JP7640986B2 - Method for assisting in diagnosis of crush syndrome and program used therein - Google Patents

Description

This disclosure relates to aiding in the diagnosis of crush syndrome.

Crush syndrome refers to a condition in which muscle tissue is compressed and becomes ischemic due to an accident or disaster, and when the compression is released, symptoms such as fatal arrhythmia, cardiac arrest, acute renal failure, uremia, pulmonary edema, respiratory failure, and/or other organ failure throughout the body are caused. These symptoms are thought to be caused by potassium, myoglobin, lactic acid, creatine kinase, and other substances accumulating at the compressed area over time during compression, and then suddenly circulating throughout the body as blood flow resumes when the compression is released.

According to Non-Patent Document 1, the conventional method for diagnosing crush syndrome is based on early symptoms such as disproportionate pain, sensory abnormalities, swelling of the hands and feet, and cramps in the hands and feet. Diagnosis is also performed using blood tests to measure creatine concentration and pH.

Ingrassia et al. , Ciottone’s Disaster Medicine 16:180, 2016

Crush syndrome includes fatal symptoms caused by pressure release, and early diagnosis is important. The early symptoms described in Non-Patent Document 1 are very similar to typical symptoms of external wounds, making them difficult to diagnose. Furthermore, it is even more difficult to accurately diagnose them in emergencies such as accidents and disasters.
The conventional diagnostic method, blood tests, mainly detect substances that enter the bloodstream from the crush site. Therefore, they cannot detect substances before or immediately after the release of pressure, or the sensitivity is poor, making them insufficient for early diagnosis. In addition, by the time crush syndrome is diagnosed, it is often already too late, making it difficult to diagnose crush syndrome early with blood tests.
The present disclosure provides a method for early diagnosis of crush syndrome using MR spectroscopy measurements.

The gist of the present invention is as follows.
[1] A method for assisting in the diagnosis of crush syndrome, comprising:
A method comprising the steps of: analyzing ³¹ P spectrum data of a compressed site of a subject obtained by MR spectroscopy; and presenting a determination result indicating crush syndrome when the ³¹ P spectrum data satisfies the following formula (1):
PCr/(Pi+PCr)≦0.50 (1)
[In formula (1), Pi represents the height of the spectrum peak corresponding to phosphate ion, and PCr represents the height of the spectrum peak corresponding to creatine phosphate.]
[2] The method according to [1], wherein in the step of presenting a result of the determination that the patient has crush syndrome, the patient is determined to have crush syndrome when the ³¹ P spectrum satisfies the following formula (2):
PCr/(Pi+PCr)≦0.20 (2)
[3] A method for assisting in the diagnosis of crush syndrome according to [1] or [2], comprising:
The method further comprises a step of presenting a determination result indicating crush syndrome when no spectral peak corresponding to creatine phosphate is present in ³¹ P spectral data of the compressed site of the subject obtained by MR spectroscopy.
[4] A method for assisting in the diagnosis of crush syndrome according to any one of [1] to [3], comprising:
The method further includes a step of presenting a determination result indicating crush syndrome when no spectral peak corresponding to the β-phosphorus of ATP is present in the ^31P spectral data of the compressed site of the subject obtained by MR spectroscopy.
[5] The method according to any one of [1] to [4], wherein the compressed site is compressed muscle tissue.
[6] A program for determining crush syndrome, comprising:
A step of analyzing ³¹ P spectrum data of the compressed part of the subject by MR spectroscopy and calculating the height of the spectrum peak corresponding to phosphate ion and the height of the spectrum peak corresponding to creatine phosphate;
A program for executing a step of displaying a determination result that the patient has crush syndrome when the ^31P spectrum satisfies the following formula (1).
PCr/(Pi+PCr)≦0.50 (1)
[In formula (1), Pi represents the height of the spectrum peak corresponding to phosphate ion, and PCr represents the height of the spectrum peak corresponding to creatine phosphate.]
[7] Further, the following steps are executed:
The program described in [6] includes a means for detecting a spectrum corresponding to the beta phosphorus of ATP, and a means for displaying a determination result that the patient has crush syndrome when no peak in the spectrum corresponding to the beta phosphorus of ATP is present. [8] An MR spectroscopy device capable of measuring ^31P spectra, the device being equipped with the program described in [6] or [7].

The present disclosure provides a method for assisting in the early diagnosis of crush syndrome. It also provides a program and device for the early diagnosis of crush syndrome.

Photograph of the right groin of a rat. ³¹ P spectrum before avascularization (PRE) in Group A. ³¹ P spectrum after 2 hours of avascularization (ACS 120 min) in Group A. ³¹ P spectrum in Group A 1.5 hours after release of avascularization (RPF 90 min). FIG. 1 shows the value of PCr/(Pi+PCr) over time in the ³¹ P spectrum of Group A. FIG. 1 shows blood CPK concentrations over time in Group A. ³¹ P spectrum before avascularization (PRE) in Group B. ³¹ P spectrum in Group B after 3 hours of avascularization (ACS 180 min). ³¹ P spectrum in Group B, 1.5 hours after release of avascularization (RPF 90 min).

According to the present disclosure, the ³¹ P spectrum can be used to assist in the early diagnosis of crush syndrome.
That is, the method of the present invention is a method for assisting in the diagnosis of crush syndrome, comprising:
The method includes a step of presenting a determination result that the subject has a crush syndrome when ^31P spectrum data of a compressed part of the subject obtained by MR spectroscopy satisfies the following formula (1):
Pi ≧ PCr (1)
In the formula (1), P _i represents the height of the spectral peak corresponding to phosphate ion, and PC _r represents the height of the spectral peak corresponding to creatine phosphate.

Crush syndrome occurs when tissue is compressed, becomes ischemic, and then the compression is released. The compressed tissue typically includes muscle tissue. Tissue compression includes compression with ischemia. Tissue compression typically includes compression with complete ischemia.

Release of compression typically involves resumption of blood flow. Thus, by way of example, crush syndrome includes the phenomenon that occurs when muscle tissue and/or vascular tissue is compressed with ischemia and then released with resumption of blood flow.

Compression of tissues can be due to external factors such as being pinched between heavy objects such as rubble or blood flow from a string-like object, or it can be due to internal factors such as increased pressure within a compartment due to hematoma formation or muscle swelling. Crush syndromes caused by internal factors are also called compartment syndromes.

Crush syndrome can be reproduced experimentally. For example, crush syndrome can be reproduced by tightly tying the groin of a subject with a cable tie and avascularization. The subject may be a mouse or a rat, and is not particularly limited as long as it is not a human, but is preferably a rat.

The above method is excellent as a model of crush syndrome because it allows avascularization by compression accompanied by complete ischemia. Avascularization in the above method is preferably performed for 2 hours or more, and more preferably for 3 hours or more.

In crush syndrome, substances derived from the compressed tissue, such as potassium, myoglobin, lactate, and creatine kinase, accumulate at the site of compression. These substances are then released into the bloodstream, causing symptoms such as fatal arrhythmias, cardiac arrest, acute renal failure, uremia, pulmonary edema, respiratory failure, and/or other organ failures throughout the body.

In conventional methods, crush syndrome is diagnosed by detecting an increase in substances derived from the compressed tissue in the blood. An example of the substance derived from the compressed tissue used for diagnosis is creatine phosphokinase (CPK). In other words, crush syndrome may be diagnosed when the concentration of CPK in the blood increases.

The substances derived from the compressed tissue are accumulated at the compressed site and released into the blood when the compressed tissue is damaged. Therefore, the degree of damage to the compressed tissue is an important indicator of the crush syndrome.
Thus, crush syndrome can be diagnosed based on the state of the compressed tissue, which can be shown, for example, by measuring the compressed area using nuclear magnetic resonance spectroscopy (MR spectroscopy: MRS).

In view of the above, the method for assisting in the diagnosis of crush syndrome uses the results of measuring the compressed area. Also, preferably, the results of measuring the compressed muscle tissue are used.

The concentrations of inorganic phosphate, creatine phosphate, and ATP change due to tissue damage, and therefore the degree of tissue damage can be known by measuring inorganic phosphate, creatine phosphate, and ATP.
Measurement of inorganic phosphate, creatine phosphate, and ATP can be achieved, for example, by measuring phosphorus by MR spectroscopy, which is typically represented by ³¹ P spectral data.

In the method for assisting in the diagnosis of crush syndrome of the present invention, ³¹ P spectrum data of the compressed area obtained by MR spectroscopy is used. By using the ³¹ P spectrum data of the compressed area obtained by MR spectroscopy, it is possible to determine the presence of crush syndrome even before or immediately after the release of compression, and the method can be used for early diagnosis of crush syndrome.

MR spectroscopy is one of the techniques of nuclear magnetic resonance imaging (MRI), which is a measurement method that utilizes the phenomenon of nuclear magnetic resonance.
In MRS, the signal intensity of each resonance frequency can be measured, and for example, a spectrum can be obtained in which the horizontal axis represents frequency and the vertical axis represents signal intensity. The signal intensity is proportional to the concentration.

In measurements that utilize the phenomenon of nuclear magnetic resonance, atoms of the same isotope species will show slightly different resonance frequencies depending on the magnetic environment of each atom. With MRS, the signal strength of atoms in each magnetic environment can be measured by measuring the signal strength for each different resonance frequency.

Differences in the magnetic environment of atoms depend, for example, on the bonding state of the atoms. That is, atoms of the same isotope species will show different resonant frequencies depending on the structure of the molecule that contains those atoms.

As described above, MRS can measure the signal strength of the bond state of the measured atoms and the molecular structure having the atoms, separated by frequency. The signal for each bond state and molecular structure is seen as a peak in a spectrum with the horizontal axis being frequency and the vertical axis being signal strength. Furthermore, the signal strength for each bond state and molecular structure can be calculated as the height of a peak in a spectrum with the horizontal axis being frequency and the vertical axis being signal strength.

The strength of the signal is proportional to the concentration of the molecule, and the height of the peak is proportional to the strength of the signal. In other words, based on the spectrum obtained from measurements using MR spectroscopy, the concentration of molecules can be calculated for each atomic bonding state and molecular structure.

The frequency can be expressed, for example, as a shift in resonant frequency. The shift in resonant frequency is calculated, for example, by dividing the difference between the resonant frequency of an atom in a reference substance (reference frequency) and the resonant frequency of an atom in a substance to be measured by the reference frequency, and is also called a chemical shift. The chemical shift is typically expressed in parts per million (ppm).
Therefore, the measurement results of MRS can be expressed, for example, as a spectrum in which the horizontal axis represents chemical shift (unit: ppm) and the vertical axis represents signal intensity (relative value to a standard substance).

For MR spectroscopy measurements, an MR device such as an MRI device can be used. The magnetic field output of the device for measuring MR spectroscopy is preferably 1.5 T or more, and more preferably 3 T or more. Since the higher the magnetic field, the higher the sensitivity, no upper limit is set for the magnetic field output.

The spectral data used to determine crush syndrome may be data measured before or after the release of compression, but is preferably data measured before the release of compression.

^{The 31} P spectrum data is obtained by measuring ³¹ P, which is one of the isotopes of phosphorus, by MR spectroscopy. To measure ³¹ P by MR spectroscopy, for example, a probe for measuring ³¹ P can be used. In addition, preferably, a probe for measuring ³¹ P that can measure each muscle compartment can be used.

Signal peaks detected in the ³¹ P spectrum of a living body under normal conditions include signal peaks of inorganic phosphate, creatine phosphate, and phosphorus at the α-, β-, or γ-position of ATP.
In a ³¹ P spectrum, the signal peaks are typically arranged in descending order of resonance frequency as follows: inorganic phosphate, creatine phosphate, γ-phosphorus of ATP, α-phosphorus of ATP, and β-phosphorus of ATP.

In the ^31P spectrum, the horizontal axis may represent, for example, chemical shifts (ppm) based on an 85% aqueous phosphoric acid solution, and the vertical axis may represent, for example, relative values or concentrations (absolute mmol: A mmol) calculated by analysis software such as jMRUI.

As an example, the frequency at which each signal peak exists is shown below in the case of a ³¹ P spectrum in which the horizontal axis is expressed as chemical shift (ppm) based on an 85% aqueous phosphoric acid solution.

That is, the signal peak of inorganic phosphate in the ^31P spectrum is a peak appearing at 0 ppm to 5 ppm, preferably a peak appearing at 2 ppm to 4 ppm. Furthermore, in the ^31P spectrum, the signal peak of inorganic phosphate is preferably appearing at a higher ppm than the signal peak of creatine phosphate.
In the ³¹ P spectrum, the signal peak of creatine phosphate is a peak appearing between -5 ppm and 0 ppm, preferably between -3 ppm and 0 ppm. Furthermore, in the ³¹ P spectrum, the signal peak of creatine phosphate is preferably appearing at a ppm lower than the signal peak of inorganic phosphate and higher than the signal peak of phosphorus at the γ position of ATP.

In the ^31P spectrum, the signal peak of phosphorus at the γ-position of ATP is a peak observed at -8 ppm to -3 ppm, preferably a peak observed at -7 ppm to -4 ppm. Furthermore, in the ^31P spectrum, the signal peak of phosphorus at the γ-position of ATP is preferably observed at a ppm lower than the signal peak of creatine phosphate and higher than the signal peak of phosphorus at the α-position of ATP.
In the ³¹ P spectrum, the signal peak of phosphorus at the α-position of ATP is a peak observed at -12 ppm to -7 ppm, preferably a peak observed at -11 ppm to -8 ppm. Furthermore, in the ³¹ P spectrum, the signal peak of phosphorus at the α-position of ATP is preferably observed at a lower ppm than phosphorus at the γ-position of ATP and at a higher ppm than the signal peak of phosphorus at the β-position of ATP.

In the ³¹ P spectrum, the signal peak of phosphorus at the β-position of ATP is a peak observed at -20 ppm to -15 ppm, preferably a peak observed at -19 ppm to -17 ppm. Furthermore, in the ³¹ P spectrum, the signal peak of phosphorus at the β-position of ATP is preferably observed at a lower ppm than phosphorus at the α-position of ATP.
In the ^31P spectrum, the height of the signal peak of inorganic phosphate is Pi, the height of the signal peak of creatine phosphate is PCr, the height of the signal peak of phosphorus at the α-position of ATP is ATPα, the height of the signal peak of phosphorus at the β-position of ATP is ATPβ, and the height of the signal peak of phosphorus at the γ-position of ATP is ATPγ.

At this time, in the ³¹ P spectrum of a healthy subject under normal conditions, the value of PCr/(Pi+PCr) is typically greater than 0.50.

In crush syndrome, the ³¹ P spectrum of the compressed site of the living body has a PCr/(Pi+PCr) value of 0.50 or less, typically 0.20 or less, and more typically 0.10 or less.
In addition, in the ^31P spectrum of the compressed site of the living body in the case of crush syndrome, typically, there is no spectral peak corresponding to creatine phosphate and/or no spectral peak corresponding to phosphorus at the β position of ATP. The absence of a spectral peak corresponding to creatine phosphate and/or no spectral peak corresponding to phosphorus at the β position of ATP includes the substantial absence of a spectral peak corresponding to creatine phosphate and/or no spectral peak corresponding to phosphorus at the β position of ATP.

The absence of a signal peak of creatine phosphate may refer to a PCr value of 1/10 or less, preferably 1/100 or less, compared to that in the normal state. In addition, when the vertical axis is the concentration, it may refer to a value of 1.0 A mmol or less, preferably 0.10 A mmol or less, and more preferably 0.01 A mmol or less.
Furthermore, the absence of a signal peak of phosphorus at the β-position of ATP may refer to an ATP β value of 1/10 or less, preferably 1/100 or less, compared to that in the normal state. Furthermore, when the vertical axis is the concentration, it may refer to a value of 1.0 A mmol or less, preferably 0.10 A mmol or less, and more preferably 0.01 A mmol or less.

Therefore, the method for assisting in the diagnosis of crush syndrome may include a step of presenting a determination result that the patient has crush syndrome when the ³¹ P spectrum data satisfies the following formula (1).
PCr/(Pi+PCr)≦0.50 (1)
At this time, the ³¹ P spectrum is ³¹ P spectrum data of the compressed region of the subject obtained by MR spectroscopy.

In the above step, when the following formula (2) is satisfied instead of formula (1), a determination result indicating the occurrence of crush syndrome may be presented.
PCr/(Pi+PCr)≦0.20 (2)

In addition, in the above step, when the following formula (3) is satisfied instead of formula (1), a judgment result indicating that crush syndrome occurs may be presented.
PCr/(Pi+PCr)≦0.10 (3)

The method for assisting in the diagnosis of crush syndrome may include a step of presenting a result of determination that crush syndrome exists when a peak corresponding to creatine phosphate does not exist in the ^31P spectrum. In addition, in this case, it may be determined that crush syndrome exists severely. The absence of a peak corresponding to creatine phosphate includes a case where a peak corresponding to creatine phosphate does not exist substantially.

The method for assisting in the diagnosis of crush syndrome may include a step of presenting a result of determination that crush syndrome exists when a peak of a spectrum corresponding to phosphorus at the β position of ATP does not exist in the ^31P spectrum. In addition, in this case, it may be determined that crush syndrome exists as severe. The absence of a peak of a spectrum corresponding to phosphorus at the β position of ATP includes a case where a peak of a spectrum corresponding to phosphorus at the β position of ATP does not exist substantially.

The present invention further relates to a program for determining crush syndrome. The program may be a program for causing a computer to execute the above method.

The program for determining crush syndrome includes a means for executing a step of calculating the height of a spectral peak corresponding to phosphate ion and the height of a spectral peak corresponding to creatine phosphate. Furthermore, the program of the present invention may include a means for executing a step of calculating the height of a spectral peak corresponding to phosphorus at the gamma position of ATP, the height of a spectral peak corresponding to phosphorus at the alpha position of ATP, and the height of a spectral peak corresponding to phosphorus at the beta position of ATP.

As an example of a method for analyzing ^31P spectrum data and calculating the height of the spectrum peak, the following will show a case where the horizontal axis is represented as chemical shift ( ^ppm ) based on an 85% aqueous phosphoric acid solution, but the present invention is not limited to this and any appropriate method can be used.

In ^{the 31} P spectrum data, the peaks observed between 0 ppm and 5 ppm, preferably between 2 and 4 ppm, are taken as signal peaks of inorganic phosphate.
In the ^31P spectrum data, a peak occurring between -5 ppm and 0 ppm, preferably between -3 ppm and 0 ppm, is taken as a signal peak of creatine phosphate. The signal peak of creatine phosphate is preferably a peak at a lower ppm than the signal peak of inorganic phosphate.

In the ^31P spectrum data, a peak occurring between -8 ppm and -3 ppm, preferably between -7 ppm and -4 ppm, is taken as the signal peak of phosphorus at the γ-position of ATP. Note that the signal peak of phosphorus at the γ-position of ATP is preferably taken as a peak at a lower ppm than the signal peak of creatine phosphate.
In the ^31P spectrum data, the peaks observed between -12 ppm and -7 ppm, preferably between -11 ppm and -8 ppm, are regarded as signal peaks of phosphorus at the α-position of ATP. The signal peak of phosphorus at the α-position of ATP is preferably a peak at a lower ppm than phosphorus at the γ-position of ATP.

In the ^31P spectrum data, the peaks observed between -20 ppm and -15 ppm, preferably between -19 ppm and -17 ppm, are regarded as signal peaks of phosphorus at the β-position of ATP. Note that the signal peak of phosphorus at the β-position of ATP is preferably a peak at a lower ppm than phosphorus at the α-position of ATP.

The height of the apex of each of the above spectral peaks is calculated as the height of the spectral peak. For example, the height of the apex of the spectral peak of an 85% phosphoric acid aqueous solution is set to 1, and the height of the apex of each spectral peak can be calculated as a relative value.

By using the above-mentioned method, the ^31P spectral data of the compressed area of a living body obtained by MR spectroscopy can be analyzed, and the height of the peak of the spectrum corresponding to inorganic phosphate, the height of the peak of the spectrum corresponding to creatine phosphate, the height of the peak of the spectrum corresponding to phosphorus at the γ-position of ATP, the height of the peak of the spectrum corresponding to phosphorus at the α-position of ATP, and the height of the peak of the spectrum corresponding to phosphorus at the β-position of ATP can be calculated.

The calculated signal peak height of inorganic phosphate is designated Pi, the signal peak height of creatine phosphate is designated PCr, the signal peak height of phosphorus at the α-position of ATP is designated ATPα, the signal peak height of phosphorus at the β-position of ATP is designated ATPβ, and the signal peak height of phosphorus at the γ-position of ATP is designated ATPγ.

The program for diagnosing the crush syndrome includes a means for executing a step of displaying the result of the diagnosis that the patient has the crush syndrome from the ³¹ P spectrum.

The step of displaying the determination result that the patient has crush syndrome may be a step of displaying the determination result that the patient has crush syndrome when the following formula (1) is satisfied, preferably a step of displaying the determination result that the patient has crush syndrome when the following formula (2) is satisfied, and more preferably a step of displaying the determination result that the patient has crush syndrome when the following formula (3) is satisfied: PCr/(Pi+PCr)≦0.50 (1)
PCr/(Pi+PCr)≦0.20 (2)
PCr/(Pi+PCr)≦0.10 (3)

Furthermore, the step of displaying the determination result that there is crush syndrome may be a step of displaying the determination result that there is crush syndrome when there is no spectral peak corresponding to creatine phosphate and/or no spectral peak corresponding to phosphorus at the β position of ATP. The absence of a spectral peak corresponding to creatine phosphate and/or no spectral peak corresponding to phosphorus at the β position of ATP includes the substantial absence of a spectral peak corresponding to creatine phosphate and/or no spectral peak corresponding to phosphorus at the β position of ATP.
The absence of a signal peak of creatine phosphate may refer to a PCr value of 1/10 or less, preferably 1/100 or less, compared to that in the normal state. In addition, when the vertical axis is the concentration, it may refer to a value of 1.0 A mmol or less, preferably 0.10 A mmol or less, and more preferably 0.01 A mmol or less.
Furthermore, the absence of a signal peak of phosphorus at the β-position of ATP may refer to an ATP β value of 1/10 or less, preferably 1/100 or less, compared to that in the normal state. Furthermore, when the vertical axis is the concentration, it may refer to a value of 1.0 A mmol or less, preferably 0.10 A mmol or less, and more preferably 0.01 A mmol or less.

The program for determining crush syndrome may execute the step of displaying the determination result that crush syndrome is present, either alone or in combination, but includes means for executing at least one or more steps of displaying the determination result that crush syndrome is present.

The program for diagnosing the crush syndrome may include, for example, a means for issuing an alert when at least one of the above conditions is satisfied in the step of displaying the determination result that the crush syndrome is present. The means may be a means for executing the step of displaying the determination result.
The alert may be issued by any suitable means, including but not limited to emitting a sound, displaying a warning on a screen, or turning on a lamp.

The program for determining crush syndrome may be stored in a CD-ROM, DVD-ROM, USB drive, or other appropriate storage medium and used. The program for determining crush syndrome may also be installed in an apparatus, an analysis computer, or other appropriate device and used. The program for determining crush syndrome may also be stored in the above-mentioned storage medium and installed in the above-mentioned device and used.

The present invention further relates to a device for determining crush syndrome.

The device for determining crush syndrome uses MR spectroscopy to measure the pressure on the subject's body.
The device for measuring the ³¹ P spectrum includes a means for measuring the ³¹ P spectrum. The means for measuring the 31 P spectrum may measure the ³¹ P spectrum using, for example, an MR device and a probe for measuring ³¹ P. That is, the device for determining the crush syndrome may be, for example, a device including an MR device and a probe for measuring ³¹ P.
In addition, the MR device and/or the probe for ³¹ P measurement is preferably an MR device and/or a probe capable of measuring each muscle compartment.

The device for determining crush syndrome includes a means for determining the presence of crush syndrome using the ³¹ P spectrum obtained by the measuring means.
The means for determining the presence of crush syndrome may be a means for determining the presence of crush syndrome when the following formula (1) is satisfied, preferably a means for determining the presence of crush syndrome when the following formula (2) is satisfied, and more preferably a means for determining the presence of crush syndrome when the following formula (3) is satisfied. Furthermore, these means may be based on a program incorporated in the device.
PCr/(Pi+PCr)≦0.50 (1)
PCr/(Pi+PCr)≦0.20 (2)
PCr/(Pi+PCr)≦0.10 (3)

The means for determining the presence of crush syndrome may be a means for determining the presence of crush syndrome when a peak in the spectrum corresponding to creatine phosphate and/or a peak in the spectrum corresponding to phosphorus at the β position of ATP is not present. These means may be implemented by a program installed in the device.
The absence of a spectral peak corresponding to creatine phosphate and/or a spectral peak corresponding to the beta phosphorus of ATP includes the substantial absence of a spectral peak corresponding to creatine phosphate and/or a spectral peak corresponding to the beta phosphorus of ATP.
The absence of a signal peak of creatine phosphate may refer to a PCr value of 1/10 or less, preferably 1/100 or less, compared to that in the normal state. In addition, when the vertical axis is the concentration, it may refer to a value of 1.0 A mmol or less, preferably 0.10 A mmol or less, and more preferably 0.01 A mmol or less.
Furthermore, the absence of a signal peak of phosphorus at the β-position of ATP may refer to an ATP β value of 1/10 or less, preferably 1/100 or less, compared to that in the normal state. Furthermore, when the vertical axis is the concentration, it may refer to a value of 1.0 A mmol or less, preferably 0.10 A mmol or less, and more preferably 0.01 A mmol or less.

The device for determining crush syndrome may include a means for issuing an alert when crush syndrome is determined to be present. The alert may be issued by issuing a sound, displaying a warning on a screen, or turning on a lamp, but is not limited to these and may be issued by any suitable means.

By using the method, program, or device of the present invention, early diagnosis of crush syndrome is possible, which allows appropriate treatment to be administered and facilitates the decision to select the appropriate treatment.
An appropriate treatment may be, for example, but is not limited to, treatment including compression relief, limb amputation, or treatment based on a prediction of functional outcome.
Furthermore, the method, program, or device of the present invention may be used to perform early diagnosis of severe crush syndrome, which may facilitate the decision to select an appropriate treatment for severe crush syndrome, such as amputation of a lower limb to save a life.

The present invention will be explained below by showing specific experimental data, but the present invention is not limited to the following aspects.

Crush syndrome model animals were prepared according to the following procedure, and ³¹ P spectrum was measured.
Male normotensive SD rats, 9-12 weeks old and weighing 276-499 g, were purchased from Japan SLC. They were induced and maintained with 2-3% isoflurane (Pfizer Pharmaceuticals), appropriately adjusted within the range of 1.5-3% depending on the respiratory rate. This concentration of isoflurane is a concentration commonly used in MRI experiments without affecting the results obtained.
First, the rat was placed in a supine position and, after sufficient warming, a 22G Surflow (Terumo) was percutaneously inserted into the ventral tail artery and only the outer tube was placed and fixed. 0.25 ml of arterial blood was collected from the Surflow and an arterial blood collection line filled with heparinized saline (Terumo) was connected. Then, as shown in Figure 1, a cable tie for avascularization was loosely wrapped around the right groin and sutured to the skin in three places to prevent the band from shifting position.
The rats were then placed in a supine position on an MR cradle connected to a small animal ventilator (Shinano SF486, Shinano Seisakusho) and their hind limbs were firmly fixed with tape. Body temperature was maintained at 37°C using a circulating hot water system to the MRI scanner.
A complete avascularization of the right lower limb was achieved by fastening a cable tie. The subjects were divided into two groups based on the duration of avascularization: 2 hours and 3 hours, with the 2 hours group designated Group A and the 3 hours group designated Group B. After that, the cable tie was cut to allow reperfusion, and the avascularization was released.
The ^31P spectrum was measured on the right thigh using an MR device (manufactured by Bruker) and a ^31P measurement probe (manufactured by Bruker). The ^31P spectrum was measured before the start of avascularization, at the end of the avascularization duration, and 1.5 hours after the avascularization was released. In addition, measurements were also taken over time every 12 to 20 minutes from the start of avascularization until 2 hours after the avascularization was released. The results of the ^31P spectrum measurement are shown as chemical shift (ppm) on the horizontal axis and relative value on the vertical axis.
At the same time, as a comparative example, the blood concentration of creatine phosphokinase (CPK) was measured using arterial blood obtained from the tail artery with a blood analyzer i-STAT1 (Abbott) and a blood tester (Fujifilm). Measurements using arterial blood were performed before the start of avascularization, every hour during avascularization, and 5 minutes, 60 minutes, and 90 minutes after the end of avascularization. Furthermore, the respiratory rate of the rats was continuously monitored (SA Instruments, Stony Brook).

For Group A, the ^31P spectrum before avascularization is shown in Fig. 2, the ^31P spectrum after 2 hours of avascularization is shown in Fig. 3, and the ^31P spectrum 1.5 hours after the release of avascularization is shown in Fig. 4. In Figs. 2 to 4, Pi indicates the apex and height of the signal peak of inorganic phosphate, PCr indicates the apex and height of the signal peak of creatine phosphate, γ indicates the apex and height of the signal peak of ATPγ, α indicates the apex and height of the signal peak of ATPα, and β indicates the apex and height of the signal peak of ATPβ.
Before the start of avascularization, the spectrum had a high PCr and a slight peak for Pi, but after 2 hours of avascularization, the heights of the peaks were reversed, with Pi being high and PCr only slightly peaking. At this time, the value of PCr/(Pi+PCr) was below 0.10. 1.5 hours after the end of avascularization, the spectrum had a high PCr and only slightly peaking for Pi, recovering to a spectrum similar to that before the start of avascularization.
From the above, it can be determined that the tissue is in an ischemic state when the value of PCr/(Pi+PCr) is below 0.10, based on PCr and Pi calculated from the ³¹ P spectrum, and this can be an index of crush syndrome.

Furthermore, for Group A, the time-dependent measurement results of ^31P spectrum showed that PCr/
The value of (Pi+PCr) was calculated and is shown in FIG.
The value of PCr/(Pi+PCr) decreased over time after the start of avascularization, and fell below 0.50 about 30 minutes after the start of avascularization, i.e., the peak height was reversed. 80 minutes after the start of avascularization, the value of PCr/(Pi+PCr) fell below 0.20, and 2 hours later, the value of PCr/(Pi+PCr) fell below 0.10. After the release of avascularization, the value of PCr/(Pi+PCr) recovered, and 3 hours after the start of avascularization (1 hour after the release of avascularization), the value of PCr/(Pi+PCr) exceeded 0.50, but the variance was large and it was not stable.
From the above, it was found that in tissues in an ischemic state, PCr decreases and Pi increases over time. Therefore, by measuring the ^31P spectrum, it is possible to determine the crush syndrome earlier based on the value of PCr/(Pi+PCr) calculated from PCr and Pi. In addition, although the tissue damage caused by complete avascularization for 2 hours is recoverable, it is considered that the concentration of inorganic phosphate and creatine phosphate was unstable and therefore did not recover completely.

The results of measuring the blood CPK concentration using arterial blood for Group A are shown in Figure 6. In Figure 6, Pre indicates the time before the start of avascularization, Isc indicates the time elapsed during the continuation of avascularization, and Rep indicates the time elapsed after the release of avascularization.
The blood CPK concentration did not change from the start of avascularization until avascularization was continued. Five minutes after the release of avascularization after two hours, the blood CPK concentration increased slightly, but no significant difference was observed before and after the release of avascularization. One hour after the release of avascularization, a significant increase in the blood CPK concentration was observed compared to before avascularization and while avascularization was continued.
From the above, it was found that the increase in the blood CPK concentration was observed in Group A, reproducing the crush syndrome. Furthermore, in conventional blood tests, there was no significant difference in the blood CPK concentration during and immediately after the release of avascularization, making it difficult to determine the crush syndrome at an early stage.

For Group B, the ^31P spectrum before avascularization is shown in Fig. 7, the ^31P spectrum after 2 hours of avascularization is shown in Fig. 8, and the ^31P spectrum 1.5 hours after the release of avascularization is shown in Fig. 9. In Figs. 7 to 9, Pi indicates the apex and height of the signal peak of inorganic phosphate, PCr indicates the apex and height of the signal peak of creatine phosphate, γ indicates the apex and height of the signal peak of ATPγ, α indicates the apex and height of the signal peak of ATPα, and β indicates the apex and height of the signal peak of ATPβ.
Before the start of avascularization, the spectrum showed high PCr and only a slight peak for Pi, but after 3 hours of avascularization, the spectrum showed high Pi and PCr decreased to the extent that no peak existed. Furthermore, after 3 hours of avascularization, ATPγ, ATPα, and ATPβ were significantly decreased compared to before the start of avascularization, and in particular, ATPβ was decreased to the extent that no peak existed. In the spectrum 1.5 hours after the release of avascularization, Pi was high and PCr recovered to the extent that a slight peak was observed, while ATPγ, ATPα, and ATPβ remained significantly low and did not recover or had no peak.

In addition, gait disturbance persisted in Group B.
From the above, it was found that irreversible damage occurred to the tissue when avascularization was continued for 3 hours. It was also found that, at this time, the peak of PCr disappeared, and ATPγ and ATPα decreased, and the peak of ATPβ disappeared.

Claims (11)

1. A method for aiding in the diagnosis of crush syndrome, comprising:
A method comprising the steps of: analyzing ³¹ P spectrum data of a compressed region of a subject obtained by MR spectroscopy; determining whether the ³¹ P spectrum data satisfies the following formula (1); and presenting the determination result:
PCr/(Pi+PCr)≦0.50 (1)
[In formula (1), Pi represents the height of the spectrum peak corresponding to phosphate ion, and PCr represents the height of the spectrum peak corresponding to creatine phosphate.] The method according to claim 1 , wherein in the step of presenting the determination result, it is determined whether or not the ³¹ P spectrum data satisfies the following formula (2), and the determination result is presented.
PCr/(Pi+PCr)≦0.20 (2) A method for assisting in the diagnosis of crush syndrome according to claim 1 or 2, comprising:
The method further comprises the step of determining whether or not a spectral peak corresponding to creatine phosphate is present in ³¹ P spectrum data of the compressed site of the subject obtained by MR spectroscopy, and presenting the determination result. A method for assisting in the diagnosis of crush syndrome according to any one of claims 1 to 3, comprising:
The method further includes a step of determining whether or not a spectral peak corresponding to β-position phosphorus of ATP is present in ^31P spectral data of the compressed site of the subject obtained by MR spectroscopy, and presenting the determination result. A method for assisting in the diagnosis of crush syndrome according to claim 3 or 4, comprising:
The method, wherein said diagnosis of crush syndrome is a diagnosis of severe crush syndrome. The method according to any one of claims 1 to 5, wherein the compression site is compressed muscle tissue. A program for determining crush syndrome, comprising:
Analyzing ³¹ P spectrum data of the subject's compression site by MR spectroscopy;
calculating the height of the spectral peak corresponding to phosphate ion and the height of the spectral peak corresponding to creatine phosphate; and
A program for executing a step of displaying a judgment result indicating crush syndrome when the ^31P spectrum data satisfies the following formula (1).
PCr/(Pi+PCr)≦0.50 (1)
[In formula (1), Pi represents the height of the spectrum peak corresponding to phosphate ion, and PCr represents the height of the spectrum peak corresponding to creatine phosphate.] Furthermore, the following steps are performed:
The program according to claim 7, comprising: a step of detecting a spectrum corresponding to the beta phosphorus of ATP; and a step of displaying a result indicating crush syndrome when no peak in the spectrum corresponding to the beta phosphorus of ATP is present. The program according to claim 8, in the step of displaying the result of the determination that there is crush syndrome when there is no spectrum peak corresponding to phosphorus at the β position of ATP, displays the result of the determination that there is severe crush syndrome. An MR spectroscopy apparatus capable of measuring ^31P spectrum data, comprising the program according to any one of claims 7 to 9. The apparatus of claim 10 , wherein the MR spectroscopy apparatus is an MR spectroscopy apparatus equipped with a probe capable of measuring each muscle compartment.

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