N-Acetylcysteine Administration in the ICU Patient - a Double-Edged Sword?

Zusammenfassung

Der erhöhte oxidative Stress bei kritisch Kranken legt die Gabe von N-Acetylcystein (NAC) zur antioxidativen Therapie nahe. In entsprechenden Tiermodellen verminderte NAC den oxidativen Stress, zeigte antiinflammatorische Eigenschaften und konnte so Organfunktion und Überlebensraten verbessern. Demgegenüber hatten klinische Studien an Intensivpatienten bislang widersprüchliche Ergebnisse. Einerseits beobachtete eine Reihe von Untersuchern, dass durch hoch dosierte Applikation von NAC die verminderten intrazellulären Spiegel des essenziellen Antioxidans Glutathion normalisiert und Parameter der Lipidperoxidation gesenkt werden können. Andererseits sind die Berichte über einen Einfluss dieser Therapie auf die Hämodynamik, den Gasaustausch und den Sauerstoffmetabolismus uneinheitlich. Obwohl Hinweise auf einen protektiven Effekt von NAC bei akuter Lungenschädigung vorliegen, erbrachten alle bisherigen Studien an Patienten mit ARDS, Polytrauma, Sepsis und großen abdominal-chirurgischen Eingriffen keinen Überlebensvorteil durch eine antioxidative Therapie mit NAC. Teilweise kann dieser fehlende Effekt auf das Outcome sicherlich den jeweils geringen Patientenzahlen in den einzelnen Untersuchungen zugeschrieben werden. Allerdings bleiben Fragen hinsichtlich des Therapiebeginns und der optimalen Dosierung weiter ungelöst. NAC scheint die Produktion reaktiver Sauerstoffspezies in phagozytären Zellen zu hemmen und könnte deshalb die körpereigene Immunabwehr beeinträchtigen. Die klinische Relevanz dieses Aspekts bleibt jedoch unklar, da bisher keine Berichte über eine erhöhte Inzidenz nosokomialer Infektionen unter Therapie mit NAC vorliegen. Die Substanz unterliegt einer durch Metallionen katalysierten Autooxidation, die in Abhängigkeit vom lokalen Milieu in prooxidativen Eigenschaften resultieren kann. Trotz des etablierten Einsatzes von NAC als Antidot bei Paracetamolvergiftung und als Mukolytikum muss seine Wirksamkeit im Rahmen der antioxidativen Therapie von Intensivpatienten noch nachgewiesen und potenzielle Nebenwirkungen beachtet werden.

Abstract

Evidence of increased oxidative stress in the pathophysiology of critical illness suggests N-acetylcysteine (NAC) administration for antioxidant therapy. In animal models, NAC successfully attenuated oxidative stress, displayed anti-inflammatory properties and, thus, was able to improve organ dysfunction and survival. However, clinical studies in critically ill patients had equivocal results. On the one hand, some trials demonstrated NAC to replenish depleted intracellular stores of the crucial antioxidant glutathione and to decrease markers of lipid peroxidation. On the other hand, reports of effects on hemodynamics, gas exchange and oxygen metabolism are inconsistent. Although there is some evidence that NAC attenuates human lung injury, all past investigations failed to show an improved survival of NAC treated patients with ARDS, multiple trauma, major surgery, and sepsis. To some extent, this can be attributed to the relatively small numbers of patients included in the respective trials. However, questions as to the right timing for intervention and the appropriate dose and rate of administration remain unresolved. NAC seems to decrease phagocytic burst activity and may therefore influence host defense. However, the clinical relevance of this aspect remains unclear since there are no reports indicating an increase in nosocomial infection rates in patients receiving NAC. The drug can undergo metal-catalyzed auto-oxidation that results in rather pro-oxidative properties, depending upon the local milieu. Despite NAC's proven usefulness as a safe drug for acetaminophen poisoning and mucolysis, the efficacy of its antioxidant therapy in critical illness has yet to be demonstrated and potential side effects have to be considered.

N-Acetylcystein - Antioxidans - Sepsis - ARDS - Immunabwehr - Infektion

N-acetylcysteine - antioxidants - sepsis - ARDS - host defence - infection

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