Introduction
Adequate tissue oxygenation is a key determinant of diabetic foot ulcer (DFU) outcomes [1,2]. Insufficient oxygenation in DFUs is associated with an increased risk of major amputation [3]. Therefore, precise assessment of tissue perfusion is essential for predicting prognosis [4]. Transcutaneous oxygen pressure (TcPO2) is widely regarded as the most reliable, representative, and sensitive method for evaluating tissue perfusion and wound healing potential in patients with DFUs [5].
However, there are practical limitations in measuring TcPO2, including the high cost of equipment and the need for trained personnel. Additionally, because TcPO2 assesses oxygen diffusion through the skin, thorough preparation is crucial. It is essential to remove skin keratin and foreign substances to prevent pore blockage, and to heat the skin to ensure adequate pore opening. Consequently, the process is time-intensive—often requiring nearly an hour—and demands expert execution to ensure accuracy.
Therefore, to determine tissue perfusion in patients with DFUs, many institutions still primarily rely on methods that assess intravascular blood flow, such as computed tomographic (CT) angiography, Doppler ultrasonography, or measurement of the ankle-brachial index [6,7]. However, our previous study demonstrated that CT angiography and Doppler ultrasonography showed no relationship with TcPO2 [7].
Meanwhile, toe pressure measures the blood pressure within the digital arteries, which are less affected by medial arterial calcification, thereby reducing the likelihood of falsely elevated values [8,9]. As it reflects terminal arterial flow near the tissue level, it may correlate more closely with tissue perfusion. The relationship between TcPO2 and toe pressure, nonetheless, remains to be clinically investigated. The objective of this study was to quantify the correlation between TcPO2 and toe pressure and evaluate their agreement to determine whether the two measurements can be used interchangeably in patients with DFUs.
Methods
Data source and study patients
This study retrospectively analyzed medical records of 1,663 patients with DFUs who were admitted to the authors’ diabetic wound center between January 2008 and December 2023. Our center is part of a tertiary hospital that provides standardized clinical care to patients with diabetic wounds. Patient information was retrieved from the hospital’s electronic medical record system and linked with the institution’s Admitted Data Collection database, which is routinely audited for accuracy and completeness. At the time of hospital admission, comprehensive clinical and demographic data were collected, including demographic information, baseline vascular assessments, ulcer characteristics, wound bioburden, and relevant serologic markers. Inclusion criteria were: (1) confirmed diagnosis of diabetes for more than 5 years; (2) available TcPO2 measurements; (3) available toe pressure measurements; and (4) adequate clinical follow-up data. Patients whose vascular assessment values were available only after percutaneous transluminal angioplasty were excluded from the analysis.
Measurements of the TcPO2 and toe pressure
TcPO2 measurement is a noninvasive diagnostic method used to evaluate the partial pressure of oxygen at the epidermal surface. Because TcPO2 data can be affected by various external technical factors, all measurements were performed at a constant room temperature (25–26 °C) by a well-trained, certified wound care nurse at our institution. To ensure measurement accuracy, measurements were delayed for up to 2 weeks in cases with significant infection or swelling. Once clinical conditions permitted, a thorough cleansing of the feet was performed for each patient. For patients with excessive keratin, the feet were soaked in saline for 30 minutes to soften and remove callused tissue.
TcPO2 was primarily measured at the distal aspect of the ulcer. In cases where distal placement was not feasible, such as toe ulcers, measurements were taken at the metatarsophalangeal joint. The skin was cleansed with alcohol before electrode placement, and all measurements were obtained with the patient in a resting supine position. TcPO2 measurements were obtained using a PF5040 TcPO2 unit (PeriFlux System 5000; Perimed AB) along with PeriSoft software (PeriSoft for Windows 2.50; Perimed AB). The TcPO2 values were recorded at 43 ºC after a 20-minute equilibration period (Fig. 1A). Toe pressure was measured using the PeriFlux 5000 system (Perimed AB) with a miniature cuff placed around the base of the great toe. When measurement of the great toe was not feasible, the second toe was used instead. A laser Doppler perfusion monitor was employed to detect the point at which blood flow resumed during gradual cuff deflation from suprasystolic levels. The measuring probe was positioned at the tip of the selected toe (Fig. 1B).
Statistical analysis
Scatter plots were used to assess the linear relationship between TcPO2 and toe pressure and to screen for potential outliers. In addition, distributional characteristics were assessed for each variable using Q–Q plots as well as skewness and kurtosis values. After confirming these assumptions, Pearson correlation analysis was performed to quantify this association, providing the correlation coefficient (R) and corresponding P-value. Statistical significance was defined as P<0.05.
The strength of the correlation was categorized according to conventional criteria as follows: |R|<0.10, negligible; 0.10–0.30, weak; 0.30–0.60, moderate; 0.60–0.90, strong; 0.90–0.99, very strong; and 1.00, perfect [10,11]. The scatter plot included a linear regression trend line with a shaded 95% confidence interval (CI) for the fitted line.
Agreement between TcPO2 and toe pressure measurements was assessed using Bland–Altman analysis. The mean difference (bias) and the 95% limits of agreement (mean±1.96 standard deviation [SD]) were calculated and visualized in a Bland–Altman plot. The plot displays the difference between the two methods against their mean to evaluate systematic bias and random variability. To assess the proportional bias, a linear regression analysis of the differences in mean values was performed, and the regression coefficient with its 95% CI was reported.
Data collection was performed using Microsoft Excel (Microsoft Corp.). All analyses, including Pearson correlation and Bland–Altman analyses, were performed with R software for Windows version 4.4.1 (the R Foundation for Statistical Computing; http://www.r-project.org). Data were then visualized using figures processed by the ggplot2 R package (v.3.5.1; Wickham, H. 2016; https://ggplot2.tidyverse.org). All P-values were two-sided, and statistical significance was established at P<0.05.
Ethics statement
This retrospective study was approved by the Institutional Review Board (IRB) of Korea University Guro Hospital (IRB No. 2015GR0181) and conducted in full accordance with the principles of the Declaration of Helsinki. All study procedures were monitored to ensure compliance with institutional and international ethical standards for human research. The requirement for informed consent was waived by the IRB.
Results
A total of 837 patients were included in our study (617 men, 220 women) with a mean age of 61.4±11.9 years. Their mean diabetes duration was 17.6±10.7 years, and the mean HbA1c level was 8.0±2.1%. Table 1 presents detailed baseline characteristics.
The mean TcPO2 was 35.3±17.3 mmHg (range, 0.5–79 mmHg), and the mean toe pressure was 62.2±36.8 mmHg (range, 0–148 mmHg). Both variables showed approximately symmetric distributions without substantial deviation from normality (TcPO2: skewness −0.19, kurtosis −0.74; toe pressure: skewness 0.13, kurtosis −0.87). Pearson’s correlation analysis demonstrated a significant positive linear relationship between TcPO2 and toe pressure. The correlation coefficient was 0.66 (95% CI, 0.62–0.70; P<0.001), indicating a strong association between the two vascular parameters. This finding indicates that higher TcPO2 values were generally associated with higher toe pressure values (Fig. 2).
Bland–Altman analysis demonstrated a mean bias of 26.9 mmHg (SD of differences: 28.8 mmHg, 95% limits of agreement: –28.9 to 82.6 mmHg) between toe pressure and TcPO2. These results indicate that toe pressure values were generally higher than TcPO2 measurements, with limits of agreement that were too wide for clinical equivalence. A significant proportional bias was identified, with a positive slope in the regression of differences on mean values (β=0.85; 95% CI, 0.79–0.90; P<0.001), indicating that disagreement increased as perfusion increased. Therefore, the two methods cannot be used interchangeably, particularly in the high-perfusion group (Fig. 3).
Discussion
In patients with DFUs, tissue oxygenation in the foot can be accurately assessed using TcPO2. However, in routine clinical practice, due to practical limitations, tissue oxygenation is often inferred indirectly using CT angiography, Doppler ultrasonography, or toe pressure. Therefore, understanding how closely each of these measurements relates to TcPO2, and whether any of them can be used interchangeably with TcPO2, is clinically important. In our previous study, CT angiography and Doppler ultrasonography showed no relationship with TcPO2, whereas in the present study toe pressure demonstrated a strong correlation with TcPO2 [7]. This discrepancy suggests that toe pressure may reflect TcPO2-measured tissue oxygenation more closely than CT angiography or Doppler ultrasonography.
Given the large cohort (n=837), the study’s high statistical power allowed even weak correlations to reach significance. Consequently, the P-value offered limited interpretative value regarding the clinical relevance of the findings. We therefore interpreted the association primarily based on the correlation coefficient (R=0.66) and its narrow 95% CI, which together provided a precise estimate of a strong association. This approach aligns with methodological recommendations that emphasize effect estimates and confidence intervals, rather than P-values, when evaluating correlations between continuous variables [11]. However, correlation alone could not determine whether the two measurements are interchangeable because association and agreement represent distinct statistical concepts. Therefore, we performed a Bland–Altman analysis to evaluate the agreement between toe pressure and TcPO2.
A Bland–Altman plot is a statistical visualization used to assess agreement between two measurement methods. Commonly applied in clinical medicine and biostatistics, it evaluates how closely a new method or device matches an established one when measuring the same variable [12]. Several types of bias may be present in this analysis, including fixed bias, random bias, and proportional bias. Fixed bias occurs when a constant difference exists between two methods; random bias reflects non-systematic measurement errors; and proportional bias arises when the difference varies systematically with the magnitude of measurement. In our results, a proportional bias was observed, indicating that differences increased as measurements became larger [13].
In the overall cohort, the limits of agreement ranged from 28.9 to 82.6 mmHg, indicating that an individual’s TcPO2 may be nearly 30 mmHg lower or more than 80 mmHg higher than their corresponding toe pressure. For example, a toe pressure of 40 mmHg may span a TcPO2 range from approximately 10 to 120 mmHg. Previous studies have reported that TcPO2 ≥40 mmHg is associated with DFU healing, whereas TcPO2 ≤20 mmHg is associated with failure of wound healing [14,15]. Consequently, inferring TcPO2 from a toe pressure of 40 mmHg does not provide a reliable prognosis. Because of the wide variance, a single toe pressure value could reflect TcPO2 levels spanning from the non-healing threshold (≤20 mmHg) to a clearly favorable range (≥40 mmHg).
To explore whether toe pressure might serve as a clinically useful surrogate within specific perfusion ranges and to account for proportional bias, we performed subgroup analyses based on mean TcPO2–toe pressure values. In the very low-perfusion subgroup (mean ≤20 mmHg; n=137), the mean bias was 0.4 mmHg (SD, 15.2 mmHg; limits of agreement, −29.3 to 30.1 mmHg), indicating persistent patient-level disagreement of approximately ±30 mmHg. In the very high-perfusion subgroup (mean ≥70 mmHg; n=194), the mean bias increased markedly to 59.1 mmHg (SD, 19.3 mmHg; limits of agreement, 21.3–97.0 mmHg), demonstrating a consistent overestimation of TcPO2 by toe pressure, together with wide patient-level disagreement of roughly 20–100 mmHg. Accordingly, despite the observed correlation, the two measurements could not be considered interchangeable even within specific perfusion ranges.
Possible explanations for the discrepancy between toe pressure and tissue oxygenation in diabetic patients involve three main mechanisms. First, even though diabetic patients have a skin capillary density similar to that of nondiabetic individuals, their capillary basement membranes tend to be substantially thickened. This discrepancy likely arises from sustained hydrostatic pressure in the lower extremities, which damages capillary endothelial cells. Chronic exposure to such pressure promotes arteriole hyalinosis and thickening of the capillary basement membrane, ultimately impairing vasodilatory capacity and disrupting normal capillary autoregulation [16,17]. Secondly, the accumulation of nonenzymatic advanced glycation end-products (AGEs) associated with chronic hyperglycemia further contributes to microcirculatory impairment. Elevated AGE concentrations in the serum, vessel walls, and extracellular matrix are commonly observed in individuals with diabetes mellitus. Their accumulation promotes microangiopathy by thickening and decreasing the permeability of the capillary basement membrane, ultimately leading to impaired vasodilatory function [18]. Lastly, the two measurement sites have inherent anatomical differences. Differences in anatomical distance, skin thickness, and the underlying microvascular bed are potential contributors to proportional bias, as TcPO2 measures local tissue oxygenation at the distal ulcer margin or metatarsophalangeal joint, whereas toe pressure is measured at the great toe.
Studies investigating agreement between measurement methods are important because they directly influence the grading systems used to evaluate ischemia in patients with DFUs. For example, both TcPO2 and toe pressure are incorporated into the ischemia component of the WIfI classification, a system that stratifies the risk of amputation based on wound, ischemia, and infection severity [19,20]. In the WIfI classification, toe pressure and TcPO2 are considered equivalent parameters for ischemia grading, sharing the same category and cutoff thresholds, unlike the ankle-brachial index or ankle systolic pressure [19]. When both measurements are available, the classification does not define an explicit hierarchy. In such cases, discrepancies should be interpreted according to the clinical context and the reliability of each test. In this regard, our findings hold clinical significance. Although TcPO2 and toe pressure may fall within the same ischemia score category, their actual agreement is not guaranteed. Therefore, careful interpretation is warranted when two patients are classified into the same ischemia grade but are assessed using different tests. A substantial difference in actual tissue oxygenation may exist between them.
Previously published studies have primarily focused on evaluating how well each individual assessment method predicts prognosis. Findings by Londahl et al. [21] indicate that TcPO2 is a more reliable predictor of foot ulcer healing outcomes than toe pressure. Similarly, Kalani et al. [22] found TcPO2 to be a superior predictor of healing in patients with DFU. Salaun et al. [6] compared ankle pressure (AP), toe pressure, and TcPO2 for predicting major amputation at 1 year in the COPART (Cohorte des Patients ARTe’ riopathes) cohort of patients hospitalized with peripheral arterial disease. While their research was limited to nondiabetic peripheral arterial disease patients, they questioned the utility of AP and concluded that toe pressure and TcPO2 better predicted amputation risk.
Overall, these prognostic studies suggest that TcPO2 generally outperforms toe pressure and that both are superior to AP. However, none of these investigations directly compared TcPO2 and toe pressure or assessed whether the two measurements could be used interchangeably in patients with DFUs. Unlike previous studies that compared the predictive utility of individual tests across different populations, this study concurrently measured both TcPO2 and toe pressure in the same patients to visualize and analyze their correlation and clinical agreement. To our knowledge, no prior study has conducted a direct comparative analysis of these two methods in this manner. These findings provide important insight into how these measurements behave in clinical settings.
This study has some limitations, most notably those inherent to its retrospective design. Nevertheless, the large sample size (n=837) provides sufficient power for clinically meaningful correlation and agreement analyses. Although adjusting the analyses for additional demographic and clinical variables (such as age, sex, infection status, and comorbidities) that may have affected the correlation and agreement between toe pressure and TcPO2 would have been desirable, modeling all these complex interrelationships within the scope of this study was not feasible. Hence, further analyses incorporating these variables will be performed in a future study, including more detailed evaluations of subgroup-specific discrepancies and clinical factors that may contribute to variations in the relationship between the two measurements. Additionally, this study focused only on the relationship between the two tests, without evaluating their association with clinical outcomes such as wound healing or major amputation. Nonetheless, this study provides valuable insight into the relationship between these two commonly used perfusion measurement tests in patients with DFUs.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation 
Print 
