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Determinants and estimation of healing times in diabetic foot ulcers
Journal of Diabetes and Its Complications 16 (2002) 327 – 332
Determinants and estimation of healing times in diabetic foot ulcers Stefan Zimny*, Helmut Schatz, Martin Pfohl Berufsgenossenschaftliche Kliniken Bergmannsheil Universita¨tsklinik, Ruhr-Universita¨t Bochum, Medizinische Klinik und Poliklinik, Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany Received 30 May 2001; accepted 8 October 2001
Abstract Aims: To assess the wound size reduction and time course for healing and to establish equations to predict the time course of wound healing in neuropathic, neuroischemic, and ischemic diabetic foot ulcers. Methods: This prospective study evaluates wound healing over at least a 10-week period in 31 Type 1 or Type 2 diabetic patients with plantar foot ulcers. Thirteen consecutive diabetic patients with neuropathic foot ulceration, 10 consecutive diabetic patients with neuroischemic ulceration, and 8 diabetic patients with peripheral occlusive vascular disease were selected for the study. All patients received identical ulcer wound care including use of proper footwear, non-weightbearing limb support, use of appropriate antibiotics, debridement, tight control of serum glucose levels, and careful monitoring of the ulcer. Ulcer healing was assessed by planimetric measurement of the wound area every second week until wound healing. The time course of wound healing was calculated by the daily wound radius reduction. Results: The wound area (mean ± S.E.) in the patients with neuropathic foot ulceration was 61.2 ± 17.1 at the beginning and 3.2 ± 1.5 mm2 after 70 days ( P = .005). The wound radius decreased by 0.045 mm (95% confidence interval [CI] 0.039 – 0.055) per day, with most of the wound healing being achieved between the first and seventh week of ulcer care. The average healing time was 77.7 (95% CI 62 – 93) days. In the neuroischemic group, the initial average wound area was 26.6 ± 7.0 mm2, and 6.25 ± 1.7 mm2 after 10 weeks ( P = .007). The wound radius reduction was 0.019 mm/day (95% CI 0.017 – 0.023) with an average healing time of 123.4 (95% CI 101 – 145) days. The diabetic patients with peripheral occlusive vascular disease had an average wound size of 32.6 ± 13.1 at the beginning and 23.9 ± 10.7 mm2 after 70 days of ulcer care ( P = .06). The daily wound radius reduction was 0.0065 mm (95% CI 0.0039 – 0.0091). Average ulcer duration was 133 (95% CI 116 – 149) days, but three of eight patients achieved no wound healing. Conclusions: Providing standard care, the time course of wound healing in diabetic foot ulcers is predominantly determined by etiologic factors, and less by wound size. Taking wound etiology and wound radius into account, the expected healing time can reliably be estimated in neuropathic and neuroischemic ulcers. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Diabetic foot ulcer; Healing time; Neuropathy; Peripheral vascular occlusive disease; Wound size
1. Introduction Foot ulcerations in diabetic patients are a major health problem, often leading to lower limb amputations and an increased death rate (Apelqvist, 1998; Apelqvist, RagnarsonTennvall, Larsson, & Persson, 1995; Bello & Phillips, 2000; Boyko, Ahroni, Smith, & Davignon, 1996; Lavery, van Houtum, & Harkless, 1996; Sanders, 1994). Therefore, the management of diabetic foot ulcers is causing considerable costs, estimated about US$1.5 billion in the US Medicare system in 1995 (Harrington, Zagari, Corea, & Klitenbic,
* Corresponding author. Tel.: +49-234-302-6401; fax: +49-234-3026403. E-mail address: [email protected] (S. Zimny).
2000). Diabetic peripheral neuropathy and peripheral vascular disease are the most important etiologic factors, but there is a complex interplay between these abnormalities and a number of other contributory factors, such as altered foot pressures, limited joint mobility, glycaemic control, ethnic background, and cardiovascular variables (Caputo, Cavanagh, Ulbrecht, Gibbons, & Karchmer, 1994; Frykberg, 1998; McNeely et al., 1995). In diabetic foot, ulcers can lead directly to the loss of a limb, and they may be life threatening if the patient is not provided effective intervention directed at healing (Shaw & Boulton, 1997). The principles of good wound care include use of proper footwear, non-weightbearing limb support, use of appropriate antibiotics, debridement, revascularization, control of serum glucose levels, and careful monitoring of the ulcer (Mason et al., 1999; Steed, 1998; Steed, Donohoe, Webster, & Lindsley, 1996).
1056-8727/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 1 0 5 6 - 8 7 2 7 ( 0 1 ) 0 0 2 1 7 - 3
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S. Zimny et al. / Journal of Diabetes and Its Complications 16 (2002) 327–332
This study reports on the wound size reduction, the time course of wound healing, and the healing times of diabetic foot ulcers due to neuropathic, neuroischemic, and ischemic origin.
2. Subjects and methods 2.1. Patients This prospective study evaluates wound healing over at least a 10-week period until the ulcers healed (in total 25 weeks) in 31 Type 1 or Type 2 diabetic patients with plantar foot ulcers. Patients attending our clinic were consecutively invited to take part in the study. Thirteen patients with diabetes and neuropathic foot ulceration, 10 diabetic patients with neuroischemic ulceration, and 8 patients with diabetes and peripheral occlusive vascular disease were included into the study. The history evaluation of the patients included age, sex, weight, height, body mass index (BMI), type of diabetes, and diabetes duration. HbA1c was measured to assess the quality of blood glucose control within the last months. Physical examination included the inspection of the foot, the palpation of the peripheral pulses, measurement of the transcutaneous oxygen tension of the skin (TcPO2) by comparing the TcPO2 on the foot with the simultaneous value on the chest calculating the regional perfusion index (RPI) using heated Clark O2 electrodes. TcPO2 levels below 7.5 kPa were regarded suggestive for peripheral occlusive disease, as were RPI values below 0.70. Peripheral diabetic neuropathy was evaluated measuring the vibration perception threshold with the calibrated Rydell – Seiffer tuning fork. To further exclude peripheral vascular disease or mediasclerosis as potential source of errors in the neuropathic foot ulcer group, the ankle pressures were measured with a 10-cm-wide pneumatic cuff and a Doppler flow probe (Huntleigh Diagnostics, Cardiff, UK). Multiple readings, usually three, were always obtained, and the pressure recorded was the average of these readings. Ankle –brachial indexes were calculated by dividing the pressure at the ankle by the brachial pressure. The pressure in the arm with the higher pressure was used as dominator. A Doppler index below 0.7 confirmed the peripheral vascular occlusive disease in the patients with neuroischemic and ischemic foot ulcers. With an angiographic status of the lower limb arteries, a possible intervention with angioplasty or bypass surgery in the latter two groups was ruled out. Patients with Doppler index above 1.3 were not included into the study because of suspected mediasclerosis. 2.2. Treatment and calculations of the wound size reduction All patients received identical standard ulcer wound care including use of proper footwear, non-weight-bearing limb support, debridement, and daily careful monitoring of the
ulcer. When there were clinical signs of soft tissue infection, appropriate antibiotics according to the predominant bacterial flora in the Gram staining were given, i.e., chinolones, aminopenicillines, or second-generation cephalosporines. All patients received insulin therapy aiming to fasting serum glucose levels below 6 mmol/l. At the end of the observation period, the glycated hemoglobin A1c was below 7.5% in all patients. The patients were engaged to be totally non-weight-bearing and were supplied with a half-shoe (Thanner, Hoechstaedt, Germany) that transferred weight to their heel and could be used for balance. In addition, the patients used wheelchairs or crutches to avoid any weight bearing. Ulcer healing was assessed by planimetric measurement of the wound area (mm2) using a foil with millimeter scales, which was laid on the ulcer every second week. The wound margins were traced with an indelible marker for subsequent calculation of the wound area and perimeter. The largest and the smallest diameter of the skin defects were measured perpendicularly to each other. The wound area was calculated by multiplication of the two diameters. The time course of wound healing was measured by daily wound radius reduction by plotting the virtual wound radius against the time derived from the measurements every fortnight. This wound radius reduction is calculated from the ffi virtual radius of the wound by the pffiffiffiffiffiffiffiffi equation R ¼ A=p and the healing time of the wound. R is the radius and A is the planimetric wound area (mm2). The slope of the regression curve is interpreted as the daily reduction of the wound radius (Martin, 1994). 2.3. Statistical analyses Statistical analyses included descriptive statistics, the standard error of the mean, and analyses of the variance using the t test. Differences between the groups regarding the patients’ sex and type of diabetes were calculated using the Fisher’s Exact Test. The correlations between wound size reduction and healing duration were calculated with linear regression analysis. The statistical analyses were done using JMP V4.0 for windows (SAS Institutes, Cary, NC, USA).
3. Results Thirteen patients with diabetes (eight males, five females, age 63.2 ± 2.7 years) were included into the neuropathic foot ulcer group, 10 patients (seven males, three females, age 66.8 ± 2.7 years) were studied in the neuroischemic foot ulcer group. In the peripheral occlusive vascular disease group, eight patients with diabetes (six males, two females, age 70.1 ± 1.9 years) were included. There was no significant difference of age, sex, body mass index (BMI), and HbA1c between each group (Table 1). In the neuropathic and neuroischemic foot ulcer group, there were more patients with Type 1 diabetes mellitus, compared to the
S. Zimny et al. / Journal of Diabetes and Its Complications 16 (2002) 327–332
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Table 1 Characteristics of 31 diabetic patients with neuropathic, neuroischemic, and ischemic foot ulcer due to peripheral occlusive vascular disease
Age (years) BMI (kg/m2) Male/female Type 1 diabetes Type 2 diabetes Diabetes duration (years) HbA1c (%) TcPO2 (kPa) RPI
Neuropathic group (n = 13)
Neuroischemic group (n = 10)
Ischemic group (n = 8)
63.2 ± 2.7 26.5 ± 0.5 8/5 7* 6 14.9 ± 1.6y 8.1 ± 0.2 8.67 ± 0.4zx 0.88 ± 0.02zx
66.8 ± 2.7 25.9 ± 0.8 7/3 2* 8 11.5 ± 0.9 8.4 ± 0.2 7.2 ± 0.5# 0.67 ± 0.03#
70.1 ± 1.9 28.3 ± 1.0 6/2 0 8 12.8 ± 1.4 8.6 ± 0.1 2.97 ± 0.3 0.24 ± 0.03
Data are n or means ± S.D. Age, BMI, sex, HbA1c, and Type 2 diabetes did not differ between the groups. * P < .0001 comparing the frequency of Type 1 diabetes between the neuropathic or neuroischemic and the ischemic foot ulcer groups. y P = .025 comparing diabetes duration between the neuropathic and ischemic foot ulcer groups. z P = .035 for TcPO2 and RPI comparing the neuropathic and neuroischemic groups. x P < .0001 comparing the neuropathic and ischemic foot ulcer groups. # P = .0006 comparing the neuroischemic and ischemic foot ulcer group.
peripheral occlusive vascular disease group ( P < .0001). In the neuropathic foot ulcer group, the diabetes duration was slightly longer compared to diabetes duration in the neuroischemic foot ulcer group ( P = .025), but there was no difference compared to the peripheral occlusive vascular disease group. The TcPO2 and RPI differed significantly between the three groups. The wound area (mean ± S.E.) in the neuropathic foot ulcer group was 61.2 ± 17.1 mm2 at the beginning, and 3.2 ± 1.5 mm2 after 70 days ( P = .005) (Table 2). The calculated wound radius decreased by 0.045 mm (95% confidence interval [CI] 0.039 – 0.055) per day. The average healing time was 77.7 (95% CI 62 –93) days. In the neuroischemic foot ulcer group, the average wound area was 26.6 ± 7.0 at the start of the ulcer care, and 6.25 ± 1.7 mm2 after 10 weeks ( P = .007). Daily wound radius reduction was calculated by 0.019 mm (95% CI 0.017 – 0.023) with an average healing time of 123.4 (95% CI 101 –145) days. The diabetic patients with peripheral occlusive vascular disease had an average wound size of 32.6 ± 13.1 at the beginning and 23.9 ± 10.7 mm2 after 70 days of ulcer care ( P = .06). The daily wound radius reduction was 0.0065 mm (95% CI
0.0039 – 0.0091). Average ulcer duration was 133 (95% CI 116 – 149) days but three of eight patients achieved no wound healing. The time course of healing in the neuropathic foot ulcer group was four times and six times faster compared to the neuroischemic and peripheral occlusive vascular disease group, respectively. In the neuroischemic foot ulcer group, the time course of healing was only one and a half faster compared to the peripheral occlusive vascular disease group. The fastest time course of healing determined by the daily wound radius reduction was achieved in the neuropathic foot ulcer group between the first and seventh week. In the patients with neuropathic and neuroischemic foot ulcers, the wound area at the start of the study was significantly correlated with healing duration. The correlation coefficient was r = .65 in neuropathic foot ulcers ( P = .015), and r = .83 in neuroischemic foot ulcers ( P = .003). In contrast, in the ischemic foot ulcers, wound healing time and ulcer size were not correlated with each other (r = .23, P = .70). Regarding the reduction of the wound area in neuropathic and — although less impressive — in neuroischemic ulcers, there is an exponential relationship with healing
Table 2 Wound parameters and healing times of 31 diabetic patients with neuropathic, neuroischemic, and ischemic foot ulcer due to peripheral occlusive vascular disease 2
Wound area at Day 0 (mm ) Wound area at Day 70 (mm2) Wound radius at Day 0 (mm) Wound radius at Day 70 (mm) Wound radius reduction (mm) Healing times (days)
Neuropathic group (n = 13)
Neuroischemic group (n = 10)
Ischemic group (n = 8)
61.2 ± 17.1 3.2 ± 1.5* 3.88 ± 0.6 0.66 ± 0.22x 0.045 (0.039 – 0.055) 77.7 (62 – 93)
26.6 ± 7.0 6.25 ± 1.7y 2.62 ± 0.4 1.27 ± 0.2# 0.019 (0.017 – 0.023) 123.4 (101 – 145)
32.6 ± 13.1 23.9 ± 10.7z 2.85 ± 0.6 2.39 ± 0.52## 0.0065 (0.0039 – 0.0091) 133 (116 – 149)
Data are means ± S.E. or means (95% CI). * P = .005, comparing the wound area at Day 0 and Day 70. y P = .007 comparing the wound area at Day 0 and Day 70. z P = .06 comparing the wound area at Day 0 and Day 70. x P < .0002 comparing the wound radius at Day 0 and Day 70. # P = .0008 comparing the wound radius at Day 0 and Day 70. ## P = .07 comparing the wound radius at Day 0 and Day 70.
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healing time, with radius reductions of 0.045 mm in neuropathic and 0.019 mm per day in neuroischemic foot ulcers (Fig. 2).
Fig. 1. Wound areas of 13 neuropathic, 10 neuroischemic, and 8 ischemic diabetic foot ulcers. Plots (solid lines) show wound areas of each patient and mean (interrupted bold line) wound area in the study period over 70 days.
duration, with most of the wound size reduction taking place within the first weeks of treatment (Fig. 1). The calculated wound radius appears to have a linear relationship with the
Fig. 2. Calculated wound radius in 13 neuropathic, 10 neuroischemic, and 8 ischemic diabetic foot ulcers. Plots show mean calculated wound radius at the study points every fortnight (solid dots) and the linear regression curve (solid line) with 95% CI (dotted lines).
S. Zimny et al. / Journal of Diabetes and Its Complications 16 (2002) 327–332
4. Discussion The diabetic foot syndrome is a major health problem and one of the most important causes of disability in patients with diabetes (Apelqvist, 1998; Apelqvist et al., 1995; Boyko et al., 1996). In addition, it is associated with significantly increased mortality (Apelqvist et al., 1995; Sanders, 1994). The main problems in the treatment of diabetic foot ulcers are prolonged wound healing and unnecessary amputations, which may sometimes be caused by the impression that the results of conservative treatment are somewhat unpredictable (Cavanagh, Ulbrecht, & Caputo, 1998; Margolis, Kantor, & Berlin, 1999; Sinacore, 1998). Therefore, it is an important issue to define reliable predictors for the assessment of wound healing in diabetic foot ulcers. Up to now, the percentage of healed wounds within a defined time period has predominantly been used as the main predictor for the assessment of these wounds. This approach is not necessarily able to provide an estimate of the time needed for healing in individual patients (Lavery, Armstrong, & Walker, 1997; Sinacore, 1999). It was known that after 20 weeks of good ulcer care, approximately 31% of neuropathic ulcer healed (Margolis et al., 1999). A recent study has shown that the ulcer area in neuroischemic and ischemic diabetic foot ulcers is positively correlated with the healing time (Oyibo et al., 2001). In addition, the healing rate in diabetic foot ulcers can be predicted to some extent from the wound size reduction within the first 4 weeks of treatment (Pham, Falanga, Sabolonski, & Veves, 2000). We aimed to verify whether the type of diabetic foot ulcers and the wound size enable an estimation of the healing time, and to establish a range of reduction of wound size reduction in neuropathic, neuroischemic, and ischemic diabetic foot ulcers. As expected, our findings confirm previous studies (Edelson, 1998; Kalani, Brismar, Fagrell, Ostergren, & Jorneskog, 1999; McNeely et al., 1995; Padberg, Back, Thompson, & Hobson, 1996) showing that healing times and the time courses of healing in diabetic foot ulcers are predominantly depending on the etiological causes of the ulcerations. The shortest healing time was observed in the neuropathic foot ulcer group, compared to the neuroischemic and ischemic foot ulcer group. Our findings are well in accordance with the previous findings of Pecoraro, Ahroni, Boyko, and Stensel (1991), who described a clear relationship of wound healing rates with the periwound TcPO2. After 70 days of study, there was a significant decrease of the wound area in the neuropathic and neuroischemic foot ulcer groups, but not in the diabetic patients with foot ulcers due to peripheral occlusive vascular disease. In the neuroischemic foot ulcer group, the time course of healing was only 1.5 times faster compared to the peripheral occlusive vascular disease group. The fastest time course healing determined by the daily wound radius reduction was achieved in the neuropathic foot ulcer group between the first and seventh week, compared to the other groups. Regarding the reduction of the wound area in
331
neuropathic and — although less impressive — in neuroischemic ulcers, there is an exponential relationship with the healing time, with most of the wound size reduction taking place within the first weeks of treatment (Fig.p1). ffiffiffiffiffiffiffiffiffi The wound radius calculated with the equation R ¼ A=p appears to have a linear relationship with the healing time, with radius reductions of 0.045 mm (95% CI 0.039– 0.055) in neuropathic and 0.019 mm (95% CI 0.017 – 0.023) per day in neuroischemic foot ulcers (Fig. 2). In the ischemic foot ulcer group, the daily wound radius reduction was only 0.0065 mm (95% CI 0.0039 – 0.0091). These reductions of the calculated wound radius may enable us to predict the time needed for healing in individual patients with neuropathic and neuroischemic diabetic foot ulcers, and possibly can be used to recognize cases in which the healing process is delayed for any reason. At present, these considerations are still somewhat speculative, and our findings and calculations will have to be confirmed by larger trials. However, such estimations of the time needed for healing in diabetic foot ulcers might make it easier to await wound healing for both patients and doctors, and could possibly help in the prevention of some of the unnecessary amputations in diabetic patients.
References Apelqvist, J. (1998). Wound healing in diabetes. Outcome and costs. Clinics in Podiatric Medicine and Surgery, 15, 21 – 39. Apelqvist, J., Ragnarson-Tennvall, G., Larsson, J., & Persson, U. (1995). Long-term costs for foot ulcers in diabetic patients in a multidisciplinary setting. Foot and Ankle International, 16, 388 – 394. Bello, Y. M., & Phillips, T. J. (2000). Recent advances in wound healing. Journal of the American Medical Association, 283, 716 – 718. Boyko, E. J., Ahroni, J. H., Smith, D. G., & Davignon, D. (1996). Increased mortality associated with diabetic foot ulcer. Diabetic Medicine, 13, 967 – 972. Caputo, G. M., Cavanagh, P. R., Ulbrecht, J. S., Gibbons, G. W., & Karchmer, A. W. (1994). Assessment and management of foot disease in patients with diabetes. New England Journal of Medicine, 331, 854 – 860. Cavanagh, P. R., Ulbrecht, J. S., & Caputo, G. M. (1998). The non-healing diabetic foot wound: fact or fiction? Ostomy Wound Management, 44, 6S – 12S. Edelson, G. W. (1998). Systemic and nutritional considerations in diabetic wound healing. Clinics in Podiatric Medicine and Surgery, 15, 41 – 48. Frykberg, R. G. (1998). Diabetic foot ulcers: current concepts. Journal of Foot and Ankle Surgery, 37, 440 – 446. Harrington, C., Zagari, M. J., Corea, J., & Klitenic, J. (2000). A cost analysis of diabetic lower-extremity ulcers. Diabetes Care, 23, 1333 – 1338. Kalani, M., Brismar, K., Fagrell, B., Ostergren, J., & Jorneskog, G. (1999). Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers. Diabetes Care, 22, 147 – 151. Lavery, L. A., Armstrong, D. G., & Walker, S. C. (1997). Healing rates of diabetic foot ulcers associated with midfoot fracture due to Charcot’s arthropathy. Diabetic Medicine, 14, 46 – 49. Lavery, L. A., van Houtum, W. H., & Harkless, L. B. (1996). In-hospital mortality and disposition of diabetic amputees in The Netherlands. Diabetic Medicine, 13, 192 – 197. Margolis, D. J., Kantor, J., & Berlin, J. A. (1999). Healing of diabetic neuropathic foot ulcers receiving standard treatment. A meta-analysis. Diabetes Care, 22, 692 – 695.
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Martin, M. (1994). Dynamic wound healing profile of venous ulcus cruris. Vasa — Journal of Vascular Diseases, 23, 228 – 233. Mason, J., O’Keeffe, C., Hutchinson, A., McIntosh, A., Young, R., & Booth, A. (1999). A systematic review of foot ulcer in patients with Type 2 diabetes mellitus: II: Treatment. Diabetic Medicine, 16, 889 – 909. McNeely, M. J., Boyko, E. J., Ahroni, J. H., Stensel, V. L., Reiber, G. E., Smith, D. G., & Pecoraro, R. F. (1995). The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration. How great are the risks? Diabetes Care, 18, 216 – 219. Oyibo, S. O., Jude, E. B., Tarawneh, I., Nguyen, H. C., Armstrong, D. G., Harkless, L. B., & Boulton, A. J. M. (2001). The effects of ulcer size and site, patient’s age, sex and type and duration of diabetes on the outcome of diabetic foot ulcers. Diabetic Medicine, 18, 133 – 138. Padberg, F. T., Back, T. L., Thompson, P. N., & Hobson, R. W. (1996). Transcutaneous oxygen (TcPO2) estimates probability of healing in the ischemic extremity. Journal of Surgical Research, 60, 365 – 369. Pecoraro, R. E., Ahroni, J. H., Boyko, E. J., & Stensel, V. L. (1991). Chronology and determinants of tissue repair in diabetic lower-extremity ulcers. Diabetes, 40, 1305 – 1313.
Pham, H., Falanga, V., Sabolonski, M. L., & Veves, A. (2000). Healing rate measurement can predict complete wound healing rate in chronic diabetic foot ulceration. Diabetologia, 43. Sanders, L. J. (1994). Diabetes mellitus. Prevention of amputation. Journal of the American Podiatric Medical Association, 84, 322 – 328. Shaw, J. E., & Boulton, A. J. M. (1997). The pathogenesis of diabetic foot problems: an overview. Diabetes, 46 (Suppl. 2), S58 – S61. Sinacore, D. R. (1998). Healing times of diabetic ulcers in the presence of fixed deformities of the foot using total contact casting. Foot and Ankle International, 19, 613 – 618. Sinacore, D. R. (1999). Healing times of pedal ulcers in diabetic immunosuppressed patients after transplantation. Archives of Physical Medicine and Rehabilitation, 80, 935 – 940. Steed, D. L. (1998). Foundations of good ulcer care. American Journal of Surgery, 176, 20S – 25S. Steed, D. L., Donohoe, D., Webster, M. W., & Lindsley, L. (1996). Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group. Journal of the American College of Surgery, 183, 61 – 64.
Determinants and estimation of healing times in diabetic foot ulcers Stefan Zimny*, Helmut Schatz, Martin Pfohl Berufsgenossenschaftliche Kliniken Bergmannsheil Universita¨tsklinik, Ruhr-Universita¨t Bochum, Medizinische Klinik und Poliklinik, Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, Germany Received 30 May 2001; accepted 8 October 2001
Abstract Aims: To assess the wound size reduction and time course for healing and to establish equations to predict the time course of wound healing in neuropathic, neuroischemic, and ischemic diabetic foot ulcers. Methods: This prospective study evaluates wound healing over at least a 10-week period in 31 Type 1 or Type 2 diabetic patients with plantar foot ulcers. Thirteen consecutive diabetic patients with neuropathic foot ulceration, 10 consecutive diabetic patients with neuroischemic ulceration, and 8 diabetic patients with peripheral occlusive vascular disease were selected for the study. All patients received identical ulcer wound care including use of proper footwear, non-weightbearing limb support, use of appropriate antibiotics, debridement, tight control of serum glucose levels, and careful monitoring of the ulcer. Ulcer healing was assessed by planimetric measurement of the wound area every second week until wound healing. The time course of wound healing was calculated by the daily wound radius reduction. Results: The wound area (mean ± S.E.) in the patients with neuropathic foot ulceration was 61.2 ± 17.1 at the beginning and 3.2 ± 1.5 mm2 after 70 days ( P = .005). The wound radius decreased by 0.045 mm (95% confidence interval [CI] 0.039 – 0.055) per day, with most of the wound healing being achieved between the first and seventh week of ulcer care. The average healing time was 77.7 (95% CI 62 – 93) days. In the neuroischemic group, the initial average wound area was 26.6 ± 7.0 mm2, and 6.25 ± 1.7 mm2 after 10 weeks ( P = .007). The wound radius reduction was 0.019 mm/day (95% CI 0.017 – 0.023) with an average healing time of 123.4 (95% CI 101 – 145) days. The diabetic patients with peripheral occlusive vascular disease had an average wound size of 32.6 ± 13.1 at the beginning and 23.9 ± 10.7 mm2 after 70 days of ulcer care ( P = .06). The daily wound radius reduction was 0.0065 mm (95% CI 0.0039 – 0.0091). Average ulcer duration was 133 (95% CI 116 – 149) days, but three of eight patients achieved no wound healing. Conclusions: Providing standard care, the time course of wound healing in diabetic foot ulcers is predominantly determined by etiologic factors, and less by wound size. Taking wound etiology and wound radius into account, the expected healing time can reliably be estimated in neuropathic and neuroischemic ulcers. D 2002 Elsevier Science Inc. All rights reserved. Keywords: Diabetic foot ulcer; Healing time; Neuropathy; Peripheral vascular occlusive disease; Wound size
1. Introduction Foot ulcerations in diabetic patients are a major health problem, often leading to lower limb amputations and an increased death rate (Apelqvist, 1998; Apelqvist, RagnarsonTennvall, Larsson, & Persson, 1995; Bello & Phillips, 2000; Boyko, Ahroni, Smith, & Davignon, 1996; Lavery, van Houtum, & Harkless, 1996; Sanders, 1994). Therefore, the management of diabetic foot ulcers is causing considerable costs, estimated about US$1.5 billion in the US Medicare system in 1995 (Harrington, Zagari, Corea, & Klitenbic,
* Corresponding author. Tel.: +49-234-302-6401; fax: +49-234-3026403. E-mail address: [email protected] (S. Zimny).
2000). Diabetic peripheral neuropathy and peripheral vascular disease are the most important etiologic factors, but there is a complex interplay between these abnormalities and a number of other contributory factors, such as altered foot pressures, limited joint mobility, glycaemic control, ethnic background, and cardiovascular variables (Caputo, Cavanagh, Ulbrecht, Gibbons, & Karchmer, 1994; Frykberg, 1998; McNeely et al., 1995). In diabetic foot, ulcers can lead directly to the loss of a limb, and they may be life threatening if the patient is not provided effective intervention directed at healing (Shaw & Boulton, 1997). The principles of good wound care include use of proper footwear, non-weightbearing limb support, use of appropriate antibiotics, debridement, revascularization, control of serum glucose levels, and careful monitoring of the ulcer (Mason et al., 1999; Steed, 1998; Steed, Donohoe, Webster, & Lindsley, 1996).
1056-8727/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 1 0 5 6 - 8 7 2 7 ( 0 1 ) 0 0 2 1 7 - 3
328
S. Zimny et al. / Journal of Diabetes and Its Complications 16 (2002) 327–332
This study reports on the wound size reduction, the time course of wound healing, and the healing times of diabetic foot ulcers due to neuropathic, neuroischemic, and ischemic origin.
2. Subjects and methods 2.1. Patients This prospective study evaluates wound healing over at least a 10-week period until the ulcers healed (in total 25 weeks) in 31 Type 1 or Type 2 diabetic patients with plantar foot ulcers. Patients attending our clinic were consecutively invited to take part in the study. Thirteen patients with diabetes and neuropathic foot ulceration, 10 diabetic patients with neuroischemic ulceration, and 8 patients with diabetes and peripheral occlusive vascular disease were included into the study. The history evaluation of the patients included age, sex, weight, height, body mass index (BMI), type of diabetes, and diabetes duration. HbA1c was measured to assess the quality of blood glucose control within the last months. Physical examination included the inspection of the foot, the palpation of the peripheral pulses, measurement of the transcutaneous oxygen tension of the skin (TcPO2) by comparing the TcPO2 on the foot with the simultaneous value on the chest calculating the regional perfusion index (RPI) using heated Clark O2 electrodes. TcPO2 levels below 7.5 kPa were regarded suggestive for peripheral occlusive disease, as were RPI values below 0.70. Peripheral diabetic neuropathy was evaluated measuring the vibration perception threshold with the calibrated Rydell – Seiffer tuning fork. To further exclude peripheral vascular disease or mediasclerosis as potential source of errors in the neuropathic foot ulcer group, the ankle pressures were measured with a 10-cm-wide pneumatic cuff and a Doppler flow probe (Huntleigh Diagnostics, Cardiff, UK). Multiple readings, usually three, were always obtained, and the pressure recorded was the average of these readings. Ankle –brachial indexes were calculated by dividing the pressure at the ankle by the brachial pressure. The pressure in the arm with the higher pressure was used as dominator. A Doppler index below 0.7 confirmed the peripheral vascular occlusive disease in the patients with neuroischemic and ischemic foot ulcers. With an angiographic status of the lower limb arteries, a possible intervention with angioplasty or bypass surgery in the latter two groups was ruled out. Patients with Doppler index above 1.3 were not included into the study because of suspected mediasclerosis. 2.2. Treatment and calculations of the wound size reduction All patients received identical standard ulcer wound care including use of proper footwear, non-weight-bearing limb support, debridement, and daily careful monitoring of the
ulcer. When there were clinical signs of soft tissue infection, appropriate antibiotics according to the predominant bacterial flora in the Gram staining were given, i.e., chinolones, aminopenicillines, or second-generation cephalosporines. All patients received insulin therapy aiming to fasting serum glucose levels below 6 mmol/l. At the end of the observation period, the glycated hemoglobin A1c was below 7.5% in all patients. The patients were engaged to be totally non-weight-bearing and were supplied with a half-shoe (Thanner, Hoechstaedt, Germany) that transferred weight to their heel and could be used for balance. In addition, the patients used wheelchairs or crutches to avoid any weight bearing. Ulcer healing was assessed by planimetric measurement of the wound area (mm2) using a foil with millimeter scales, which was laid on the ulcer every second week. The wound margins were traced with an indelible marker for subsequent calculation of the wound area and perimeter. The largest and the smallest diameter of the skin defects were measured perpendicularly to each other. The wound area was calculated by multiplication of the two diameters. The time course of wound healing was measured by daily wound radius reduction by plotting the virtual wound radius against the time derived from the measurements every fortnight. This wound radius reduction is calculated from the ffi virtual radius of the wound by the pffiffiffiffiffiffiffiffi equation R ¼ A=p and the healing time of the wound. R is the radius and A is the planimetric wound area (mm2). The slope of the regression curve is interpreted as the daily reduction of the wound radius (Martin, 1994). 2.3. Statistical analyses Statistical analyses included descriptive statistics, the standard error of the mean, and analyses of the variance using the t test. Differences between the groups regarding the patients’ sex and type of diabetes were calculated using the Fisher’s Exact Test. The correlations between wound size reduction and healing duration were calculated with linear regression analysis. The statistical analyses were done using JMP V4.0 for windows (SAS Institutes, Cary, NC, USA).
3. Results Thirteen patients with diabetes (eight males, five females, age 63.2 ± 2.7 years) were included into the neuropathic foot ulcer group, 10 patients (seven males, three females, age 66.8 ± 2.7 years) were studied in the neuroischemic foot ulcer group. In the peripheral occlusive vascular disease group, eight patients with diabetes (six males, two females, age 70.1 ± 1.9 years) were included. There was no significant difference of age, sex, body mass index (BMI), and HbA1c between each group (Table 1). In the neuropathic and neuroischemic foot ulcer group, there were more patients with Type 1 diabetes mellitus, compared to the
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Table 1 Characteristics of 31 diabetic patients with neuropathic, neuroischemic, and ischemic foot ulcer due to peripheral occlusive vascular disease
Age (years) BMI (kg/m2) Male/female Type 1 diabetes Type 2 diabetes Diabetes duration (years) HbA1c (%) TcPO2 (kPa) RPI
Neuropathic group (n = 13)
Neuroischemic group (n = 10)
Ischemic group (n = 8)
63.2 ± 2.7 26.5 ± 0.5 8/5 7* 6 14.9 ± 1.6y 8.1 ± 0.2 8.67 ± 0.4zx 0.88 ± 0.02zx
66.8 ± 2.7 25.9 ± 0.8 7/3 2* 8 11.5 ± 0.9 8.4 ± 0.2 7.2 ± 0.5# 0.67 ± 0.03#
70.1 ± 1.9 28.3 ± 1.0 6/2 0 8 12.8 ± 1.4 8.6 ± 0.1 2.97 ± 0.3 0.24 ± 0.03
Data are n or means ± S.D. Age, BMI, sex, HbA1c, and Type 2 diabetes did not differ between the groups. * P < .0001 comparing the frequency of Type 1 diabetes between the neuropathic or neuroischemic and the ischemic foot ulcer groups. y P = .025 comparing diabetes duration between the neuropathic and ischemic foot ulcer groups. z P = .035 for TcPO2 and RPI comparing the neuropathic and neuroischemic groups. x P < .0001 comparing the neuropathic and ischemic foot ulcer groups. # P = .0006 comparing the neuroischemic and ischemic foot ulcer group.
peripheral occlusive vascular disease group ( P < .0001). In the neuropathic foot ulcer group, the diabetes duration was slightly longer compared to diabetes duration in the neuroischemic foot ulcer group ( P = .025), but there was no difference compared to the peripheral occlusive vascular disease group. The TcPO2 and RPI differed significantly between the three groups. The wound area (mean ± S.E.) in the neuropathic foot ulcer group was 61.2 ± 17.1 mm2 at the beginning, and 3.2 ± 1.5 mm2 after 70 days ( P = .005) (Table 2). The calculated wound radius decreased by 0.045 mm (95% confidence interval [CI] 0.039 – 0.055) per day. The average healing time was 77.7 (95% CI 62 –93) days. In the neuroischemic foot ulcer group, the average wound area was 26.6 ± 7.0 at the start of the ulcer care, and 6.25 ± 1.7 mm2 after 10 weeks ( P = .007). Daily wound radius reduction was calculated by 0.019 mm (95% CI 0.017 – 0.023) with an average healing time of 123.4 (95% CI 101 –145) days. The diabetic patients with peripheral occlusive vascular disease had an average wound size of 32.6 ± 13.1 at the beginning and 23.9 ± 10.7 mm2 after 70 days of ulcer care ( P = .06). The daily wound radius reduction was 0.0065 mm (95% CI
0.0039 – 0.0091). Average ulcer duration was 133 (95% CI 116 – 149) days but three of eight patients achieved no wound healing. The time course of healing in the neuropathic foot ulcer group was four times and six times faster compared to the neuroischemic and peripheral occlusive vascular disease group, respectively. In the neuroischemic foot ulcer group, the time course of healing was only one and a half faster compared to the peripheral occlusive vascular disease group. The fastest time course of healing determined by the daily wound radius reduction was achieved in the neuropathic foot ulcer group between the first and seventh week. In the patients with neuropathic and neuroischemic foot ulcers, the wound area at the start of the study was significantly correlated with healing duration. The correlation coefficient was r = .65 in neuropathic foot ulcers ( P = .015), and r = .83 in neuroischemic foot ulcers ( P = .003). In contrast, in the ischemic foot ulcers, wound healing time and ulcer size were not correlated with each other (r = .23, P = .70). Regarding the reduction of the wound area in neuropathic and — although less impressive — in neuroischemic ulcers, there is an exponential relationship with healing
Table 2 Wound parameters and healing times of 31 diabetic patients with neuropathic, neuroischemic, and ischemic foot ulcer due to peripheral occlusive vascular disease 2
Wound area at Day 0 (mm ) Wound area at Day 70 (mm2) Wound radius at Day 0 (mm) Wound radius at Day 70 (mm) Wound radius reduction (mm) Healing times (days)
Neuropathic group (n = 13)
Neuroischemic group (n = 10)
Ischemic group (n = 8)
61.2 ± 17.1 3.2 ± 1.5* 3.88 ± 0.6 0.66 ± 0.22x 0.045 (0.039 – 0.055) 77.7 (62 – 93)
26.6 ± 7.0 6.25 ± 1.7y 2.62 ± 0.4 1.27 ± 0.2# 0.019 (0.017 – 0.023) 123.4 (101 – 145)
32.6 ± 13.1 23.9 ± 10.7z 2.85 ± 0.6 2.39 ± 0.52## 0.0065 (0.0039 – 0.0091) 133 (116 – 149)
Data are means ± S.E. or means (95% CI). * P = .005, comparing the wound area at Day 0 and Day 70. y P = .007 comparing the wound area at Day 0 and Day 70. z P = .06 comparing the wound area at Day 0 and Day 70. x P < .0002 comparing the wound radius at Day 0 and Day 70. # P = .0008 comparing the wound radius at Day 0 and Day 70. ## P = .07 comparing the wound radius at Day 0 and Day 70.
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healing time, with radius reductions of 0.045 mm in neuropathic and 0.019 mm per day in neuroischemic foot ulcers (Fig. 2).
Fig. 1. Wound areas of 13 neuropathic, 10 neuroischemic, and 8 ischemic diabetic foot ulcers. Plots (solid lines) show wound areas of each patient and mean (interrupted bold line) wound area in the study period over 70 days.
duration, with most of the wound size reduction taking place within the first weeks of treatment (Fig. 1). The calculated wound radius appears to have a linear relationship with the
Fig. 2. Calculated wound radius in 13 neuropathic, 10 neuroischemic, and 8 ischemic diabetic foot ulcers. Plots show mean calculated wound radius at the study points every fortnight (solid dots) and the linear regression curve (solid line) with 95% CI (dotted lines).
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4. Discussion The diabetic foot syndrome is a major health problem and one of the most important causes of disability in patients with diabetes (Apelqvist, 1998; Apelqvist et al., 1995; Boyko et al., 1996). In addition, it is associated with significantly increased mortality (Apelqvist et al., 1995; Sanders, 1994). The main problems in the treatment of diabetic foot ulcers are prolonged wound healing and unnecessary amputations, which may sometimes be caused by the impression that the results of conservative treatment are somewhat unpredictable (Cavanagh, Ulbrecht, & Caputo, 1998; Margolis, Kantor, & Berlin, 1999; Sinacore, 1998). Therefore, it is an important issue to define reliable predictors for the assessment of wound healing in diabetic foot ulcers. Up to now, the percentage of healed wounds within a defined time period has predominantly been used as the main predictor for the assessment of these wounds. This approach is not necessarily able to provide an estimate of the time needed for healing in individual patients (Lavery, Armstrong, & Walker, 1997; Sinacore, 1999). It was known that after 20 weeks of good ulcer care, approximately 31% of neuropathic ulcer healed (Margolis et al., 1999). A recent study has shown that the ulcer area in neuroischemic and ischemic diabetic foot ulcers is positively correlated with the healing time (Oyibo et al., 2001). In addition, the healing rate in diabetic foot ulcers can be predicted to some extent from the wound size reduction within the first 4 weeks of treatment (Pham, Falanga, Sabolonski, & Veves, 2000). We aimed to verify whether the type of diabetic foot ulcers and the wound size enable an estimation of the healing time, and to establish a range of reduction of wound size reduction in neuropathic, neuroischemic, and ischemic diabetic foot ulcers. As expected, our findings confirm previous studies (Edelson, 1998; Kalani, Brismar, Fagrell, Ostergren, & Jorneskog, 1999; McNeely et al., 1995; Padberg, Back, Thompson, & Hobson, 1996) showing that healing times and the time courses of healing in diabetic foot ulcers are predominantly depending on the etiological causes of the ulcerations. The shortest healing time was observed in the neuropathic foot ulcer group, compared to the neuroischemic and ischemic foot ulcer group. Our findings are well in accordance with the previous findings of Pecoraro, Ahroni, Boyko, and Stensel (1991), who described a clear relationship of wound healing rates with the periwound TcPO2. After 70 days of study, there was a significant decrease of the wound area in the neuropathic and neuroischemic foot ulcer groups, but not in the diabetic patients with foot ulcers due to peripheral occlusive vascular disease. In the neuroischemic foot ulcer group, the time course of healing was only 1.5 times faster compared to the peripheral occlusive vascular disease group. The fastest time course healing determined by the daily wound radius reduction was achieved in the neuropathic foot ulcer group between the first and seventh week, compared to the other groups. Regarding the reduction of the wound area in
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neuropathic and — although less impressive — in neuroischemic ulcers, there is an exponential relationship with the healing time, with most of the wound size reduction taking place within the first weeks of treatment (Fig.p1). ffiffiffiffiffiffiffiffiffi The wound radius calculated with the equation R ¼ A=p appears to have a linear relationship with the healing time, with radius reductions of 0.045 mm (95% CI 0.039– 0.055) in neuropathic and 0.019 mm (95% CI 0.017 – 0.023) per day in neuroischemic foot ulcers (Fig. 2). In the ischemic foot ulcer group, the daily wound radius reduction was only 0.0065 mm (95% CI 0.0039 – 0.0091). These reductions of the calculated wound radius may enable us to predict the time needed for healing in individual patients with neuropathic and neuroischemic diabetic foot ulcers, and possibly can be used to recognize cases in which the healing process is delayed for any reason. At present, these considerations are still somewhat speculative, and our findings and calculations will have to be confirmed by larger trials. However, such estimations of the time needed for healing in diabetic foot ulcers might make it easier to await wound healing for both patients and doctors, and could possibly help in the prevention of some of the unnecessary amputations in diabetic patients.
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