Diabetic foot ulcers (DFUs) are a common problem in the care of patients with diabetes. As many as 25% patients with diabetes develop DFUs in their lifetime,1–3 and DFUs often result in lower limb amputations in patients with diabetes. The pathogenesis of DFU is complex and often involves three components: neuropathy, vasculopathy, and weakened immune or nutrition status. Peripheral arterial disease (PAD) is also common in patients with diabetes and can manifest as asymptomatic intermittent claudication and pain at rest. In extreme cases, PAD is first detected because of unhealed wounds, ulcers, and gangrene on the feet. Timely restoration of peripheral circulation in the feet of patients with diabetes is vital for both symptomatic relief and amputation prevention.4–7
Buerger exercises are designed to improve circulation in the feet and legs. These exercises empty engorged vessels via gravity and muscle contractions and then stimulate peripheral circulation, thereby relieving symptoms in patients with arterial insufficiency of the lower limbs. Buerger exercises are believed to improve unhealed ulcers on diabetic feet; however, clinical evidence for increased peripheral circulation is scant, and access to literature on this subject is limited.8,9
Previously, the authors of this study used near-infrared spectroscopy (NIRS) to estimate blood circulation in the brain and other organs in animal models.10,11 Further, researchers developed wearable NIRS for assessing the perfusion status and its effect on wound healing in DFUs. In this study, the authors used the wearable NIRS to determine the effect of Buerger exercises on wound healing parameters in patients with DFUs.
The Institutional Review Board of Chang Gung Memorial Hospital approved this study (IRB no. 105-0737C) and confirmed that all experiments were performed in accordance with relevant guidelines and regulations.
Researchers prospectively collected information on consecutive patients who had received a diagnosis of DFU in a wound care center of a tertiary hospital between January 2015 and August 2015. Patients with poor adherence to treatment, cigarette exposure within the 24-hour period prior to the wearable NIRS examination, a history of amputation, a surgical history of vascular bypass surgery, and venous ulcers were excluded. Informed consent was obtained from all patients before performing the procedures.
Procedures and Data Collection
Once a patient was diagnosed and recruited, researchers conducted a primary interview and established a patient profile. Data collected included sex, age, hemoglobin A1c (HbA1c), diabetes duration, substance use, glycemic control, comorbidities, previous foot ulcer, previous amputation, Wagner ulcer classification, the Society for Vascular Surgery Lower Extremity Threatened Limb classification (risk stratification based on Wound, Ischemia, and foot Infection [WIfI]), vascular status, and wound outcomes. (Wound healing was defined as no further need to visit the wound care center or outpatient clinics for that ulcer.)
Each participant’s peripheral circulation was screened by determining his or her ankle-brachial index (ABI) using the Cardio-Vision Model (MS-2000; Osachi Co Ltd, Nagano, Japan). If the ABI was less than 0.9, the presence of PAD was further investigated by a cardiologist by using a duplex ultrasound (iE33 Ultrasound; Philips Co Ltd, Amsterdam, the Netherlands). Based on the results, patients were divided into group A (no PAD, n = 11), group B (PAD without angioplasty, n = 26), and group C (PAD with angioplasty, n = 13).
The authors attempted to predict wound healing through the real-time NIRS data and relevant wound parameters.
Tissue blood volume (HbT), oxyhemoglobin (HbO2), deoxyhemoglobin (Hb), and tissue oxygen saturation (StO2) were recorded through wearable NIRS. All of the patients were taught to perform Buerger-Allen exercises in the first interview, and NIRS data from the surrounding tissue were analyzed before and after Buerger-Allen exercise sessions (Figure 1).
Patients were followed up via phone call; no new patients were recruited after August 2015, and all interviews were complete by the end of 2015.
A specialist taught patients to perform Buerger-Allen exercises after joining this study, and all exercises were supervised. First, the patients performed the exercises in the supine position. Then, their legs were elevated between 45° and 60°, supported by pillows for 3 minutes. In the third stage, patients sat on the edge of a bed with their feet suspended from the bed. In the fourth stage, patients performed feet exercises with alternating dorsiflexion and plantarflexion positions and moved their feet inward and outward for 3 minutes. At the end of the fifth stage of the exercises, patients lay in a supine position with a blanket for 3 minutes.
Wearable Near-Infrared Spectroscopy
Wearable NIRS was designed for monitoring the variations in relative hemoglobin concentrations in DFUs in real time. The wearable NIRS system consists of a light emitting-detecting probe, a wireless signal acquisition module, and a wearable mechanical design (Figure 1). The light emitting-detecting probe was designed to make contact with the morbid limb at the dorsal foot, provide a dual-wavelength near-infrared light source, and detect diffusely reflected near-infrared light. Here, the near-infrared light-emitting diode (SMT735/850; EPITEX, Kyoto, Japan) and the photodiode (PD15-22 C/TR8; EVERLIGHT, New Taipei City, Taiwan) provide the dual-wavelength near-infrared light source (<3 mW) and detect the reflected light, respectively. The wireless signal acquisition module is designed to amplify and digitize the reflected light and then transmit the signal to the back-end laptop. For this study, the sampling rate was set at 20 Hz.
The wearable NIRS is a continuous-wave system, and its wavelengths were 640, 700, and 910 nm. The distance between the light source and the detector was 5 mm, and the penetration depth of the probe was about 2.5 mm.12,13 The modified Beer-Lambert law was used to estimate the change in the relative hemoglobin concentrations.14–16 The probe could be firmly attached to the dorsal foot. The probe provided a light source to penetrate biologic tissues. These photons were scattered and absorbed, and some photons passed through these tissues. Therefore, the diffusely reflected light contained physiologic information related to the biologic tissues through which it penetrated.17,18
The change in each participant’s relative HbO2 (CHbO2) and Hb (CHb) concentrations was calculated using the modified Beer-Lambert law based on the difference between the HbO2 and Hb absorbance values. The HbT concentration (CHbT) and StO2 were obtained using the following equations:
Continuous variables were compared using the unpaired two-tailed Student t test/one-way analysis of variance test, and discrete variables were compared using two-tailed Fisher exact test. Further, the relative importance of clinical variables was assessed using a Cox proportional hazard model for wound response. Clinical parameters associated with wound outcome were tested using the log-rank analysis. All statistical analyses were conducted using STATA statistics/Data Analysis 8.0 software (Stata Corporation, College Station, Texas). The results are presented as means and SDs. Statistical significance was defined as P < .05.
Investigators enrolled 50 patients with DFU in this study. The descriptive characteristics of this population are listed in Table 1. The age of the patients ranged from 50 to 88 years, with the mean age of 66.1 ± 11.6 years. The mean duration of confirmed diabetes mellitus was 14.2 ± 10.6 years, which was mostly controlled by oral antihyperglycemic agents (n = 36; 72%), and 14 patients required additional insulin for optimal diabetes treatment. Their mean HbA1c was 8.4 ± 2.1%. During the study, 19 patients (38%) actively smoked, and 12 patients (24%) were addicted to alcohol and betel nut chewing. The prevalence of cardiovascular disease in these patients with chronic DFU was very high (82%). Renal insufficiency was observed in 23 patients (46%), and 9 patients required renal replacement therapy. In total, 39 patients (78%) had documented PAD.
Participants were divided into group A (n = 11), group B (n = 26), and group C (n = 13). The comparisons among groups A, B, and C are summarized in Table 2. The sex ratio, duration of diabetes mellitus, glycemic control status, HbA1c values, substance use, and most of the comorbidities were similar across groups. The patients in group C (PAD with angioplasty) were older and more likely to have had an amputation than did the patients in other groups.
Wound characteristics, including severity according to the Wagner classification, WIfI classification, number of DFUs, and locations, are summarized in Table 3.19,20 The patients in group C had the highest percentage of wounds with bone exposure (grade 3 in Wagner classification) and the most advanced WIfI staging. The patients in group C had a lower number of wounds on the plantar foot than did the patients in other groups. The patients in group A had more wounds located on the plantar foot (45.5%) than did the patients in groups B and C.
Further, investigators compared patient characteristics between the healed and nonhealed groups and summarized the results in Table 4. The distributions of sex, age, history of recurrent foot ulcer or amputation, status of diabetes mellitus, comorbidities, and substance use were similar in both groups. In this study, 31 patients with DFU exhibited successful wound healing. However, 19 patients had nonhealed DFUs during the follow-up.
Risk factors potentially affecting wound outcomes were examined using a Cox proportional hazard model (Table 5). The use of insulin injection for diabetes mellitus control (odds ratio, 2.72; P = .039) was a positive predictor of nonhealing. Multiple wounds in the same limb (odds ratio, 0.28; P = .043) did not predict adverse wound response.
The Kaplan-Meier survival curve for treatment failure was not significantly different among groups (P = .45). However, the requirement of insulin injection for diabetes mellitus control was significantly different among the groups (P = .024) according to the Kaplan-Meier curve for the failure of treatment in DFU (Figure 2).
Tissue Perfusion Assessed through Wearable NIRS
Researchers analyzed the three groups by the NIRS parameters at rest and after the exercises (Figure 3). After the exercises, HbO2 and HbT increased the most in group C. Group B had higher Hb and the lowest StO2 concentration elevation, which indicated higher oxygen consumption in the morbid limb. In contrast, the decrease in Hb concentration and elevated StO2 in the patients in group C implied that the diseased limb had higher perfusion flow with relatively lower O2 consumption. Figure 4 shows the comparison of resting NIRS parameters between healed and nonhealed patients in each group. Group B showed higher HbO2, Hb, and HbT concentrations among nonhealed patients. Group C showed higher Hb concentration in nonhealed patients at rest (before the exercises).
Figure 5 shows the comparison of the NIRS parameters after the Buerger-Allen exercises. Group B showed higher Hb concentrations among nonhealed patients, and group A showed higher HbT concentration in nonhealed patients. Figure 6 demonstrates the NIRS parameters changing between Burger-Allen exercises in individual patients of the three groups and their relationship to the wound prognosis. Almost all patients had higher HbO2, Hb, and HbT after Burger-Allen exercises, except the nonhealed patients in group C, who had a paradoxically lower Hb concentration after the exercises. In group A, the healed patients had a paradoxically lower elevation of HbT concentration than nonhealed patients.
The precursors to diabetic ulceration are subtle, particularly in a neuropathic foot.1,2,21,22 Even when patients are treated in high-quality medical centers with aggressive medical and surgical interventions, one-third to two-thirds of DFUs do not heal within 12 to 24 months.1,2 In this study, 38% (n = 19) of the patients with DFUs did not heal within the first year. These patients were older, had multiple comorbidities, and received irregular medical treatment after developing the leg ulcer (Table 1).
The correlation between DFUs and existing PAD has been extensively discussed. However, not all patients with DFUs have PAD, and only a few of them require angioplasty for an unhealed foot ulcer. An ideal PAD monitoring technique should be noninvasive, consistent, reliable, timely, convenient, and inexpensive. Noninvasive methods, such as ABI, Doppler echogram, and skin perfusion pressure, are valuable as screening tools of vascular lesions in DFUs.23–25 However, those noninvasive tools, particularly volumetric tests such as ABI and skin perfusion pressure, are not precise and tend to provide false-negative results in heavily calcified vessels. Duplex and color duplex echograms are not preferred because they require experienced operators and are time consuming. Invasive procedures, such as angiography, computed tomography angiography, and magnetic resonance angiography, can directly determine the severity of vascular stenosis with the highest accuracy.23–25 However, these invasive procedures require the injection of a contrast medium and radiation exposure, which can impair renal function and enhance malignancy, respectively.26,27 Further, these invasive methods have drawbacks, such as high costs, inconvenience, and inability to present timely changes in circulation. Finally, angiography, computed tomography angiography, and magnetic resonance angiography can only localize potential anatomical lesions over main arteries; however, they do not provide real-time monitoring of microvascular blood flow, which is the major factor in the peripheral tissue regeneration and healing of ulcerations.
Relevant studies on the use of noncontact near-infrared light for detecting diabetes, wound imaging, and home care are available.28–31 The NIRS system has also been used to monitor flap circulation after reconstruction surgery,32 and NIRS is a reliable method to identify the early stages of arterial and venous thrombosis. However, data on the relationship between NIRS parameters (ie, HbT, HbO2, Hb, and StO2) and chronic wound prognosis are scant.
As in this study, applied near-infrared rays of two wavelengths (830 and 690 nm), which are absorbed by HbO2 and Hb, respectively, have been reported. In 2013, a Japanese group used the NIRS parameter StO2 for assessing tissue perfusion in patients with critical limb ischemia with a commercialized near-infrared tissue oximeter monitor (OXY-2; ViOptix Inc, Fremont, California). In that study, the authors compared a foot StO2 and limb angiogram within a short interval and concluded that the obstruction of a feeding artery and its main branches detected using angiography does not cause a corresponding regional StO2 change in an angiosome. Therefore, they proposed that noninvasive StO2 foot mapping might be more appropriate than the traditional angiogram to assess underperfused areas in patients with critical limb ischemia.33
This study builds on previous publications in two aspects. First, the authors used NIRS to estimate patients’ responses to different variables (ie, Buerger exercises and angioplasty in PAD). Second, the wireless, wearable NIRS evaluated DFU with midterm wound prognosis analysis. The traditional angiosome concept was traced through angiography by representing the arterial territory by ink injection, dissection, perforator locations, and radiographic comparison using cadavers with less degenerated arteries. In patients with DFUs, the wounds might be supplied by small collateral arterial branches, capillary system, and even small veins, in which the total StO2 value might reflect the actual perfusion of the wound in that situation.
Few studies used NIRS or other estimating tools (such as skin perfusion pressure) for chronic ulcers. Aging patients with diseased legs encounter difficulties in accessing wound centers without their caregivers’ assistance; therefore, they tend to not follow up after the chronic wound has healed. In this study, researchers achieved 100% interview contact at outpatient clinics and verified participant conditions via telephone calls.
The authors classified participants into three groups depending on their peripheral arterial status; patients in group C (DFU with PAD receiving angioplasty) were older, had a higher incidence of hypertension, and were more likely to have had an amputation (Table 2). The wound location and the Wagner classification did not differ significantly among the three groups. However, group C had more advanced WIfI stages, especially by foot infection and ischemia (Table 3).
In this study, 31 patients exhibited healed DFUs after treatment, whereas 19 patients exhibited poor wound outcomes (nonhealed wound or amputation). The characteristics and comorbidities were similar between the healed and nonhealed patients (Table 4). However, the authors found that the patients with nonhealed wounds had a higher insulin requirement for diabetes control (hazard ratio, 2.72; P = .039), fewer wounds (hazard ratio, 0.28; P = .043), and a tendency toward poor glycemic control (hazard ratio, 3.73; P = .079) in the proportional hazard model. Authors further stratified those patients by the number of DFUs they had (Supplemental Table). Researchers found that patients with multiple wounds had better blood sugar control and lower HbA1c compared with patients with single wounds (HbA1c value in multiple wound/single wound = 6.9/8.9, P = .004). One possible explanation for this is that better diabetes control may enhance wound healing and enable the healing of multiple wounds on the same limb.
The NIRS parameters revealed some clues regarding the eventual healing status of participants. As Figure 3A shows, the HbO2 and HbT concentrations were the highest in group A (no PAD) and the lowest in group B (PAD without intervention) at rest. Most nonhealing patients in groups B and C shared similar parameters at rest, that is, higher HbO2, Hb, and HbT concentration and lower StO2, which indicated that ongoing inflammation caused more blood flow and higher oxygen consumption (Figures 3B, C).
In group A, the nonhealed patients had higher HbO2 and HBT concentration elevation than did those who eventually healed. This implied that other factors, such as immunity or nutrition, might be more important than tissue oxygenation or perfusion in this group (Figure 3D). Interestingly, the nonhealed patients in group C showed paradoxically reduced Hb and HbT. This might indicate that wound necrosis without adequate perfusion dominated the wound, thus reducing the oxygen consumption recorded by NIRS. The authors previously observed a similar phenomenon in a mouse model of massive brain infarct where the StO2 elevation was the highest in brains after infarct.
Despite appropriate wound care and vascular intervention, DFUs remain a clinical challenge. Changes in NIRS parameters after Buerger-Allen exercises could predict medium-term wound outcomes and possibly assist clinicians in adjusting individual therapeutic strategies. Further research is imperative to establish NIRS’ ability to predict wound outcomes as a treatment guide.
The major limitation of this investigation is that it is a nonrandomized study with a small number of patients. With such limitations, the authors nonetheless attempted to identify variables associated with poor prognosis in DFU and the influence of Buerger exercises. This is the first prospective study to apply a wearable NIRS for assessing DFU healing prognosis. Future applications of wearable NIRS may provide useful information regarding optimal therapeutic protocols in DFUs.
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