The Effects of Remote Ischemic Preconditioning on the Inflammatory Cytokine Response to Free Flap Head and Neck Reconstruction: A Randomized Controlled Trial

Introduction

Ischemia–reperfusion injury due to vascular pedicle occlusion is one of the most common causes of free flap failure in head and neck cancer reconstruction. Remote ischemic preconditioning (RIPC) has been proposed as an experimental, non‐invasive intervention to attenuate flap ischemia–reperfusion injury; however, the tissue‐protective mechanisms remain unclear. RIPC may have multiple effects on the inflammatory system, which plays a central part in the pathophysiology of ischemia–reperfusion injury. The aim of the present study was to evaluate the effect of RIPC on inflammatory cytokine plasma levels during free flap reconstruction.

Methods

Head and neck cancer patients ( n  = 60) undergoing tumor resection and subsequent free flap reconstruction between August 2015 and November 2017 at Aarhus University Hospital, Denmark were randomized 1:1 to RIPC or sham intervention in a single‐center, single‐blinded, randomized controlled trial (RCT) ( ClinicalTrials.gov: NCT02548377). The study was approved by The Central Denmark Region Committees on Health Research Ethics (journal no. 1‐10‐72‐140‐15) and reported following the CONSORT guidelines. RIPC was administered intraoperatively as four 5‐min cycles of upper extremity occlusion and reperfusion with an inflatable tourniquet. Blood samples were collected before surgery, 6 h after RIPC/sham intervention, and on the 1st postoperative day. Tumor necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐2, IL‐4, IL‐6, IL‐8, IL‐10, IL‐12p70, IL‐13, and interferon (IFN)‐gamma were analyzed using a multiplex immunoassay.

Results

The average age of the RIPC group was 67 years (±10) and 64 years (±12) in the sham group. Plasma levels of the pro‐inflammatory cytokines changed significantly between preoperative measures to 1 ^st postoperative day between RIPC and sham; TNF‐α ( p  < 0.001), IL‐6 ( p  < 0.001), IL‐8 ( p  < 0.001), IL‐12p70 ( p  < 0.001), and IFN‐γ ( p  < 0.001). No significant differences in cytokine levels were shown between groups at any specific time points.

Conclusion

RIPC does not attenuate pro‐inflammatory cytokine release in head and neck cancer patients undergoing free flap reconstruction.

Trial Registration: ClinicalTrials.gov identifier: NCT02548377