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Indomethacin Reduces Cell Damage: Shedding New Light on Compartment Syndrome

Manjoo, Ajay MD, FRCS(C)*; Sanders, David MD, MSc, FRCS(C)*; Lawendy, Abdel MD, FRCS(C)*; Gladwell, Michael MD*; Gray, Daryl BSc, MD, FRCS(C)*; Parry, Neil MD, MSc, FRCS(C); Badhwar, Amit PhD

doi: 10.1097/BOT.0b013e3181f2247e
Original Article
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Introduction: Indomethacin may preserve tissue viability in compartment syndrome. The mechanism of improved tissue viability is unclear, but the anti-inflammatory effects may alter the relative contribution of tissue necrosis versus apoptosis to cellular injury. Existing studies have only considered indomethacin administration before induction of elevated intracompartment pressure. The purpose of this study was to determine the effect of timing of indomethacin administration on muscle damage in elevated intracompartment pressure and to assess apoptosis as a cause of tissue demise.

Methods: Twenty-four Wistar rats were randomized to elevated intracompartmental pressure (EICP) for either 45 or 90 minutes (30 mmHg). In the 45-minute cohort, indomethacin was withheld in Group 1 (CS45), given before induction of EICP in Group 2 (CS45Indo0), or given after 30 minutes of EICP/15 minutes before fasciotomy in Group 3 (CS45Indo30). In the 90-minute cohort, indomethacin was withheld in Group 4 (CS90) or given after 30 or 60 minutes of EICP in Groups 5 (CS90Indo30) and 6 (CS90Indo60). Intravital microscopy and fluorescent staining assessed capillary perfusion, cell damage, and inflammatory activation within extensor digitorum longus muscle. Apoptosis was assessed using spectrophotometric assessment of caspase levels. Groups 1 to 3 and 4 to 6 were compared using analysis of variance with P < 0.05 deemed significant.

Results: Perfusion and tissue viability improved in indomethacin-treated groups. Nonperfused capillaries decreased from Group 1 (CS45) (50.1 ± 2.5) to Group 2 (CS45Indo0) (38.4 ± 1.8) and Group 3 (CS45Indo30) (14.13 ± 1.73) (P < 0.05). Similarly, Group 5 (CS90Indo30) and Group 6 (CS90Indo60) had 25% fewer nonperfused capillaries compared with Group 4 (CS90) (P < 0.0001). Group 2 (CS45Indo0) and Group 3 (CS45Indo30) showed fewer damaged cells (1% ± 0.5% and 8.7% ± 2%) compared with Group 1 (CS45) (20% ± 14%) (P < 0.0001). Group 5 (CS90Indo30) showed decreased cell damage (13% ± 1%) compared with Group 4 (CS90) (18% ± 1%) (P < 0.01). Group 6 (CS90Indo60) also showed decreased cell damage (11% ± 1%) compared with Group 4 (CS90) (18% ± 1%); however, this difference was not significant (P > 0.05). Apoptotic activity was present with elevated intracompartment pressure. At 30 minutes, there were elevated caspase levels in Group 4 and Group 6 EICP groups (0.47 ± 0.08) compared with control subjects (0.19 ± 0.02) (P < 0.003). However, indomethacin-treated groups did not differ from control subjects with regard to caspase levels (P > 0.05).

Conclusion: Indomethacin decreased cell damage and improved perfusion in elevated intracompartment pressure. The benefits of indomethacin were partially time-dependent; some improvement in tissue viability occurred regardless of timing of administration. Although apoptosis was common in elevated intracompartment pressure, the protective effect of indomethacin does not appear to be related to apoptosis.

Clinical Relevance: Adjuvant treatment with indomethacin may improve outcome in compartment syndrome.

From the Departments of *Orthopedic Surgery and †General Surgery and ‡Centre for Critical Illness Research, Departments of Surgery and Medical Biophysics, University of Western Ontario, London, Ontario, Canada.

Accepted for publication July 15, 2010.

This work was Supported by an AIOD (OTC) Foundation Grant.

Investigation performed at the Centre for Critical Illness Research, Lawson Health Research Institute, London, Ontario, Canada.

Reprints: David Sanders, MD, MSc, FRCS(C), Associate Professor, Orthopedic Surgery, 800 Commissioners Road East, Room E4-123, London, Ontario N6A 4G5, Canada (e-mail: david.sanders@lhsc.on.ca).

© 2010 Lippincott Williams & Wilkins, Inc.