Eur J Vasc Endovasc Surg (2015) 49, 77e82
Second Toe Systolic Pressure Measurements are Valid Substitutes for First Toe Systolic Pressure Measurements in Diabetic Patients: A Prospective Study 5 V. Bhamidipaty a, A. Dean a b c
a,*
, S.L. Yap a, J. Firth b, M. Barron b, B. Allard a, S.T.F. Chan
c
Department of Vascular Surgery, Western Health, Footscray, Victoria, Australia Department of Podiatry, Western Health, Footscray, Victoria, Australia NorthWest Academic Centre, The University of Melbourne, Sunshine Hospital, St Albans, Victoria, Australia
WHAT THIS PAPER ADDS Toe systolic pressure is a simple, yet effective component of standard vascular and diabetic foot assessment. Until now, clinicians have been unable to measure systolic toe pressure on the second to fifth toes given a lack of evidence. In this study, a strong positive correlation was found between the first and second toe pressure measurements in patients with diabetes. The ability to utilize second toe pressures expands the opportunity to use toe pressures in the clinical setting and has the potential to alter clinical practice significantly with very little extra effort, expertise, and personnel requirements.
Objective: Toe systolic pressure is a component of the standard vascular and diabetic foot assessment. Until now, clinicians have measured only first toe pressure given a lack of evidence for measurements of the other toes. In diabetic patients, first toe measurements are often not possible because of ulceration or amputation. It was hypothesized that the adjacent second toe systolic pressure measurements would be interchangeable with those of the first toe. Methods: A prospective study was performed on 100 participants with diabetes mellitus. Duplicate systolic toe pressures were measured in the first toe and adjacent second toe using the Systoe Automated Toe Pressure System, Systoe Photophlethysmograph Sensor Cuff, and occlusion cuffs measuring 120 25 mm for the first toe and 90 15 mm for the second toe. Correlation analysis was followed by Ordinary Least Products regression to detect and distinguish fixed and proportional bias between the two toe measurements. The acceptable limits of interchangeable results were defined as 5e10 mmHg. Results: Correlation coefficient r ¼ 0.908; p < 0.001. Eighty-two percent of the variations in the second toe measurements were accounted for by knowing the first toe measurements and vice versa. Ordinary Least Products regression showed no fixed or proportional bias between the two methods of measurement: second toe systolic pressure ¼ (0.579) þ (1.038) * first toe systolic pressure. Repeatability analysis showed a 0.5% variation between duplicate measurements. Conclusions: This is the first study which demonstrates that second toe systolic pressures are interchangeable with those of the first toe. Second toe pressures can be used in diabetic patients whose first toe pressures cannot be assessed. Ó 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 14 July 2014, Accepted 30 September 2014, Available online 3 November 2014 Keywords: Diabetic foot, Toe-brachial index, Ankle-brachial index, Peripheral arterial disease
INTRODUCTION 5
Presented at Mayo Clinic International Vascular Symposium 2014, March 27, 2014, Buenos Aires, Argentina; and American Professional Wound Care Association National Clinical Conference 2014, March 20e23, 2014, Philadelphia, USA. * Corresponding author. A. Dean, 19 Kerferd Road, Glen Iris 3146, Victoria, Australia. E-mail address: [email protected] (A. Dean). 1078-5884/$ e see front matter Ó 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2014.09.011
The best technique to accurately measure lower limb and foot perfusion in diabetic patients has long been debated. Several methods have been proposed, including anklebrachial pressure index, skin perfusion pressures, and transcutaneous oxygenation measurements to name a few. What is well recognized is that assessment of perfusion at the level of the ankle is often not a true reflection of distal foot perfusion, owing to the nature of peripheral microvascular dysfunction in diabetes.1,2 Furthermore, ankle
78
pressures are often falsely elevated in diabetic patients because of non-compressibility of calcified infra-popliteal vessels, known as Mönckeberg’s sclerosis.3e5 As such, toebrachial pressure index (TBI) has been used in many institutions worldwide as the primary objective marker for distal foot perfusion.6e8 In the European Consensus Document on Critical Limb Ischaemia, critical limb ischemia is defined on the basis of clinical findings (rest pain, ulcerations, and gangrene) and ankle pressure less than 50 mmHg or toe pressure less than 30 mmHg.9 Toe pressures are commonly measured using photophlethysmography with an inflatable cuff around the hallux of the foot in question. Not uncommonly, patients with significant peripheral arterial occlusive disease (PAOD) have significant tissue loss, painful ulceration, isolated toe ischemia (in cases of distal embolization), or amputation of the first toe, making the measurement of first toe pressure not tolerable or possible. It was theorized that in such situations, the adjacent second toe could be used to obtain a toe pressure with good agreement to the first toe pressure as an objective marker of forefoot perfusion.
V. Bhamidipaty et al. Table 1. Demographic details and diabetic status of the 100 participants. Variable Age, years Mean (SD) Range Gender Male Female Diagnosis Type 1 diabetes mellitus Type 2 diabetes mellitus Diabetes treatment Insulin Oral hypoglycemic agents Diet control
Participants (n ¼ 100) 67.30 (15.25) 29e90 66 34 12 88 47 43 10
mellitus; 12 had type 1 diabetes mellitus. Most were being treated with insulin (47) or oral hypoglycemic agents (43); only 10 were being managed with dietary changes. Instrument and procedure
MATERIALS AND METHODS Participants From October to December 2013, 100 participants with a formal diagnosis of diabetes mellitus were recruited from diabetes out-patient clinics and in-patient wards at the authors’ centre. Inclusion criteria included a diagnosis of diabetes mellitus, confirmed by review of medical records and recent pathology results (HbA1C 6.5% and fasting glucose 7 mmol/L), and having adjacent first and second toes present on one foot or both feet. Participants were excluded if they were under 18 years old, were unable to consent, had active ulceration on their first and/or second toes, had a vasomotor condition such as Raynaud’s disease, were unable to lie still for the duration of the test, or had ingested caffeine or smoked within the previous hour. Patients were also excluded if the application and inflation of the pressure cuff proved to be prohibitively painful, or if the toe was too large to fit the maximum occlusion cuff size. Institutional ethics approval was granted by the Low Risk Ethics Committee at the regional hospital network. Patients were informed about the study verbally and provided with written information by either the treating podiatrist or the vascular physician before consent was gained. Participants were asked to rest in a supine position for 15 minutes prior to measurements being taken. Restrictive clothing, such as shoes and tight socks, was removed and the temperature of the room was measured and maintained at a minimum of 22 C to avoid error from vasoconstriction. Two measurements were taken on both the first and second toes of the eligible foot and recorded on an electronic spreadsheet. Patient demographics are shown in Table 1. There was a preponderance of males (66) in the 100 patients studied with a mean age of 67.30 (15.25) years (range 29e90). Of the participants, 88 had a diagnosis of type 2 diabetes
Toe systolic pressure measurements were taken with the Systoe Automated Toe Pressure System (Atys Medical, Soucieu-en-Jarrest, France), which included the Systoe Photophlethysmograph (PPG) Sensor Cuff and two occlusion cuffs measuring 120 mm 25 mm for the first toe and 90 mm 15 mm for the second toe. This unit was chosen as it was familiar to the authors’ staff; has an automated cuff inflator and the option to change the cuff size; can measure systolic toe pressures to less than 20 mmHg; and has been shown to have excellent interobserver and intraobserver reproducibility.10 Firstly, an occlusion cuff was placed around the base of the first toe (Fig. 1). Distal to this, the PPG sensor was secured to the pulp of the hallux with a double-sided transparent adhesive tape supplied by the manufacturer. The sensor was maintained in position with a second pneumatic cuff, which also acted as a blood draining cuff. If applied correctly, a pulse waveform would appear on the device screen. Activating the machine commenced an
Figure 1. Systoe automated toe pressure system (Atys medical, Soucieu-en-Jarrest, France).
Second Toe Systolic Pressure Measurements
79
automatic sequence in which the blood draining cuff would inflate first, followed by the occlusion cuff e which would inflate to 200 mmHg e followed by the deflation of the blood drainage cuff. Finally, the occlusion cuff deflated at a slow, controlled rate. Concurrently, the infrared PPG system provided skin penetration approximately 3 mm deep (800 nm wavelength, 75 mW fixed power). The investigators noted the point at which the direct current curve showed a continuous upstroke, which correlated with the return of perfusion to the toe. After a minute had lapsed, the same process was then repeated on the same toe, after which duplicate measures were taken on the adjacent second toe using a smaller occlusive cuff and the same technique. Figure 2. Scatterplot of second toe on first toe systolic pressures.
Statistical analyses Pearson’s productemoment correlation was used to determine the correlation coefficient and the coefficient of determination. No assumption was made that the conventional first toe systolic pressure measurements were errorfree. In that correlation analysis only calculates a relationship between two measurements, it is inadequate for a method-comparison study.11e14 Analyses of measurement errors in the two methods (first toe versus second toe) were hence conducted using Ordinary Least Product (OLP) regression to uncover systematic differences and, in particular, to detect and distinguish fixed and proportional bias between the two methods.15,16 Fixed bias: where one method gives values that are higher (or lower) by a constant amount. Proportional bias: where one method gives values that are higher (or lower) by an amount that is proportional to the level of the measured variable. Assumptions for using OLP regression including linearity and equality of variance in the scatterplot were tested. A “folded empirical cumulative distribution plot” was additionally performed to detect measurement biases. Coefficients of repeatability were calculated for duplicate measurements. Ninety-five percent tolerance intervals were constructed. The acceptable limits of interchangeable results were defined as 5e10 mmHg. Sample size considerations: the minimum sample size with a confidence interval of 0.2 which corresponds to correlations of 0.82 or higher between first toe and second toe pressures was calculated to be 45 measurements. Continuous data are presented as mean (SD) if distributed normally. All tests were two-sided, and p < .050 was considered significant. Statistical analyses were performed using: Systat v12 (Systat Software, Inc., Chicago, IL, USA) for OLP; “R” v3.0.1 (R Foundation for Statistical Computing, Vienna, Austria) for constructing tolerance intervals17; MedCalc v13.0 (MedCalc Statistical Software, Ostend, Belgium) for “folded empirical cumulative distribution plot”.18
wound (9), previous amputation (7), or an occlusive dressing such as a total contact cast (4). One patient had an acute episode of gout in his first metatarsophalangeal joint making the inflation of the pressure cuff too painful, another patient’s toes were deformed such that the cuff could not be correctly applied, and finally one patient was wearing restrictive clothing which she preferred not to remove. Finally, eight patients only consented to having one foot measured because of time constraints. A scatterplot of second toe on first toe systolic pressure is shown in Fig. 2. This was tested for heteroskedasticity and was shown to be homoskedastic (c2 4.19, df 2, p ¼ .123). The correlation coefficient (r) ¼ 0.908; 95% confidence interval (CI): 0.877 to 0.931; p < .001; and the coefficient of determination (r2) ¼ 0.824, which implied that 82% of the variation in the second toe measurements is accounted for by knowing the first toe measurements and vice versa. The variance (or scatter) of second toe pressures was constant across all values of first toe pressures, an essential assumption for using OLP regression. Fig. 3 shows the residual plot of the regression model, the residual is the difference between the observed and predicted value of the second toe measurements. The random pattern of the residuals around the horizontal axis supported a linear model. The results of OLP regression are shown in Table 2. The 95% CI for the intercept (7.487e6.329) included a zero(0) value implied no fixed bias; the 95% CI for the slope
RESULTS Sixty-nine patients had systolic toe pressures measured on both feet e 31 patients had systolic toe pressures measured only on one foot with reasons for not obtaining contralateral measurements including the presence of an overlying
Figure 3. Residual plot of the regression model.
80
V. Bhamidipaty et al.
Table 2. Results of OLP regression. Parameter
Estimate
Asymptotic standard Parameter/ASE error (ASE) Intercept 0.579 3.499 0.166 Slope 1.038 0.034 30.125 95% CI for the intercept includes a 0 value; 95% CI for the slope includes a 1 value.
(0.970e1.106) included a one(1) value implied no proportional bias. The regression equation for the model is: second toe ¼ (0.579) þ (1.038)* first toe.
The analysis of duplicate measurements is shown in Table 3. There is 0.5% less variation between duplicate measurements made with the first toe compared with the second toe, with coefficient of repeatability of 11.640 and 11.697, respectively. Fig. 4 is the plot of the 95% tolerance intervals (with 95% confidence), indicating the range within which a single, new observation should lie if it is drawn from the same population studied. A “folded empirical cumulative distribution plot” (Mountain plot) of the distribution of differences between the two methods of measurements is shown in Fig. 5. The “mountain” is approximately centered over zero, indicating that the two methods of measurements were unbiased with respect to each other.18
Wald 95% confidence interval 7.487 to 6.329 0.970 to 1.106
five, leaving only 24 successful measurements out of 50.20 Hirai et al. took measurements from all five toes in 106 limbs and found that 41% of cases had a difference in blood pressure of more than 15 mmHg between any two toes; however, they used an unconventional ‘bladder-free cuff’ technique that is otherwise untested, and unfeasible outside of the laboratory setting.21 De Graaff et al. investigated the reproducibility of first toe and second toe pressure measurements in 54 patients e they did not, however, investigate the relationship between the two.22 A handful of studies measured the second toe pressure if the first toe pressure was unable to be taken given amputation
DISCUSSION The principal finding from this study was that second toe systolic pressure measurements were interchangeable with those of the first toe within acceptable limits of 5e 10 mmHg. Analyses of measurements showed no evidence of detectable biases. A literature search reveals few studies that measured second toe systolic pressures e none of which provide conclusive evidence on which to base clinical decisionmaking. In 1971, Carter et al. measured the second toe systolic pressure in 51 individuals, ten of whom had diabetes - no first toe pressures were measured.19 Accuracy of the measurements is questioned in this early study given that the occlusive cuff was constructed out of a Penrose drain backed in adhesive tape, and reperfusion was detected by either a color change in the digit or by an increase in volume of the digit recorded using a strain-gauge technique. Kröger et al. attempted to compare first and second toe pressures using a Doppler technique; however, in 21 out of 50 participants a Doppler signal could not be measured; and of the remaining 29, the optical measurement failed in
Figure 4. 95% tolerance intervals with 95% confidence.
Table 3. Analysis of duplicate measurements (n ¼ 169). FT2eFT1 ST2eST1 x̄ 0.189 1.302 SD 5.939 5.968 CR 11.640 11.697 FT2eFT1: differences of first toe duplicate readings; ST2eST1: differences of second toe duplicate readings. ForP each toe Coefficient of Repeatability (CR) ¼ 1.96 O (duplicate differences)/n 1.13
Figure 5. “Mountain plot”: percentile for each ranked difference between second and first toe pressures plotted against the differences of the second and first toe pressures.
Second Toe Systolic Pressure Measurements
or ulceration, or took the highest reading of the two digits; however, none of them mention how many second toe readings were used.4,10,23,24 It is in this context that clinicians have erred away from using second toe pressures given the lack of clear evidence. The main diagnostic limitation of toe perfusion measurements has always been the variability and reproducibility of results depending on a number of variables, not least of which includes operator experience with the technique. Ubbink suggested that to reduce this uncertainty, repetition of a measurement will help in reducing the variability as it causes regression to the mean, i.e. will give a better estimate of the true value after averaging the two results.25 The same author went on to suggest that to minimize any doubt about the validity and reproducibility of the result, that it be repeated immediately in the same diagnostic setting and session, and the mean measurement be used. This appeared to the authors’ group to be the most sensible and pragmatic way to approach this diagnostic challenge. Another issue that is often touted as producing large variability in results is that of cuff sizing and sensor placement, both of which require standardization for obtaining toe pressures. For the purpose of the present study, the same size cuff (120 25 mm) was used on the large toe of all patients with the sensor placed on the pulp of the hallux. Similarly the same size cuff (90 15 mm) and sensor placement was used to obtain second toe pressures of all patients. Although in an ideal setting, only one cuff size would be used on all toes of all patients to reduce or prevent inter-cuff variability, this is neither practical nor technically possible given that the large cuff often was not able to obtain a satisfactory reading on the second toe. This remains a problem without a logical feasible solution. It was noted that with differing sensor placements and cuff sizes, the authors’ values differed from those when the technique was standardized as it was in the reported results. Unfortunately, there are no particular strategies that can be implanted to reduce this error apart from ensuring that staff who are most familiar with the equipment and technique are the ones performing the procedure as often as possible. There are some limitations to this study. Patients were not specifically selected or excluded based on the degree of ischemia, pain, tissue loss, or other symptoms attributable to peripheral occlusive arterial disease. However, the heterogeneous nature of the patient group is reflective of the ‘real world experience’ and may be considered as a relative strength of the study and add further support to the results published. The results achieved strengthen the argument that in any diabetic patient population, regardless of type or extent of disease, second toe pressures can be used as a valid measurement as part of the clinical assessment. To the authors’ knowledge, this is the first study that has documented the interchangeability of systolic toe pressure measurements between the first and second toe. Although the definition of critical leg ischemia as per the European Consensus Document does not include pressure obtained
81
from the second toe, it seems reasonable to use the second toe pressure, when first toe pressure cannot be obtained, as a surrogate marker in assessing distal perfusion and in aiding clinic decision-making. CONFLICT OF INTEREST None. FUNDING None. ACKNOWLEDGEMENTS We would like to thank Briggate Medical Company, Melbourne for loaning us the Systoe Automated Toe Pressure System (Atys Medical, Soucieu-en-Jarrest) for the duration of the study. REFERENCES 1 Faglia E, Clerici G, Clerissi J, Gabrielli L, Losa S, Mantero M, et al. Long-term prognosis of diabetic patients with critical limb ischemia: a population-based cohort study. Diabetes Care 2009;32:822e7. 2 Lepäntalo M, Apelqvist J, Setacci C, Ricco JB, de Donato G, Becker F, et al. Chapter V: the diabetic foot. Eur J Vasc Endovasc Surg 2011;42:S60e74. 3 Aboyans V, Ho E, Denenberg JO, Ho LA, Natarajan L, Criqui MH. The association between elevated ankle systolic pressures and peripheral occlusive arterial disease in diabetic and nondiabetic subjects. J Vasc Surg 2008;48:1197e203. 4 Vincent DG, Salles-Cunha SX, Bernhard VM, Towne JB. Noninvasive assessment of toe systolic pressures with special reference to diabetes mellitus. J Cardiovasc Surg 1983;24:22e8. 5 Mönckeberg JG. Uber die reine Mediaverkalkung der Extremitätenarterien und ihr Verhalten zur Arteriosklerose. Virch Arch (Pathol Anat) 1903;171:141e67. 6 Sahli D, Eliasson B, Svensson M, Blohmé G, Eliasson M, Samuelsson P, et al. Assessment of toe blood pressure is an effective screening method to identify diabetes patients with lower extremity arterial disease. Angiol 2004;55:641e51. 7 Brooks B, Dean R, Patel S, Wu B, Molyneaux L, Yue DK. TBI or not TBI: that is the question. Is it better to measure toe pressure than ankle pressure in diabetic patients? Diabet Med 2001;18:528e52. 8 Ramsey DE, Manke DA, Sumner DS. Toe blood pressure: a valuable adjunct to ankle pressure measurement for assessing peripheral arterial disease. J Cardiovasc Surg (Torino) 1983;24: 43e8. 9 Dormandy J, editor. European consensus document on critical limb ischaemia. Berlin Heidelberg New York: Springer; 1989. 10 Pérez-Martin A, Meyer G, Demattei C, Böge G, Laroche JP, Quéré I, et al. Validation of a fully automatic photoplethysmographic device for toe blood pressure measurement. Eur J Vasc Endovasc Surg 2010;40:515e20. 11 Ludbrook J. Comparing methods of measurement. Clin Exp Pharmacol Physiol 1997;24:193e203. 12 Batterham AM. Commentary on bias in Bland-Altman but not regression validity analyses. Sportscience 2004;8:47e9. 13 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307e10.
82 14 Ludbrook J. Confidence in AltmaneBland plots: a critical review of the method of differences. Clin Exp Pharmacol Physiol 2010;37:143e9. 15 Ludbrook J. Linear regression analysis for comparing two measurers or methods of measurement: but which regression? Clin Exp Pharmacol Physiol 2010;37:692e9. 16 Ludbrook J. A primer for biomedical scientists on how to execute model II regression analysis. Clin Exp Pharmacol Physiol 2012;39:329e35. 17 Young DS. Tolerance: an R package for estimating tolerance intervals. J Stat Softw 2010;36:1. 18 Krouwer JS, Monti KL. A simple, graphical method to evaluate laboratory assays. Eur J Clin Chem Clin Biochem 1995;33:525e 7. 19 Carter SA, Lezack JD. Digital systolic pressures in the lower limb in arterial disease. Circulation 1971;43:905e14. 20 Kröger K, Stewen C, Santosa F, Rudofsky G. Toe pressure measurements compared to ankle artery pressure measurements. Angiol 2003;54:39e44.
V. Bhamidipaty et al. 21 Hirai M, Kawai S, Ohta T, Seko T, Shionoya S. Measurement of blood pressure in all toes in arterial occlusive disease of the leg. Angiol 1982;33:418e26. 22 de Graaff JC, Ubbink DT, Legemate DA, de Haan RJ, Jacobs MJHM. Interobserver and intraobserver reproducibility of peripheral blood and oxygen pressure measurements in the assessment of lower extremity arterial disease. J Vasc Surg 2001;33:1033e40. 23 Ubbink DT, Tulevski II, den Hartog D, Koelemay MJ, Legemate DA, Jacobs MJ. The value of non-invasive techniques for the assessment of critical limb ischaemia. Eur J Vasc Endovasc Surg 1997;13:296e300. 24 Høyer C, Sandermann J, Petersen LJ. Randomised diagnostic accuracy study of a fully automated portable device for diagnosing peripheral arterial disease by measuring the toebrachial index. Eur J Vasc Endovasc Surg 2013;45:57e64. 25 Ubbink DT. Toe blood pressure measurements in patients suspected of leg ischaemia: a new laser Doppler device compared with photoplethysmography. Eur J Vasc Endovasc Surg 2004;27:629e34.
Second Toe Systolic Pressure Measurements are Valid Substitutes for First Toe Systolic Pressure Measurements in Diabetic Patients: A Prospective Study 5 V. Bhamidipaty a, A. Dean a b c
a,*
, S.L. Yap a, J. Firth b, M. Barron b, B. Allard a, S.T.F. Chan
c
Department of Vascular Surgery, Western Health, Footscray, Victoria, Australia Department of Podiatry, Western Health, Footscray, Victoria, Australia NorthWest Academic Centre, The University of Melbourne, Sunshine Hospital, St Albans, Victoria, Australia
WHAT THIS PAPER ADDS Toe systolic pressure is a simple, yet effective component of standard vascular and diabetic foot assessment. Until now, clinicians have been unable to measure systolic toe pressure on the second to fifth toes given a lack of evidence. In this study, a strong positive correlation was found between the first and second toe pressure measurements in patients with diabetes. The ability to utilize second toe pressures expands the opportunity to use toe pressures in the clinical setting and has the potential to alter clinical practice significantly with very little extra effort, expertise, and personnel requirements.
Objective: Toe systolic pressure is a component of the standard vascular and diabetic foot assessment. Until now, clinicians have measured only first toe pressure given a lack of evidence for measurements of the other toes. In diabetic patients, first toe measurements are often not possible because of ulceration or amputation. It was hypothesized that the adjacent second toe systolic pressure measurements would be interchangeable with those of the first toe. Methods: A prospective study was performed on 100 participants with diabetes mellitus. Duplicate systolic toe pressures were measured in the first toe and adjacent second toe using the Systoe Automated Toe Pressure System, Systoe Photophlethysmograph Sensor Cuff, and occlusion cuffs measuring 120 25 mm for the first toe and 90 15 mm for the second toe. Correlation analysis was followed by Ordinary Least Products regression to detect and distinguish fixed and proportional bias between the two toe measurements. The acceptable limits of interchangeable results were defined as 5e10 mmHg. Results: Correlation coefficient r ¼ 0.908; p < 0.001. Eighty-two percent of the variations in the second toe measurements were accounted for by knowing the first toe measurements and vice versa. Ordinary Least Products regression showed no fixed or proportional bias between the two methods of measurement: second toe systolic pressure ¼ (0.579) þ (1.038) * first toe systolic pressure. Repeatability analysis showed a 0.5% variation between duplicate measurements. Conclusions: This is the first study which demonstrates that second toe systolic pressures are interchangeable with those of the first toe. Second toe pressures can be used in diabetic patients whose first toe pressures cannot be assessed. Ó 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 14 July 2014, Accepted 30 September 2014, Available online 3 November 2014 Keywords: Diabetic foot, Toe-brachial index, Ankle-brachial index, Peripheral arterial disease
INTRODUCTION 5
Presented at Mayo Clinic International Vascular Symposium 2014, March 27, 2014, Buenos Aires, Argentina; and American Professional Wound Care Association National Clinical Conference 2014, March 20e23, 2014, Philadelphia, USA. * Corresponding author. A. Dean, 19 Kerferd Road, Glen Iris 3146, Victoria, Australia. E-mail address: [email protected] (A. Dean). 1078-5884/$ e see front matter Ó 2014 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2014.09.011
The best technique to accurately measure lower limb and foot perfusion in diabetic patients has long been debated. Several methods have been proposed, including anklebrachial pressure index, skin perfusion pressures, and transcutaneous oxygenation measurements to name a few. What is well recognized is that assessment of perfusion at the level of the ankle is often not a true reflection of distal foot perfusion, owing to the nature of peripheral microvascular dysfunction in diabetes.1,2 Furthermore, ankle
78
pressures are often falsely elevated in diabetic patients because of non-compressibility of calcified infra-popliteal vessels, known as Mönckeberg’s sclerosis.3e5 As such, toebrachial pressure index (TBI) has been used in many institutions worldwide as the primary objective marker for distal foot perfusion.6e8 In the European Consensus Document on Critical Limb Ischaemia, critical limb ischemia is defined on the basis of clinical findings (rest pain, ulcerations, and gangrene) and ankle pressure less than 50 mmHg or toe pressure less than 30 mmHg.9 Toe pressures are commonly measured using photophlethysmography with an inflatable cuff around the hallux of the foot in question. Not uncommonly, patients with significant peripheral arterial occlusive disease (PAOD) have significant tissue loss, painful ulceration, isolated toe ischemia (in cases of distal embolization), or amputation of the first toe, making the measurement of first toe pressure not tolerable or possible. It was theorized that in such situations, the adjacent second toe could be used to obtain a toe pressure with good agreement to the first toe pressure as an objective marker of forefoot perfusion.
V. Bhamidipaty et al. Table 1. Demographic details and diabetic status of the 100 participants. Variable Age, years Mean (SD) Range Gender Male Female Diagnosis Type 1 diabetes mellitus Type 2 diabetes mellitus Diabetes treatment Insulin Oral hypoglycemic agents Diet control
Participants (n ¼ 100) 67.30 (15.25) 29e90 66 34 12 88 47 43 10
mellitus; 12 had type 1 diabetes mellitus. Most were being treated with insulin (47) or oral hypoglycemic agents (43); only 10 were being managed with dietary changes. Instrument and procedure
MATERIALS AND METHODS Participants From October to December 2013, 100 participants with a formal diagnosis of diabetes mellitus were recruited from diabetes out-patient clinics and in-patient wards at the authors’ centre. Inclusion criteria included a diagnosis of diabetes mellitus, confirmed by review of medical records and recent pathology results (HbA1C 6.5% and fasting glucose 7 mmol/L), and having adjacent first and second toes present on one foot or both feet. Participants were excluded if they were under 18 years old, were unable to consent, had active ulceration on their first and/or second toes, had a vasomotor condition such as Raynaud’s disease, were unable to lie still for the duration of the test, or had ingested caffeine or smoked within the previous hour. Patients were also excluded if the application and inflation of the pressure cuff proved to be prohibitively painful, or if the toe was too large to fit the maximum occlusion cuff size. Institutional ethics approval was granted by the Low Risk Ethics Committee at the regional hospital network. Patients were informed about the study verbally and provided with written information by either the treating podiatrist or the vascular physician before consent was gained. Participants were asked to rest in a supine position for 15 minutes prior to measurements being taken. Restrictive clothing, such as shoes and tight socks, was removed and the temperature of the room was measured and maintained at a minimum of 22 C to avoid error from vasoconstriction. Two measurements were taken on both the first and second toes of the eligible foot and recorded on an electronic spreadsheet. Patient demographics are shown in Table 1. There was a preponderance of males (66) in the 100 patients studied with a mean age of 67.30 (15.25) years (range 29e90). Of the participants, 88 had a diagnosis of type 2 diabetes
Toe systolic pressure measurements were taken with the Systoe Automated Toe Pressure System (Atys Medical, Soucieu-en-Jarrest, France), which included the Systoe Photophlethysmograph (PPG) Sensor Cuff and two occlusion cuffs measuring 120 mm 25 mm for the first toe and 90 mm 15 mm for the second toe. This unit was chosen as it was familiar to the authors’ staff; has an automated cuff inflator and the option to change the cuff size; can measure systolic toe pressures to less than 20 mmHg; and has been shown to have excellent interobserver and intraobserver reproducibility.10 Firstly, an occlusion cuff was placed around the base of the first toe (Fig. 1). Distal to this, the PPG sensor was secured to the pulp of the hallux with a double-sided transparent adhesive tape supplied by the manufacturer. The sensor was maintained in position with a second pneumatic cuff, which also acted as a blood draining cuff. If applied correctly, a pulse waveform would appear on the device screen. Activating the machine commenced an
Figure 1. Systoe automated toe pressure system (Atys medical, Soucieu-en-Jarrest, France).
Second Toe Systolic Pressure Measurements
79
automatic sequence in which the blood draining cuff would inflate first, followed by the occlusion cuff e which would inflate to 200 mmHg e followed by the deflation of the blood drainage cuff. Finally, the occlusion cuff deflated at a slow, controlled rate. Concurrently, the infrared PPG system provided skin penetration approximately 3 mm deep (800 nm wavelength, 75 mW fixed power). The investigators noted the point at which the direct current curve showed a continuous upstroke, which correlated with the return of perfusion to the toe. After a minute had lapsed, the same process was then repeated on the same toe, after which duplicate measures were taken on the adjacent second toe using a smaller occlusive cuff and the same technique. Figure 2. Scatterplot of second toe on first toe systolic pressures.
Statistical analyses Pearson’s productemoment correlation was used to determine the correlation coefficient and the coefficient of determination. No assumption was made that the conventional first toe systolic pressure measurements were errorfree. In that correlation analysis only calculates a relationship between two measurements, it is inadequate for a method-comparison study.11e14 Analyses of measurement errors in the two methods (first toe versus second toe) were hence conducted using Ordinary Least Product (OLP) regression to uncover systematic differences and, in particular, to detect and distinguish fixed and proportional bias between the two methods.15,16 Fixed bias: where one method gives values that are higher (or lower) by a constant amount. Proportional bias: where one method gives values that are higher (or lower) by an amount that is proportional to the level of the measured variable. Assumptions for using OLP regression including linearity and equality of variance in the scatterplot were tested. A “folded empirical cumulative distribution plot” was additionally performed to detect measurement biases. Coefficients of repeatability were calculated for duplicate measurements. Ninety-five percent tolerance intervals were constructed. The acceptable limits of interchangeable results were defined as 5e10 mmHg. Sample size considerations: the minimum sample size with a confidence interval of 0.2 which corresponds to correlations of 0.82 or higher between first toe and second toe pressures was calculated to be 45 measurements. Continuous data are presented as mean (SD) if distributed normally. All tests were two-sided, and p < .050 was considered significant. Statistical analyses were performed using: Systat v12 (Systat Software, Inc., Chicago, IL, USA) for OLP; “R” v3.0.1 (R Foundation for Statistical Computing, Vienna, Austria) for constructing tolerance intervals17; MedCalc v13.0 (MedCalc Statistical Software, Ostend, Belgium) for “folded empirical cumulative distribution plot”.18
wound (9), previous amputation (7), or an occlusive dressing such as a total contact cast (4). One patient had an acute episode of gout in his first metatarsophalangeal joint making the inflation of the pressure cuff too painful, another patient’s toes were deformed such that the cuff could not be correctly applied, and finally one patient was wearing restrictive clothing which she preferred not to remove. Finally, eight patients only consented to having one foot measured because of time constraints. A scatterplot of second toe on first toe systolic pressure is shown in Fig. 2. This was tested for heteroskedasticity and was shown to be homoskedastic (c2 4.19, df 2, p ¼ .123). The correlation coefficient (r) ¼ 0.908; 95% confidence interval (CI): 0.877 to 0.931; p < .001; and the coefficient of determination (r2) ¼ 0.824, which implied that 82% of the variation in the second toe measurements is accounted for by knowing the first toe measurements and vice versa. The variance (or scatter) of second toe pressures was constant across all values of first toe pressures, an essential assumption for using OLP regression. Fig. 3 shows the residual plot of the regression model, the residual is the difference between the observed and predicted value of the second toe measurements. The random pattern of the residuals around the horizontal axis supported a linear model. The results of OLP regression are shown in Table 2. The 95% CI for the intercept (7.487e6.329) included a zero(0) value implied no fixed bias; the 95% CI for the slope
RESULTS Sixty-nine patients had systolic toe pressures measured on both feet e 31 patients had systolic toe pressures measured only on one foot with reasons for not obtaining contralateral measurements including the presence of an overlying
Figure 3. Residual plot of the regression model.
80
V. Bhamidipaty et al.
Table 2. Results of OLP regression. Parameter
Estimate
Asymptotic standard Parameter/ASE error (ASE) Intercept 0.579 3.499 0.166 Slope 1.038 0.034 30.125 95% CI for the intercept includes a 0 value; 95% CI for the slope includes a 1 value.
(0.970e1.106) included a one(1) value implied no proportional bias. The regression equation for the model is: second toe ¼ (0.579) þ (1.038)* first toe.
The analysis of duplicate measurements is shown in Table 3. There is 0.5% less variation between duplicate measurements made with the first toe compared with the second toe, with coefficient of repeatability of 11.640 and 11.697, respectively. Fig. 4 is the plot of the 95% tolerance intervals (with 95% confidence), indicating the range within which a single, new observation should lie if it is drawn from the same population studied. A “folded empirical cumulative distribution plot” (Mountain plot) of the distribution of differences between the two methods of measurements is shown in Fig. 5. The “mountain” is approximately centered over zero, indicating that the two methods of measurements were unbiased with respect to each other.18
Wald 95% confidence interval 7.487 to 6.329 0.970 to 1.106
five, leaving only 24 successful measurements out of 50.20 Hirai et al. took measurements from all five toes in 106 limbs and found that 41% of cases had a difference in blood pressure of more than 15 mmHg between any two toes; however, they used an unconventional ‘bladder-free cuff’ technique that is otherwise untested, and unfeasible outside of the laboratory setting.21 De Graaff et al. investigated the reproducibility of first toe and second toe pressure measurements in 54 patients e they did not, however, investigate the relationship between the two.22 A handful of studies measured the second toe pressure if the first toe pressure was unable to be taken given amputation
DISCUSSION The principal finding from this study was that second toe systolic pressure measurements were interchangeable with those of the first toe within acceptable limits of 5e 10 mmHg. Analyses of measurements showed no evidence of detectable biases. A literature search reveals few studies that measured second toe systolic pressures e none of which provide conclusive evidence on which to base clinical decisionmaking. In 1971, Carter et al. measured the second toe systolic pressure in 51 individuals, ten of whom had diabetes - no first toe pressures were measured.19 Accuracy of the measurements is questioned in this early study given that the occlusive cuff was constructed out of a Penrose drain backed in adhesive tape, and reperfusion was detected by either a color change in the digit or by an increase in volume of the digit recorded using a strain-gauge technique. Kröger et al. attempted to compare first and second toe pressures using a Doppler technique; however, in 21 out of 50 participants a Doppler signal could not be measured; and of the remaining 29, the optical measurement failed in
Figure 4. 95% tolerance intervals with 95% confidence.
Table 3. Analysis of duplicate measurements (n ¼ 169). FT2eFT1 ST2eST1 x̄ 0.189 1.302 SD 5.939 5.968 CR 11.640 11.697 FT2eFT1: differences of first toe duplicate readings; ST2eST1: differences of second toe duplicate readings. ForP each toe Coefficient of Repeatability (CR) ¼ 1.96 O (duplicate differences)/n 1.13
Figure 5. “Mountain plot”: percentile for each ranked difference between second and first toe pressures plotted against the differences of the second and first toe pressures.
Second Toe Systolic Pressure Measurements
or ulceration, or took the highest reading of the two digits; however, none of them mention how many second toe readings were used.4,10,23,24 It is in this context that clinicians have erred away from using second toe pressures given the lack of clear evidence. The main diagnostic limitation of toe perfusion measurements has always been the variability and reproducibility of results depending on a number of variables, not least of which includes operator experience with the technique. Ubbink suggested that to reduce this uncertainty, repetition of a measurement will help in reducing the variability as it causes regression to the mean, i.e. will give a better estimate of the true value after averaging the two results.25 The same author went on to suggest that to minimize any doubt about the validity and reproducibility of the result, that it be repeated immediately in the same diagnostic setting and session, and the mean measurement be used. This appeared to the authors’ group to be the most sensible and pragmatic way to approach this diagnostic challenge. Another issue that is often touted as producing large variability in results is that of cuff sizing and sensor placement, both of which require standardization for obtaining toe pressures. For the purpose of the present study, the same size cuff (120 25 mm) was used on the large toe of all patients with the sensor placed on the pulp of the hallux. Similarly the same size cuff (90 15 mm) and sensor placement was used to obtain second toe pressures of all patients. Although in an ideal setting, only one cuff size would be used on all toes of all patients to reduce or prevent inter-cuff variability, this is neither practical nor technically possible given that the large cuff often was not able to obtain a satisfactory reading on the second toe. This remains a problem without a logical feasible solution. It was noted that with differing sensor placements and cuff sizes, the authors’ values differed from those when the technique was standardized as it was in the reported results. Unfortunately, there are no particular strategies that can be implanted to reduce this error apart from ensuring that staff who are most familiar with the equipment and technique are the ones performing the procedure as often as possible. There are some limitations to this study. Patients were not specifically selected or excluded based on the degree of ischemia, pain, tissue loss, or other symptoms attributable to peripheral occlusive arterial disease. However, the heterogeneous nature of the patient group is reflective of the ‘real world experience’ and may be considered as a relative strength of the study and add further support to the results published. The results achieved strengthen the argument that in any diabetic patient population, regardless of type or extent of disease, second toe pressures can be used as a valid measurement as part of the clinical assessment. To the authors’ knowledge, this is the first study that has documented the interchangeability of systolic toe pressure measurements between the first and second toe. Although the definition of critical leg ischemia as per the European Consensus Document does not include pressure obtained
81
from the second toe, it seems reasonable to use the second toe pressure, when first toe pressure cannot be obtained, as a surrogate marker in assessing distal perfusion and in aiding clinic decision-making. CONFLICT OF INTEREST None. FUNDING None. ACKNOWLEDGEMENTS We would like to thank Briggate Medical Company, Melbourne for loaning us the Systoe Automated Toe Pressure System (Atys Medical, Soucieu-en-Jarrest) for the duration of the study. REFERENCES 1 Faglia E, Clerici G, Clerissi J, Gabrielli L, Losa S, Mantero M, et al. Long-term prognosis of diabetic patients with critical limb ischemia: a population-based cohort study. Diabetes Care 2009;32:822e7. 2 Lepäntalo M, Apelqvist J, Setacci C, Ricco JB, de Donato G, Becker F, et al. Chapter V: the diabetic foot. Eur J Vasc Endovasc Surg 2011;42:S60e74. 3 Aboyans V, Ho E, Denenberg JO, Ho LA, Natarajan L, Criqui MH. The association between elevated ankle systolic pressures and peripheral occlusive arterial disease in diabetic and nondiabetic subjects. J Vasc Surg 2008;48:1197e203. 4 Vincent DG, Salles-Cunha SX, Bernhard VM, Towne JB. Noninvasive assessment of toe systolic pressures with special reference to diabetes mellitus. J Cardiovasc Surg 1983;24:22e8. 5 Mönckeberg JG. Uber die reine Mediaverkalkung der Extremitätenarterien und ihr Verhalten zur Arteriosklerose. Virch Arch (Pathol Anat) 1903;171:141e67. 6 Sahli D, Eliasson B, Svensson M, Blohmé G, Eliasson M, Samuelsson P, et al. Assessment of toe blood pressure is an effective screening method to identify diabetes patients with lower extremity arterial disease. Angiol 2004;55:641e51. 7 Brooks B, Dean R, Patel S, Wu B, Molyneaux L, Yue DK. TBI or not TBI: that is the question. Is it better to measure toe pressure than ankle pressure in diabetic patients? Diabet Med 2001;18:528e52. 8 Ramsey DE, Manke DA, Sumner DS. Toe blood pressure: a valuable adjunct to ankle pressure measurement for assessing peripheral arterial disease. J Cardiovasc Surg (Torino) 1983;24: 43e8. 9 Dormandy J, editor. European consensus document on critical limb ischaemia. Berlin Heidelberg New York: Springer; 1989. 10 Pérez-Martin A, Meyer G, Demattei C, Böge G, Laroche JP, Quéré I, et al. Validation of a fully automatic photoplethysmographic device for toe blood pressure measurement. Eur J Vasc Endovasc Surg 2010;40:515e20. 11 Ludbrook J. Comparing methods of measurement. Clin Exp Pharmacol Physiol 1997;24:193e203. 12 Batterham AM. Commentary on bias in Bland-Altman but not regression validity analyses. Sportscience 2004;8:47e9. 13 Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986;1:307e10.
82 14 Ludbrook J. Confidence in AltmaneBland plots: a critical review of the method of differences. Clin Exp Pharmacol Physiol 2010;37:143e9. 15 Ludbrook J. Linear regression analysis for comparing two measurers or methods of measurement: but which regression? Clin Exp Pharmacol Physiol 2010;37:692e9. 16 Ludbrook J. A primer for biomedical scientists on how to execute model II regression analysis. Clin Exp Pharmacol Physiol 2012;39:329e35. 17 Young DS. Tolerance: an R package for estimating tolerance intervals. J Stat Softw 2010;36:1. 18 Krouwer JS, Monti KL. A simple, graphical method to evaluate laboratory assays. Eur J Clin Chem Clin Biochem 1995;33:525e 7. 19 Carter SA, Lezack JD. Digital systolic pressures in the lower limb in arterial disease. Circulation 1971;43:905e14. 20 Kröger K, Stewen C, Santosa F, Rudofsky G. Toe pressure measurements compared to ankle artery pressure measurements. Angiol 2003;54:39e44.
V. Bhamidipaty et al. 21 Hirai M, Kawai S, Ohta T, Seko T, Shionoya S. Measurement of blood pressure in all toes in arterial occlusive disease of the leg. Angiol 1982;33:418e26. 22 de Graaff JC, Ubbink DT, Legemate DA, de Haan RJ, Jacobs MJHM. Interobserver and intraobserver reproducibility of peripheral blood and oxygen pressure measurements in the assessment of lower extremity arterial disease. J Vasc Surg 2001;33:1033e40. 23 Ubbink DT, Tulevski II, den Hartog D, Koelemay MJ, Legemate DA, Jacobs MJ. The value of non-invasive techniques for the assessment of critical limb ischaemia. Eur J Vasc Endovasc Surg 1997;13:296e300. 24 Høyer C, Sandermann J, Petersen LJ. Randomised diagnostic accuracy study of a fully automated portable device for diagnosing peripheral arterial disease by measuring the toebrachial index. Eur J Vasc Endovasc Surg 2013;45:57e64. 25 Ubbink DT. Toe blood pressure measurements in patients suspected of leg ischaemia: a new laser Doppler device compared with photoplethysmography. Eur J Vasc Endovasc Surg 2004;27:629e34.
