Treatment of Nonreconstructable Critical Limb Ischemia With Ischemic Wounds Utilizing a Noninvasive Intermittent Pneumatic Compression Device Monitored With Fluorescence Angiography

Introduction. Critical limb ischemia (CLI) is a leading cause of lower extremity amputation. When CLI is identified, revascularization should be performed if possible. When options for revascularization do not exist, use of a noninvasive intermittent pneumatic compression device (NPCD) can be considered. Objective. Presented here are 2 cases of patients with nonreconstructable CLI at risk for limb loss who were serially assessed with indocyanine green fluorescence angiography (ICGFA) to determine the effects of NPCD use on local tissue perfusion. Materials and Methods. Both patients were treated with the NPCD for 1 hour, 3 times per day, for 4 weeks. Serial ICGFA utilizing a ICGFA device was performed at various time points to monitor the effects of NPCD use on tissue perfusion. Results. The treatment of both patients with serial ICGFA provided limited objective evidence of increased local tissue perfusion which expedited wound resolution. Conclusions. Larger randomized control trials of this modality of perfusion assessment and NPCD use are recommended.

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Critical limb ischemia (CLI) affects 765 000 to 1 million people in the United States annually — about 5% of people < 40 years of age and 15% of people > 70 years.^1-6 The prevalence of CLI is predicted to increase due to an aging population and an increasing prevalence of diabetes.^4,6 Up to 30% of patients will undergo an amputation within the first year after diagnosis.^6,7 The mortality rate within the first year is 25%.⁶

Lifestyle modifications and medical management are the first line of treatment for this condition, although about half will require revascularization.^6,8 Vascular intervention, however, is not without risk. Eighty-six percent of patients will require repeat hospitalizations and multiple interventions, during which time they will have a declining functional status and significantly reduced quality of life.^4,7 The remaining half of patients will face a primary amputation.⁶ Both of these treatment pathways result in a declining functional status, a reduced quality of life, increased mortality rates, and significant health care costs.⁹

The use of a noninvasive intermittent pneumatic compression device (NPCD), incorporating both the foot and calf, in patients with CLI has been shown to increase popliteal artery flow and distal skin perfusion, resolve rest pain, reduce claudication symptoms, and assist in wound resolution and limb salvage in patients with peripheral arterial disease (PAD).^{1,3,4,8,10-15} Reported limb salvage rates in patients with CLI who have exhausted further vascular reconstruction options range from 70% to 90% compared with 17% in similar patients not treated with NPCD.^12,15-17 Although the exact mechanisms of action remain unknown, it is theorized that a NPCD increases arterial inflow through augmentation of the arteriovenous gradient, reduction in peripheral arterial resistance, increased vessel shear stress (causing the release of nitric oxide and other vasoactive, antiplatelet, and antithrombotic substances), and transient attenuation of the venoarteriolar myogenic reflex.^4,6,8,14,15

Toe pressures and transcutaneous oxygen pressure measurements (TCOM) are the only 2 vascular studies that have been utilized to assess changes in skin perfusion of the foot with NPCD use.^6,18-23 The results of both of these tests may be limited by infection, edema, anemia, wound location, and previous amputation. In addition, these tests only provide assessment of the site of probe placement. Indocyanine green fluorescence angiography (ICGFA) is a minimally invasive, minimal risk procedure that allows for rapid, real-time visualization and objective assessment of tissue perfusion of the entire area being imaged.²⁴ It is readily performed in the outpatient setting. Presented here are 2 cases of patients with nonreconstructable CLI at risk for limb loss who were serially assessed with ICGFA to determine the effects of NPCD use on local tissue perfusion.

Two patients with CLI who were not candidates for revascularization and at risk for limb loss were treated with a NPCD (ArtAssist; ACI Medical, San Marcos, CA) in addition to receiving local wound care at a military treatment facility in Tacoma, Washington.

Both patients were treated with the NPCD for 1 hour, 3 times per day, for 4 weeks. Serial ICGFA utilizing the LUNA Device (Stryker, Kalamazoo, MI) was performed at various time points to monitor the effects of NPCD use on tissue perfusion. The ICGFA device used consists of a near infrared 40 mW/cm laser light with an optical power output of 0.16 W for excitation and a near infrared sensitive charge-coupled device camera for static and video image capture. Indocyanine green (ICG), a second-generation, sterile, water soluble, nonradioactive, nontoxic and inert, hepatically cleared, tricarbocyanine dye, serves as the imaging agent; it was approved for intravenous injections in adults by the US Food and Drug Administration since 1959.²⁴ The imaging head of this ICGFA device was positioned so the inferior aspect was parallel and ~12 inches from the area imaged. A white light image was obtained. The patient then received 2.5 mL of a 2.5 mg/mL ICG solution followed by a 10 mL normal saline bolus via rapid intravenous injection. Image recording began once the bolus was administered and ran for a total of 2 minutes and 30 seconds.

The clinical photograph from the initial ICGFA was reviewed prior to each subsequent ICGFA performed to ensure the position of the foot was similar, as previously recommended,²⁵ to obtain optimal serial image analysis. The ingress rate (increase in grayscale units 0–256/time in seconds) and egress rate (decrease in grayscale units 0–256/time in seconds) for 2 Regions of Interest (ROI), ROI 1 and ROI 2, were determined. The ingress rate is a measure of arterial inflow to the foot. The egress rate is a measure of venous outflow. As validated range of values exists for these parameters, the imaging sequence itself also was reviewed.

Case 1

The first patient was a 61-year-old Caucasian man, active tobacco user, who presented with intermittent claudication symptoms in the calf and a noninfected stage IV pressure ulcer of the left heel, measuring 2 cm x 1 cm. The wound had failed to progress after 8 months of standard wound care with hydrogel and absorptive dressings. He had a history of angioplasty and stenting of the left superficial femoral artery. An ankle-brachial index (ABI) was unobtainable due to noncompressible arteries. Waveforms of the posterior tibial artery were monophasic, and digital waveforms ranged from dampened to absent. Duplex arterial ultrasound demonstrated patent common femoral and deep arteries with multiple collaterals in the distal thigh. No flow was noted in the superficial femoral, popliteal, posterior tibial, or anterior tibial arteries. As no options existed for revascularization, the recommendation was made for NPCD use and local wound care.

The ICGFA obtained prior to initiation of NPCD use revealed a mottled pattern of fluorescence signal filling of the foot and hypofluorescence within the clinically visible wound bed. No periwound fluorescence was seen. Using the default sizes, the ROI 1 was placed on the central heel, and the ROI 2 was placed over the clinically visible wound bed. The ICGFA performed after the index hour of NPCD use revealed a decrease in the egress rate of both ROIs 1 and 2. The ingress rate within the wound bed also decreased.

After 3 weeks of NPCD use, the patient reported improvement of his claudication symptoms. Wound resolution was achieved after 4 weeks of NPCD use. At that time, the ICGFA revealed reduced fluorescence signal intensity compared with the previous week, although peak ingress and egress rates for both ROIs 1 and 2 were determined with analytic assessment. The ICGFA performed 3 months after wound resolution and discontinuation of NPCD use revealed a continued increase in fluorescence intensity about the heel compared with the baseline study. The ingress rate for ROI 1 remained above baseline, while that for ROI 2 decreased. Egress rates for both ROIs 1 and 2 decreased below the baseline assessment (Figure 1). The patient remains free of claudication symptoms and wound recurrence 1 year after wound resolution and discontinuation of NPCD use.

Case 2

The second patient was a 51-year-old African American man, who did not have diabetes but had a history of hypertension, hyperlipidemia, and chronic renal failure, and presented with dry gangrene of the right second toe. The patient’s past medical history was significant for tobacco use and multiple embolic events of unknown etiology, which had caused bowel gangrene with perforation and bilateral renal infarcts. An arteriogram and echocardiogram with bubble study failed to reveal an embolic source. He had an ABI of 1 on the left foot and 0.3 on the right. Digital subtraction angiogram revealed occlusion of the peroneal and posterior tibial arteries in the midleg, occlusion of the anterior tibial/dorsalis pedis arteries at the level of the midfoot, and minimal collateralization of the left lower extremity. The ICGFA performed at this time revealed a minimal fluorescence signal to the dorsal foot.

Using the default sizes, the ROI 1 was placed just proximal to the amputation site, and the ROI 2 was placed over the clinically visible wound bed. The patient’s gangrene progressed to the third toe and converted from dry to wet gangrene, necessitating an open amputation of the second and third toes. As the patient was deemed to have no options for revascularization, and now had an open amputation, recommendation was made for NPCD use and local wound care consisting of silver alginate (Aquacel; ConvaTec, Bridgewater, NJ), silver hydrogel (SilvaSorb Silver Antimicrobial Wound Gel; Medline Industries, Northfield, IL), and 2 applications of a dehydrated human amnion/chorion membrane allograft (Epifix; MiMedix, Marietta, GA).

After 3 weeks of NPCD use, the ICGFA revealed increased signal intensity in the dorsal foot and a slight increase in the fluorescence signal in the immediate periwound around and within the wound bed. Peak ingress rates were observed for both ROIs 1 and 2. Wound resolution occurred at 4 weeks. At that time, the ICGFA revealed a reduced fluorescence signal intensity and a drop in ingress and egress rates for both ROIs 1 and 2, although they remained above those obtained on the baseline ICGFA (Figure 2). The patient was lost to follow-up upon wound resolution and discontinuation of NPCD use at 4 weeks.

Increased site-specific local tissue perfusion during the course of healing was able to be visualized in real time with the use of serial ICGFA. Although ICGFA analytic parameters obtained from the device used have not been validated and review of the imaging sequence appears more quantitative than qualitative in nature, the pathophysiology and mechanism of fluorescence of ICG make it an attractive agent for vascular imaging.²⁴ More than 90% of ICG binds to large lipoproteins in the blood, minimizing capillary leakage. The ICG absorbs light in the near infrared range (760 nm to 805 nm), with fluorescence occurring around 835 nm to 845 nm. This lies within the “optical window” of the skin (600 nm to 900 nm).²⁵ The low absorbance and high scattering properties of tissues in this range of wavelengths allows for diffuse propagation and deep tissue penetration (up to 20 mm reported) while minimizing autofluorescence contribution.²⁶ Thus, ICGFA use can allow for visualization of the subdermal vascular plexus at a minimum.^25,26

Intraoperative ICGFA use has demonstrated its ability to provide rapid, real-time assessment following open and endovascular intervention.^6,13,26 Review of the raw imaging sequence also has been reported to be critical in utilizing ICGFA for local tissue perfusion assessment in wound care since fluorescence signal intensity can be affected by factors that may not be captured by the analytic software (eg, the pattern of fluorescence signal appearance and disappearance in various areas of the site being imaged; tissue thickness; infection; inflammation; angiogenesis; and eschar, fibrotic tissue, coagulum, and/or placement of advanced tissue products in the wound bed). Chronic, nonhealing wounds have been shown to begin with periwound hyperfluorescence and wound bed hyperfluorescence due to the wound being stalled in the inflammatory phase of healing. Increasing wound bed fluorescence and decreasing periwound fluorescence are seen as the wound transitions to the proliferative phase due to reduced inflammation and increased angiogenesis in the wound bed. Peripheral arterial disease is associated with a late time to onset of fluorescence and has a mottled pattern of fluorescence signal appearance.^25,26 This mottled pattern of fluorescence filling was noted in the cases presented here.

Objectively, intermittent pneumatic compression (IPC) applied to the foot and calf has been shown to increase arterial inflow in the popliteal, anterior tibial, posterior tibial, and peroneal arteries by 13% to 240%; increase flow velocity by 15% to 320%; increase resting ABIs by 17% to 20%; and increase foot skin perfusion (assessed via toe pressures) by 57% to 246%.¹⁷ Pressure-based noninvasive vascular studies, however, have been shown not to be predictive of outcomes in subjects with PAD.¹⁸

Although resting ABIs have been shown to improve by 20% following endovascular intervention and utilization of supervised exercise programs, functional benefits often do not follow suit. In a pilot study¹⁸ on the effects of NPCD use on foot perfusion and amputation rates in patients with CLI and a failed bypass graft or nonreconstructable distal disease, 40% of patients had an ABI consistent with Rutherford Grade 2 while their clinical presentation was consistent with Rutherford Grade 6 (Table^18,27). Toe pressures were the only vascular study found to have a statistically significant increase after 3 months of use (19 mm Hg vs. 29 mm Hg).¹⁸ Alteration in lower extremity blood flow and collateralization of the microvasculature is postulated to be the cause of these findings.¹⁸ Thus, other studies have utilized TCOM, toe pressures, and laser Doppler flux (LDF) of the hallux to assess changes in microvascular flow to the foot related to NPCD use.^19,22,23

Abu-Own et al²² were the first to report on the effects of venous foot pump activation on the microcirculation of the foot in healthy patients and severe claudicants with CLI utilizing toe pressures and TCOM. Toe pressures increased significantly in both the supine and seated positions after a single 10-minute session. The TCOM results also increased but not significantly.²² The greatest increase in LDF of the hallux was found to occur with combined foot and calf IPC.²¹ Eighty-eight percent of the increased blood flow was determined to be an increase in arterial flow.²⁰ A prospective study of 20 patients²⁸ determined that a significant increase in blood flow occurred in muscular and collateral arteries below the knee, contradicting the theory that these vessels already are maximally dilated in patients with CLI. A retrospective review of NPCD use in 187 patients (262 limbs)⁶ reported a statistically significant increase in toe pressures after 4 months of use (61 mm Hg vs. 65 mm Hg). Rest pain and minor amputation rates also were reduced significantly during this time period.⁶ A 5-year prospective study of NPCD use in 171 patients with nonreconstructable CLI⁷ also reported a significant increase in toe pressures (40 mm Hg vs. 55 mm Hg).

A retrospective, observational study¹⁹ on NPCD use in 107 patients with severe nonreconstructable CLI and tissue loss in which TCOM was utilized revealed a 47% wound healing and limb salvage rate. Forty percent of the 58 (54.2%) patients with a TCOM  ≤ 20 mm Hg achieved wound resolution and resultant limb salvage.¹⁹ Similar rates were observed for patients without and with diabetes (47% vs. 42%, respectively).¹⁹

A second study²³ also reported a statistically significant increase in TCOM results (65 mm Hg vs. 93 mm Hg). A statistically significant increased quality of life, physical function and physical role functioning, emotional role and social functioning, mental and general health perceptions, and a reduction in bodily pain also was observed on the 36-Item Short Form Survey scoring system review.²³

Laser Doppler flux and toe pressures are based on red blood cell concentration and velocity. Both of these studies and TCOM results also are dependent on the number of capillaries present beneath the site of probe placement, which can vary by 6-fold in a 1-mm² area of skin.²⁹ The presence of infection, edema, a wound, previous amputation, and site of probe placement can affect toe pressure and TCOM results. Obtaining TCOM results also is time consuming and operator dependent. Originally developed to assess PAD, ICGFA has been utilized for decades to assess perfusion during cardiac, plastic, and gastrointestinal surgery.^13,24,30

Recently, ICGFA has returned to use in vascular surgery and expanded to local tissue perfusion assessment in wound care.^24,28 Use of ICGFA is attractive due to its being a minimally invasive and minimal risk procedure easily performed in the outpatient setting that allows for rapid, real-time perfusion assessment and objective analysis to the specific area of concern. This has potential implications in wound evaluation and treatment, empowering the provider to develop individualized treatment plans, such as when to utilize hyperbaric oxygen therapy or when optimal wound bed preparation has been obtained for application of advanced tissue products.

Potential variables that could have affected ICGFA images include alterations in patient and ambient temperatures and minor differences in foot position between the studies.²⁵ Although this could have affected the results observed in the cases presented herein, it is unlikely the change would be significant as the same room was always utilized for testing. In addition, the patient’s foot remained covered to maintain temperature until just prior to testing, and the authors made attempts to maintain a similar foot position between studies.

The use of a NPCD provides an alternative adjunct treatment for patients with nonreconstructable CLI and tissue loss that are at risk for major lower extremity amputation. Use of a NPCD has minimal risk and a high reported compliance rate due to its ability to be a home-based, patient-directed therapy that has been shown to eliminate or reduce pain symptoms, reduce healing times, and prevent amputation in patients with and without diabetes who failed peripheral bypass surgery or are not candidates for reconstruction.^{1-4,10,12,15-21,31}

Although long-term results of NPCD use have yet to be studied to determine if life-long use once prescribed is required, the primary disadvantage of NPCD use is that it is currently nonreimbursable due to the lack of large, randomized controlled trials.^2,28,32,33 Serial ICGFA is a rapid, easily performed, well-tolerated, minimal risk procedure that provides real-time, limited objective feedback on the response of local tissue perfusion to the foot with NPCD use.

The results of this study warrant further investigation via large randomized controlled trials of the use of serial ICGFA in addition to routine vascular assessment modalities to determine the effects of NPCD use on the microcirculation of the foot and to determine if a short-term course of treatment or life-long use is necessary.

Affiliations: Madigan Army Medical Center, Tacoma, WA; Midwest Podiatry Services, Wichita, KS; BSN Medical, Tacoma, WA; and Scriptum Medica, University Place, WA

Correspondence: Valerie Marmolejo, DPM, Scriptum Medica, PO BOX 65965, University Place, WA 98466; www.scriptummedica.com; vlsdpm@gmail.com

Disclosure: At the time of the study, Dr. Charles Andersen was a consultant for NOVADAQ Technologies, Inc (Mississauga, Ontario, Canada; previous manufacturer of the LUNA Device) and was a member of their speaker’s bureau. The opinions or assertions contained herein are the private view of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.