Indomethacin reduces cell damage: shedding new light on compartment syndrome.
BACKGROUND
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).


CONCLUSIONS
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.


CONCLUSIONS
Adjuvant treatment with indomethacin may improve outcome in compartment syndrome.
Manjoo
Ajay
A
Department of Orthopedic Surgery, University of Western Ontario, London, Ontario, Canada.
Sanders
David
D
Lawendy
Abdel
A
Gladwell
Michael
M
Gray
Daryl
D
Parry
Neil
N
Badhwar
Amit
A
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D003161:Compartment Syndromes / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004195:Disease Models, Animal; D005205:Fascia / Q000293:injuries; D007213:Indomethacin / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000473:pathology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D017695:Soft Tissue Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007213:Indomethacin