacid and fibrinolytic systems, seen after a short endotoxin infusion, correspondedwith the activation seen afterrelease of the aortic cross-clamp in patients undergoingCPB. All rabbits died upon the endotoxin infusion after about 48 hours. This studyshowed that endotoxin is indeed a strong activator of blood cells and plasmaticsystems with deleterious effects and therefore can contribute to a whole bodyinflammatory reaction.In chapter 6 we investigated if corticosteroids could prevent the activationprocess and deleterious effects of endotoxin in rabbits. The effects of a prophylacticlow and high dose methylprednisolone treatment were evaluated, to determine if alow dose corticosteroid treatment with less side effects could be as effective as a highdose. Both corticosteroid treatments were not able to inhibit the complementactivation, but both effectively inhibited the activation of leukocytes, platelets andtheir release products and prevented death of all animals. So prophylactic corticosteroidtreatment, both alow andahighdose, prevents thedeleterious effects of endotoxemiaand supports the beneficial effects of corticosteroid treatment on the materialindependent activation observed in patients undergoing CPB.We evaluated in chapter 7 the effect of corticosteroid treatment on complernentinduced white blood cell and platelet aggregation, as is known to occur bycomplement activation during CPB. Complement activated plasma and serum wereinfused in rabbits, prophylacticaly treated with a high dose methylprednisolone ora placebo. We showed that high dose methylprednisolone treatment was able toinhibit in serum the complement induced blood cell aggregation, but not in plasma.We concluded therefore that corticosteroids are not able in vivo to inhibit comple-t t2ment IplasmaI n ion thereleaseTNF, Cfocus cdescribendotoCtWtcausin6reactiohemodcouldirso prevanimalof cort:vation,We themediatdependand/orespecia19 cPBtt bloodrr in therendenthibitoryPB, we:gimens. A highnaterialv, moreeatmentI action.nt bloodells andfects of:hidonicipondedlergoingris studylasmatic,le body:tivationhylacticnine if aas a highplement:lets and:osteroidtoxemiamaterialplernentccur bylm wereolone ori able toplasma.comple-ment induced blood cell aggregation and that other simultaneously activatedplasmatic components, such as fibrin monomers, play arole in blood cell aggregation.In an epilogue (chapter 8) the role of the material independent blood activationon the development of the whole body inflammatory reaction is described. Therelease of endotoxin into the systemic circulation, especially by the formation ofTNF, can be responsible for the adverse effects in CPB. Therefore it is important tofocus on the endotoxin release to improve the clinical course following CPB. Wedescribe the possibilities of preventing systemic endotoxemia and treatment ofendotoxemia in patients undergoing CPB.CoNcr,usloNWe demonstrated a significant increase in endotoxin concentration during CPB,causing a material lndependent blood activation with a strong leukocyte inflammatoryreaction. Especially the formation of TNF by endotoxin correlated with thehemodynamic instabillity seen in the post operative period. Corticosteroid treatmentcould inhibitthe leukocyte inflammatory reaction, including theTNFformation, andso prevented the hemodynamic instability after CPB in a dose dependent way. In theanimal studies we could mimic these effects of endotoxin and the protective effectsof corticosteroid treatment. Furthermore we demonstrated that complement acti-vation, induced by blood surface interaction, couldnotbe inhibited by corticosteroids.We therefore postulate that the material independent blood activation is the mainmediator in the development of the post pedusion syndrome instead of the materialdependent blood activation. Therefore attention has to be focussed on the inhibitionand/or prevention of the material independent blood activation during CPB, andespecially on the endotoxin release.1 1 3

Blood activation by cardiopulmonary bypass and endotoxin

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