Original Article pissn 1738-3757 eissn 2288-8551 J Korean Foot Ankle Soc 2016;20(3):121-125 http://dx.doi.org/10.14193/jkfas.2016.20.3.121 당뇨병성족부궤양환자의진단 1 년내의절단율및위험인자의분석 천동일, 전민철, 최성우, 김용범, 노재휘, 원성훈 순천향대학교서울병원정형외과 The Amputation Rate and Associated Risk Factors within 1 Year after the Diagnosis of Diabetic Foot Ulcer Dong-Il Chun, Min Chul Jeon, Sung-Woo Choi, Yong-Beom Kim, Jae-Hwi Nho, Sung Hun Won Department of Orthopaedic Surgery, Soonchunhyang University Seoul Hospital, Seoul, Korea Purpose: This study investigates the amputation rate within 1 year after the diagnosis of diabetic foot ulcer and its associated risk factors. Materials and Methods: This study enrolled 60 patients with diabetic foot ulcer. The mean and standard deviation age was 64.4±12.8 years (range, 32 89 years); the mean and standard deviation prevalence period for diabetes mellitus was 21.0±7.5 years (range, 0.5 36 years). The amputation rate was evaluated by dividing the subjects into two groups the major and minor amputation groups within 1 year following the initial diagnosis of diabetic foot ulcer. Multivariate Cox proportional hazards regression analysis was used to identify the risk factors for amputation. Results: The total amputation rate of 38.3% (n=23) was comprised of the amputation rate for the major amputation group (10.0%) and rate for the minor amputation group (23.8%). There was a high correlation between peripheral artery disease (toe brachial pressure index <0.7) and amputation (hazard ratio [HR] 5.81, confidence interval [CI] 2.09 16.1, p<0.01). Nephropathy was significantly correlated with the amputation rate (HR 3.53, CI 1.29 9.64, p=0.01). Conclusion: Clinicians who treat patients with diabetic foot complications must understand the fact that the amputation rate within 1 year is significant, and that the amputation rate of patients with peripheral artery disease or nephropathy is especially high. Key Words: Diabetic foot ulcer, Amputation rate, Risk factor 서 당뇨병성족부병변은당뇨병의합병증중하나로당뇨환자의약 15% 25% 정도에서평생한번은경험하는것으로알려져있다. 1,2) 당뇨병성족부병변은만성고혈당에의한신경병증및말초혈관질환이주원인으로, 이차적으로감염증등이동반되어족부궤양으로진행한다. 3) 진행된족부궤양은치료에잘반응하지않 Received June 30, 2016 Revised July 30, 2016 Accepted August 1, 2016 Corresponding Author: Sung Hun Won Department of Orthopaedic Surgery, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea Tel: 82-2-709-9250, Fax: 82-2-710-3191, E-mail: orthowon@gmail.com Financial support: None. Conflict of interest: None. 론 는경우가많으며절단을해야하는경우가생긴다. 4) 당뇨병성족부병변으로인한하지절단은환자에게신체적기능소실을야기하며, 이로인해삶의질감소및실직등의심각한사회적손실을초래한다. 비교적최근에시행된대규모전향적연구에의하면 18개월의추시기간동안당뇨환자에서첫당뇨병성족부궤양을진단받은후약 84.5% 에서절단없이살수있었다 (amputation free survival) 고하며, 5) 이와유사하게 Morbach 등은 1년의추시기간동안처음당뇨병성족부궤양진단후약 15.4% 에서절단술이시행되었다고하였다. 6,7) 두연구모두처음당뇨병성족부궤양진단 12 18개월후약 15% 에서절단술을시행한것으로보고하고있다. 또한절단술후에 1년사망률이 13% 40%, 3년사망률이 35% 65%, 그리고 5년사망률이약 39% 80% 로보고되고있으며이는대부분의 Copyright c2016 Korean Foot and Ankle Society. All rights reserved. CC This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
122 Vol. 20 No. 3, September 2016 악성종양에비해높은수치이다. 2) 따라서당뇨병성족부병변환자들에서절단율과절단에미치는인자에대하여알아보는것은임상적으로의의가있을것으로생각된다. 이에본연구에서는당뇨병성족부궤양을가진환자들에서처음당뇨병성족부궤양진단후 1년의추시기간동안절단을하는비율과이에영향을미치는요인에대하여분석해보고자한다. 특히절단에관한위험인자로서본원에서시행하는발가락-상완지수 (toe-brachial pressure index) 와절단율을추가적으로분석해보고자한다. 대상및방법 을 group 1로, grade 3 이상의궤양을 group 2로분류하였다. 궤양의유병기간은환자가처음궤양을인지한때를의무기록을통하여알아보았으며, 당화혈색소는최초내원시를기준으로하였다. 대혈관합병증은협심증또는심근경색의기왕력, 심장스트레스검사에서양성및심혈관조형술에서의병적병변등이있는경우로정의하였고, 5,6) 소혈관합병증은망막혈관병변으로정의하였다. 5) 신장합병증은현저한알부민뇨또는현재투석하고있는환자로정의하였다. 5) 또한말초신경병증은전족부에서 Semmes- Weinstein monofilament (5.07) 를사용하여 10 g의압력을인지하지못하는경우로정의하였다. 2) 뇌혈관합병증은신경학적증상의유무에대하여알아보았고, 지속유무는고려하지않았다. 6) 1. 연구대상 본연구는후향적연구로본원의생명윤리위원회로부터연구승인을받았다. 초진환자를기준으로 2010년 1월부터 2014년 12월까지본원에내원한당뇨병성족부병변환자중에서 International Classification of Diseases (ICD)-10 code를기준으로하여당뇨병성족부병변에부합하는 codes (E10.7 당뇨발, 제 1형, E11.7 당뇨발, 제 2형, E14.70 궤양이동반된당뇨발, E14.71 궤양과괴저가동반된당뇨발, 그리고 E14.78 많은합병증이동반된당뇨발 ) 를이용하여전산팀의협조하에 200명의환자를선별하였다. 이중추시기간이 1년이상인환자중에서족부의허혈을검사하기위한발목-상완지수 (ankle-brachial index) 및발가락-상완지수 (toe-brachial index) 를시행한환자를포함하였다. 또한족부궤양의발견시점이불분명한환자와피부병변이없는 Wagner grade 0 환자및과거에소절단술을시행한환자를제외한총 60명을대상으로하였다. 2. 연구방법저자들은환자의의무기록을통하여나이, 성별, 당뇨의종류, 당뇨치료의종류및당뇨의유병기간등을조사하였다. 또한문헌조사후에당뇨병성족부병변의절단에영향을끼친다고알려진흡연유무, 말초혈관질환, 당뇨병성족부궤양의심한정도, 궤양의유병기간, 당화혈색소 (HbA1c) 수치, 투석여부및당뇨와관련된합병증 ( 대혈관 [macrovascular], 소혈관 [microvascular], 신성 [nephropathy], 신경성 [neuropathy] 및뇌혈관 [cerebrovascular]) 유무에대하여알아보았다. 소절단군은발목관절 (ankle) 원위부절단으로, 대절단군은발목관절근위부절단으로정의하였다. 8) 흡연에관하여서는의무기록을통하여파악하였으며, 파악이안되는환자들에대해서는전화문의로흡연의유무를알아보았다. 말초혈관질환에대해서는발목-상완지수및발가락-상완지수를파악하였고, 발목-상완지수 0.9 미만또는발가락-상완지수 0.7 미만을말초혈관질환으로정의하였다. 9,10) 궤양의심한정도에대해서는 Wagner classification에따랐으며, 11) grade 2 이하의궤양 Table 1. Demographic and Clinical Patient Characteristics Characteristic Value Mean age (yr) 64.4±12.8 Sex Male 34 (56.7) Female 26 (43.3) Type of diabetes Type 1 4 (6.7) Type 2 56 (93.3) Treatment Insulin 29 (48.3) Tablet 31 (51.7) Current smoking status Non- or ex-smoker 34 (56.7) Smoker 26 (43.3) Mean duration of diabetes (yr) 21.0±7.5 Mean glycosylated hemoglobin level (%) 7.3±1.2 Wagner classification Grade 1 26 (43.3) Grade 2 9 (15.0) Grade 3 15 (25.0) Grade 4 10 (16.7) Grade 5 0 Duration of ulcer (mo) 4.1±2.3 ABPI 0.9 39 (65.0) <0.9 21 (35.0) TBPI 0.7 40 (66.7) <0.7 20 (33.3) Complication Macrovascular 14 (23.3) Microvascular 21 (35.0) Nephropathy 24 (40.0) Neuropathy 46 (76.7) Cerebrovascular 10 (16.7) Amputation Major (above the ankle) 6 (10.0) Minor (below the ankle) 17 (28.3) Values are presented as mean±standard deviation or number (%). ABPI: ankle brachial pressure index, TBPI: toe-brachial pressure index.
Dong-Il Chun, et al. Risk Factor Analysis of Diabetic Foot Amputation 123 3. 통계방법통계처리는 PASW Statistics 18.0 (IBM Co., Armonk, NY, USA) 프로그램을이용하였다. 첫궤양발견후 1년추시동안하지절단의시행여부에대하여알아보았으며, 다중 Cox 회기분석을통하여절단에영향을미치는각각의요인을분석하였다. 결과 평균추시기간은 12.9±7.3개월 ( 범위 9 32개월 ) 이었다. 56 명의환자 (93.3%) 가제 2형당뇨병이었고, 29명의환자 (48.3%) 가인슐린치료를받고있었다. 평균당뇨병유병기간은 21.0± 7.5년 ( 범위 0.5 36년 ) 이었다. 23명의환자 (38.3%) 가절단술을시행받았으며, 6명의환자 (10.0%) 에서는대절단술을, 17명의환자 (28.3%) 에서는소절단술을받았다. 26명의환자 (43.3%) 는추시당시흡연자였고, 34명의환자 (56.7%) 는비흡연자혹은흡연을중단한자였다. Grade 1 궤양이 26명 (43.3%) 으로가장많았고, 다음으로는 grade 3 궤양 (15명, 25.0%), grade 4 궤양 (10명, 16.7%), grade 2 궤양 (9명, 15.0%) 순이었다. 평균궤양유병기간은 4.1±2.3개월 ( 범위 1 10개월 ) 이었다. 평균당화혈색소수치는 7.3%±1.2% ( 범위 6.1% 15.0%) 였다. 발목-상완지수가 0.9 미만인환자는 21명 (35.0%) 이었으며, 발가락-상완지수가 0.7 미만인환자는 20명 (33.3%) 이었다. 당뇨합병증은신경병증이 46명 (76.7%) 으로가장많았고, 다음으로는신병증 (24명, 40.0%), 소혈관 (21명, 35.0%), 대혈관 (14명, 23.3%) 및뇌혈관 (10명, 16.7%) 순이었다 (Table 1). 절단과관련된요인분석을위한단변량분석에서는발목-상완지수 0.9 미만, 특히발가락-상완지수 0.7 미만, 궤양의심한정도및신병증이합병증발생에유의하게관련되었다 (Table 2). 다변 량분석에서는발가락-상완지수 0.7 미만 (hazard ratio [HR] 5.81, confidence interval [CI] 2.09 16.1, p<0.01; Fig. 1) 및신병증 (HR 3.53, CI 1.29 9.64, p=0.01; Fig. 2) 등이중요한절단과관련된위험인자로분석되었다 (Table 3). 고찰 본연구에서는당뇨가있는환자에서처음당뇨병성족부궤양을인지한후 1년동안의절단율및절단에영향을끼치는위험인자를분석하여보았다. 1년기간동안의절단율은 38.3% 로나타났으며, 소절단율은 28.3%, 대절단율은 10.0% 로나타났다. 동반된말초혈관질환, 특히발가락-상완지수 0.7 미만과신병증등이다변량분석에서통계적으로유의하게높은위험인자로분석되었다. 이전에도당뇨병성족부병변이있는환자에서절단율에관하여많은연구들이시행되었다. 여러저자들은궤양발생후 1년에서 18개월사이의기간동안약 15% 에서절단을시행한다고보고하였는데, 이는본연구에서의절단율과는다소차이가있다. 5,6) 하지만이러한연구들이대절단율만을반영하였고, 소절단은반영하지않았기때문인것으로생각되며, 대절단율만비교하면본연구에서의절단율은이전의연구들과비슷하거나조금낮은수치이다. 한연구에서는소절단까지포함하여 1년의기간동안에약 35% 정도로보고하고있으며, 본연구에서도유사하게나타났다 (38.3%). 7) 많은이전의연구에서말초혈관질환과절단과의높은상관관계를보고하고있다. 7,12) 본연구에서도말초혈관질환이있는환자에서높은절단율을보였다 (HR 5.81, CI 2.09 16.1, p<0.01). 하지만많은이전의연구들이발목-상완지수를기준으로하여보고하고있으며, 발가락-상완지수와절단과의관계에대해서보고하고 Table 2. Univariate Cox Proportional Hazards Regression Models Explanatory variable All amputation (n=23) Major amputation (n=6) Minor amputation (n=17) HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value Age 1.01 (0.98 1.05) 0.31 1.05 (0.98 1.12) 0.15 1.00 (0.97 1.03) 0.87 Sex (male vs female) 1.67 (0.71 3.89) 0.23 0.50 (0.16 1.59) 0.24 1.98 (0.89 4.44) 0.09 Duration of diabetes 1.03 (0.97 1.09) 0.33 0.98 (0.93 1.04) 0.5 0.99 (0.96 1.02) 0.66 Smoking (current smoker) 1.07 (0.59 1.97) 0.82 0.03 (0.00 13.17) 0.28 1.29 (0.69 2.42) 0.43 ABPI (<0.9) 5.83 (2.27 14.9) <0.01 11.11 (1.29 96.17) 0.02 4.79 (1.66 13.8) <0.01 TBPI (<0.7) 7.64 (2.81 20.7) <0.01 8.12 (0.96 52.3) 0.05 5.03 (1.74 14.5) <0.01 Severity of ulcer 4.12 (1.61 10.5) <0.01 8.07 (0.94 68.9) 0.05 3.35 (1.16 9.65) 0.02 Duration of ulcer 1.18 (0.99 1.40) 0.76 1.00 (0.93 1.09) 0.89 0.99 (0.94 1.05) 0.72 HbA1c (>7.5%) 1.06 (0.52 2.14) 0.87 1.01 (0.32 3.22) 0.99 0.50 (0.26 0.95) 0.08 Macrovascular 2.04 (0.78 5.32) 0.14 2.04 (0.55 7.59) 0.29 1.10 (0.62 1.97) 0.74 Microvascular 1.13 (0.46 2.76) 0.77 0.91 (0.29 2.89) 0.88 0.67 (0.36 1.26) 0.22 Nephropathy 5.19 (1.99 13.5) <0.01 10.03 (1.17 86.5) 0.03 4.19 (1.41 12.47) 0.01 Neuropathy 0.41 (0.14 1.18) 0.10 24.8 (0.01 81893.46) 0.44 1.13 (0.44 2.89) 0.81 Cerebrovascular 1.53 (0.50 4.60) 0.45 1.16 (0.31 4.29) 0.83 0.60 (0.27 1.36) 0.22 HR: hazard ratio, CI: confidence interval, ABPI: ankle brachial pressure index, TBPI: toe-brachial pressure index.
124 Vol. 20 No. 3, September 2016 1.0 1.0 Cumulative survival 0.8 0.6 0.4 TBPI TBPI >0.7 TBPI <0.7 0.2 0-Censored 1-Censored p<0.01 0 0 10 20 30 40 Survival period (mo) Cumulative survival 0.8 0.6 0.4 Renal Control Nephropathy 0.2 0-Censored 1-Censored p<0.01 0 0 10 20 30 40 Survival period (mo) Figure 1. Kaplan-Meier curves depending on toe-brachial pressure index (log-rank test p<0.01). TBPI: toe-brachial pressure index. Figure 2. Kaplan-Meier curves depending on nephropathy (log-rank test p<0.01). Table 3. Multivariate Cox Proportional Hazards Regression Models Explanatory variable All amputation (n=23) Major amputation (n=6) Minor amputation (n=17) HR (95% CI) p-value HR (95% CI) p-value HR (95% CI) p-value ABPI (<0.9) 1.46 (0.27 7.78) 0.66 1.05 (0.06 12.3) 0.65 2.02 (0.25 16.6) 0.51 TBPI (<0.7) 5.81 (2.09 16.1) <0.01 5.97 (1.52 14.9) 0.02 4.07 (1.39 11.9) 0.01 Severity of ulcer 0.72 (0.17 2.99) 0.65 0.56 (0.08 6.36) 0.73 0.84 (0.16 4.36) 0.83 Nephropathy 3.53 (1.29 9.64) 0.01 4.23 (1.04 10.0) 0.04 3.23 (1.04 10.0) 0.04 HR: hazard ratio, CI: confidence interval, ABPI: ankle brachial pressure index, TBPI: toe-brachial pressure index. 있는연구는매우드문실정이다. 7,10,12) 발목-상완지수는경화가진행된혈관이나, 동맥경화초기단계에서는신뢰도가떨어지는것으로알려져있으며, 이러한혈관질환이있는환자에서는발가락- 상완지수가민감도와특이도가좀더높은것으로알려져있다. 10) 본연구에서는다중 Cox 회기분석으로절단의여러위험인자에대하여분석하여보았으며, 이중에서발가락-상완지수가가장높은위험인자로분석되었다 (HR 5.81, CI 2.09 16.1, p<0.01). 이는당뇨병성족부병변을치료하는의사들에게발가락-상완지수의중요성을일깨워줄수있는중요한결과로생각된다. 또한본연구에서는신병증이있는환자들에서절단의위험성이높은것으로확인되었다 (HR 3.53, CI 1.29 9.64, p=0.01). 신부전과당뇨발의절단율과의관계는이전의연구를통해서도확인된바있으며, Miyajima 등 13) 은당뇨발환자에서여러인자들과절단율과의관계를분석한연구에서투석환자들이투석하지않는환자들에비해절단율이높은것을확인하였다 (HR 2.14). 또한 Kaminski 등 14) 은당뇨병과말기신부전이같이있는환자들이당뇨병만있는환자들에비해서절단율뿐만아니라족부궤양에이환된확률이높으며, 이는말초신경병증혹은말초혈관질환과연관이있다고하였다. 당뇨병이있는환자가신부전을함께가지고있다면, 궤양등의당뇨병성족부병변에대한주의깊은관찰과교육이더욱중요하며, 족부병변이확인된환자는병변의악화가절단 으로이어질확률이높기때문에이에대한더욱세심한관찰이필요하겠다. 본연구는몇가지제한점을가진다. 첫째로후향적연구디자인으로환자에대한정보를의무기록을바탕으로하였기때문에부정확한정보획득의가능성이있다. 둘째로발가락-상완지수를연구에포함함으로써발가락-상완지수를시행하지않았던과거의대부분의많은환자들이본연구의선택기준에맞지않아제외되었다. 이로인해연구에포함되어있는환자의수가단일기관을대표하기에는제한적이라생각한다. 하지만본연구에서는발가락-상완지수가당뇨발의예후에매우중요한것으로분석되었고, 이는당뇨발을치료하는많은의사들에게발가락-상완지수의중요성을알릴수있을것으로생각된다. 셋째로본연구에서는궤양의심한정도에대하여 Wagner classification을기준으로하여분석해보았으나, 이는당뇨발절단에서중요한위험인자인골수염에대해잘반영이안되었을가능성이있을것으로생각된다. 추후골수염이잘반영될수있는기준으로연구가필요할것으로생각된다. 결론 당뇨병성족부병변을치료하는의사들은환자에게항상그들의
Dong-Il Chun, et al. Risk Factor Analysis of Diabetic Foot Amputation 125 발상태를면밀하게관찰할것을인지시켜주며, 특히동반된말초혈관질환이나신병증을가지고있는환자에서는상처발생시병원에조기방문하여치료할것을주지시켜주는것이필요할것으로생각된다. REFERENCES 111 Boulton AJ. The pathway to foot ulceration in diabetes. Med Clin North Am. 2013;97:775-90. 222 Singh N, Armstrong DG, Lipsky BA. Preventing foot ulcers in patients with diabetes. JAMA. 2005;293:217-28. 333 Stiegler H. Das diabetische Fußsyndrom [Diabetic foot syndrome]. Herz. 2004;29:104-15. German. 444 Gregg EW, Sorlie P, Paulose-Ram R, Gu Q, Eberhardt MS, Wolz M, et al. Prevalence of lower-extremity disease in the US adult population >=40 years of age with and without diabetes: 1999-2000 national health and nutrition examination survey. Diabetes Care. 2004;27:1591-7. 555 Winkley K, Stahl D, Chalder T, Edmonds ME, Ismail K. Risk factors associated with adverse outcomes in a population-based prospective cohort study of people with their first diabetic foot ulcer. J Diabetes Complications. 2007;21:341-9. 666 Morbach S, Furchert H, Gröblinghoff U, Hoffmeier H, Kersten K, Klauke GT, et al. Long-term prognosis of diabetic foot patients and their limbs: amputation and death over the course of a decade. Diabetes Care. 2012;35:2021-7. 777 Won SH, Chung CY, Park MS, Lee T, Sung KH, Lee SY, et al. Risk factors associated with amputation-free survival in patient with diabetic foot ulcers. Yonsei Med J. 2014;55:1373-8. 888 Faglia E, Clerici G, Caminiti M, Curci V, Somalvico F. Prognostic difference between soft tissue abscess and osteomyelitis of the foot in patients with diabetes: data from a consecutive series of 452 hospitalized patients. J Foot Ankle Surg. 2012;51:34-8. 999 Beks PJ, Mackaay AJ, de Neeling JN, de Vries H, Bouter LM, Heine RJ. Peripheral arterial disease in relation to glycaemic level in an elderly Caucasian population: the Hoorn study. Diabetologia. 1995;38:86-96. 1111 Høyer C, Sandermann J, Petersen LJ. The toe-brachial index in the diagnosis of peripheral arterial disease. J Vasc Surg. 2013;58:231-8. 1111 Sharp CS, Bessman AN, Wagner FW Jr, Garland D. Microbiology of deep tissue in diabetic gangrene. Diabetes Care. 1978;1:289-92. 1111 Pscherer S, Dippel FW, Lauterbach S, Kostev K. Amputation rate and risk factors in type 2 patients with diabetic foot syndrome under real-life conditions in Germany. Prim Care Diabetes. 2012;6:241-6. 1111 Miyajima S, Shirai A, Yamamoto S, Okada N, Matsushita T. Risk factors for major limb amputations in diabetic foot gangrene patients. Diabetes Res Clin Pract. 2006;71:272-9. 1111 Kaminski M, Frescos N, Tucker S. Prevalence of risk factors for foot ulceration in patients with end-stage renal disease on haemodialysis. Intern Med J. 2012;42:e120-8.