Assessing The Potential Impact Of Fluorescence Angiography In Preventing Limb Loss

There are approximately 29 million people in the United States (9.3 percent of the population) living with diabetes.^1,2 Approximately 25 percent of patients with diabetes will develop a foot ulcer at some point during their lifetime. It has been well documented that more than half of these wounds will become infected and require hospitalization, and that nearly 20 percent of these infections result in lower extremity amputation.

Of these types of amputation, partial foot amputation occurs nearly twice as frequently as either the transfemoral or transtibial amputations in the United States.^1,2 In the U.S., approximately 618,000 individuals have had some form of partial foot amputation and considering the current population, that translates to approximately two out of every 1,000 people who suffer with partial foot amputation.³
This is a staggering statistic, especially considering that the number of people living with limb loss will likely double by 2050 as the population ages and the increasing number of people who suffer with concomitant comorbidities, such as diabetes and vascular disease.⁴ Consequently, those clinicians involved in the management of lower extremity wounds are truly facing an epidemic of limb loss.

The pathogenesis of ulceration and limb loss is multifactorial. Vascular insufficiency, neuropathy and musculoskeletal deformity are known contributors to progression to limb loss in patients with diabetes.

One must address each factor to progress the patient adequately through wound healing. Perhaps the most challenging factor to address is the potential for vascular compromise.

Patients with diabetes often suffer from peripheral arterial disease with elements of both microvascular and macrovascular disease.^5-7 While critical limb ischemia (CLI) is predominantly secondary to macrovascular disease, patients with diabetes can demonstrate microvascular disease even in the context of palpable pulses. While we understand that patients with CLI are at significant risk for limb loss and require timely intervention to improve distal lower extremity perfusion, those patients who present with palpable pulses and microvascular disease are much more difficult to treat and present a management challenge for those clinicians involved in limb salvage.^8-11 Among those patients who present with both vascular compromise and lower extremity ulceration, it is necessary to address the patient’s vascular status in order to promote effective wound healing and reduce amputation risk.

Angiogenesis is a critical process in wound healing. Newly formed vessels contribute to granulation tissue development and the delivery of oxygen, micronutrients and paracrine survival factors to proliferating tissue after injury. Notably, angiogenesis is compromised in virtually all wounds with delayed healing and this compromise lends itself to wound propagation and chronicity. Historically, clinicians performed microvascular assessment via noninvasive vascular studies that utilize ultrasound, segmental pressures and pulse volume recordings, and transcutaneous oximetry (TcPO₂) to assess distal perfusion.¹² However, these modalities do not truly provide adequate assessment of microvascular patency and endothelial function.

A Closer Look At The Efficacy Of Fluorescence Angiography
Fluorescence angiography has become increasingly valuable to provide clinicians more focused, quantifiable information regarding a patient’s microvascular status.^13-15 This modality can provide real-time assessment of the efficacy of vascular intervention as well as direct focused surgical debridement. Surgeons adapted this modality for medical use in the 1950s and it utilizes indocyanine green (ICG), a biocompatible dye that is detectable in blood. The FDA approved fluorescence angiography in 1956 for use by cardiologists to measure cardiac output. As the liver exclusively excretes the dye, physicians used fluorescence angiography for hepatic angiography as well. Ophthalmologists began using ICG angiography to assess the choroidal vasculature in the eye.^15-18

More recently, other specialties including plastic, vascular and podiatric surgery have adapted fluorescence microangiography to obtain real-time visualization of tissue perfusion in patients with diabetic ulcers, venous ulcers, ischemic ulcers and other types of non-healing wounds.¹⁹ In reconstructive breast surgery post-mastectomy, research has shown that the use of fluorescence angiography (SPY Elite, Novadaq) predicts subclinical mastectomy flap necrosis at surgery, days before it would become clinically apparent.²⁰ Researchers have also shown that this perfusion assessment tool reduces complication rates in immediate breast reconstruction from 15 to 4 percent.²¹ In the same way, fluorescence angiography may provide a tool for objective evaluations of tissue viability in the diabetic foot, which is an important indicator of the ability of the diabetic ulcer to heal adequately.

The SPY system uses a combination of a low-power laser with a charge-coupled device camera and indocyanine green to sequence perfusion at the surface of the skin.²² The specific advantage is that SPY can provide visual as well as quantitative assessment of wound and periwound perfusion in a manner that is not possible with TcPO₂ measurements or calculation of the ankle brachial index (ABI).^15,23

There are many uses for this technology in the realm of lower extremity limb salvage. Fluorescence angiography can allow the clinician to evaluate the effectiveness of endovascular or bypass intervention with pre- and post-intervention quantitative assessments, in which one can actually visualize the improved perfusion patterns via the distribution of the indocyanine green dye.²⁴ Additionally, this modality can provide a visual indicator as to the level of tissue compromise to allow for minimal tissue removal during debridement and amputation, thus allowing for “tissue sparing” limb salvage procedures.^25-27 In soft tissue reconstructive surgery, surgeons can employ this modality to assess flap viability pre- and post-harvest, and evaluate wound bed health prior to flap or graft placement.^22,25

Case Study: How Fluorescence Angiography Facilitated Perfusion Assessment And A Healed TMA Wound
A 55-year-old female patient with a past medical history of type 2 diabetes, previous contralateral below-knee amputation, chronic renal disease and peripheral vascular disease received a referral to the Greenville Health System Center for Amputation Prevention. She had a chief complaint of dry gangrene and a non-healing surgical wound site from a previous fourth digit amputation from her left foot.
Treatment involved a left lower extremity angiogram with subsequent angioplasty of the posterior tibial, peroneal and popliteal arteries. The following day, the podiatric surgical team performed primary wound closure of the previously dehisced fourth digit amputation site.

Several months later, the patient returned with breakdown at the previously closed fourth digit amputation site with exposed bone and osteomyelitis of the fourth metatarsal head, and evidence of dysvascularity of the third and fifth digits of the left foot. The patient did not have a pedal pulse. The vascular surgery team subsequently performed a left lower extremity angiogram with angioplasty of the distal posterior tibial artery. Following the vascular intervention, the patient underwent a transmetatarsal amputation with primary wound closure.

Three weeks later, the patient returned to the clinic with a non-healing transmetatarsal amputation site with underlying soft tissue infection. The patient was admitted to the hospital and had an infectious disease consultation. The hospital scheduled the patient for revision surgery.

The following day, the podiatric surgical team performed debridement with revision of the transmetatarsal amputation with primary wound closure. The surgeons used fluorescence angiography with SPY technology pre-and post-procedure. With this modality, they noted poor perfusion along the wound margins and decreased perfusion in the central portion of the wound prior to debridement, and improved perfusion following debridement.

Confirming clinical observations with intraoperative fluorescence angiography, the surgeons noted diminished perfusion along the suture line and recognized that breakdown along the incision was inevitable from the original transmetatarsal amputation. Once the surgeons debrided the non-perfusing tissue, they re-inspected the wound via intraoperative fluorescence angiography and found it to be appropriately perfused. They subsequently closed the wound, which progressed to complete healing without further incident.

In Conclusion
Fluorescence angiography is a modality that can provide critical information regarding the microvascular status in patients to allow clinicians involved in limb preservation to adequately assess and quantify the degree of tissue perfusion prior, during and after surgical intervention. Additionally, the capacity to visualize the specific degree of perfusion allows surgeons to perform focused limb salvage via selective debridement and amputation, thus leading to tissue sparing surgery.

This can provide a significant impact to patients via reduced morbidity and mortality, reduced trips to the operating room, and more efficient and effective delivery of care. Fluorescence angiography devices are increasingly available in community and university healthcare systems, and physicians can use these devices both in the clinic and OR setting. The indocyanine green dye that this modality uses is metabolized by the liver. Accordingly, it is safe for use in patients with renal disease, which is a common comorbidity in patients with vascular disease.

Dr. Fitzgerald is affiliated with the Greenville Health System Center for Amputation Prevention in Greenville, SC. He is an Assistant Professor of Surgery at the University of South Carolina School of Medicine in Greenville, SC.

References

1. Owings MF, Kozak LJ. Ambulatory and inpatient procedures in the United States, 1996. Vital Health Stat. 1998; 13(139):1-119.
2. Capobianco CM, Stapleton JJ. Diabetic foot infections: a team-oriented review of medical and surgical management. Diabet Foot Ankle. 2010; epub Sept. 13.
3. Dillingham TR, Pezzin LE, MacKenzie EJ. Limb amputation and limb deficiency: epidemiology and recent trends in the United States. South Med J. 2002; 95(8):875-83.
4. Ziegler-Graham K, MacKenzie EJ, Ephraim PL, et al. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Arch Phys Med Rehabil. 2008; 89(3):422-9.
5. Mills JL, Beckett WC, Taylor SM. The diabetic foot: consequences of delayed treatment and referral. South Med J. 1991; 84(8):970-4.
6. Stiegler H, Standl E, Hufen V. [Macroangiopathy in diabetes mellitus]. Z Gesamte Inn Med. 1993; 48(3):150-6.
7. Algenstaedt P, Schaefer C, Biermann T, et al. Microvascular alterations in diabetic mice correlate with level of hyperglycemia. Diabetes. 2003; 52(2):542-9.
8. Sumpio BE, Lee T, Blume PA. Vascular evaluation and arterial reconstruction of the diabetic foot. Clin Podiatr Med Surg. 2003; 20(4):689-708.
9. Mills JL Sr. Open bypass and endoluminal therapy: complementary techniques for revascularization in diabetic patients with critical limb ischaemia. Diabetes Metab Res Rev. 2008; 24(Suppl 1):S34-9.
10. Mollazadegan K, Ludvigsson JF. Diabetes: Microvascular complications in T1DM and coeliac disease. Nat Rev Endocrinol. 2015; 11(6):320-2.
11. Rohrer TR, Wolf J, Liptay S, et al. Microvascular complications in childhood-onset type 1 diabetes and celiac disease: a multicenter longitudinal analysis of 56,514 patients from the German-Austrian DPV Database. Diabetes Care. 2015; 38(5):801-7.
12. Turner J, Belch JJ, Khan F. Current concepts in assessment of microvascular endothelial function using laser Doppler imaging and iontophoresis. Trends Cardiovasc Med. 2008; 18(4):109-16.
13. Baran U, Shi L, Wang RK. Capillary blood flow imaging within human finger cuticle using optical microangiography. J Biophotonics. 2015; 8(1-2):46-51.
14. Wang H, Baran U, Li Y, et al. Does optical microangiography provide accurate imaging of capillary vessels?: validation using multiphoton microscopy. J Biomed Opt. 2014; 19(10):106011.
15. Yousefi S, Qin J, Dziennis S, Wang RK. Assessment of microcirculation dynamics during cutaneous wound healing phases in vivo using optical microangiography. J Biomed Opt. 2014; 19(7):76015.
16. Zhi Z, Yin X, Dziennis S, et al. Optical microangiography of retina and choroid and measurement of total retinal blood flow in mice. Biomed Opt Express. 2012; 3(11):2976-86.
17. Zhang Q, Huang Y, Zhang T, et al. Wide-field imaging of retinal vasculature using optical coherence tomography-based microangiography provided by motion tracking. J Biomed Opt. 2015; 20(6):066008.
18. Hallock GG. The first dorsal metatarsal artery perforator propeller flap. Ann Plast Surg. 2014;  epub Aug. 29.
19. Liu DZ, Mathes DW, Zenn MR, Neligan PC. The application of indocyanine green fluorescence angiography in plastic surgery. J Reconstr Microsurg. 2011; 27(6):355-64.
20. Newman MI, Samson MC, Tamburrino JF, Swartz KA. Intraoperative laser-assisted indocyanine green angiography for the evaluation of mastectomy flaps in immediate breast reconstruction. J Reconstr Microsurg. 2010; 26(7):487-92.
21. Komorowska-Timek E, Gurtner GC. Intraoperative perfusion mapping with laser-assisted indocyanine green imaging can predict and prevent complications in immediate breast reconstruction. Plast Reconstr Surg. 2010; 125(4):1065-73.
22. Kanuri A, Liu AS, Guo L. Whom should we SPY? A cost analysis of laser-assisted indocyanine green angiography in prevention of mastectomy skin flap necrosis during prosthesis-based breast reconstruction. Plast Reconstr Surg. 2014; 133(4):448e-54e.
23. Wang H, Baran U, Wang RK. In vivo blood flow imaging of inflammatory human skin induced by tape stripping using optical microangiography. J Biophotonics. 2015; 8(3):265-72.
24. Abdul-Jabbar A, Takemoto S, Weber MH, et al. Surgical site infection in spinal surgery: description of surgical and patient-based risk factors for postoperative infection using administrative claims data. Spine. 2012; 37(15):1340-5.
25. Hayashi A, Yoshizawa H, Tanaka R, et al. Intraoperative use of indocyanine green fluorescence angiography during distally based radial artery perforator flap for squamous cell carcinoma of the thumb. Plast Reconstr Surg Glob Open. 2015; 3(2):e310.
26. Frattini F, Lavazza M, Mangano A, et al. Indocyanine green-enhanced fluorescence in laparoscopic sleeve gastrectomy. Obes Surg. 2015; 25(5):949-50.
27. Connolly PH, Meltzer AJ, Spector JA, Schneider DB. Indocyanine green angiography aids in prediction of limb salvage in vascular trauma. Ann Vasc Surg. 2015; 29(7):1453.