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Diabetes Watch

A Closer Look At The Complexity Of PAD Screening In Patients With Diabetes

Peripheral arterial disease (PAD) is a condition affecting approximately 8.5 million Americans over the age of 40 and more than 20 million people worldwide.1 Thiruvoipati has defined PAD as atherosclerotic disease of the lower extremity with increased risk of limb amputation as well as a marker of atherothrombosis in both cardiovascular and cerebrovascular disease.2 Diabetes mellitus is a major risk factor for developing PAD with this detrimental disease combination leading to increased morbidity and mortality.2 

Yet in terms of diabetic limb salvage, screening for PAD to assess the healing potential for foot ulcerations remains quite challenging.3 While there are many established non-invasive screening methods, there remains a lack of consensus regarding which is the most efficient modality.3 Accordingly, let us review the epidemiology of PAD in patients with diabetes and take a closer look at current screening methods as well as some newer modalities. 

The clinical features of diabetes, including hyperglycemia, insulin resistance and dyslipidemia, also foster the development of PAD through blood vessel damage.2 Inflammation is a key factor in both PAD and diabetes with biomarkers like C-reactive protein, tumor necrosis factor (TNF) and interleukin-6 associated with endothelial cell adhesion leading to plaque formation.2 

Endothelial cells release vital substances, such as nitric oxide (NO), which is essential for proper blood vessel function and structure.2 Hyperglycemia and insulin resistance reduce the bioavailability of nitric oxide.2 Platelet function maintains the critical balance between vascular function and thrombosis while the uptake of glucose promotes platelet aggregation and adhesion in those with diabetes.2 

Overall, poor glycemic control amounts to a more severe manifestation of PAD with a higher prevalence of lower extremity bypass surgery, amputation and death.2 

Standard Noninvasive Vascular Assessment: Pearls And Pitfalls 

Traditionally, noninvasive vascular testing, such as the ankle-brachial index (ABI), most commonly assesses lower extremity large vessel circulation and diagnoses PAD in patients with diabetes. While ABIs are inexpensive and easy to perform in the clinical setting, this test has a reported sensitivity as low as 38 percent and can be falsely negative in those with diabetes due to vascular calcification.4 The toe-brachial index (TBI) is less affected by large vessel calcification in comparison to the ABI and is also a low-cost tool.5 However, there are limitations to performing a TBI including the presence of digital ulcerations or previous amputation.5 

Clinicians commonly obtain pulse volume recordings (PVRs) along with ankle- and toe-brachial indices as the pulse volume recording is a pneumoplethysmography exam to detect segmental volume change throughout multiple levels along the lower extremity.6 The main drawbacks of pulse volume recordings are that the results are subjective and technician skill-dependent.6 

Transcutaneous oxygen pressure (TcPO2) measurement allows for the analysis of oxygen delivery and consumption in a specific anatomic region and the presence of vessel calcification does not affect this particular evaluation.7 Favorable transcutaneous oxygen pressure readings are a good predictive indicator for wound healing potential along with a likelihood of positive response to hyperbaric oxygen therapy (HBOT).7 However, the accuracy of transcutaneous oxygen pressure measurements can vary by both probe placement and probe temperature.8 

What Are Some Alternatives To Traditional Vascular Testing? 

Addressing the need for early detection and intervention for patients with diabetes and PAD as a means to prevent lower extremity amputation inspires limb salvage clinicians to look beyond the standard non-invasive vascular studies in the hope of finding new screening methods. 

One such promising modality is indocyanine green (ICG) angiography, which can be beneficial in assessing large and small vasculature of the lower extremity. Indocyanine green is a non-radioactive, non-toxic, hepatically-excreted contrast agent. When one injects this agent, it rapidly disperses through the intravascular space.8 Using a laser light source with a camera, indocyanine green fluoresces in proportion to perfusion throughout the entire limb.8 These captured images provide an accurate real-time assessment 

of the macro- and microvascular status of the lower extremity in comparison to the limited large vessel assessment of the standard ABI.9 The United States Food and Drug Administration (FDA) classifies indocyanine green angiography as a Class II pre-amendment medical device, which is not identified as a significant risk device.10 

The imaging agent, indocyanine green, has had FDA approval for human use since 1959.11 Use of this modality is expensive but it has a low reported rate of adverse reactions ranging between 0.002 to 0.3 percent and a short half-life of two to four minutes.12 Indocyanine green angiography assessment parameters include: time to initial visualization of fluorescence (time to first blush); average ingress; reference ingress; region of interest (ROI); reference egress; average egress; and ROI ingress/egress ratio.12 

Indocyanine green is readily available. One may employ this modality in the clinic setting or the operating room. It is also minimally invasive as this imaging agent only requires peripheral intravenous (IV) access. Indocyanine green could improve practice paradigms for diagnosis and management for patients with diabetes and PAD. 

Near infrared spectroscopy (NIRS) is a non-invasive technology that provides dynamic measurements of oxygen-bound hemoglobin and myoglobin in the skeletal musculature of the calf.13 This modality provides a window into the state of the muscle environment focused on oxygen delivery, demand and use.13 Previous studies of this modality revealed that patients with PAD have a greater magnitude of oxygen desaturation and a delayed return to baseline after exercise in comparison to healthy individuals.13 Near infrared spectroscopy can be costly but may be valuable for diagnosing and monitoring the treatment response to PAD in those with diabetes.13 

In Conclusion 

The need for a reliable screening tool for PAD in the presence of diabetes continues to be a dilemma in the multidisciplinary approach to diabetic limb salvage. The standard non-invasive studies all have worthwhile aspects along with clinical limitations. 

The novel uses of indocyanine green angiography offers the benefit of real-time perfusion imaging to specific regions of interest in the lower extremity that one can use to predict wound healing or amputation level. However, this contrast agent is expensive. Near infrared spectroscopy provides a glimpse into the oxygen environment at the muscular level, which can be an indicator of PAD even before the patient experiences claudication, but this modality can have a steep price tag as well. 

It is clear that future research into the complexity of diabetes with concomitant PAD is still very necessary. For the time being, utilizing all screening tools that are most appropriate and accessible to the health-care team is advisable until we see the development and acceptance of a definitive algorithm. 

Dr. Miller is the Medical Director of Wound Care and Limb Salvage at the University of Florida College of Medicine in Jacksonville, Fla. She is on the Board of Directors of the American College of Clinical Wound Specialists and is the Secretary-Treasurer of the American Society of Forensic Podiatry. 

Diabetes Watch
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By Christine Miller, DPM, PhD, FACCWS
References

1. Fuglestad MA, Hernandez H, Gao Y, et al. A low-cost, wireless near-infrared spectroscopy device detects the presence of lower extremity atherosclerosis as measured by computed tomographic angiography and characterizes walking impairment in peripheral artery disease. J Vasc Surg. 2020;71(3):946-957. 

2. Thiruvoipati T. Peripheral artery disease in patients with diabetes: Epidemiology, mechanisms, and outcomes. World J Diabetes. 2015;6(7):961-966. 

3. Lavery LA, Crisologo PA. Non-invasive vascular screening test to diagnose peripheral vascular disease. Ann Transl Med. 2018;6(S2):1-2. 

4. Abouhamda A, Alturkstani M, Jan Y. Lower sensitivity of ankle-brachial index measurements among people suffering with diabetes-associated vascular disorders: a systematic review. SAGE Open Med. 2019;7. Available at: https://doi. org/10.1177/2050312119835038 . Published March 1, 2019. Accessed January 6, 2021. 

5. Tehan P, Bray A, Keech R, Rounsley R, Carruthers A, Chuter VH. Sensitivity and specificity of the toe-brachial index for detecting peripheral arterial disease. J Ultrasound Med. 2015;34(10):1737-1743. 

6. Mammano B, Sadra S. Lower extremity noninvasive vascular testing update. Lower Extremity Review. Available at: https://lermagazine.com/article/lower-extremity-noninvasive-vascular-testing-update . Published March 2020. Accessed January 6, 2021. 

7. Leenstra B, Wijnand J, Verhoeven B, et al. Applicability of transcutaneous oxygen tension measurement in the assessment of chronic limb-threatening ischemia. Angiology. 2019;71(3):208-216. 

8. Unno N, Suzuki M, Yamamoto N, et al. Indocyanine green fluorescence angiography for intraoperative assessment of blood flow: a feasibility study. Eur J Vasc Endovasc Surg. 2008;35(2):205-207. 

9. Braun JD, Trinidad-Hernandez M, Perry D, Armstrong DG, Mills Sr JL. Early quantitative evaluation of indocyanine green angiography in patients with critical limb ischemia. J Vasc Surg. 2013;57(5):1213-1218. 

10. Schlanger R. Clinical case update: using fluorescence angiography to help assess lower extremity wounds. Wounds. 2014;26(Suppl):1-4. 

11. Kamisaka K, Yatsuji Y, Yamada H, Kameda, H. The binding of indocyanine green and other organic anions to serum proteins in liver diseases. Clin Chim Acta. 1974;53(2):255–264. 

12. Kim PJ, Attinger CE, Akbari CM, Ward C. Correlation of values for indocyanine green angiography in the arterographically normal lower extremity. Surg Technol Int. 2017;31:156-161. 

13. Fuglestad MA, Hernandez H, Gao Y, et al, A low-cost, wireless near-infrared spectroscopy device detects the presence of lower extremity atherosclerosis as measured by computed tomographic angiography and characterizes walking impairment in peripheral artery disease. J Vasc Surg. 2020;71(3):946-957. 

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