Early Therapeutic Intervention for Crush Syndrome: Characterization of Intramuscular Administration of Dexamethasone by Pharmacokinetic and Biochemical Parameters in Rats

• Published in: Biological & pharmaceutical bulletin Vol. 39; no. 9; pp. 1424 - 1431
• Main Authors: Murata, Isamu, Goto, Mai, Komiya, Masahiro, Motohashi, Risa, Hirata, Momoko, Inoue, Yutaka, Kanamoto, Ikuo
• Format: Journal Article
• Language: English; Japanese
• Published: Japan The Pharmaceutical Society of Japan 2016; Pharmaceutical Society of Japan
• Subjects: Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacokinetics; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Arterial Pressure - drug effects; crush syndrome; Crush Syndrome - blood; Crush Syndrome - drug therapy; Crush Syndrome - metabolism; dexamethasone; Dexamethasone - administration & dosage; Dexamethasone - pharmacokinetics; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; disaster medical care; Injections, Intravenous; Interleukin-6 - blood; intramuscular injection; Lung - drug effects; Lung - metabolism; Male; Muscle, Skeletal - metabolism; Peroxidase - metabolism; Rats, Wistar; Thiobarbituric Acid Reactive Substances - metabolism
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b15-01034

Crush syndrome (CS) is the systemic manifestation of muscle cell damage resulting from pressure and crushing. It is associated with a high mortality rate, even when patients are treated with conventional therapy. We demonstrated the utility of intramuscular administration of dexamethasone (DEX) in disaster medical care by using a model of CS to characterize the pharmacokinetics and biochemical parameters. We compared intravenous (IV) and intramuscular (IM) injection. The IM sites were the right anterior limb (AL), bilateral hind limbs (bHL), and unilateral hind limb (uHL). DEX (5.0 mg/kg) was administered in sham-operated (sham, S-IV, S-AL, S-bHL, S-uHL groups) and CS rats (control, C-IV, C-AL, C-bHL, C-uHL groups). The survival rate in the IM groups was lower than that in the C-IV group. Survival was highest in the C-AL group, followed by the C-uHL and C-bHL groups. The blood DEX concentration of the C-AL group was similar to that in the C-IV group. The C-bHL and C-uHL groups had decreased blood DEX concentrations. Moreover, inhibition of inflammation was related to these changes. Administration of DEX to non-injured muscle, as well as IV administration, increased the survival rate by modulating shock and inflammatory mediators, consequently suppressing myeloperoxidase activity and subsequent systemic inflammation, resulting in a complete recovery of rats from lethal CS. These results demonstrate that injection DEX into the non-injured muscle is a potentially effective early therapeutic intervention for CS that could easily be used in transport to the hospital.