THE ROLE OF THE ANTIOXIDANTS ASCORBIC ACID AND N-ACETYLCYSTEINE IN THE ATTENUATION OF ISCHAEMIA REPERFUSION INJURY IN A HUMAN CLINICAL MODEL

Abstract

Objectives: Ischaemia reperfusion injury (IRI) is one of the most common metabolic insults in orthopaedic clinical practice. Oral ascorbate and both oral and intravenous n-acetylcysteine (NAC) have shown definitive beneficial effects in animal skeletal muscle IRI models. The authors hypothesized that a similar protective effect could be demonstrated in a well designed clinical trial.

Materials and Methods: A EudraCT registered, prospective, randomized, controlled, double blind trial was performed to assess the hypothesis. Ethical approval was obtained from the competent authority. Patients (n=18) undergoing elective knee arthroscopy were randomised to one of 3 groups. The NAC group received IV NAC and preoperative oral placebo. The ascorbate group received oral ascorbate and IV placebo. The placebo group received both oral and IV placebo. Anaesthetic protocols were standardized across all groups. Phlebotomy was performed preoperatively and at 3 post-operative time points. IL-1, 2, 6 and 10, ICAM, VCAM, Selectins, TNF-alpha and malondialdehyde (MDA) were measured in systemic and local blood samples. Physiological parameters were recorded in the peri-operative period. Post-operative analgesic requirements and visual analogue scores were recorded. Leg oedema was measured using volumetric analysis and figure-of-eight tape measurement.

Results: There were no differences between the groups pre-operatively. In the post-operative period the analgesic requirements were lower in the NAC group compared to ascorbate and placebo groups. CRP and d-dimers were found to peak in the early post operative period. White cell counts decreased in all groups in the early post-operative period, with a lesser reduction in the NAC and ascorbate groups. Elevation of MDA was noted in all groups but was significantly less in the NAC group. There was a trend towards increasing IL-6 and IL-8. There was a trend towards decreasing TNF-alpha and IL-1.

Conclusions: Ascorbate and NAC appear to attenuate the inflammatory response to IRI in a clinical model. These cheap, readily available medications which are acceptable to patients and doctors alike appear offer a potential benefit to patients. Further studies are required to clarify the extent of the benefit and to examine the role of these medications in trauma and in the setting of more extensive ischaemic insults.