Crush injury is the damage of muscles, blood vessels, and other internal structures resulting from excessive pressure to an area causing local ischemia. Vehicular collisions, industrial incidents, natural disasters, particularly earthquakes or where buildings have collapsed due to bombing are among some of the typical cases in crush injuries.
Crush syndrome, also known as traumatic rhabdomyolysis is a systemic manifestation of crush injury. It involves the liberation of components, damaged proteins, ions from skeletal muscle into the circulation. The syndrome was first reported by Bywater’s and Stead in a case of 5 patients who were trapped under debris in London during World War II, which presented with injury to their extremities, following swollen limbs, hypovolemic shock, dark urine and renal failure leading to individual’s demise. The skeletal muscle is one of the significant muscle tissues in the human body with essential roles such as body movement, maintenance of posture, temperature regulation, storage and movement of materials and support, hence severe damage to it as extensive crush injury can result in high mortality.
A first characteristic in the pathogenesis of crush injury is the disruption of sarcolemma, resulting in becoming leaky. When the skeletal muscle is compressed from a crush injury, ion channels open in response to triggering off stretch receptors resulting in the influx of fluid and electrolytes, including sodium and calcium into the muscle fibres and release of large toxic skeletal muscle components into the circulation. Potassium, myoglobin, uric acid and phosphorus move out of the skeletal muscle into the surrounding extracellular environment, while sodium, calcium and water move down their concentration gradient into the intracellular environment, which results in swelling to the skeletal muscle cells.
Hypovolemia and toxin exposure are the major systematic features of crush syndrome. With the capillaries damaged, their permeability increases and large volumes of intravascular fluid accumulating the damaged muscles and the plasma will accumulate in the traumatised extremities leading to depleting intravascular volume and resulting in shock. Signs of shock include fast pulse rate, lowering of blood pressure, pale skin, nausea, dizziness and thirstiness. In addition to intravascular depletion, patients with crush syndrome are faced with a large toxin load and can develop life-threatening electrolyte abnormalities.
Hypocalcemia occurs resulting from the massive influx of calcium into the affected muscle tissue. Hypocalcemia is especially dangerous when combined with hyperkalemia both which can occur upon reperfusion of ischemic tissue. Hyperkalemia arising from high levels of potassium entering into the systemic circulation can result in cardiac toxicity and death. High levels of potassium are known to be the second most common cause of early deaths following crush injury.
Prolonged compression from extensive crush injury leads to ischemia. Different tissues have different tolerances to the reduction in blood supply, and this is determined by how much energy the tissue consumes at rest and what capacity it has to generate this energy in anaerobic conditions. The peripheral nerves show the least resistance to ischemia, giving their high energy demands, minimal energy reserve and little capacity for anaerobic respiration. The limit blood supply, which in turn limits oxygen delivery, nutrient delivery and waste removal leads to severe damage to the function and structure of peripheral nerves and ultimately, the detrimental diminishment of peripheral pulses.
The duration of ischemia determines the degree of muscle injury. Skeletal muscle can tolerate warm ischemia for up to 2 hours without permanent histologic damage. Two to four hours of ischemia leads to irreversible anatomic and functional changes as a consequence of ischemia itself exhausting the muscles capacity for anaerobic respiration.
Accumulation of sarcoplasmic calcium in the skeletal muscle triggers contraction in attempt to contract, and ATP is diminished. Anaerobic respiration begins and increases amounts of lactate, that dissociates into lactic acid and hydrogen ions. Lactic acid diffuses out of the skeletal muscle, lowering pH and leading to acidosis, which when exposed to ischemia can cause damage to vital protein structures. The resulting calcium overload activates cytoplasmic neutral proteases that lead to the degradation of myofibrillar proteins. Calcium dependent phosphorylases are activated, and cell membranes are degraded. Additionally, nucleases are activated, and mitochondrial ATP production is reduced because of an inhibition of cellular respiration. The development of muscle necrosis will be most apparent in 6 hours of ischemia. If the ischemia persists, the injury due to ischemia and the histological changes will be maximum at 24 hours.
While reperfusion is critical, for reverse ischemia, it also exacerbates the injuries that are already present. Release of entrapments or reperfusion revascularisation results in an ischemia-reperfusion injury. Once compression is relieved, hypoxanthine is converted to xanthine with the use of oxygen which generates the formation of oxygen free radicals that cause damage to the skeletal muscle fibre by targeting the lipid-bilayer. The increase membrane permeability, results in oedema, the influx of fluid and ions. The breakdown products of cell membrane endothelial cells act as a chemoattractant that draws neutrophils to the damaged area. Although neutrophils have useful properties in terms of removing debris, they also promote the formation of cytotoxic substances which in turn produce damaging substances known as myeloperoxidase, that generate more damage within the skeletal muscle fibre.
Another event of traumatic rhabdomyolysis is acute kidney injury, which leads to kidney failure. Damage to the skeletal muscle results in the movement of fluid into the skeletal muscle which causes fluid depletion from the rest of the body causing hypoperfusion, and ultimately ischemia of the kidney, so the blood flow through the kidney is reduced. Another damaging effect of rhabdomyolysis is the allowance of myoglobin held within the skeletal muscle fibre into the circulation as well as into the kidneys where it can dissociate in acidic conditions and result in the formation of intratubular casts. These tubular casts are damaging to the structure and function of the kidney.
Myoglobin vaguely related to haemoglobin is a cytoplasmic hemoprotein consisting of a single polypeptide chain of 154 amino acids, expressed solely in both cardiomyocytes and oxidative skeletal muscle fibres. Containing various ligands, myoglobin can bind not only to oxygen but also carbon monoxide and nitric oxide. Myoglobin reversibly binds oxygen and facilitates its transport from the red blood cells to the mitochondria in the skeletal muscles during periods of increased metabolic activity. It also serves as an oxygen reservoir during periods of inactivity and helps to compensate for falling levels of oxygen.
The myoglobin released into the circulation is taken up by haptoglobin, an alpha two globulin, and disposed of by the reticuloendothelial system. In rhabdomyolysis, the binding capacity of haptoglobin becomes saturated, and free plasma levels rise. When myoglobin reaches between 0.5 and 1.5 mg / dL, myoglobinuria occurs. Myoglobin is not reabsorbed in the renal tubules, and when water reabsorption occurs, it becomes concentrated, resulting in dark tea-coloured urine. In the nephron, myoglobin reacts with Tamm-Horsfall that can obstruct the urine flow and result in leakage of the glomerular filtrate. When it is in an acidic environment, it dissociates into protein and ferrihemates.
Ferrihemates catalyses the formation of free radicals which in turn lead to lipid peroxidation in the renal tubules. The presence of myoglobin itself within the kidneys also triggers the production of vasoconstrictors that will contribute to renal dysfunction. Myoglobin then will scavenge nitric oxide and therefore reduce blood flow and vassal dilation. Besides, high levels of myoglobin are toxic to the kidneys resulting in nephrotoxicity.
Other secondary problems such as the development of compartment syndrome may also occur in crush injury. The skeletal muscle is located in compartments rigid non-compliant fascia; therefore, the pressure within a compartment is usually low, from 0 to 20mmHg. If compression remains, oedema or blood can accumulate due to its inability to expand, restricting the perfusion of that muscle fibre and hinder the function of the tissue. If that pressure is not released, it will lead to tissue necrosis, muscle tamponade and severe damage to skeletal muscle fibre and muscle as a whole. Signs of compartment syndrome include swell and muscle compartment, pain in that area, numbness and as pressure increases it can lead to weakness and even paralysis of that part of the body, developing ischemia and diminished peripheral pulses.
Muscle necrosis from extensive crush injury cannot be reversed. Therefore, it is vital to undertake interventions to limit the pathology of rhabdomyolysis. Volume resuscitation should be the priority to prevent the severe effects of crush injury. Undergoing intravenous isotonic saline, ideally one litre of fluid per hour until six litres of fluid in total is given before releasing the compression can reverse the hypovolaemic shock and minimise the electrolyte imbalances that are part of rhabdomyolysis and crush syndrome process.
Extensive crush injury to skeletal muscle is not compatible with life due to systemic and irreversible effects of crush syndrome. Ischemia-reperfusion injury is the primary mechanism of muscle injury which can result in sudden death. Further studies of new therapeutic agents including, ischemic preconditioning, and the use of medical gases or vitamin therapy, could significantly help experts develop strategies to inhibit ischemia-reperfusion injury.