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Medicine, General & Internal
Crush syndrome (CS), also known as traumatic rhabdomyolysis, is a syndrome with a wide clinical spectrum; it is caused by external compression, which often occurs in earthquakes, wars, and traffic accidents, especially in large-scale disasters. A series of clinical complications caused by crush syndrome, including hyperkalemia, myoglobinuria, and, in particular, acute kidney injury (AKI), is the main cause of death in crush syndrome. The early diagnosis of crush syndrome, the correct evaluation of its severity, and accurate predictions of a poor prognosis can provide personalized suggestions for rescuers to carry out early treatments and reduce mortality.
- crush syndrome
- crush injury
- diagnosis
- biomarker
1. Introduction
Crush injury (CI) refers to direct injury to the body (trunk, limbs, etc.) caused by external compression. Crush syndrome (CS) occurs when the symptoms and signs of CI are not limited to the directly compressed part but show systemic manifestations [1]. In CS, also known as traumatic rhabdomyolysis, injured skeletal muscle cells collapse and release their contents, including myoglobin, creatine kinase, and electrolytes, into the circulation, leading to clinical complications such as myoglobinuria, acute kidney injury (AKI), electrolyte disorders, hypovolemic shock, and multiple-organ dysfunction (MODS) [2,3]. CS affects all vital organs of the body, but the damage to the kidneys is the most prominent, and AKI has become an important factor that threatens the lives of CS patients [4,5,6,7,8]. True CS may require approximately four hours of compression, although this claim has not been systematically investigated [9].
The first mention of rhabdomyolysis in human history is in the Bible, in which quail poisoning was considered to be the cause. German surgeon Frankenthal first reported cases of traumatic rhabdomyolysis and acute kidney injury during the First World War [10]. In 1941, Bywaters and Beall described four patients with crush injuries buried in rubble, with the clinical manifestations of swollen limbs, red-to-brown urine, and shock, and introduced the terminology of ‘crush syndrome’. The four patients died within a week, and the autopsies revealed a brown-pigmented tubular pattern in the renal tubules, similar to that of thrombosis [11,12].
CS often occurs in natural disasters (earthquakes, volcanic eruptions, and landslides) and man-made disasters (wars, traffic accidents, and stampedes), especially in large-scale disasters, which result in heavy property losses and casualties [13]. CS is the second leading cause of death after direct trauma in earthquakes [3,14]. It has been reported that the incidence of CS in earthquake victims is as high as 25%, and the mortality rate can be as high as 21% [15,16]. In addition, CS can be encountered in the emergency room for routine reasons, such as poisoning, stroke, and falling, which can lead to long-term braking, in which the patient’s own body weight becomes the source of compression [17]. Theoretically, any condition that results in prolonged immobility can lead to the development of CS [9].
CS is characterized by systemic involvement, and many of its clinical manifestations are nonspecific. Victims may experience sickness, fever, edema, tachycardia, nausea, vomiting, confusion, anxiety, delirium, tea-colored urine, or anuria [18]. The most common clinical feature is the triad of myalgia, myoglobinuria, and elevated serum muscle enzyme levels; however, the degree and severity of these clinical manifestations vary widely [19]. Therefore, the early diagnosis of CS and the correct evaluation of its severity are crucial for a good prognosis.
2. Diagnostic Evaluation of Crush Syndrome
2.1. Urine Dipstick Test (UDT)
Traumatic rhabdomyolysis is an inexact syndrome with a broad clinical spectrum, and urinalysis can be used as a traditional screening test for rhabdomyolysis. When muscle fibers are damaged by external forces, myoglobin is released during muscle decomposition. The serum myoglobin level increases and reaches the renal threshold, at which point it can be detected in the urine. Orthotoluidine on a urine dipstick (UD) can react with heme molecules in myoglobin and cause hemoglobin molecules to turn blue [20]; therefore, the occurrence of rhabdomyolysis manifests as nonerythrocytic urine and UD positivity. In other words, in the absence of red blood cells in fresh urine, a positive test paper can be used as a surrogate marker for myoglobin. In prehospital settings and emergency conditions, urine paper testing is a highly sensitive and simple screening tool to identify patients at high risk of acute renal failure (ARF) due to crushing, which allows rescuers to perform an initial triage of patients requiring prompt management [21,22].Urine dipstick tests were used in earthquake scenes since as early as the 1995 Kobe earthquake in Japan and the 2003 Bam earthquake in Iran [23,24]. The urine dipstick test is easy to perform and can even be conducted by the patient himself. The patient simply dips the test strip into the urine, compares the color change to the reference label in the instructions, and calls a medical professional for relevant treatment if necessary [25]. However, the lack of means to detect red blood cells under disaster conditions and the presence of blood in the urine may lead to false-positive results. A negative UDT result also cannot completely exclude rhabdomyolysis, and there is a confounding effect of human error in reading dipstick test results. Furthermore, Sameir et al. presented a different view; after retrospectively analyzing the medical records of 228 patients with rhabdomyolysis, they concluded that urine microscopy without red blood cells but with positive urine test paper is not a sensitive screening method for rhabdomyolysis [20]. Although urine is not considered a body fluid, a growing body of research shows the significance of urine as a source of novel biomarkers [26]. A recent study found that urinary tissue inhibitor metal proteinase-2, insulin growth-factor-binding protein-7 (TIMP2*IGFBP7) can be unaffected by pre-existing CKD, enabling the early identification of people at high risk of AKI, especially after cardiac surgery. Based on TIMP2*IGFBP7 levels, AKI can be diagnosed before changes in renal function occur [27]. Due to the ease and non-invasive nature of urine collection, it has significant potential for use in early disease diagnosis in humans. However, due to confounding factors related to human urine, new urine markers face significant challenges in entering clinical practice [28].
2.2. Traditional Biomarkers
Currently, the diagnosis of CS relies on a history of injury from prolonged heavy crushing and the results of related laboratory tests. Biomarkers serve as indicators to distinguish between normal and diseased bodily states, and their early detection can improve the success of treatment [29]. Traditional biomarkers for the diagnosis of CS include the following: creatine kinase (CK), serum potassium, myoglobin (Mb), liver enzymes, and bicarbonates, etc.
2.3. Non-Traditional Biomarkers
With the development of multiomics, some relatively innovative, “non-traditional” biomarkers have also been proposed recently for the early diagnosis and evaluation of the occurrence and development of CS.
2.3.1. Neutrophil-Gelatinase-Associated Lipocalin (NGAL)
Neutrophil-gelatinase-associated lipocalin (NGAL), also known as lipocalin-2 (LCN2), siderocalin, or 24p3, is a member of the lipocalin family [68,69]. NGAL is a 25-kDa, small-molecular-weight, secreted protein that was initially identified in activated neutrophils but has since been described in many other cell types, including kidney cells, endothelial cells, liver cells, smooth muscle cells, cardiomyocytes, neurons, and various immune cell populations [68,70]. NGAL has powerful functions that are related to inflammation, embryonic development, immune responses, chemotaxis, signal transduction, differentiation and proliferation, and tumorigenesis and development, in addition to the function of transporting small hydrophobic molecules [71]. In the last decade, NGAL has received much attention from nephrologists as a noninvasive early biomarker of AKI. After acute kidney injury, NGAL is synthesized and secreted by the thick ascending limb of Henle’s loop and the collecting duct and becomes a sensitive and specific biomarker of kidney injury detectable in urine and blood [72,73]. Traditional kidney injury markers such as serum creatinine (Scr) and blood urea nitrogen (BUN) are delayed and unreliable indicators of AKI and are only relevant when there is a substantial loss of kidney function [70,74,75]. Although NGAL is not a direct diagnostic indicator of CS, early monitoring of NGAL levels can detect crush-related AKI in good time. Elevated NGAL levels have been reported in two patients with CS in mudslide disasters as a good predictor of acute kidney injury and as a precursor to increased serum creatinine levels [8].
2.3.2. Alpha-1-Acid Glycoprotein (a1-AGP)
Alpha-1-acid glycoprotein (a1-AGP) is a nonspecific acute-phase protein with inflammatory and immunomodulatory properties that is mainly synthesized by the liver [76,77]. In mouse experiments, a1-AGP has been shown to protect against ischemia–reperfusion injury through anti-apoptotic and anti-inflammatory effects [77,78]. Researchers previously used isobaric tags for relative and absolute quantitation (iTRAQ) combined with liquid chromatography–tandem mass spectrometry (LC–MS/MS) to identify serum biomarkers in CS rats. The findings suggest that a1-AGP is a nonnegligible biomarker in CS and is of great significance not only in predicting the severity of CS but also as a mediator of CS-induced AKI; however, its use as a target in the treatment of CS-induced AKI requires detailed mechanistic studies in future work [3].
2.3.3. MicroRNA (miRNA)
Circulating microRNAs (miRNAs), newly discovered small noncoding RNAs that regulate protein levels through transcription, are expected to constitute unique accessible biomarkers for detecting tissue injury due to their size, abundance, tissue specificity, and relative stability in plasma [79]. In rat experiments, Laterza et al. observed increased plasma concentrations of miR-122 and miR-133a, which could correspond to liver and muscle damage, respectively [80]. Bailey et al. performed a comprehensive assessment of liver- and skeletal-muscle-specific miRNAs and found that miR-122 and miR-192 in liver and miR-1, miR-133a, miR-133b and miR-206 in skeletal muscle all outperformed ALT and AST as traditional liver injury biomarkers and CK as a skeletal muscle injury marker [81], allowing for the detection of different miRNAs to differentiate between muscle and liver injury. This indicates their potential as useful diagnostic biomarkers.
2.4. Imaging Methods
Ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) can confirm and support the diagnosis of rhabdomyolysis.
2.4.1. Ultrasound (US)
Ultrasound (US) is a nonradiative, simple, rapid examination that can feasibly be performed at the bedside and is often used in the diagnosis of acute muscular lesions [82]. After the occurrence of disasters such as earthquakes, US is a relatively practical examination method. US can potentially be used to detect patients without clinical symptoms or signs and achieve an early diagnosis [83,84]. US can clearly show the extent of muscle lesions and the presence of internal fluid accumulation in patients with rhabdomyolysis caused by compression. Ultrasound-guided aspiration can be performed in cases where there is a large amount of fluid accumulation in muscle tissue. When the etiology is unknown, ultrasound-guided muscle puncture can also be used as a pathological examination [84]. Compared with other imaging modalities, US is more suitable for follow-up examinations to track the effect of treatment. After the Wenchuan earthquake in 2008, conventional ultrasound was used to diagnose rhabdomyolysis and acute osteofascial compartment syndrome (AOCS) due to compression [84]. Zhang C-D et al. constructed a skeletal muscle CI model using a balloon cuff to compress the hind limbs of rabbits and found that contrast-enhanced ultrasound (CEUS) was more sensitive than conventional ultrasound in identifying the initial microcirculatory changes in crushed muscles; thus, it may play an important role in the early diagnosis of muscle crush injuries [82]. In addition, a recent study by Zhao et al. demonstrated that CEUS is a sensitive tool for assessing renal perfusion changes in rhabdomyolysis-induced acute kidney injury [85].
2.4.2. Computed Tomography (CT)
Muscles with rhabdomyolysis often show focal shadows of hypodensity on CT, but this feature is often nonspecific. Similar signs can be found in cases of suppurative myositis, abscesses, and tumors [86]. However, Russ et al. found that CT images in four of eight patients with rhabdomyolysis showed areas of abnormally high density, consistent with skeletal muscle calcification; this is the opposite of the conventional CT presentation and could help to diagnose occult rhabdomyolysis [87]. Similarly, in the 1995 Kobe earthquake, Nakanishi, K. et al. observed muscle calcification shadows on CT images of five patients with crush injuries, three of whom showed a decrease in calcification over time [88].
2.4.3. Magnetic Resonance Imaging (MRI)
Magnetic resonance imaging (MRI), as an imaging tool with good soft tissue contrast, is the method of choice for assessing the extent and distribution of rhabdomyolysis. Many scholars have compared the performance of ultrasound, CT, and MRI in evaluating rhabdomyolysis and found that the sensitivity of MRI in detecting abnormal muscles was higher than that of CT and ultrasound (100%, 62%, and 42%, respectively) [18,36,86,89]. The affected muscles show an increased signal intensity on T2-weighted spin echo imaging and a decreased signal intensity on T1-weighted imaging. In the acute phase, the abnormal signal is associated with an increase in the cross-sectional diameter of the affected muscle [18,88,89,90]. Zhang, L. et al. suggested that the combined application of MRI and magnetic resonance angiography (MRA) to locate the affected muscles and distinguish them from unaffected muscles would be more helpful in assessing the need for surgical treatment [89]. In addition, Chia-Hung et al. retrospectively analyzed the MRI and CT images of ten patients with rhabdomyolysis and distinguished two different types based on the imaging, which could help to identify rhabdomyolysis with different etiologies [35].
Although imaging methods for the diagnosis of rhabdomyolysis are not specific and often require a combination of clinical and laboratory data, radiographic images provide information that can help assess the extent and distribution of rhabdomyolysis. Osteofascial compartment syndrome (OCS) is a common complication of CS. Radiological techniques, especially MRI, allow for the precise identification of the affected muscles and subsequent targeted decompression therapy. In addition, near-infrared spectroscopy (NIRS) can be used to detect OCS by measuring tissue oxygenation [91]. In conclusion, the use of radiographic techniques is important to localize diseased muscles and differentiate them from nondiseased muscles.
This entry is adapted from the peer-reviewed paper 10.3390/diagnostics13193034
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