KR20220120089A - Method for predicting a response to the lower extremity amputation - Google Patents

Abstract

The present invention relates to a method for predicting prognosis of surgery before performing lower extremity amputation surgery caused by diabetes. It is expected to be able to provide accurate basic clinical information quickly and accurately such as a death rate or whether a diabetic patient should be hospitalized for a long time after lower extremity amputation of the patient only with a low-cost blood test.

Description

Method for predicting a response to the lower extremity amputation

The present invention relates to a method for providing information for predicting the treatment responsiveness of lower extremity amputation due to various causes such as diabetes.

Diabetes mellitus is a chronic metabolic disease characterized by prolonged high blood sugar levels (hyperglycemia), and the impact of the global burden on diabetes is increasing over time. The number of people with diabetes worldwide is expected to increase by 51%, from 466 million in 2019 to 700 million in 2045. Due to the explosive increase in diabetes, diabetic diseases including various complications due to diabetes increase. Among diabetic diseases, the longer one has diabetes, the higher the risk of developing diabetic foot diseases including ulcers and gangrene. changes in the body, foot ulcers, infections, and vascular diseases. When diabetes develops, blood circulation is not good and resistance to bacterial infection is lowered. Wound healing ability and resistance to bacteria are lowered, so even minor wounds progress rapidly, leading to serious complications such as ulcers and gangrene. corresponds to

For advanced diabetic foot disease that does not respond to such appropriate management, amputation is performed, and this operation is performed every 30 seconds on earth. The 5-year survival rate of patients with diabetic foot disease is similar to that of patients with malignant tumors, and the resulting medical or social burden is very high. In addition, diabetic patients have various complications, and in the case of diabetic foot disease, since neuropathy, angiopathy, and other underlying conditions are associated with complex interactions, it is difficult to adequately evaluate clinically.

The red blood cell size distribution width (RDW), which indicates the heterogeneity of the red blood cell size, corresponds to one of the factors used for differential diagnosis of anemia so far. In recent decades, a lot of research has been done on the relationship between RDW and other diseases. The clinical usefulness of RDW as a prognostic marker has been demonstrated in cardiovascular disease, cancer, kidney disease, diabetes, and the like. However, studies on the clinical role of RDW in diabetic foot disease are still insufficient.

The present inventors have completed the present invention because they newly discovered the value of red blood cell size distribution width (RDW) as a survival prognostic parameter of a patient before amputation due to diabetic foot disease.

One object of the present invention is to provide an apparatus and method for predicting the therapeutic responsiveness of lower extremity amputation surgery.

However, the technical task to be achieved by the present invention is not limited to the tasks mentioned above, and other tasks not mentioned will be clearly understood by those of ordinary skill in the art from the following description.

BRIEF DESCRIPTION OF THE DRAWINGS Various embodiments described herein are described below with reference to the drawings. In the following description, various specific details are set forth, such as specific forms, compositions and processes, and the like, for a thorough understanding of the present invention. However, certain embodiments may be practiced without one or more of these specific details, or in conjunction with other known methods and forms. In other instances, well-known processes and manufacturing techniques have not been described in specific detail in order not to unnecessarily obscure the present invention. Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, form, composition, or characteristic described in connection with the embodiment is included in one or more embodiments of the invention. Thus, references to "in one embodiment" or "an embodiment" in various places throughout this specification do not necessarily refer to the same embodiment of the invention. Additionally, the particular features, forms, compositions, or characteristics may be combined in any suitable manner in one or more embodiments.

Unless otherwise defined in the specification, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

According to one embodiment of the present invention, it relates to an apparatus for providing information for predicting treatment responsiveness of lower extremity amputation surgery.

The apparatus of the present invention includes an input unit for inputting a measurement value for a factor of a mean corpuscular volume (MCV) from a biological sample obtained from a subject; and a calculation unit for calculating a red blood cell size distribution width (RDW) from the mean blood cell volume measurement value obtained from the input unit.

In the present invention, the "target individual" means a body part due to an accident or disease, particularly diabetic disease, etc., or various other causes. It may mean a person, but is not limited thereto. In the present invention, the subject is a mammal including a human, for example, a human, a rat, a mouse, a guinea pig, a hamster, a rabbit, a monkey, a dog, a cat, a cow, a horse, a pig, a sheep and a goat selected from the group consisting of It may be, and preferably may be a human, but is not limited thereto.

The "diabetic disease" of the present invention is diabetes, diabetic foot disease, diabetic acidosis, diabetic xanthoma, diabetic muscle atrophy, diabetic ketosis, diabetic coma, diabetic gastrointestinal disorder, diabetic gangrene, diabetes mellitus. Sexual ulcers, diabetic complications, diabetic diarrhea, diabetic microangiopathy, diabetic body sclerosis, diabetic myocardial infarction, diabetic neuropathy, diabetic renal failure, diabetic blisters, diabetic cataract, diabetic skin disease, diabetes mellitus It may be at least one selected from the group consisting of sexual sclerosis edema, diabetic retinopathy, diabetic lipoid necrosis, diabetic blood circulation disorder and diabetic ketoacidemia, and may preferably be diabetes or diabetic foot disease, but this It is not limited.

In the present invention, the "amputation" refers to an operation to cut off the appendages of the upper or lower body due to tissue necrosis or infection, for example, partial foot amputation, ankle disarticulation. , transtibial amputation, knee disarticulation, transfemoral amputation, hip disarticulation, transpelvic amputation, translumbar amputation, hemicorporectomy, partial hand amputation, wrist disarticulation, transradial amputation, elbow disarticulation, transhumeral amputation, shoulder disarticulation, or forequarter amputation, Preferably, it may be a lower extremity amputation (LEA) operation for cutting the appendages of the lower body, and more preferably a foot amputation operation. wherein the foot amputation is from the group consisting of toe amputation, transmetatarsal amputation, Lisfranc's amputation, Chopart's amputation, Pirogoff's amputation, and Boyd's amputation. It may correspond to at least one selected, but is not limited thereto.

In the present invention, the biological sample is whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, serum, sputum , tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva, peritoneal washings), ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid ), nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cell, cell extract And it may be at least one selected from the group consisting of cerebrospinal fluid, etc., and preferably whole blood, but is not limited thereto.

The "mean corpuscular volume (MCV)" used in the input unit of the device of the present invention is a measure of the size of a single red blood cell or the average volume of red blood cells, and corresponds to a factor useful for classifying anemia. The average hematocrit may be calculated by dividing the total number of red blood cells by a hematocrit value.

The calculating unit of the device of the present invention may perform a function of calculating a red blood cell size distribution width (RDW) from the mean blood cell volume measurement value obtained from the input unit.

In the present invention, the "red blood cell distribution width RDW" is a test for determining the degree of distribution of the size of red blood cells in a red blood cell population, and corresponds to a test parameter useful for diagnosing and determining the type of anemia. Based on the various morphological characteristics of the size of red blood cells, many studies are being conducted because it can be used for diagnosis of various diseases and prediction of prognosis. When calculating the red blood cell size distribution width of the present invention, the standard deviation of RBC size may be divided by the mean blood cell volume (MCV) value to determine the degree of dispersion from the mean to be converted into a percentage.

The calculating unit of the device of the present invention may predict the prognosis of amputation of a target individual from the derived red blood cell size distribution width. In more detail, the calculation unit may determine a target subject with a predicted poor prognosis by generating and classifying information about the prognosis of amputation surgery according to the derived red blood cell size distribution width.

In one example of the present invention, when the calculated red blood cell size distribution width (RDW) value is 14.5% or less, the calculation unit of the present invention predicts that the survival rate after amputation is high and the hospitalization period is short, and the information can be output. .

In another example of the present invention, when the calculated red blood cell size distribution width (RDW) is greater than 14.5%, the calculation unit of the present invention predicts a high mortality rate after amputation and a long hospitalization period and outputs the information. have.

The apparatus of the present invention may further include an output unit for outputting the prognosis of the amputation surgery predicted by the operation unit.

According to another embodiment of the present invention, it relates to a method of providing information for predicting the treatment responsiveness of lower extremity amputation surgery.

In the present invention, the method comprises the steps of (a) measuring a mean corpuscular volume (MCV) from a biological sample obtained from a subject; and (b) calculating a red blood cell size distribution width (RDW) from the measured mean blood cell volume.

In the present invention, the mean blood cell volume may be measured using a hemocytometer (blood analysis device), and the hemocytometer is an automatic or semi-automatic hemocytometer, preferably a measuring device used in the art, Sysmex XN-2000 , Beckman Coulter GEN-S, CELL-DYN Sapphire, XE-2100, ADVIA-120, Hemavet 950FS, Mindray BC-6800, XN-V, etc. If it is a device that can measure the diagnostic information related to it, it is not limited thereto.

In one example of the present invention, the method may further include predicting that the survival rate after amputation is high and the hospitalization period is short when the value of the red blood cell size distribution width calculated above is 14.5% or less.

In another example of the present invention, the method may further include predicting that the mortality rate after amputation is high and the hospitalization period is long when the value of the red blood cell size distribution width calculated above is greater than 14.5%.

In the present invention, the description of the subject, biological sample, mean blood cell volume and red blood cell size distribution width, diabetes, amputation, etc. are the same as those described in the device for predicting the treatment responsiveness of lower extremity amputation surgery, so excessive complexity of the present specification omitted to avoid

The present invention relates to a method for predicting the prognosis after surgery in advance before the implementation of lower extremity amputation due to diabetes. When the prognosis prediction method according to the present invention is used, it is possible to predict the prognosis after surgery, in particular, whether high mortality or more than 1 month of hospitalization will be required, only by a simple blood test before lower extremity amputation surgery, saving time and money can do.

1 is a diagram showing the results of deriving the optimal cutoff value of the preoperative red blood cell size distribution width (RBC distribution width; RDW) as a reference value for predicting the prognosis of amputation surgery according to an embodiment of the present invention.
2 is a diagram confirming that the red blood cell size distribution width (RDW) is an important prognostic predictor of amputation surgery using ROC analysis according to an embodiment of the present invention.
Figure 3 shows the survival rate after lower extremity amputation (LEA) of the preoperative high RDW group (> 14.5%) and the preoperative low RDW group (≤ 14.5%) through the cumulative survival curve according to an embodiment of the present invention. It is a diagram showing the results of comparison and confirmation.

Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .

Preparation Example 1: Recruitment of the patient group

The present inventors performed all experiments with the approval of the Institutional Review Board (IRB), Yonsei University College of Medicine, with diabetes who underwent lower extremity amputation (LEA) between January 2009 and January 2019. In order to perform a retrospective cohort analysis of podiatric patients, we reviewed the electronic medical records and databases of patients eligible for this study to obtain statistical information of the study population, including age, gender, and body mass index (BMI) at the time of amputation. collected.

Lower extremity amputation (LEA) during the study period was performed on 444 patients with diabetes mellitus. Amputation of the lower extremity (LEA) is a treatment for non-recoverable wet gangrene despite aggressive conservative treatment, dry gangrene with peripheral arterial disease (wet gangrene), osteomyelitis, and It was applied in case of severe pain of moderate degree and reconstruction failure of Charcot arthropathy. Patients with traumatic lower extremity amputation and soft tissue malignancies were excluded, and patients with a history of LEA within 1 year were excluded to reduce the carryover effect. The final cohort included 415 patients.

Preparation Example 2: Securing database of patients before lower extremity amputation surgery

Preoperative examination was performed on the final cohort patients selected in Preparation Example 1. Hypertension, coronary artery disease, cerebrovascular accident, obstructive pulmonary disease, end-stage renal disease on hemodialysis or peritoneal dialysis, and solid organ (liver or kidney) transplantation were evaluated as underlying diseases. Hemoglobin (g/dL), red blood cell size distribution width (red) blood cell distribution width; RDW, %), white blood cell count (WBC, Х10 ³ /μL), lymphocyte count (Х10 ³ /μL), erythrocyte sedimentation rate (ESR, mm/hr) , C-reactive protein (CRP, mg/L), glycated hemoglobin (HbA1c, %), albumin (g/dL), and modification of diet for people with kidney disease in renal disease; MDRD, mL/min/1.73 m ² ) and estimates glomerular filtration rate (eGFR) were collected prior to amputation. The test results that were closest to the date of surgery were used as it was done within 60 days before surgery, and the BMI was divided into normal and obese groups based on 25 kg/m ² , and evaluation of kidney function and kidney disease was based on eGFR and dialysis. The evaluation was divided into three groups (normal group was 60 mL/min/1.73 m ² or more, chronic kidney disease group was 15 mL/min/1.73 m ² or more and less than 60 mL/min/1.73 m ² , and ESRD group was 15 mL less than /min/1.73m ² ).

Preparation Example 3: Securing patient database after lower extremity amputation surgery

All lower extremity amputations were performed under general, spinal or local anesthesia. Amputation levels were performed while maintaining maximum length, removing all non-viable or infected tissue, and ensuring sufficient soft tissue coverage. Amputations above the ankle joint were considered major amputations, and amputations below the ankle joint were considered minor amputations. After amputation, wounds at the amputation site were managed by daily sterile compression dressings. There were no signs of additional infection, the wound healing was stable, and the patient's past medical history and current condition were consulted with a clinician to confirm whether or not to be discharged.

Preparation Example 4: Statistical Analysis Method

In the statistical analysis of the present invention, all values of patient characteristics and clinical data are expressed as mean ± standard deviation or number (%). In order to obtain the optimal cutoff value of the predictor, it was confirmed through a maximally selected statistic test for survival analysis and receiver operating characteristic (ROC) curve analysis for length of stay (LOS).

The optimal cutoff value of red blood cell size distribution width (RDW) was derived as a prognostic predictor of lower extremity amputation due to diabetes, and important prognostic variables related to mortality and LOS were evaluated using Cox proportional hazard and logistic regression models. Significant factors (P <0.05) in univariate analysis were reflected in multivariate Cox and logistic regression analysis, and were considered statistically significant if P value was less than 0.05, and all statistical analyzes were performed in R (version 4.0.0, R Foundation for Statistical Computing).

Example 1: Validation of RDW evaluation as a prognostic factor in lower extremity amputation surgery

The Cox proportional hazards model was used to compare the survival rates for RDW prognostic factors under the control of various variables, and the results are shown in Table 1 below.

Table 2 below shows the results of analysis using univariate and multivariate logistic regression models.

According to the above results, the mean follow-up period after lower extremity amputation (LEA) was 3.12 ± 2.85 years, the mean age of the cohort was 64.13 ± 11.86 years, and 75.66% of the patients were male. Hypertension was the most frequent underlying disease, followed by coronary artery disease and kidney disease, with an average preoperative hemoglobin (Hb) of 10.50 ± 1.78 g/dL and an erythrocyte size distribution (RDW) of 14.29 ± 1.80. %, HbA1c was 7.94 ± 1.88. Minor amputations accounted for 88.92% of total lower extremity amputations (LEA) and the remaining 11.08% corresponded to major amputations.

After adjusting for significant variables in one-variable regression, if the RDW level before lower extremity amputation was greater than 14.5%, it was found to be significantly associated with mortality after amputation (see Table 1). At this time, it was confirmed that the adjusted hazard ratio ([HR]) of the RDW was 2.55, the 95% confidence interval ([CI]) was 1.55 to 4.19, and P <0.001. Another variable positively associated with mortality, age, was found to have an adjusted hazard ratio of 1.06, a 95% confidence interval of 1.04 to 1.08, and P < 0.001. Another variable, ESRD, had an adjusted hazard ratio of 2.29 and a 95% confidence interval. was confirmed as 1.27 to 4.11, P = 0.006.

According to the maximally selected statistic test, the optimal cutoff value of the preoperative red blood cell size distribution width (RDW) for predicting mortality was 14.5% (see FIG. 1 ). 2 shows the results of confirming that the red blood cell size distribution width (RDW) is an important prognostic factor for lower extremity amputation surgery using Receiver Operation Characteristic (ROC) analysis. Referring to FIG. 2 , it was confirmed that the area under the curve (AUC) was 0.619, an important predictor of the long-term hospitalization period (LOS) after amputation of the lower extremities. % and specificity of 67.1%, confirming that it corresponds to the optimal threshold reference value.

Example 2: Validation of RDW as a prognostic factor in lower extremity amputation surgery

Finally, the primary endpoint was mortality, and the survival period was calculated based on the last day of admission to the hospital. The secondary endpoint was the length of hospital stay (LOS) 30 days after amputation, and LOS was defined as the period from the day of amputation to the day of discharge.

For every 1 percentage point increase in RDW, the risk of death increased by 29%. The cumulative survival curve showed a superior survival rate after lower extremity amputation in the preoperative low RDW (≤ 14.5%) group compared to the preoperative high RDW (> 14.5%) group (see Fig. 3).

The average length of hospital stay was 24.62 ± 24.70 days, and according to the results of univariable and multivariable logistic regression model, a high preoperative RDW level of >14.5% was associated with an extended hospital stay of 30 days or more after adjustment. was confirmed to be the only variable. At this time, the adjusted odds ratio ([OR]) was 2.17, the 95% confidence interval was 1.29 to 3.66, and P = 0.004. As a result of analyzing the RDW as a continuous variable, each time the RDW increased by 1% It was confirmed that the LOS increased by 20% for 30 days.

This is the first study to evaluate the effect of RDW on the survival of diabetic amputees. RDW of >14.5% before amputation was associated with high mortality, as well as long-term hospitalization for diabetic amputation. was confirmed.

Combining the above results, it can be seen that a high RDW value of more than 14.5% is an independent prognostic factor that can be determined as an increase in mortality or a prolonged hospital stay as a prognosis after lower extremity amputation surgery. Because it can be measured, it suggests that time and cost can be saved by predicting the preoperative risk of patients who are expected to have lower extremity amputation due to diabetes.

As described above in detail a specific part of the present invention, for those of ordinary skill in the art, this specific description is only a preferred embodiment, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims (13)

(a) an input unit for inputting a measurement value for a factor of mean corpuscular volume (MCV) from a biological sample obtained from a target individual; and
(b) an operation unit for calculating a red blood cell size distribution width (RDW) from the mean blood cell volume measurement value obtained from the input unit; comprising, a device providing information for predicting treatment responsiveness of lower extremity amputation surgery. The method of claim 1,
The device further comprises an output unit for outputting the prognosis of amputation surgery predicted by the calculating unit. The method of claim 1,
The subject subject is a subject having a diabetic disease. 4. The method of claim 3,
The diabetic disease is diabetes, diabetic foot disease, diabetic acidosis, diabetic xanthoma, diabetic muscle atrophy, diabetic ketosis, diabetic coma, diabetic gastrointestinal disorder, diabetic gangrene, diabetic ulcer, diabetic Complications, diabetic diarrhea, diabetic microangiopathy, diabetic body sclerosis, diabetic myocardial infarction, diabetic neuropathy, diabetic renal failure, diabetic blisters, diabetic cataract, diabetic skin disease, diabetic sclerosis, diabetes mellitus Any one or more selected from the group consisting of retinopathy, diabetic lipoid necrosis, diabetic blood circulation disorder and diabetic ketoacidemia, the device. The method of claim 1,
The lower extremity amputation (LEA) includes partial foot amputation, ankle disarticulation, transtibial amputation, knee disarticulation, transfemoral amputation, and hip disarticulation. (hip disarticulation), pelvic amputation (transpelvic amputation) and lower body amputation (translumbar amputation, hemicorporectomy) any one or more selected from the group consisting of, the device. 6. The method of claim 5,
The foot amputation is selected from the group consisting of toe amputation, transmetatarsal amputation, Lisfranc's amputation, Chopart's amputation, Pirogoff's amputation, and Boyd's amputation. any one or more of the devices. (a) measuring a mean corpuscular volume (MCV) from a biological sample obtained from a subject; and
(B) calculating a red blood cell size distribution width (RBC distribution width; RDW) from the measured mean blood cell volume value; comprising, a method of providing information for predicting treatment responsiveness of lower extremity amputation surgery. 8. The method of claim 7,
(c) predicting that the survival rate after amputation is high and the hospitalization period is short when the value of the calculated red blood cell size distribution width is 14.5% or less. 8. The method of claim 7,
(c) predicting a high mortality rate after amputation and a long hospital stay if the calculated red blood cell size distribution width is greater than 14.5%. 8. The method of claim 7,
The method of claim 1, wherein the subject is a subject with diabetic disease. 11. The method of claim 10,
The diabetic disease is diabetes, diabetic foot disease, diabetic acidosis, diabetic xanthoma, diabetic muscle atrophy, diabetic ketosis, diabetic coma, diabetic gastrointestinal disorder, diabetic gangrene, diabetic ulcer, diabetic Complications, diabetic diarrhea, diabetic microangiopathy, diabetic body sclerosis, diabetic myocardial infarction, diabetic neuropathy, diabetic renal failure, diabetic blisters, diabetic cataract, diabetic skin disease, diabetic sclerosis, diabetes mellitus Any one or more selected from the group consisting of retinopathy, diabetic lipoid necrosis, diabetic blood circulation disorder and diabetic ketoacidemia, the method. 8. The method of claim 7,
The lower extremity amputation (LEA) includes partial foot amputation, ankle disarticulation, transtibial amputation, knee disarticulation, transfemoral amputation, and hip disarticulation. (hip disarticulation), pelvic amputation (transpelvic amputation) and lower body amputation (translumbar amputation, hemicorporectomy) any one or more selected from the group consisting of, the method. 13. The method of claim 12,
The foot amputation is selected from the group consisting of toe amputation, transmetatarsal amputation, Lisfranc's amputation, Chopart's amputation, Pirogoff's amputation, and Boyd's amputation. any one or more, the method.

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