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DOI: 10.1055/s-2006-921386
© Georg Thieme Verlag Stuttgart · New York
Perspektiven der adjuvanten Sepsistherapie - hat das Konzept der spezifischen Immunmodulation versagt?
Perspectives of Adjunctive Sepsis TherapyPublication History
Publication Date:
03 February 2006 (online)
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Zusammenfassung
Trotz kontinuierlicher medizinischer Fortschritte in den letzten Jahrzehnten bleibt die Mortalität der Sepsis weiterhin unakzeptabel hoch. In multiplen Phase-III-Studien wurden in der letzten Dekade spezifische immunmodulatorische Ansätze bei der Sepsis getestet (Anti-Endotoxin-Antikörper, Anti-Zytokin-Antikörper, Zytokinrezeptorantagonisten, Cyclooxygenaseinhibitoren usw.) mit dem Ziel, die proinflammatorische Immunantwort zu modifizieren. Bei hervorragenden Ergebnissen im Tierexperiment mit hoher modellimmanenter Mortalität und meist prophylaktischem Einsatz waren diese Strategien bei humaner Sepsis erfolglos. Dies mag daran liegen, dass wesentliche Aspekte der Sepsispathophysiologie (Redundanz der Systeme, Phasen der Immunantwort bei der Sepsis, Veränderung der Immunantwort im Alter, Gerinnungsbeteiligung) nicht beachtet wurden und dass nicht nach Fokussanierung stratifiziert wurde. Mit natürlichen Gerinnungsinhibitoren (aktiviertes Protein C, Antithrombin und Gewebsfaktorinhibitor (TFPI)) stehen heutzutage Substanzen zur Verfügung, die neben ihren antikoagulatorischen Eigenschaften auch direkt immunmodulatorisch wirken. Erstmalig konnte in einer Phase-III-Studie durch die exogene Applikation von aktiviertem Protein C die 28-Tage-Mortalität von Patienten mit schwerer Sepsis signifikant gesenkt werden. Die Antithrombin-Gabe hingegen senkte in einer Phase-III-Studie nur in der Untergruppe der nicht gleichzeitig mit Heparin behandelten Patienten die 90-Tage-Mortalität signifikant, was auf einen klinisch relevanten Antagonismus zwischen Antithrombin und Heparin hinweist. Die Mechanismen der Immunmodulation durch Gerinnungsinhibitoren werden in dieser Arbeit diskutiert: Gerinnungsinhibitoren können durch Zellkernfaktor Beta (NFkB) Hemmung (aktiviertes Protein C, Antithrombin) und Prostazyklinfreisetzung (Antithrombin) nicht nur die Leukozyten-Thrombozyten-Endothelzell-Interaktion beeinflussen, sondern hierdurch auch die kapillare Perfusion verbessern. Die Perfusionsverbesserung stellt eine Voraussetzung zum Erhalt und zur Verbesserung der Organfunktion dar und sollte als Zielkriterium zur Effektivitätsbeurteilung einer adjuvanten Sepsistherapie etabliert werden. Dies impliziert, dass zur Beurteilung der mikrovaskulären Perfusion geeignete, am Menschen anwendbare Untersuchungsmethoden, für die Mikrozirkulation etabliert werden müssen.
Abstract
Mortality of sepsis is remaining high despite continuous improvements in intensive care medicine. In multiple phase III studies specific immunomodulatory therapies (endotoxin scavenging, anti-cytokine antibodies, cytokine receptor antagonists, cyclooxygenase inhibitors) were tested under clinical conditions aiming at the reduction of the proinflammatory response. All these strategies have not been successful. One reason might be that important aspects of sepsis pathophysiology (redundancy of inflammatory cascades, phases of immune response, clearance of the septic focus) have not been taken into consideration. Although specific immunomodulatory strategies showed excellent results in preclinical models during prophylactic use, they did not succeed under clinical conditions. In the recent years, natural coagulatory inhibitors (activated protein C, antithrombin, and tissue factor pathway inhibitor) have been tested under clinical conditions. Only activated protein C, however, has been shown to significantly reduce mortality in one phase III trial in patients with severe sepsis. Antithrombin and tissue factor pathway inhibitor did not succeed in the ITT population. When analysing patients without concomitant heparin, however, antithrombin reduced significantly 90-day mortality of severe sepsis, indicating a clinically relevant antagonism between heparin and antithrombin. Activated protein C and antithrombin provided anticoagulatory effects and also showed direct immunomodulatory capacities. Besides theses actions, these substances basically modulate the microcirculation. Microcirculatory effects are mainly mediated via nuclear factor beta inhibition (activated protein C, antithrombin) and endothelial prostacyclin release (antithrombin). The subsequent increase in capillary and nutritive perfusion is a precondition for preserved organ function, and should be defined as a major target of future adjunctive sepsis therapy.
Schlüsselwörter
Sepsis - Immunmodulation - Gerinnungsinhibitoren - Mikrozirkulation - Organversagen
Key words
sepsis - immunomodulation - coagulatory inhibitors - microcirculation - organ failure
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