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

Abstract

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. Key words crush syndrome; dexamethasone; intramuscular injection; disaster medical careCrush syndrome (CS) is often reported as a traumatic disorder with high mortality and occurs after sudden catastrophes, such as the Hanshin-Awaji, Marmara, and Wenchan earthquakes.1-3) CS is defined as the systemic manifestation of muscle cell damage resulting from pressure and crushing. 4)The typical clinical and pathological features of CS result predominantly from traumatic rhabdomyolysis and subsequent release of muscle cell contents upon rescue.5-7) Systemic manifestations may include bleeding, hypovolemic shock, cardiac failure, arrhythmia, electrolyte disturbance, psychological trauma, acute kidney injury (AKI), sepsis, systemic inflammatory response syndrome (SIRS), acute respiratory distress syndrome (ARDS), multiple organ dysfunction syndrome (MODS), and disseminated intravascular coagulation (DIC). 8)After major earthquakes, up to 20% of deaths occur shortly after extrication. 9) Some of these deaths include victims who were relatively stable before extrication, but deteriorated suddenly thereafter, and this phenomenon is called rescue death. Consequently, for affected victims and patients, it is necessary to identify who should receive an intensive care strategy. Most victims survive upon volume replacement or massive fluid resuscitation at the disaster site. However, this treatment improves symptoms of the acute phase (e.g., hyperkalemia, hypovolemic shock...

Systemic Review of Animal Models Used in the Study of Crush Syndrome

“…Some experiments used a press exerting a force of 100 kg per kg of animal body weight (100:1). In a series studies of tourniquet-induced CS models by the Murata research group, the survival rates of rats in the CS group were nearly 91%, 82%, 36%, 13%, and 13% at 1, 3, 6, 24, and 48 h after reperfusion, respectively (24), which were consistent with the results of the same teams other investigations since 2012 (49–53).…”

Astragaloside-IV prevents acute kidney injury and inflammation by normalizing muscular mitochondrial function associated with a nitric oxide protective mechanism in crush syndrome rats

“…CS rats displayed characteristic PK of impaired drug metabolism (i.e., inhibition of liver drug-metabolizing enzymes and the formation of the third space) [ 33 ], but we conclude that the high blood concentration of AS (Additional file 13 : Fig. S4) occurred because AS was not renally excreted in CS rats [renal clearance (CL r )/CL tot ratio: 0.159 ± 0.018/0.180 ± 0.012, as measured by HPLC].…”

Emerging medical therapies in crush syndrome – progress report from basic sciences and potential future avenues

“…Since the CS involves excessive inflammation in the body, researchers have tried to use DXM to treat CS rat models. Murata et al [24][25][26] found that high-dose DXM injections exerted antiinflammatory effects and reduced ischemia/reperfusion injury (IRI) through the PI3K-Akt-eNOS signaling pathway. This significantly improved the early survival rate of CS rat model.…”

“…Murata et al. [ 24–26 ] found that high-dose DXM injections exerted anti-inflammatory effects and reduced ischemia/reperfusion injury (IRI) through the PI3K-Akt-eNOS signaling pathway. This significantly improved the early survival rate of CS rat model.…”