How Fluorescence Angiography Illuminates The Potential For Limb Salvage

Having an adequate vascular supply is a key tenet in wound care and limb salvage. Proper vascular assessment begins with pulse palpation and Doppler evaluation of the major arteries supplying the foot.

Absent or weakly palpable pulses in conjunction with weak or non-Dopplerable signals should prompt referral to a vascular surgeon and ordering noninvasive vascular studies. The assessment of tissue perfusion is critical to predicting healing, predicting if an amputation is required and predicting the level that an amputation will most likely heal. Traditional methods of assessing tissue perfusion include clinical judgment, an ankle brachial index (ABI), toe pressures and a toe brachial index (TBI), toe arterial pulse waveforms, forefoot pulse volume recordings (PVRs), duplex scanning, transcutaneous oxygen pressure measurements (TcPO₂) and skin perfusion pressure (SPP).

Current methods of evaluating tissue perfusion are often limited by medial calcinosis, scarring, wounds, prior amputations and infection.^1–3 Current methods are also technically challenging, costly and time consuming, and do not provide information on the global perfusion of the foot. When it comes to minimally invasive vascular studies (i.e. computed tomography angiography (CTA) and magnetic resonance angiography (MRA)), and invasive arteriograms, one must exercise caution with these studies in patients with renal insufficiency. Also bear in mind that these studies only provide information regarding the anatomic, or structural, blood flow to the extremity.³ None of the above studies assesses the functional skin perfusion to the specific region of interest on the lower extremity.²

While the results of these studies guide the physician in decision making, they are not always reliable, making preoperative patient counseling and education difficult. The need for partial foot or major lower extremity amputation or reconstruction when deformity is present, or when the wound encompasses only one or two toes, particularly after successful vascular intervention, can be difficult for patients to comprehend.

Understanding How Fluorescence Angiography Works
When the results from traditional methods of measuring tissue perfusion are indeterminate and there is a question of whether the patient requires a major versus a minor amputation, fluorescence angiography offers an additional method to measure tissue perfusion. Fluorescence angiography debuted in 1934 to assess circulation times, capillary permeability and tissue perfusion in cases of peripheral arterial disease (PAD). Its first clinical application was in liver function testing in 1957.⁴ The FDA approved it for use in 1959. Since that time, fluorescence angiography has been in use for retinal and choroidal imaging, and to assess perfusion in cardiac, colorectal, plastic and neurosurgery. Now the use of fluorescence angiography is circling back to its origins in vascular surgery and expanding into the fields of wound care and limb salvage.^2,4,5

Since 1976, indocyanine green, a second-generation, water-soluble, nonradioactive, nontoxic and inert tricarbocyanine dye, has been in use in fluorescence angiography. Indocyanine green is superior to its predecessor, fluorescein, for several reasons.^2-4 The short half-life (two to four minutes versus 24 to 48 hours for fluorescein) and hepatic clearance of indocyanine green allow for multiple image runs to be captured without concern in patients with renal insufficiency. Up to 98 percent of the dye remains within the intravascular space due to binding to large plasma proteins, which prevents capillary leakage from occurring.³ Indocyanine green also has a low reported rate of adverse reactions (0.002 to 0.3 percent).

The absorption spectrum of indocyanine green lies within the “optical window” of the skin at 600 to 900 nm. Light activated near the infrared range (760 to 805 nm) is absorbed with fluorescence occurring around 835 to 845 nm. This allows tissue penetration up to 10 mm in depth, capturing the vasculature in the deep dermal plexus and subcutaneous fat without the risk for damage to the tissue.^2,4

Practical Pearls On Using This Technology
Indocyanine green angiography use in vascular surgery, wound care and limb salvage can occur in both the operative and outpatient clinical settings. One would obtain peripheral access and ensure supine positioning of the patient. Reconstitute the indocyanine green dye with 10 cc of water and inject 1 to 4 cc rapidly. One would follow this with a rapid flush of 10 cc of normal saline. In a dark room, image capture begins at the time of injection. The machine for image capture contains a near infrared 40 mW/cm laser light with an optical power outlet of 0.16 W for excitation and a near infrared sensitive charge-coupled device camera. Position the camera 30 to 100 cm from the skin of the region of interest. Each recording runs for a total of five minutes per the most recent recommendations.^2,4

Researchers are still determining optimal measurements to quantify perfusion and their normal range values. Measurements can be based on either time or intensity. However, measurements based on time are reportedly more reliable as intensity can vary due to the distance of the camera from the skin, the patient’s skin color, the ambient light in the testing room and the presence of periwound inflammation and/or infection.^2,3 A perfusion rate (fraction of blood exchanged in the vascular volume/minute, percentage/minute) of 24 reportedly predicts the presence of PAD, defined as an ABI ≤ 0.90 and a TBI ≤ 0.70, with a sensitivity of 92 percent and a specificity of 90 percent irrespective of the presence of the comorbidities of tobacco use, diabetes mellitus, hypertension and hyperlipidemia.^1,5

Braun and colleagues have reported a time from maximum intensity to 90 percent intensity (Td90 percent) of 25 seconds to accurately predict PAD secondary to isolated infrapopliteal lesions of >50 percent stenosis present on CTA, MRA, duplex ultrasound or digital subtraction angiography with a sensitivity and specificity of 83 percent and 73 percent respectively.² A time from the onset of fluorescence to half maximum intensity (T½) of 20 seconds in the area of the distal first metatarsal reportedly correlates with a toe pressure of 50 mmHg with a sensitivity and specificity of 77 and 80 percent respectively.³

Recognizing The Benefits Of Fluorescence Angiography
Fluorescence angiography assesses global perfusion of the foot. It allows assessment of perfusion to each of the angiosomes of the foot.^1-3,5 Revascularization may improve perfusion to the foot but may not restore perfusion to the angiosome where a wound is located. For example, revascularization of the anterior tibial artery may improve perfusion to the dorsum of the foot and the toes, but perfusion to the heel may remain inadequate. Fluorescence angiography can therefore become a guide to focused revascularization of the foot.

Direct visualization of the functional perfusion of the region of interest on the lower extremity allows one to determine:

• the impact on the vascular supply to the lower extremity following vascular intervention or the use of noninvasive modalities purported to increase circulation;
• the adequacy of wound debridement;
• the local perfusion present to heal a wound;
• vascular response to advanced wound care modalities (i.e., hyperbaric oxygen therapy);
• the most distal level of amputation most likely to primarily heal; and
• flap and tissue viability following incision closure.^1-6

The most recent statistics regarding lower extremity amputation related to complications of diabetes found toe amputations to be the most common level of amputation.⁷ These patients often have some degree of PAD, increasing their risk for postoperative healing complications. Whether it is inconclusive or unobtainable data from noninvasive vascular studies or data involving only the anatomic blood flow to the lower extremity from minimally invasive and invasive vascular studies, providers are often basing their treatment plans on this limited data and their level of experience. This may account for the 50 to 75 percent of isolated toe amputations that lead to major lower extremity amputation.⁷

Researchers have reported that indocyanine green angiography accurately predicts the need for revisional surgery following major amputation when physicians perform the modality at 72 hours postoperative.⁶ This has led to the recommendation that surgeons perform indocyanine green angiography both intraoperatively and on postoperative day one to allow for early intervention when perfusion deficits are present.⁶ We can expand these results to use in partial foot amputations and advanced surgical techniques for wound closure, potentially minimizing postoperative complications related to wound healing, the need for revisional surgical procedures and a prolonged and costly postoperative recovery course.

The visual results of indocyanine green angiography also make preoperative patient counseling and education much easier. Patients can easily comprehend that brighter intensity is equivalent to more blood. This makes for an easier understanding of why a wound is not healing or why the need for a certain level of amputation is necessary.

In Conclusion
Fluorescence angiography is a safe, rapid, reproducible and time-effective minimally invasive procedure that provides objective data on the functional perfusion to a region of interest on the lower extremity.^2-4 Results of this vascular assessment are valuable when data from other studies are limited. This modality may become invaluable in cost containment due to its ability to accurately predict when tissue viability is questionable due to compromised perfusion to the region of interest, minimizing the potential for a prolonged and costly course of treatment for wound care and limb salvage. 

Dr. Schade is a Fellow of the American College of Foot and Ankle Surgeons, and the American College of Foot and Ankle Orthopedics and Medicine. She is a Clinical Educator for Novadaq Technologies.
Dr. Andersen is the Chief of the Vascular/Endovascular Surgery Service and the Medical Director of the Madigan Army Medical Center Outpatient Wound Care Clinic in Tacoma, Wash.

Lt. Dr. Omana-Daniels is a podiatrist in the Navy. She recently finished her residency at the Madigan Army Medical Center and is currently stationed at the Naval Hospital Bremerton in Bremerton, Wash.

References

1. Kang Y, Lee J, Kwon K, Choi C. Dynamic fluorescence imaging of indocyanine green for reliable and sensitive diagnosis of peripheral vascular insufficiency. Microvasc Res. 2010; 80(3):552-555.
2. Braun JD, Trinidad-Hernandez M, Perry D, Armstrong DG, Mills JL. Early quantitative evaluation of indocyanine green angiography in patients with critical limb ischemia. J Vasc Surg. 2013; 57(5):1213-1218.
3. Igari K, Kudo T, Toyofuku T, Jibiki M, Inoue Y, Kawano T. Quantitative evaluation of the outcomes of revascularization procedures for peripheral arterial disease using indocyanine green angiography. Eur J Vasc Endovasc Surg. 2013; 46(4):460-465.
4. Mothes H, Dönicke T, Friedel R, Simon M, Markgraf E, Bach O. Indocyanine-green fluorescence video angiography used clinically to evaluate tissue perfusion in microsurgery. J Trauma. 2004; 57(5):1018-1024.
5. Zimmerman A, Roenneberg C, Reeps C, Wendorff H, Holzbach T, Eckstein HH. The determination of tissue perfusion and collateralization in peripheral arterial disease with indocyanine green fluorescence angiography. Clin Hem Micro. 2012; 50(3):157-166.
6. Zimmerman A, Roenneberg C, Wendorff H, Holzbach T, Giunta RE, Eckstein HH. Early postoperative detection of tissue necrosis in amputation stumps with indocyanine green fluorescence angiography. Vas Endovas Surg. 2010; 44(4):269-273.
7. Nehler MR, Whitehill TA, Bowers SP, Jones DN, Hiatt WR, Rutherford RB, Krupski WC. Intermediate-term outcome of primary digit amputations in patients with diabetes mellitus who have forefoot sepsis requiring hospitalization and presumed adequate circulatory status. J Vasc Surg. 1999; 30(3):509-518.