Measurement of Skin Perfusion Pressure in Hemodialyzed Patients: Association with Toe/Brachial Index

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1 Measurement of Skin Perfusion Pressure in Hemodialyzed Patients: Association with Toe/Brachial Index Masaru Shimazaki, MD; Takayuki Matsuki, MD; Kazuaki Yamauchi, MD; Michihiro Iwata, MD; Hiroshi Takahashi, MD; Kenichi Sakamoto, MD; Junichi Ohata, MD; Yuichi Nakamura, MD Drs. Shimazaki, Matsuki, Iwata, Takahashi, Sakamoto, Ohata, and Nakamura are with the Department of Cardiology and Dr. Yamauchi is with the Department of Internal Medicine, Division of Hemodialysis, Shin-Nittetsu Muroran General Hospital, Muroran, Japan. BACKGROUND: Patients with diabetes mellitus or renal failure may have calcifi ed lower leg arteries, causing a falsely raised ankle/brachial index (ABI). In such cases, other combined noninvasive complementary observations may be useful. The purpose of this study was to investigate vascular complications of lower extremities in chronic hemodialyzed patients by measuring skin perfusion pressure (SPP) and the toe/brachial index (TBI). METHODS: Sixty-fi ve patients treated with regular hemodialysis were recruited. ABI, TBI, and SPP of the foot were measured in outpatient settings. RESULTS: SPP was positively correlated with toe pressure (r 0.560, p 0.001) and with TBI (r 0.481, p 0.001). On the basis of the ABI results and diabetes status of the patients, 129 limbs were divided into 4 groups. For those in the normal ABI class (ABI 0.9), SPP and TBI were decreased in the diabetic normal ABI group compared with those in the non-diabetic normal ABI group. CONCLUSIO: These fi ndings not only support that diabetes is a risk factor for arteriosclerosis but also suggest that even in a normal ABI class, diabetic patients with end-stage renal disease are already susceptible to arteriosclerotic assault of peripheral arterial complications. SPP measurement is a noninvasive, benefi cial observation for lower extremity peripheral arterial disease in hemodialyzed patients at risk. Peripheral arterial disease (PAD) is a chronic arterial occlusive disease of the lower extremities caused by atherosclerosis. Widespread atherosclerosis is common in patients with end-stage renal disease, defined as the requirement for renal replacement therapy. Also, diabetes mellitus and high blood pressure have been linked to an increased risk of PAD in most patients with end-stage renal disease. 1-3 The most common presenting symptom of PAD is intermittent claudication (IC). However, many individuals with significant PAD do not report or complain of IC pain. 4,5 Several individuals had limited mobility because of other factors, 6 such as pain from impingement on the nervous structures or arthropathy, or disability as a result of a previous stroke. As the presence of PAD has not been established by clinical assessment, detection often requires testing with the ankle/brachial index (ABI). 7,8 Measurement of the ABI is widely used in clinical and epidemiologic studies to determine the extent of atheromas in lower extremities. Although the optimal cutoff for an abnormal ABI has not yet been validated, values below 0.9 have been widely accepted as evidence of leg ischemia in most epidemiologic studies 7,9-11 and also in a study among hemodialyzed patients. 12 This is based on clinical practice, in which an ABI of less than 0.9 has been reported to be more than 90% sensitive in detecting angiogram-positive peripheral arteriosclerosis. 9 Although the ABI is relatively easy to perform, its sensitivity declines from approximately 80% for severe stenosis in 1 or more peripheral arteries to approximately 50% for mild disease. 13 Many patients with diabetes mellitus or end-stage renal disease may have calcified lower leg arteries, rendering them incompressible and causing a falsely elevated ABI. 14,15 In cases such as these, the ABI is not an indicator of arterial stenosis below the ankle, so that another noninvasive test is required for substantial arterial disease to be more reliably predicted. Measurement of skin perfusion pressure (SPP) using laser Doppler is a noninvasive test shown to be clinically useful in the assessment of PAD The toe/brachial index (TBI) is an established method for assessing digital perfusion, although SPP is an indicator of local cutaneous perfusion. The aim of this study was to demonstrate whether measuring SPP, as compared with TBI, makes surveying PAD effective and useful in chronic hemodialyzed patients with and without diabetes mellitus in an outpatient setting. Methods Between September and October 2007, 65 Japanese outpatients undergoing chronic regular hemodialysis were enrolled in this study at Shin-Nittetsu Muroran General November 2008 Dialysis & Transplantation 1

2 TABLE I. Baseline patient characteristics. Non-diabetic Patients (n 40) Diabetic Patients (n 25) p-value Age (years) Duration of dialysis (months) Male (n) 23 (58%) 17 (68%) BMI (kg/m 2 ) Impaired gait (n) 15 (38%) 16 (64%) Systolic blood pressure (mmhg) Hemoglobin (g/dl) Serum albumin (g/dl) Serum creatinine (mg/dl) TAC-urea (mg/dl) Calcium phosphorus product (mg 2 /dl 2 ) Drug therapy (n) Insulin Antiplatelets Antidyslipidemics Antihypertensives Calcium channel blocker use Angiotensin receptor blocker use Angiotensin-converting enzyme inhibitor use Alpha-blocker use Beta-blocker use Alpha methyl dopa use 0 (0%) 12 (30%) 5 (13%) 28 (70%) 17 (43%) 23 (58%) 2 (5%) 4 (10%) 15 (38%) 2 (5%) Values are mean SD. Data for the categorical variables are expressed as the number and percentage of subjects. BMI, body mass index; TAC-urea, time-averaged blood urea nitrogen concentration. 11 (44%) 16 (64%) 1 (4%) 19 (76%) 15 (60%) 14 (56%) 4 (16%) 4 (16%) 10 (40%) 3 (12%) Hospital. The study was conducted according to the Declaration of Helsinki. Before enrollment, the study was fully explained to all the patients, especially focusing on the study purpose and the precise procedures to be used. All patients agreed to participate in the research and gave oral informed consent before enrollment. Measurements of toe pressure, TBI, and SPP on the foot were carried out in 65 patients (129 limbs) on a hemodialysis-free day. Toe pressure and TBI were measured with VaSera VS-1000 (Fukuda Denshi, Tokyo, Japan), which could simultaneously monitor brachial and toe pressure wave forms using an oscillometric method. SPP was measured using SensiLase PAD3000 (Vasamed, Eden Prairie, MN) with the patient in the supine position at room temperature with a laser sensor assembly attached to the patient s foot and a pressure cuff wrapped around both the foot and laser sensor assembly. SPP was measured after having measured toe pressure and TBI in turn. Within 1 month preceding this study, 2 Dialysis & Transplantation November 2008 ABI was evaluated with form PWV/ABI (Nippon Colin, Komaki, Japan). Statistical Analysis Data are expressed as means and SD. Data for the categorical variables are expressed as the number and percentage of subjects. Comparisons between groups were made by the unpaired t test, the Fisher exact test, and one-way analysis of variance (Fisher s least-significant difference). Linear regression analysis with Pearson s coefficients was used to assess the strength of association between variables. Differences with a p 0.05 were considered statistically significant. Results The participants were 39 men and 26 women. Mean age was 63.4 years (SD 11.1, range years), and mean duration of dialysis was 76.9 months (SD 88.3, range months). Causes of renal failure were chronic glomerulonephritis in 29 patients, diabetic nephropathy in 22 patients, antineutrophil cytoplasm antibody associated glomerulonephritis in 1 patient, polycystic kidney disease in 1 patient, vesicoureteral reflux in 1 patient, lupus nephritis in 1 patient, chronic pyelonephritis in 1 patient, renal tuberculosis in 1 patient, gestational hypertension in 1 patient, and hypertension in 7 patients. Diabetes mellitus was diagnosed according to the following: fasting plasma glucose level 126 mg/dl, a random plasma glucose level 200 mg/dl or hemoglobin A1c 6.5%, or current use of oral hypoglycemic drugs or insulin injection. Twenty-five patients had diabetes mellitus. The mean hemoglobin A1c was 6.0% (SD 0.9%, range 4.0% 7.6%) in the diabetes group. Table I summarizes the baseline patient characteristics according to the presence or absence of diabetes mellitus. Of all participants, 31 had claudication or gait impairment; of these, 12 had spinal canal

3 TABLE II. Associations of arteriosclerotic parameters and skin perfusion pressure (SPP) in hemodialyzed patients. stenosis, 3 had osteoarthritis of the knee, 3 had osteoarthritis of the hip, 4 had a disability from a previous stroke, 3 had a SPP (mmhg) Coefficient p-value Age (years) Duration of dialysis (months) ABI Toe pressure (mmhg) TBI SBP (mmhg) Parameters were tested for signifi cance by Pearson s correlation coeffi cient. ABI, ankle/brachial index; TBI, toe/brachial index; SBP, systolic blood pressure. disability from diabetic neuropathy, and 1 had a major amputation. Only 5 patients seemed to have IC (considered to be at Fontaine stage II). Patients with diabetes mellitus included a higher proportion of those with impaired gait (p 0.045) compared with patients without diabetes. Duration of dialysis was shorter (p ) and systolic blood pressure was higher (p ) in diabetic patients than in non-diabetic patients, whereas there was no difference in age. There were no differences in body mass index, hemoglobin, serum albumin, calcium phosphorus product, or time-averaged concentration of blood urea nitrogen between the 2 groups. It was common for diabetic patients to be taking antiplatelet agents. Both toe pressure and TBI could not be measured in 15 limbs. SPP could not be measured in 5 limbs because of involuntary movement due to a previous stroke or restless leg syndrome. SPP correlated positively with ABI (r 0.328, p ; Figure 1A), with toe pressure (r 0.560, p ; Figure 1B), with TBI (r 0.481, p ; Figure 1C), and with brachial systolic blood pressure (r 0.560, p ), and correlated negatively with age (r 0.278, p ) but not with duration of dialysis, as summarized in Table II. A toe pressure of less than 50 mmhg is thought to be a critical level. 7 Depending on the results of the toe pressure measurement, we divided the 129 limbs into the following 2 groups: a normal toe pressure group (toe pressure 50 mmhg, n 97) and a reduced toe pressure group (toe pressure 50 mmhg, n 17). Table III shows a comparison of arteriosclerotic parameters between the normal toe pressure group and the reduced toe pressure group. The average values of ABI, TBI, and SPP in the reduced toe pressure group were significantly more decreased compared with those in the normal toe pressure group (p 0.005, p , and p , respectively). Based on the results of ABI, we divided the 129 limbs into the following 2 groups: a normal ABI group (ABI 0.9, n 117) and a reduced ABI group (ABI 0.9, n 12). Table IV shows a comparison of arteriosclerotic parameters between the normal ABI group and the reduced ABI group. The average values of toe pressure, TBI, and SPP in the reduced ABI group decreased significantly compared with those in the normal ABI group (p and p , respectively). However, the value of systolic blood pressure TABLE III. Comparisons of ankle/brachial index (ABI), toe/brachial index (TBI), and skin perfusion pressure (SPP) in the 2 study groups divided by the toe pressure measurements. Normal Toe Pressure Group (n 97) Reduced Toe Pressure Group (n 17) Age (years) Duration of dialysis (months) ABI * TBI * SPP (mmhg) * SBP (mmhg) FIGURE 1. Correlation of skin perfusion pressure (SPP) with (A) ankle/brachial index (ABI), (B) toe pressure, and (C) toe/brachial index (TBI). Values are mean SD; *p 0.05 versus normal toe pressure group. All subjects limbs were divided into 2 groups according to toe pressure measurements: the normal toe pressure group (toe pressure 50 mmhg) and reduced toe pressure group (toe pressure 50 mmhg). SBP, systolic blood pressure. November 2008 Dialysis & Transplantation 3

4 TABLE IV. Comparisons of toe pressure, toe/brachial index (TBI), and skin perfusion pressure (SPP) in the 2 study groups divided by the ankle/brachial index (ABI) measurements. Normal ABI Group (n 117) in the reduced ABI group tended to be higher compared with that in the normal ABI group. In the normal ABI group, the measured values of SPP and TBI ranged widely, from 18 to 122 mmhg and from 0.23 to 1.01, respectively. Diabetes mellitus is an independent atherosclerotic risk factor. We further divided our study subjects from the 2 groups based on ABI results into 4 groups according to their diabetes status (diabetic and non-diabetic groups). Of those classified with a normal ABI, the diabetic group had lower toe pressure, TBI, and SPP values than the non-diabetic group, as shown in Table V. Discussion Reduced ABI Group (n 12) Age (years) Duration of dialysis (months) Toe pressure (mmhg) * TBI * SPP (mmhg) * SBP (mmhg) * Values are mean SD; *p 0.05 versus normal ABI group. All subjects limbs were divided into 2 groups according to ABI measurements: the normal ABI group (ABI 0.9) and the reduced ABI group (ABI 0.9). SBP, systolic blood pressure. TABLE V. Comparisons of toe pressure, toe/brachial index (TBI), and skin perfusion pressure (SPP) in the 4 study groups divided by the ankle/brachial index (ABI) measurements in diabetic and non-diabetic hemodialyzed patients. Without Diabetes (n 78) Normal ABI Group With Diabetes (n 39) Reduced ABI Group Without Diabetes (n 2) With Diabetes (n 10) Age (years) Duration of dialysis * * (months) Toe pressure * (mmhg) TBI * SPP (mmhg) * SBP (mmhg) * Values are mean SD; *p 0.05 versus non-diabetic group in each ABI class. All subjects limbs were divided with both ABI results set at 0.9 and their diabetes status into 4 groups: the normal ABI groups with or without diabetes and the reduced ABI groups with or without diabetes. SBP, systolic blood pressure. Adera et al. 19 reported the reproducibility of the SPP measurements to be comparable to that of brachial blood pressure measured by the Riva Rocci method. The reproducibility (average of coefficient of variation) in the SPP measurement was 8.3% in our preliminary data of 30 limbs in hemodialyzed patients. If the patient is restless, it may not be possible to obtain adequate readings. The other technical problem is the presence of edema, which makes estimates of SPP unreliable. It was thought that peripheral vasoconstriction as a result of hypovolemia during hemodialysis led to a reduced SPP value after hemodialysis. As we previously reported, 20 there was no significant difference in the SPP values measured before or after hemodialysis or on a hemodialysisfree day; thus, we decided to measure SPP on a non-hemodialysis day in this study. Two methods for diagnosing PAD that are not affected by medial arterial calcification are measuring TBI and measuring SPP. 21 As regards TBI, measurement requires a small cuff to compress the great toe and careful technique to preserve accuracy. 8 If cold, the digital artery is thought to be easy to constrict, making it difficult to measure toe pressure. 22 It is necessary to keep the feet warm before and during the measurement of toe pressure. Toe pressure is difficult to measure at low levels, and in the present study, it was not possible to determine in 15 great toes with low pressures. This is a major disadvantage of TBI testing. On the other hand, some measurement failures in the SPP testing were caused by inadvertent movement of subjects. In the present study, SPP could not be measured in only 5 limbs because of involuntary movement due to a previous stroke or restless leg syndrome. We may have more confidence in the SPP testing than in the TBI testing. Patients with end-stage renal disease who require renal replacement therapy are at higher risk for PAD. 7 As dialysis patients are steadily aging year by year, 23 PAD is a common and important complication, 24 even in the Japanese hemodialysis population. 25 PAD has a large effect on daily life. Lower extremity function is an important predictor of future disability, mobility loss, and nursing home placement. 6 The cause of death in patients with PAD, however, is rarely a direct result of the lower extremity arterial disease itself, and survival is threatened by concomitant cardiac and cerebrovascular disease. 14 Because treatment options are limited to relieving complaints and slowing down disease progression, the assessment of arteriosclerotic complication is of particular importance and interest for patients on hemodialysis. The prevalence of PAD in the Japanese end-stage renal 4 Dialysis & Transplantation November 2008

5 disease patient population is 11.5% according to the Dialysis Outcomes and Practice Patterns Study. 3 PAD is frequently accompanied by exertional leg symptoms other than IC, 6 such as pain from impingement on the nervous structures or arthropathy and disability as a result of a previous stroke. Patients on hemodialysis may not have typical leg symptoms because some other condition limits exercise or they are sedentary. In this study population, many participants had PAD accompanied by exertional leg symptoms other than IC. As physical examination is insensitive for PAD, detection often requires testing with ABI. However, ABI is not always a good indicator in patients with diabetes mellitus or end-stage renal disease. 14,15 We investigated whether SPP can be applied to hemodialyzed patients with limited physical activity, as part of other combined noninvasive complementary physiologic observation. For example, Tsai et al. 26 demonstrated a strong positive correlation between SPP and toe pressure in patients with PAD. Okamoto et al. 27 reported that the sensitivity of ABI set at 0.9 was 29.9%, whereas the sensitivity of SPP set at 50 mmhg was 84.9% in 36 hemodialyzed patients with PAD who were identified using multidetector row computed tomography. Our study has demonstrated that SPP has a strong positive correlation with toe pressure and TBI in hemodialyzed patients. In the subgroup analysis, average values of ABI, TBI, and SPP were higher in the normal toe pressure group than in the reduced toe pressure group. According to the ABI class, toe pressure, TBI, and SPP were higher in the normal ABI group than in the reduced ABI group. PAD is associated not only with chronic kidney disease but also with other risk factors. 7,28 When looking at the general population, diabetes mellitus is a major traditional risk factor. The number of patients with diabetic nephropathy is steadily growing, and diabetic patients currently account for about 40% of patients newly introduced to dialysis in Japan. 23 The present study included clinically stable hemodialyzed patients of a wide age range and was performed in an outpatient setting. In this study population, diabetic patients were found to be significantly associated with the induction to dialysis at older age and after short duration of dialysis. We further divided our study subjects based on ABI results and their diabetes status into 4 groups. For those classified as having a normal ABI, defined as an ABI 0.9, average values of SPP and TBI were lower in the diabetic normal ABI group than in the non-diabetic normal ABI group. Among subjects who had a (probably) normal ABI, TBI and SPP of the foot in hemodialyzed patients with diabetes were decreased compared with those obtained from hemodialyzed patients without diabetes. These findings not only support that diabetes mellitus is a risk factor for arteriosclerosis but also suggests that even with a (probably) normal ABI class, diabetic patients with endstage renal disease are already susceptible to arteriosclerotic assault of peripheral arterial complications. This study had several potential limitations. First, we studied treated patients, and thus, medications may have affected cardiovascular responses and cutaneous perfusion. It is now considered ethically problematic to perform a complete washout of medications. Second, the presence and severity of vascular calcification in imaging were not evaluated. Our study did not define the value of SPP, TBI, and ABI related to the degree of vascular calcification. Third, a relatively small, limited number of patients were recruited in our hospital because this was a single-center research study. In particular, the number of limbs with reduced ABI was small. However, only a few studies have described the relation between laser Doppler SPP and toe pressure in patients with PAD. 26 Furthermore, few studies 27 have described the relation of SPP with TBI or with toe pressure in patients on hemodialysis, including patients with asymptomatic PAD. This is an area worthy of future investigation. In the future, further study is needed to confirm the relationships among SPP and these variables that reflect atherosclerotic status. To facilitate wider application of SPP, comparison of this test with established diagnostic methodologies in such individuals would be helpful. Our data suggest that further study is justified to determine whether SPP performs well when used to assess patients on hemodialysis with PAD. Conclusions In conclusion, our results showed that SPP had a strong positive correlation with toe pressure and with TBI. When using ABI to survey PAD in hemodialyzed patients, it is necessary to consider other noninvasive tests to be able to more reliably predict substantial arterial disease. Because patients on hemodialysis are at higher risk of PAD, we should be careful about assessment and treatment of patients on hemodialysis. The SPP measurement can be applied to exercise tolerance limited patients and is easily performed in an outpatient setting. The SPP measurement is expected to be beneficial for the evaluation of lower extremity PAD in hemodialyzed patients at risk, particularly hemodialyzed diabetic patients. Acknowledgments The authors are grateful to Ms. Ayumi Ohnuma, Ms. Junko Endoh, Mr. Masaaki Sukoh, and Mr. Fumiaki Terasawa for their valuable technical assistance. D&T References 1. Jaar BG, Astor BC, Berns JS, Powe NR. Predictors of amputation and survival following lower extremity revascularization in hemodialysis patients. 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