Zusammenfassung
Hintergrund
Die letzten Jahrzehnte waren von einer großen Zahl durchgeführter Registrierungsstudien für neue Arzneimittel gekennzeichnet, mit denen die Sepsisbehandlung hätte wirksamer werden sollen. Moderne Entzündungshemmung sollte die überwältigende Entzündungs- und Gerinnungsdysregulation korrigieren, die besonders in der frühen Sepsis vorliegt. Ferner sind immunstimulierende Therapien, mit denen die im Verlauf der Sepsis spätere kompensatorische Immunparalyse beeinflusst werden sollte, untersucht worden.
Aktuelle Studienergebnisse
Das ursprünglich nur unter Auflagen zugelassene rekombinante aktivierte Protein C, Drotrecogin-α, wurde wieder vom Markt genommen, weil sich die initial beobachtete Wirksamkeit nicht bestätigen ließ. Antithrombin, dessen Verabreichung entzündungs- und gerinnungsmodulierend wirkt, blieb im generellen Einsatz bei schwerer Sepsis ohne günstige Wirkung auf das Patientenüberleben. Wenn die Sepsis zu disseminierter intravasaler Gerinnung führt, stellt die Antithrombingabe lediglich eine Behandlungsoption dar. Auch hinsichtlich der intravenösen Gabe von Immunglobulinen, der Verabreichung von immunmodulierenden Substanzen in der Ernährung als sog. Immunonutrition sowie der Substitution von Selen blieb die vermutete Wirksamkeit in kleinen heterogenen Studien im Wesentlichen unbestätigt. Mit einer für Schwerkranke nur vorübergehend empfohlenen intensiven Blutzuckerkontrolle wird das Risiko für schädliche Hypoglykämien so stark erhöht, dass die Blutzuckerzielwerte nach der inzwischen ausreichend untersuchten Normalisierungsempfehlung wieder etwas angehoben wurden.
Zusammenfassung und Ausblick
Keines der neuen Medikamente hat sich erfolgreich als neuer allgemeiner Behandlungsstandard etablieren können. Den zahlreichen laufenden Studien zur Sepsis sollte es künftig besser gelingen, die Gruppe heterogener Patienten mit Sepsis so einzuengen, dass sich die in der Präklinik und in kleinen vorbereitenden Studien erfolgreich scheinenden Therapieprinzipien tatsächlich bestätigen und als gesicherte Therapieempfehlungen generalisieren lassen.
Abstract
Background
Recent decades have been characterized by a large number of trials for registration of new drugs or indication approvals in the field of sepsis. Modern anti-inflammatory drugs or interventions are intended to correct the overwhelming dysregulation of inflammatory and coagulation pathways seen particularly in the early phase of sepsis. Immunostimulatory therapies are also being studied in order to correct immunoparalysis, which develops later in the course of sepsis as a compensatory mechanism.
Current study results
Recombinant activated protein C, drotrecogin α, was conditionally approved and later withdrawn from the market by the producer because the initially observed beneficial effect could not be confirmed. The efficacy and safety of antithrombin, which, like drotrecogin α, also modulates inflammation and coagulation as an endogenous anticoagulant could not be confirmed when used for treating sepsis. As sepsis leads to disseminated intravascular coagulation which may be counteracted by antithrombin, new guidelines recommend antithrombin as a treatment option in this subgroup of sepsis patients. Intravenous administration of immunoglobulin, enteral administration of immunomodulating substances as immunonutrition, and the substitution of selenium, all showed some effectiveness in small heterogeneous studies, but their efficacy was not confirmed in large high-quality trials. Intensive glycemic control, which was temporarily recommended for acutely ill patients, increased the risk for adverse hypoglycemia in several clinical trials so that blood glucose target levels have been redefined and guidelines now no longer ask for normalization of blood glucose values with insulin.
Conclusion and outlook
None of the new drugs, however, has successfully become established as a new standard of care. In the future, studies of novel sepsis therapies may succeed better if suitable biomarkers allow for patient selection, reflecting key pathophysiologic mechanisms that are targeted by the innovative drugs.
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Einhaltung ethischer Richtlinien
Interessenskonflikt. C.J. Wiedermann gibt an, in den letzten 5 Jahren Honorare für Vorträge und Beratung von den Firmen CSL Behring GmbH, Baxter AG, Schweiz, und der Plasma Protein Therapeutics Association (PPTA) erhalten zu haben.
Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.
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Wiedermann, C. Adjuvante Therapie der Sepsis. Med Klin Intensivmed Notfmed 109, 583–590 (2014). https://doi.org/10.1007/s00063-014-0379-7
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DOI: https://doi.org/10.1007/s00063-014-0379-7