Fri., 10/5/12 Basic Science, PAPER #50, 1:06 pm OTA-2012
Δ The Severity of Microvascular Dysfunction Due to Compartment Syndrome Is Diminished by the Systemic Application of CO-Releasing Molecules (CORM-3)
Abdel-Rahman Lawendy, MD; Relka Bihari, MSc; David W. Sanders, MD, PhD;
Gediminas Cepinskas, PhD;
London Health Sciences Centre, London, Ontario, Canada
Background/Purpose: Compartment syndrome (CS) is a limb-threatening complication of musculoskeletal trauma, resulting in myonecrosis and cell death. Both ischemic and inflammatory pathways have been implicated in the microvascular dysfunction and parenchymal injury seen in CS. Urgent fasciotomy remains the only treatment for CS. Recently, carbon monoxide (CO) has been shown to protect microvascular perfusion and reduce inflammation in ischemic states in animal models. Unfortunately, exogenous administration of CO via inhalation results in increased carboxyhemoglobin levels (COHb), reducing the clinical applicability. Transitional metal carbonyls, or CO-releasing molecules (CORM), deliver CO in a controlled manner without altering COHb, and can be administered using various routes (intravenous, intraperitoneal [IP], subcutaneous, or tissue superfusion) to target specific tissues. The purpose of this study was to examine the protective effects of CO, liberated from a novel CORM-3 on the function of CS-challenged muscle in a rodent model. The ultimate goal is the development of a pharmacologic adjunctive treatment for CS, which would reduce the morbidity and disability in patients.
Methods: 20 male adult Wistar rats were randomized into 3 groups: sham (no CS, n = 4), CS (with inactive CORM-3, n = 8), and CS + CORM-3 (10 mg/kg IP, n = 8). CS was induced by elevation of intracompartmental pressure (ICP) to 30 mm Hg through an infusion of isotonic saline into the anterior compartment of the hind limb for 2 hours. Both CORM-3 and inactive CORM-3 were injected immediately following fasciotomy. Microvascular perfusion (% continuously perfused, intermittently perfused, and nonperfused capillaries), cellular injury (ethidium bromide:bisbenzimide staining, EB/BB), and inflammatory response (adherent and rolling leukocytes in venules) within the extensor digitorum longus muscle (EDL) were assessed using intravital video microscopy (IVVM) 45 minutes after fasciotomy (5 fields of view in each animal). Data were analyzed using one-way analysis of variance.
Results: Elevation of ICP resulted in significant microvascular perfusion deficits (23 ± 2% continuously perfused capillaries in CS vs 76 ± 4% in sham, P ≤0.0001; 55 ± 2% nonperfused capillaries in CS versus 13 ± 2% in sham, P ≤0.0001), increased tissue injury (EB/BB of 0.31 ± 0.05 in CS vs 0.05 ± 0.03 in sham, P ≤0.0001), and adherent leukocytes (13.7 ± 0.9 in CS vs 1.8 ± 0.5 in sham, P ≤0.0001). CORM-3 treatment was able to restore the number of continuously perfused capillaries (57 ± 5%, P ≤0.001), diminish tissue injury (EB/BB of 0.07 ± 0.01, P ≤0.001), and decrease leukocyte adherence (0.6 ± 0.3, P ≤0.001).
Conclusion: Application of CORM-3 to CS-challenged muscle resulted in restoration of microvascular perfusion, 8-fold decrease in leukocyte activation, and 4-fold decrease in tissue injury. The data suggest that there may be a potential therapeutic application of CORM-3 to patients at risk of developing CS.
Δ OTA Grant
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• The FDA has not cleared this drug and/or medical device for the use described in this presentation (i.e., the drug or medical device is being discussed for an “off label” use). ◆FDA information not available at time of printing. Δ OTA Grant.