Utilizing Indocyanine Green Wound Imaging In the Management of Hyperbaric Therapy

  Fluorescence vascular angiography (FVA) allows for the immediate visualization of a wound and the proximate surrounding soft tissue. Following the intravenous injection of indocyanine green (ICG), the properties of a near-infrared laser light source and a charged-coupled device (CCD) camera are used to render and record the regional macro- and microvascular blood flow without introducing ionizing radiation or the peril of nephrotoxcity. The safety and efficacy of ICG as a biocompatible dye, whose recorded density is not altered by hemoglobin oxygenation levels, dates back to the 1950s when it was first used to visualize retinal vascular architecture.¹ FVA is now employed intraoperatively in myriad surgical disciplines,^2-4 in the assessment of traumatic wounds and burns,⁵ in tumor detection,^6,7 and in lymphatic mapping.^5,8 Several even more distant horizons have been envisioned.^5,8,9

––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––
RELATED CONTENT
Enhancing Perfusion Assessment of Chronic Wounds Through the Utilization of Fluorescence Angiography
Business Briefs: Coding, Payment, & Coverage for Fluorescence Vascular Angiography
––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––

ICG Application

  The true “picture” of a chronic wound can be interpreted differently among practitioners. To a plastic surgeon, that may mean a clear, unvarnished photograph. To a practitioner of hyperbaric oxygen therapy (HBOT), it may also mean:
    • detailed clinical history, including all antecedent treatments;
    • current cultures, perhaps even quantitative ones;
    • assessment of the arterial supply to the effected region;
    • radiographic images of the site;
    • MRI;
    • radioactive tracer/gamma camera scanning; and/or
    • transcutaneous oximetry.

  The continuing search for more revealing diagnostic instruments suggests these tools, when used singly or in combination, do not offer reasonable assurance that the wound is or is not “capable of unaided secondary healing” (CUSH).

  ICG imaging or FVA yields another picture of the chronic, nonhealing wound. This depiction integrates much of the information gleaned from the analyses already listed and discloses hitherto obscured information about the wound and the periwound tissue. The traditional techniques convey a very static view of the wound. Such studies reveal details of the wound’s pathological history (eg, osteomyelitis, overwhelming bioburden, or obliterative arteritis), but are fairly silent as to its present viability and restorative potential. In contrast, FVA renders a dynamic view of the immediate microvascular perfusion circumstances. Analyses of these FVA findings have been used to quantitate just how deranged a wound’s healing capacity may be, to assess the efficacy of specific topical treatments, and to determine the need for HBOT.⁹

  Additionally, refractory wounds exist wherein no pathology is demonstrable by traditional diagnostic modalities. These wounds will invariably have an abnormal FVA profile. Once an effective therapeutic strategy is initiated, a repeat ICG study can demonstrate normalization of the aberrant FVA parameters. There also appears to be a strong indication of recidivism risk in wound sites demonstrating a wound that’s clinically “healed,” yet still expressing abnormalities in the ICG microangiogram.

  The following limited clinical précis will discuss the application of this modality in the outpatient wound/HBOT clinic and depict the format and nature of the data immediately available to the clinician. Each specific clinical condition rightly deserves its own presentation on the use, findings, and benefits of FVA.

Utilization & Logistics

  FVA was introduced as a new diagnostic procedure in the outpatient wound/HBOT clinic at Hudson Valley Hospital Center, Cortlandt Manor, NY, in 2012. This clinic had been operational for four years and employed an experienced full-time staff with multidisciplinary involvement. In the first eight months, 345 FVA studies were performed on 68 patients.

  There was a designated “FVA Day” at the facility, but several unscheduled studies (~ 8%) were performed. One physician and one staff nurse were required, and on a given day FVA exams could be done in all of the clinic’s treatment rooms by merely moving the device and those two individuals to the next treatment room. Studies were scheduled to occupy a room for less time than for a typical new-patient evaluation.

  The majority of expended time comprised the need for patient consenting and positioning, and for establishing intravenous access. Physician presence could be confined to only that time required for the CCD camera positioning, ICG injection, and sequence recording time (all typically accomplished in ~ 5 minutes). A second ICG injection can be done after only the 10-15 minutes necessary for the first injected dye to be cleared by the liver. In several patients, a repeat FVA study was conducted after a maneuver (eg, limb compression/elevation, ambient pressure O2-breathing, formal HBOT treatment) or after administration of a medication. Thus, the second (or third or fourth) injection might occur from 15-90 minutes after the preceding one. That intervening time between FVA events did not preclude those two staff members or their equipment from engagement at other locations in the clinic.

  Beyond the time for the study itself, an additional 10-15 minutes were required for documentation to be recorded within the device and for the 3-4 basic data management steps that are best executed at that time. Samples of these basic FVA results that were thus available at the end of a study will be offered.

  There were no operational difficulties expressed by the medical staff, support staff, or administration while this procedure was smoothly woven into the normal flow of all other routine clinic activities.

Basic FVA Study Contents

  Following an FVA, the patient records typically would contain the following:
    1. Letter of medical necessity composed after the consultation that led to the FVA (integral to the prior-authorization process).
    2. Copy of the actual CCD camera image capture. These recordings, usually denominated the study “sequence,” are too large for routine inter-physician communication, but can be viewed easily within the patient’s record at any time during the treatment course.
    3. The physician report of that FVA study.
    4. Single-frame snapshot exported at the point of maximal luminescence of the recorded sequence.
    5. Quantitative, pixel density map of the wound extracted at the point of maximal luminescence. In the device employed in these studies (LUNA System; Novadaq Technologies, Toronto) this is denominated the “contour analysis.”
    6. Quantitative data summary delineating the recorded pixel density versus time. This synoptic portrayal of the time course and density of ICG movement through the wound is the basis for several derived metrics useful in patient management.⁹

  Nos. 4-6 above are of use before, during, and after actual FVA. They are easily included in communications to referring physicians. Each of these is briefly described below.

FVA Study Results in Patients

  In the initial review of these patients, more than 80% had useful clinical decisions made using the FVA study results.⁹

  Single-frame snapshot at maximal luminescence: In this example, a Wagner’s Grade III+ diabetic foot ulcer (Figure 1) of several months duration, and at this point in its first week of HBOT, underwent an ICG imaging study. The single-frame images, seen in both black and white and color (Figures 2 and 3) are each a brief 1/100 of a second export at the point of maximal ICG density (24.67 seconds) into the 137-second recording.

  Contour analysis (pixel-density quantification): In this patient (Figure 4), a standard ICG imaging study was performed immediately before and after HBOT (2.4 ATA with three 30-minute O₂ periods). The reference point (100) is selected outside the penumbra of hyperluminescence. All sites selected within the high ICG density field are then quantitated based on that reference value. After the chamber treatment, changes in wound/periwound tissue can be compared to that same reference point.

  In this instance (Figure 5), all geographically matched wound and periwound sites demonstrated a lower pixel density after the HBOT session (HBO₂Rx*).

  The time when the maximum intensity was observed was virtually identical in both instances (28.93 vs. 24.67 seconds). The CCD camera angle was slightly more oblique in the post-chamber sequence, but the focal length was the same. This pattern of modestly diminished hyperluminescence after HBO₂Rx is consistently observed. This is the object of ongoing investigation. An underlying cause of wound hyper-luminescence is the aberrant vascular pattern that is pathognomonic of the arrested wound. The degree of reduction in pixel density evoked by HBOT reflects the severity and duration of the original wound and the number of HBO₂Rx sessions that the wound has received.

  Auto view (quantitative data summary): The CCD camera detects each fluorescent element passing through the acquisition window, and this quantitative data summary is immediately available for review. This microsecond graphic display (Figure 6) of the entire FVA sequence is the literal documentation counterpart of the operator’s intuitive impression of that study. Both are valuable findings, but the graphic display has recognizable landmarks and points of comparison that assist in managing the patient’s care. Among the many readily observable details of this display are:
    • point of ICG arrival at the wound;
    • point at which luminescence is maximal;
    • durations of those phases of ICG passage recognized by device software as “ingress” and “egress”; and
    • duration of the gap between ingress and egress.

  These absolute values, accumulating in the practitioner’s experience, assist in establishing the nature of a particular wound and in selecting the most effective treatment course. In the case of patients who by historical criteria are candidates for HBO₂Rx, there will be changes in several of the auto view numeral valuations confirming that decision. There have been patients who failed their transcutaneous oximetry assessment but showed a vigorous HBO₂Rx-challenge response by FVA measures. The few (three) patients with this presentation responded well to a formal course of HBO₂Rx. In routine patients, when the improvements of the auto view profile induced by an individual chamber session have reached a “certain point,” the formal HBO₂Rx course can be suspended or ended. Determining what exactly is that "certain point" remains the subject of active investigation. As a given patient’s effective treatment course proceeds, recognizable changes in the auto view metrics confirm what is seen clinically. Such changes are seen in patients receiving only topical wound care, compression bandaging therapy, HBO₂Rx, and formal interventional vascular procedures (open or endovascular).

Future Applications of FVA

  Potentially, the use of ICG imaging in HBOT is constrained only by one’s imagination. In practical terms, the horizons are a bit more limited, but are nonetheless intriguing. Emerging novel applications may be categorized broadly into those aimed at understanding the nature of complex refractory wounds and those directed at more precisely defining the best therapeutic course for each particular patient. Consider:

  1. FVA analysis of chronic wound pathophysiology
    • Utilizing pixel-subtraction techniques already employed for delineating perforators and angiosomes, the presence of periwound arteriovenous shunting can be detected and gauged. This tissue-perfusion circumvention develops as the result of the unregulated angiogenic stimulus presented by the chronic, nonhealing wound. Close scrutiny of these abnormal vessels will be a good barometer of the efficacy of specific curative efforts.

    • Heretofore, ICG imaging has been used to outline areas of a wound requiring sharp debridement. These recommendations are based on the inevitability that any tissue not perfused will not heal. A better understanding of how disordered the surrounding halo of hyperluminescent tissue is will lead to more accurate recommendations regarding excision of illuminated periwound tissue and totally unperfused areas.

    • Reducing the window of ICG detection may offer insights into the response of a wound to a particular therapeutic modality. These focused views may be obscured when the device is recording a wider field.

  2. Best practices
    • ICG imaging offers a chance for the discipline of wound management to evolve beyond the “all or none” archetype - that the wound heals or it does not. Intuition is a charming human attribute, but empiric guidance should be the first and predominant injunction. Even after the practitioner selects the optimal ministration, mid-course assessments will produce better outcomes only if refined and reliable interim measurements can be made.

    • There is a surprisingly small number of biological processes that do not behave in a dose-response fashion. Normal angiogenesis and the release of marrow-bound stem cells induced by HBO₂Rx are well-known and long-accepted examples of this principle.¹⁰ The ability of FVA to make precise measurements of HBO₂Rx effects offers the opportunity to tailor chamber profiles, producing the most effective HBO₂Rx “prescription” (dive profile, frequency, and number) for any individual patient.

    • Beyond the simple extraction of measurements from the linear graphic display, the use of derived metrics will allow summary numeric quantification of the FVA record. A patient’s individualized treatment plan would be predicated on what specific therapeutic measures most effectively drive those derived analyses towards the FVA image of a wound that has again regained its “CUSH.”

  The first five of these six innovations involve simply examining the fundamental pattern of the FVA record or extracting simple numeric measurements from those recordings. Perhaps the most compelling prospect is the last one, the use of algorithmically derived reductions of the algebraically described pixel density versus time curves. Mathematic manipulations (eg, the first derivative of the auto view curve) can distill complex, multifactorial representations into integers. Those can then be easily, and universally, recognized and communicated. Our understanding and our patient’s outcomes will advance when there is a simple scale that can stratify complex wounds and empirically assess treatment.

* Author’s term to reinforce individualized patient treatment.

Stephen D. Guthrie (stephen_guthrie@mac.com) is president and Barbara R. Guthrie is chief executive officer of Designed Altobaric Research Foundation; Livonia, MI.

References

1. Flower RW. Injection technique for indocyanine green and sodium fluorescein dye angiography of the eye. Invest Ophthalmology. 1973; 12(12):881-895.

2. Eren S, Rubben A, Krein R, Larkin G, Hettich R. Assessment of microcirculation of an axial skin flap using indocyanine green fluorescence angiography. Plast Reconstr Surg. 1995; 96(1):636.

3. Kamolz LP, Andel H, Auer T, Meissl G, Frey M. Evaluation of skin perfusion by use of indocyanine green video angiography: Rational design and planning of trauma surgery. J Trauma-Injury Infect & Crit Care. 2006; 61(3):635-641.

4. Braun JD, Trinidad-Hernandez M, Perry D, Armstrong DG, Mills JL Sr. Early quantitative evaluation of indocyanine green angiography in patients with critical limb ischemia. J Vasc Surg. 2012; 55(1S):91S.

5. Kaiser M, Yafi A, Cinat M, Choi B, Durkin AJ. Noninvasive assessment of burn wound severity using optical technology: A review of current and future modalities. Burns. 2011;37(3):377–386.

6. Madajewski B, Judy BF, Mouchli A, Kapoor V, Holt D, Wang MD, Nie S, Singhal S. Intraoperative near-infrared imaging of surgical wounds after tumor resections can detect residual disease. Clin Cancer Res. 2012;18(20):5741-5751.

7. Marshall MV, Rasmussen JC, Tan IC, Aldrich MB, Adams KE, Wang X, et al. Near-infrared fluorescence imaging in humans with indocyanine green: A review and update. Open Surg Oncol J. 2010;2(2): 12–25.

8. Alander JT, Kaartinen I, Laakso A, Pätilä T, Spillman T, Tuchin VV, Venermo M, Välisuo P. A review of indocyanine green fluorescent imaging in surgery. J Biom Imag Arch. 2012; 2012:940585. doi: 10.1155/2012/940585.

9. Guthrie SD, Salzberg AS, Hourani H, Rogers C. Indocyanine green scanning: Emerging metrics of wound analysis and hyperbaric oxygen treatment efficacy. Undersea and Hyperbaric Medical Society. 2014 ASM; 41(5):468.

10. Thom SR, Bhopale VM, Velazquez OC, Goldstein LJ, Thom LH, Buerk DG. Stem cell mobilization by hyperbaric oxygen. Am J Physiol Heart Circ Physio. 2006; 290(4):H1378-H1386.