INDOMETHACIN DECREASES CELL DAMAGE DUE TO ELEVATED COMPARTMENT PRESSURE: AN INTRAVITAL VIDEOMICROSCOPY STUDY

Abstract

Elevated intracompartmental pressure (ICP) results in muscle damage. Previous studies identified severe inflammation associated with elevated ICP. This study was designed to determine whether indomethacin, a potent anti-inflammatory agent, reduces muscle damage secondary to elevated ICP. We hypothesised that administration of indomethacin reduces muscle damage from elevated ICP.

Sixteen adult Wistar rats were randomised to four groups. In group One (control), no intervention occurred. Group Two (indo) rats were administered indomethacin (12mg/kg) with no elevation of ICP. Group Three (CS) rats had elevated ICP (30–40mmHg X 45 minutes) using saline injection. Group Four rats (CS/indo) had elevated ICP and indomethacin administration. After forty-five minutes, hindlimb fasciotomy was performed. The extensor digitorum longus muscle was reflected onto an intravital microscope. Capillary perfusion was measured by comparing the number of continuously perfused capillaries to intermittent and non perfused capillaries. Inflammation was determined using the number of activated (rolling and adherent) white blood cells. Muscle cell damage was measured using differential fluorescent staining. Perfusion, inflammation, and muscle damage were compared in all four groups using a one-way ANOVA (p< 0.05).

Perfusion: Indomethacin treatment (CS/indo) increased the proportion of intermittently perfused capillaries (39.1 ± 2.2 vs 30.3 ± 2.7) and decreased nonperfused capillaries (38.4 ± 1.8 vs 50.1 ±2.5) compared to CS (p=0.0002). Control and indo groups demonstrated more continuously perfused capillaries compared to CS or CS/indo groups (p< 0.0001). Muscle damage: Indomethacin treatment of elevated ICP reduced the proportion of damaged cells from 0.20 ± 0.14 (CS) to 0.01 ± 0.0.005 (CS/indo, p< 0.0001). There were no differences between CS/indo, control, or indo groups. Inflammation: CS and CS/indo groups demonstrated greater inflammatory activation compared to control and indo groups (p< 0.001). There were no differences in inflammatory activation between CS and CS/indo (p> 0.05).

Treatment of elevated ICP with indomethacin improved microvascular perfusion and reduced cell damage. The protective mechanism of indomethacin is unknown, but may be related to an anti-oxidative and vasodilatory effect. Treatment of elevated intracompartmental pressure with indomethacin dramatically reduces muscle damage and may have important future clinical benefit.