Abstract
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Crush injury arises from prolonged external force on soft tissues, resulting in muscle necrosis and systemic manifestations known as crush syndrome.
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Pathophysiology involves ischemia, reperfusion injury and the release of toxic metabolites, which lead to rhabdomyolysis, electrolyte imbalances, acute kidney injury and potential multi-organ failure.
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Early management emphasizes aggressive fluid resuscitation, urine alkalinization and electrolyte correction to avert life-threatening hyperkalemia and renal impairment.
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Controversies include the use of mannitol, indications for fasciotomy and optimal dialysis timing. Each must be individualized according to patient status and resource availability.
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Emerging therapies focus on addressing inflammation and oxidative stress, aiming to transition from largely supportive care to more causative interventions.
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Despite medical advances, prompt recognition, coordinated multidisciplinary care and proactive measures remain vital to reducing morbidity and mortality in crush syndrome, especially in disaster settings.
Introduction
A crush injury occurs when the soft tissues of a body part experience significant direct physical trauma due to an external force. This results in extensive muscle and nerve damage, ischemia, tissue necrosis and systemic effects. It can include both the torso and the limbs, while the involvement of limbs increases the percentage of acute renal failure, starting from 50% when one limb is involved and reaching up to 100% if more than three limbs are involved. Systemic manifestations that are induced by crush injury are referred to as crush syndrome (CS). In more severe cases, in which CS develops, severe systemic complications of muscle and end-organ injuries lead to electrolyte imbalances, rhabdomyolysis, acute kidney injury (AKI), disseminated intravascular coagulation (DIC), dysrhythmias and sepsis. The reported mortality rate in patients with crush injury is approximately 80%, whereas around 20% of these patients require admission to a hospital. Of these patients, 10% develop CS, with the remaining patients following an uneventful recovery. The most common anatomical part that is involved in these injuries is the lower extremity with around 74%, followed by the upper extremity at 10%, the trunk injury at 9% and abdominal region at 4%. The latest anatomical regions are associated with the highest mortality rate (50%) (1, 2, 3, 4, 5, 6, 7, 8). These conditions are particularly prevalent in mass casualty events, including natural disasters such as earthquakes, cyclones, hurricanes, flooding and landslides and human-made catastrophes such as terrorist attacks, industrial accidents, air or railway crushes and wars. These disasters affect millions of people annually (8, 9, 10, 11, 12, 13). The common elements of these injuries are the involvement of muscle mass, the prolonged compression up to 6 h and the compromise of the local circulation. Around 800 million people reside in regions prone to earthquakes or severe tropical cyclones. About 80% of trapped victims die rapidly due to severe injuries, while 10% endure crush injuries and another 10% sustain mild trauma. Among those with crush injuries, 40–70% go on to develop CS (11, 13). Despite advances in disaster medicine, managing CS remains challenging due to the complexity of systemic manifestations that arise from muscle cell destruction.
Historical perspective
The phenomenon of CS was first documented during World War I as Meyer-Betz syndrome, but it was not until World War II that Bywaters and Beall extensively described the condition, later known as Bywaters’ syndrome (14). Their research on British soldiers trapped under rubble during air raids provided critical insights into the pathophysiology of CS, highlighting the relationship between muscle destruction and subsequent renal failure and uremia. Since then, numerous disasters, including earthquakes in Turkey, Japan and Haiti have contributed to our understanding of the condition’s epidemiology and clinical presentation.
Pathophysiology
CS develops due to prolonged muscle compression, leading to ischemia, hypoxia and muscle necrosis. Stretching of skeletal muscle cell membranes can lead to injury by opening calcium channels. The influx of calcium triggers ATP consumption for ion balance, but excessive calcium accumulation weakens mitochondrial function and activates enzymes such as proteases and phospholipases. This cascade depletes cellular energy, disrupts sodium gradients and results in edema, further exacerbating muscle damage. Muscles located distal to pressure sites naturally become ischemic. Complete ischemia leads to edema, lysosome degranulation within 30 min and irreversible necrosis in 4–6 h. In incomplete ischemia, limited collateral circulation maintains minimal energy production, but ATP depletion still causes cellular edema. When the compressive force is released, reperfusion injury occurs. During reperfusion, ischemic damage through interaction between leukocytes and endothelial cells causes superoxide radicals to attack free fatty acids, leading to cellular edema, cell death and necrosis (15). The Na-K-ATP pump, responsible for maintaining cellular ion balance, exchanges intracellular sodium for calcium, further disrupting intracellular metabolism and exacerbating tissue damage.
The breakdown of muscle cells under direct pressure results in the release of intracellular contents into circulation, a condition known as rhabdomyolysis. These released metabolites include potassium, purines, lactic acid, phosphate, myoglobin, urate, creatinine and thromboplastin. The increase of these toxic substances disrupts homeostasis, causing hyperkalemia, metabolic acidosis, elevated creatine phosphokinase (CPK) levels and systemic inflammation. Hyperkalemia leads to arrhythmias. One of the most critical complications of rhabdomyolysis is AKI, primarily due to myoglobin accumulation in the renal tubules. Myoglobin contributes to tubular obstruction and oxidative stress, further impairing renal function (8).
The effects of these metabolic derangements include calcium imbalance, resulting in hypocalcemia, also contributing to arrhythmias. Phosphate accumulation causes hyperphosphatemia, leading to renal damage. The breakdown of purines leads to hyperuricemia, further compromising kidney function. Hypoxemia promotes lactic acid accumulation, resulting in metabolic acidosis. Thromboplastin activates the complement system, increasing the risk of DIC. Elevated creatinine levels indicate worsening kidney dysfunction, while sodium imbalances contribute to azotemia (1).
Intravascular hypovolemia, caused by fluid shifting into damaged tissues, worsens renal dysfunction and increases the risk of multi-organ failure. Vascular compromise further exacerbates soft tissue edema. Skeletal muscles, enclosed by fascia and bone, are particularly vulnerable to rising intercompartmental pressure (ICP) due to edema. Even mild compression or unnatural posture can elevate ICP, affecting all muscles within the compartment. If ICP exceeds 30–50 mmHg for 4–8 h, ischemia develops, leading to compartment syndrome. Unlike trauma-induced compartment syndrome, which results from external factors such as fractures, compression-related damage stems from muscle edema itself, creating a vicious cycle. When combined with bleeding, ICP rises further, restricting capillary, lymphatic and venous outflow. This leads to worsening tissue damage, increased edema and ultimately reduced arteriolar perfusion, culminating in compartment syndrome (16, 17).
Compartment syndrome creates a vicious cycle of worsening cell perfusion, leading to further tissue damage. Without timely intervention, this cascade can lead to severe systemic complications, including shock, organ failure and death. Early recognition and management of CS are crucial to preventing these life-threatening consequences.
Clinical features
CS presents with both local and systemic manifestations (Fig. 1), often developing in patients trapped under debris or in collapsed structures. Locally, the affected limb becomes swollen, tense and edematous with diminished sensation, pallor and in severe cases, necrosis or contusions. Systemically, CS can lead to AKI due to hypotension, metabolic acidosis and rhabdomyolysis, which manifests as muscle weakness and life-threatening arrhythmias. The influx of calcium into damaged cells results in hypocalcemia during the oliguric phase, while hypercalcemia develops later in the diuretic phase. Fluid shifts and potassium efflux following reperfusion contribute to early circulatory collapse, with hyperkalemia being a primary cause of fatal cardiac arrest. Studies from earthquake disasters indicate that most hyperkalemia-related deaths occur within the first 3 days. Acute renal failure arises due to dehydration, renal tubular ischemia and myoglobin-induced obstruction, exacerbating systemic complications. The systemic inflammatory response associated with CS can also lead to leukocytosis, increased CRP levels, high serum creatine kinase (CK), fever and remote organ failure, such as DIC, respiratory failure or liver impairment. While acute renal failure is the most significant cause of death within the first 2 weeks, later deaths often result from multiple organ failure. A key indicator of severe muscle breakdown is tea-colored urine, signifying myoglobinuria and potential renal failure (17).
Initial management
Early intervention is crucial to preventing life-threatening complications associated with CS. The cornerstone of management is appropriate fluid resuscitation to mitigate AKI even before extrication (18). Immediate intravenous hydration with isotonic saline is essential to maintaining renal perfusion and diluting toxic metabolites. Administer 5% dextrose + isotonic saline if available to provide calories and help reduce hyperkalemia. Sodium bicarbonate in half-isotonic solutions can alkalinize urine (pH > 6.5) to prevent myoglobin and uric acid deposition, improve acidosis and lower hyperkalemia. Alkaline solutions are recommended in small-scale disasters unless symptomatic alkalosis (neuromuscular irritability, somnolence or paresis) is present. However, excessive alkalinization may cause calcium phosphate deposition, worsen hypocalcemia and lead to volume overload (18). Ringer lactate should be avoided in disaster victims, as it carries the risk of fatal hyperkalemia, which can occur suddenly even in patients without renal failure (19). If mannitol is to be used, 60 mL of 20% mannitol (overall 12 g or 200 mg/kg) is given intravenously over 3–5 min as a test dose to observe urine response. If there is no significant increase in urine output, mannitol should not be continued. However, if urine output increases by at least 30–50 mL/h above baseline levels, mannitol may be added to the solutions. The usual dosage of mannitol is 1–2 g/kg per day (total 120 g/day) at a rate of 5 g/h (20%) at a dose of 0.25–1 g/kg IV over 30–60 min (9). Mannitol has diuretic, antioxidant and vasodilatory properties, helping prevent renal damage, reduce muscle edema and delay the need for fasciotomy. However, its efficacy in traumatic rhabdomyolysis is debated and it poses risks of heart failure and nephrotoxicity, requiring close monitoring, which is often unfeasible in mass disasters. It is contraindicated in oliguria, hypervolemia, hypertension and heart failure. If used, a test dose should first confirm a positive urinary response before continuing treatment (20).
Fluid resuscitation in disaster victims should be carefully managed based on several factors. The duration of entrapment influences fluid needs – longer entrapment requires more fluids, but if rescue takes several days, intake should be limited due to the risk of anuria. During extrication, fluids should be administered at 1,000 mL/h, tapering by 50% after 2 hours. Hydration must also be adjusted based on volume status, increasing fluids for hypovolemia and reducing them in cases of hypervolemia or anuria. In large-scale disasters where monitoring is limited, daily fluid intake should be restricted to 3–6 liters. Special consideration is needed for vulnerable groups such as the elderly, children and those with mild trauma, who are at higher risk of fluid overload. In addition, colder temperatures reduce fluid requirements, while warmer conditions may necessitate more hydration (10, 21). Electrolyte disturbances, particularly hyperkalemia, should be promptly corrected. For hyperkalemia, administer insulin/dextrose and nebulized albuterol. Give calcium gluconate or chloride if ECG changes or hemodynamic instability occur. In CS, sodium bicarbonate infusion is recommended, though its effect on potassium is debated without acidemia. Hyperkalemia treatments provide temporary effects. Metabolic acidemia from necrosis, uremia, lactic acid or shock can impair cardiac function; if severe, treat with isotonic sodium bicarbonate infusion. The treatment of hyperkalemia involves stabilizing cardiac membranes, shifting potassium intracellularly and enhancing its elimination (1). Pain control is achieved using opioids such as fentanyl, while continuous ECG monitoring ensures early detection of cardiac complications. Damage-control orthopedics (DCO) may be the preferred approach until definitive fixation is possible. Key aspects of DCO include hemorrhage management, wound debridement, infection control and soft tissue stabilization. External fixation plays a crucial role in managing fractures and stabilizing soft tissues, helping to prevent further complications and improve patient outcomes. Prophylactic antibiotics may be administered to reduce the risk of sepsis, particularly in patients with open wounds. Tourniquets should be used exclusively for controlling life-threatening bleeding, not for preventing CS (22).
Definitive management
Once the patient is stabilized, further interventions are required to address complications associated with CS. Dialysis is considered in cases of severe AKI or refractory metabolic abnormalities. Crush-related AKI carries a higher risk of life-threatening complications, often requiring earlier and more frequent dialysis than AKI from other causes. While evidence on early dialysis remains inconclusive, crush patients frequently experience fluid overload, hypercatabolism, acidosis, uremia and severe hyperkalemia, warranting a lower threshold for initiation. Rapidly rising potassium should also be a dialysis trigger. In disaster settings, dialysis frequency and dosing should be optimized based on both medical and logistical factors (23, 24). Intermittent hemodialysis is the preferred RRT (renal replacement therapy) for crush victims due to its efficiency in clearing potassium, treating multiple patients per day and reducing the need for anticoagulation. While all RRT modalities are equally effective, peritoneal dialysis may be better suited for small children (25, 26). Surgical interventions, including wound debridement and fasciotomy, may be necessary to alleviate compartment syndrome and prevent secondary infections. In extreme cases where limb viability is compromised, amputation may be the only viable option to prevent systemic deterioration.
Controversies in management
There remains ongoing debate regarding the role of fasciotomy in CS. While fasciotomy is a well-established treatment for compartment syndrome, its benefits in CS are less clear. Some studies suggest that early fasciotomy improves tissue perfusion and prevents necrosis (27, 28), while others indicate that it may increase the risk of infection and dialysis dependence (29). Fasciotomy should be performed only based on clear clinical indications or objective compartment pressure measurements. Indications include the absence of distal pulses, the need for radical debridement of necrotic muscle, ICPs exceeding 30–40 mmHg – especially if unchanged for 6 h – or a pressure difference of less than 30 mmHg between the compartment and diastolic blood pressure (30, 31). Similarly, the decision between limb salvage and early amputation is complex, with recent advances in vascular surgery and orthopedic stabilization improving limb salvage rates. Amputations should only be performed when necessary, such as for a nonviable limb causing life-threatening sepsis or systemic inflammatory response syndrome, not to prevent CS (32, 33).
Future directions and research gaps
CS involves severe oxidative stress, inflammation and ischemia/reperfusion injury (IRI), leading to AKI and multi-organ dysfunction. Several chemical drugs and biological agents have shown promise in mitigating these effects, but they are under investigation in order to change medical treatment of CS from the current supportive and symptomatic management gradually to preventive and etiological treatment (Tables 1 and 2).
Chemical drugs.
| Drug | Mechanism of action | Key effects | References |
|---|---|---|---|
| SkQR1 | Mitochondria-targeted antioxidant reducing oxidative stress | Protects kidneys, heart, brain; increases erythropoietin, activates ischemic preconditioning | Koyner et al. (34), Plotnikov et al. (35, 36) |
| Dexamethasone (DXM) | Glucocorticoid with anti-inflammatory properties | Reduces ischemia-reperfusion injury via PI3K-Akt-eNOS; prevents SIRS | Murata et al. (37, 38) |
| Allopurinol | Xanthine oxidase inhibitor reducing oxidative stress | Preserves kidney function, reduces apoptosis and inflammation | Gois et al. (39), Kim et al. (40) |
| Nitrite therapy | Nitric oxide donor reducing ischemia-reperfusion injury | Cost-effective intervention; improves muscle and kidney recovery | Murata et al. (41, 42); Kobayashi & Murata (43) |
| Anisodamine | Belladonna alkaloid activating nicotinic acetylcholine receptors | Reduces serum potassium, improves insulin sensitivity, lowers mortality | Yu et al. (44), Li et al. (45) |
| Astragaloside-IV | Antioxidant extracted from Astragalus | Prevents mitochondrial damage, protects against AKI, enhances nitric oxide production | Xu et al. (46, 47), Murata et al. (48) |
| Hydrogen sulfide (H2S) | Vascular relaxation and antioxidant molecule | Reduces kidney injury markers, inflammation, oxidative stress | Teksen et al. (49) |
| Bardoxolone methyl (BM) | Nrf2 activator, NF-κB inhibitor | Improves glomerular filtration, reduces inflammation (TNF-α, TGF-β) | Vaziri et al. (50), Kadioglu et al. (51) |
| NA-2 | Salicylic acid derivative with anti-inflammatory properties | Reduces BUN, creatinine, preserves renal function via COX-2 and NF-κB inhibition | Siddiqui et al. (52) |
| Ulinastatin | Serine protease inhibitor reducing inflammatory responses | Lowers BUN, CK, creatinine, reduces kidney inflammation | Yang et al. (53) |
Biological agents.
| Agent | Mechanism of action | Key effects | References |
|---|---|---|---|
| rhEPO | Cytoprotective, modulates macrophages (M2 polarization) | Reduces renal injury markers, suppresses M1 macrophages | Wang et al. (54) |
| Lf | Mac-1 inhibitor preventing METs | Reduces renal tubular injury by inhibiting ROS and histone citrullination | Okubo et al. (55) |
| Anti-HMGB1 antibody | Inhibits HMGB1, TNF-α, JNK signaling | Lowers renal apoptosis, reduces inflammation | Zhang et al. (56) |
| Anti-RAGE antibody | Blocks RAGE receptor, preventing inflammation and multi-organ failure | Improves CS prognosis, prevents MOF | Matsumoto et al. (57) |
| MSC therapy | Regenerative and immunomodulatory properties | Promotes M2 macrophage accumulation, reduces IL-6, TNF-α | Geng et al. (58) |
| CO-RBCs | Inhibits myoglobin oxidation and free heme production | Protects renal function, reduces oxidative stress | Taguchi et al. (59) |
rhEPO, recombinant human erythropoietin; Lf, lactoferrin; MSC, mesenchymal stem cell; CO-RBCs, carbon monoxide-enriched red blood cells; METs, macrophage extracellular traps.
Conclusion
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Early recognition: identifying at-risk patients promptly is vital to anticipate rhabdomyolysis, AKI and systemic complications.
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Aggressive resuscitation: fluid therapy and electrolyte management, particularly for hyperkalemia, should begin immediately – even before extrication.
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Individualized management: fasciotomy, mannitol use and dialysis must be tailored to clinical findings and resource constraints.
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Multidisciplinary approach: coordinated efforts among surgeons, nephrologists and critical care teams are crucial for addressing both local tissue damage and systemic effects.
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Future directions: novel therapies targeting ischemia-reperfusion injury and anti-inflammatory measures warrant further research to improve outcomes in CS.
ICMJE Statement of Interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding Statement
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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