Cadexomer Iodine: An Effective Palliative Dressing in Chronic Critical Limb Ischemia

Abstract: Cadexomer iodine (CI) was evaluated as a palliative wound care dressing for foot ulcers in chronic critical limb ischemia (CCLI) given its ability to prevent infection and absorb moisture. Methods. A retrospective study of 11 patients with CCLI and wounds on distal lower extremities that were treated with cadexomer iodine. The product was applied topically on a daily basis. Wounds were debrided cautiously to minimize blood loss. Patients were monitored in the clinic on a weekly to biweekly basis. Results. Seven patients in this cohort had all or some wounds on their feet close, at least temporarily. Two patients ultimately underwent proximal amputations, but the procedures were delayed 9 months in one patient, and 3 years in the other. Ischemic wounds of 3 patients were stabilized with CI allowing time for invasive revascularization followed by successful distal amputations resulting in ongoing limb salvage of 5 months to almost 4 years. Four patients currently being treated with CI have avoided proximal amputations for 4–18 months. Conclusion. Cadexomer iodine is an effective palliative dressing for wounds in CCLI. The antimicrobial effect of iodine prevents wet gangrene. The absorptive capacity of cadexomer beads dries necrotic tissue facilitating dry gangrene and auto-amputation without desiccating viable tissue. Cadexomer iodine enhances autolytic debridement, mitigates inflammation beyond the antimicrobial effects of iodine, and encourages granulation and epithelialization even in severely hypoperfused wounds. Cadexomer iodine delays proximal limb amputation in CCLI and may facilitate healing in some ischemic wounds.
Address correspondence to: Robert L. Williams, MD Southeast Texas Center for Wound Care and Hyperbaric Medicine 3817 Summer Ln. Huntsville, TX 77340 Phone: 936-295-2668 E-mail: robkarin@suddenlink.net

     Chronic critical limb ischemia (CCLI) refers to a condition manifested by rest pain, ulceration, or gangrene that is objectively demonstrated to be related to arterial occlusive disease.¹ Ulcers in patients with CCLI may arise spontaneously due to inadequate perfusion to support basal tissue metabolism or when factors such as trauma or infection elevate tissue perfusion requirements that exceed the distal circulatory system’s capacity. Patients with CCLI, regardless if wounds are present or not, have a 40% incidence of a major amputation (above or below the knee) within 6 months if their disease is not amenable to revascularization. ¹ The likelihood of major amputation is most likely greater if these individuals already have a wound. When tissue perfusion is demonstrably inadequate to support wound healing, conservative surgical interventions such as distal amputations (toe, transmetatarsal, or Chopart’s) or even local sharp debridement typically result in extension of tissue necrosis, infection, and a larger, still nonhealing wound.      The decision to amputate is usually prompted by physical manifestations (eg, gangrene, osteomyelitis, or systemic symptoms of infection), or quality of life issues such as intractable pain or negative body image. Although a major amputation can potentially “cure” a nonhealing wound associated with CCLI, the decision to amputate has many profound implications. Major amputations in the face of CCLI have a 20%–37% risk for complications such as myocardial infarction (MI), stroke, or infection, and a mortality rate as high as 30%.^2–5 Quality of life can be severely and irreparably disturbed. Major amputations, especially in the elderly, too frequently mark the end of a patient’s ambulatory existence. ⁶      Limb salvage is presently thought to be dependent on re-establishing distal tissue perfusion. Symptoms of claudication can frequently be ameliorated by less dramatic improvement of distal perfusion than is required to support healing of an existing wound. ¹ It is thought that wound healing failure can be predicted if oxygen tension of periwound tissue is less than 20 mmHg as measured by transcutaneous oximetry (TCOM). ⁷ Hanna et al⁸ demonstrated that infrapopliteal angioplasty predictably resulted in wound healing if the post-intervention TCOM exceeded 20 mmHg. It seems reasonable to assume that any intervention, whether surgical or endovascular, which successfully results in sustained tissue perfusion associated with a cutaneous oxygen tension of 20 mmHg or greater is likely to enhance the healing capacity of that limb. Therefore, the presence of an ulcer or gangrene associated with occlusive artery disease should prompt immediate assessment for possible revascularization if limb salvage is desired.

Palliative Wound Care

     When invasive vascular reconstruction is not successful or not feasible in the presence of confirmed CCLI, wound healing is usually not a reasonable wound care goal. Such wounds typically result in major amputations, but can sometimes be managed palliatively with the intent of delaying major amputation for as long as possible.      Postponing exposure to generalized anesthesia in these patients who frequently have multiple severe comorbidities delays potential life-threatening perioperative complications. Due to the associated morbidity and mortality of amputations above or below the knee, it is assumed that the patient’s life span might be prolonged by delaying proximal amputations for as long as possible. Aside from surgical complications, another premise of palliative limb salvage is that a leg with chronic wounds, and even osteomyelitis, might be functionally better than a prosthetic. The natural limb, despite its limitations and disease, does not need to be strapped on before getting up in the middle of the night.      When invoking palliative therapy it is wise to educate the patient, family, and staff. Doing so will help ensure all involved have reasonable expectations of treatment outcome. Although it should be understood that wound healing is not considered a reasonable scientific expectation, hopes for divine intervention need not be dashed. The decision to opt for palliative care does not obligate one to give up hope for miracles as long as the limitations of medicine are known from the beginning.      As palliative wound care is considered a treatment option in CCLI, it can be explained that an amputation will only be reconsidered if infection progresses to the point of causing systemic manifestations and is thought to be life threatening, or if the patient decides that quality of life would be improved with amputation. Proximal amputations can sometimes be delayed for months to even years with effective palliative wound care. Palliation may have varying ends depending on the wound, comorbid disease(s), and realistic lifestyle objectives. Palliative wound care goals may include delaying an inevitable amputation for as long as possible but ultimately ending with amputation, or delaying amputation until the patient dies of another disease process.      Major amputations can reasonably be delayed as long as infection and pain are adequately controlled. If wet gangrene erupts or osteomyelitis begins to cause systemic symptoms, the condition may become life threatening, which may preempt the original limb salvage objective.      Quality of life is another factor that might shift decision-making toward amputation over limb salvage. As infection and/or ischemia progress, the condition may begin to adversely affect quality of life to the point that amputation becomes a better alternative. Pain due to ischemia, infection, or both can markedly affect quality of life. When the pain cannot be managed adequately without causing an undesirable level of sedation, amputation should be reconsidered. Of course the patients and family should be warned that amputation does not guarantee complete pain resolution. The immediate postoperative period can be exquisitely painful, and there is also concern for the possibility of phantom pains following amputation. Another quality of life issue that might make amputation desirable over limb salvage is odor due to infected or necrotic tissue that is refractory to topical interventions and drastically impairs the patient’s social activities and/or body image.

Cadexomer Iodine

     Regarding wounds associated with CCLI, palliative objectives can be best met with a dressing that has both antimicrobial and drying effects since the onset of wet gangrene is a very common reason to abort palliative care and reconsider amputation. Cadexomer iodine (CI) is a unique product that is both antimicrobial and has tremendous absorption capacity. It is because of these properties that CI gel was considered as a potential palliative dressing for wounds associated with CCLI.      Cadexomer iodine is a complex matrix composed of hydrophilic starch polymers that form beads resembling microscopic whiffle balls in that each bead is hollow and has multiple holes in its outer shell. Iodine is physically (not chemically) trapped in the center of these microbeads at a concentration of 0.9%.⁹ One gram of cadexomer matrix can absorb 6 cc of fluid.¹⁰ As a cadexomer bead absorbs moisture, the starch matrix swells and chemical bonds binding the starch molecules break. The disruption of these bonds frees protons, which decreases the pH of the immediate environment.¹¹ As the integrity of the cadexomer starch beads becomes disturbed, the iodine molecules physically trapped inside are released in a controlled manner. A gradient of iodine arises within the wound bed, while the greatest concentration occurs at or near the beads and is nearly 1 part per million (ppm).⁹ The antimicrobial role of iodine has a long and proven history from water purification to surgical site preparation. The halide has a broad spectrum of action that is effective against bacteriae, fungi, amoebae, and viruses. The antimicrobial activity of iodine is a function of its effects on protein and lipids. Iodination of amino acids with free iodine replacing hydrogen in N-H, C-H, and S-H compounds alters the structure and function of protein.¹² Free iodine can also bind unsaturated fatty acids and alter cell membranes.¹²      Safety. With such broad-spectrum effects, there is valid concern for potential cytotoxity of iodine with respect to mammalian cells. Initially, this concern appeared to be substantiated by studies done in vitro. ^13–17 It has since been realized that the cytotoxicity of iodine reported from in-vitro studies does not apply to use of CI in vivo.¹⁸ Tissue culture cells are exquisitely sensitive and even minute variations in temperature, osmolarity, salinity, pH, or oxygen can kill them.¹⁹      There are a number of reasons tissue culture cells are more susceptible to iodine toxicity than cells growing in vivo. Cultured cells are quite different from living tissue-the cells are monoclonal and the system in which they are growing lacks the buffering capacity of blood. ¹⁹ Cultured cells are also dependent on a substantially higher oxygen concentration than living tissue, and the cytotoxicity of iodine is proportional to the concentration of oxygen present. ²⁰ Interestingly, iodine at twice the concentration released from CI did not cause any discomfort when administered into the eyes of human volunteers. ²¹      The potential effects of exogenous iodine on thyroid function should be taken into account when using an iodinated product. Effects of exogenous iodine are dependent on dose, frequency, and duration of exposure as well as the functional state of the thyroid and kidneys.²² In normal thyroid glands, excess iodine can have a temporary inhibitory effect on iodine binding, synthesis of triidothyroxine (T3) and thyroxine (T4), and organic iodine synthesis that is known as the Wolff-Chaikoff block.²³ If resumption of normal thyroid hormone production by means of an “escape” phenomenon does not occur, the Wolff-Chaikoff block can cause hypothyroidism. This form of hypothyroidism, though documented in neonates due to cutaneous use of povidone-iodine, is rare in adults.²⁴ In the face of a hyper-functioning thyroid nodule or nodular goiter, exogenous iodine can precipitate hyperthyroidism. ²⁵      Cadexomer iodine has been studied rather extensively in venostasis ulcers, and in this wound type, the product has been demonstrated to be both efficacious and safe. ^26–33 Studies reviewed by Sundberg and Meller³⁴ involving more than 12,000 patients treated with CI, all reported side effects from CI treatment were described as mild and transient. ³⁴      Cadexomer iodine is not only a safe antimicrobial dressing for other wound types, but might be safer in patients with CCLI. The greatest concentration of iodine possible in this preparation is only 1 ppm, a concentration that has been demonstrated to be noncytotoxic to mammalian cells in vivo. ^19,22,35,36 A gradient of iodine concentration arises with use of this product. As iodine is released from the cadexomer beads, much of it will immediately react with microbes and protein in the wound milieu—much less than the originally released 0.9% of iodine will actually interact with the wound bed. ⁹ Uninfected ischemic wounds are typically dry. Since iodine release from the cadexomer beads is dependent on exudate volume, the release of iodine into these wounds is usually slow and gradual. Additionally, the exposed tissue in wounds associated with CCLI is by definition hypoxic. This hypoxia markedly reduces the potential cytotoxicity of iodine, which has been demonstrated to be oxygen dependent. ²⁰      The manufacturer recommends that a single application of CI not exceed 50 g, and that the total amount used in 1 week not exceed 150 g. ¹⁰ With regard to our use of CI in ischemic foot wounds, we have had no difficulty complying with this recommendation—a 30-g tube of CI is adequate to treat most ischemic foot wounds for 1–4 weeks. Potential absorption of iodine may be a concern when this product is used in large, well perfused wounds, especially if the patient’s kidney function is impaired. ^10,37 However, considering the low concentration of iodine that is actually at the tissue interface and that the exposed tissue in CCLI patients is hypoperfused, the absorption of iodine from these wounds is negligible. Although it is prudent to screen and monitor thyroid function in patients with CCLI treated with CI, it is doubtful that sufficient levels of iodine will be absorbed to disturb a normally functioning thyroid gland. It is the opinion of this author that the manufacturer’s recommended break in therapy every 6 weeks is not warranted in ischemic wounds and may undermine the desired palliative effects of this regimen.

Clinical Experience

     The following is a report on a cohort of 11 patients. All patients had severe peripheral artery disease documented by angiography and wounds involving feet, specifically the toes. Definitive therapy of these wounds according to conventional thought would have required major amputation since wound-healing failure was predicted for distal amputation options. All cases had severe comorbid diseases (Table 1). Seven patients had diabetes; all of whom had surprisingly good glycemic control (HgA1c values ranging from 5.8 to 7.9). Ten of the patients had at least one wound involving a toe. One patient had a wound involving only the medial malleolus. Half of the wounds were precipitated by minor trauma, and a quarter of the wounds arose spontaneously. The remaining two wounds arose from a corn or ingrown toenail (Table 2). Six patients had osteomyelitis. Seven patients had normal prealbumin levels. Only 1 subject had a documented abnormally low prealbumin, but the parameter was not available in 3 patients. TCOM studies were not available for 2 patients. Of the patients for which TCOM studies were available, one third had poor values (< 20 mmHg), another one third had marginal values (20–39), and the final third had values within normal range (> 40 [Table 3]).      The longest period that any single wound was treated with CI in this cohort was 18 months (and counting). The shortest definitive treatment period was 2.5 months (definitive treatment period meaning the wound closed or was resolved by means of amputation). Three of the 4 patients who were treated for more than 10 months had both initial and subsequent TSH values available for review; all were within normal limits (Table 4). Subsequent TSH values were not available for all patients and no definitive conclusions can be drawn from available data.

Results

     Seven of the patients in this cohort had all or some wounds on their feet close, even if only temporarily. Of the wounds that closed, the periwound TCOM values ranged from 16 mmHg–66 mmHg. Two patients obtained TCOM values greater than 40 with vascular intervention, but the 3 other patients who had all or some wounds close had TCOM values 25 mmHg or less. Five of the wounds in the cohort are currently undergoing therapy for a duration ranging from 4 to 18 months. One subject in the cohort was unable to comply with the regimen. His complaint was cost of CI and inconvenience of frequent clinic visits. According to his home health agency, the wound deteriorated over the next 6 months since discontinuation of CI, but no surgical intervention has yet been required. Two cohort patients have undergone proximal amputations. One was stayed for 9 months, and the other for more than 3 years. Three patients have undergone successful distal amputations due to stabilization of ischemic wounds with CI, which allowed time for invasive revascularization resulting in ongoing limb salvage of 5 months to almost 4 years. The 4 patients currently undergoing limb salvage therapy with CI have thus far avoided proximal amputations from 4 months up to 1.5 years.

Case Reports

     The following reports on 3 patients from the 11-patient cohort who received palliative care with CI for the longest periods, each with slightly different outcomes. These cases illustrate the benefits and limitations of using CI to treat ischemic wounds in the face of end-stage peripheral artery disease.      Patient 1 (cohort subject 10): This 71-year-old woman has a history of diabetes, hypertension, coronary artery disease, and peripheral vascular disease (Figures 1–6). While recovering from coronary artery bypass grafting and right below knee amputation (BKA) in 2004, the patient developed a wound on the left hallux due to an ingrown toenail. The left lower limb underwent percutaneous angiographic studies and was determined not to be amenable to any available invasive revascularization procedures at that time. Palliative therapy was instituted to hopefully delay a second BKA for as long as possible, and to facilitate auto-amputation of the frankly necrotic part of the toe. The left hallux was dressed with CI gel daily and covered with a protective dressing. The dressing was covered with gauze and secured with minimal amount of a gentle adhesive tape to avoid injuring the fragile surrounding skin. With each daily dressing change, old dressing material was wiped away using dry gauze. Once every 1 to 2 weeks the wound was cleansed with 4% chlorhexidine gluconate and rinsed with normal saline to minimize the frequency moisture was externally applied to the wound.      The CI initially dried out the necrotic tissue, which slowly began to separate from underlying viable tissue. Conservative sharp debridement was performed approximately every 2 to 4 weeks. Periodic debridement was done to prevent old dressing material, dried exudate, and necrotic tissue from building up and forming a barrier that might mitigate the antimicrobial effect of CI. These debridements were performed with little to no blood loss in an effort to minimize any reactive inflammation that might arise from new injury. Over a period of 5 months, the necrotic toe was slowly trimmed down until only small residual necrotic bone remained that was eventually clipped with a bone Rongeur. During this process, both granulation tissue and then new epithelium was noted to form as the necrotic tissue receded. The wound was nearly closed after 9 months of CI therapy.      One month later, the same toe spontaneously became inflamed and the previously healing wound rapidly deteriorated. Clinical studies determined that the patient had Pseudomonas osteomyelitis involving the residual phalanges of hallux. Over the next 11 months the wound was treated palliatively with CI and a topical antibiotic since TCOM studies predicted wound healing failure if surgical intervention was attempted. New angioplasty techniques later became available, which encouraged the vascular interventionalist to re-attempt revascularization of the patient’s limb. The procedure was successful enough to produce TCOM values predictive of healing, and the patient underwent successful amputation of the remainder of the left great toe 25 months after initiating palliative wound therapy.      The patient did well until the following year, 10 months after hallux amputation, when the left second toe became infected without any apparent wound or history of trauma. Inflammation of the second toe and surrounding tissue caused the previously closed left hallux amputation site to spontaneously break down forming a small full-thickness wound. Intravenous broad-spectrum antibiotics and topical CI stabilized the foot. The second toe converted to dry gangrene and the hallux amputation site eventually re-closed.      At this point the limb was treated with intermittent pneumatic compression timed with diastole of the heart (Circulator Boot™, Circulator Boot Corp., Malvern, PA) for 4 weeks to improve arterial blood flow through the limb and to encourage formation of collateral blood flow. Due to pain of the second toe the patient opted to undergo amputation of left second toe despite marginal TCOM values. At the time of this writing, the patient is in her third postoperative week and appears to be healing well. To date, the above limb salvage approach has avoided proximal amputation in this patient for more than 44 months.      Patient 2 (cohort subject 7): This 84-year-old woman has a history of diabetes, hypertension, hyperlipidemia, coronary artery disease, and peripheral vascular disease (Figures 7–11). The patient’s wound on right fifth toe was the result of minor trauma. She had previously undergone percutaneous atherectomy of affected leg with limited improvement in perfusion, and her disease was not amenable to surgical bypass. The wound deteriorated further secondary to arterial insufficiency and infection. Osteomyelitis became clinically evident, as there was exposed bone and joint capsule in the wound base. Due to acutely worsened TCOM study of the wounded foot, angioplasty was repeated in the right lower extremity. Infection was treated with systemic antibiotics, and CI gel was used as contact layer of dressing with the intent of facilitating auto-amputation of the toe. The methodology used was similar to that described in the previous case. As a result of this palliative approach, the patient’s toe stabilized and her foot was temporarily spared with the wound actually closing over previously exposed bone and joint-capsule by the 14th month of therapy.      Three months after the right fifth toe healed, a wound arose spontaneously on the right hallux. The patient appropriately treated this wound herself with CI. Unfortunately, the bulk of her dressing on the hallux caused injury to the right second toe as well. Following presentation to the wound care clinic, CI was continued on both toes in much the same manner as previously discussed. Eventually, the patient was able to undergo percutaneous revascularization attempt that resulted in markedly improved TCOM allowing consideration of transmetatarsal amputation.      Her postoperative course was complicated by onset of congestive heart failure that was attributed to an acute, non-Q wave MI. The foot rapidly deteriorated despite appropriate management of her cardiac condition. The surgical wound dehisced secondary to necrosis, and the heel developed a Stage IV pressure ulcer. Ultimately, the patient underwent BKA. Although proximal amputation was not avoided, it was delayed for 38 months from onset of a wound that was not expected to heal and by conventional thought warranted proximal amputation. Due to comorbidities, this patient’s clinical course continued to deteriorate following BKA despite aggressive measures. After battling her illness valiantly, she decided to enroll in a local hospice program that she might be able to return home and be kept comfortable.      Patient 3 (cohort subject 8): This 75-year-old man has a history of diabetes, peripheral vascular disease, neuropathic pain attributed to peripheral neuropathy, and a remote history of colon cancer (Figures 12–18). The patient had undergone bilateral femoral-popliteal bypass surgery 3 years earlier. His vascular disease was now determined not to be amenable to further invasive revascularization procedures. He developed wounds on his right foot that were precipitated by minor trauma resulting from transfer into and out of a car. The wounds and surrounding tissue deteriorated due to resulting inflammation despite conservative management with enzymatic debridement of necrotic tissue. The foot subsequently stabilized with initiation of CI. Purpura in the periwound skin that was precipitated by surrounding inflammation subsequently resolved. Eschar and slough slowly softened and were cautiously removed with conservative sharp debridement. Eventually, the wound was noted to involve necrotic tendons. Ischemic limb pain was relieved by application of topical lidocaine patches. Granulation, contraction, and even epithelialization were noted in wounds of proximal foot over a period of many months. The CI facilitated auto-amputation of the ischemic toes as intended.      This patient was later diagnosed with a second primary tumor involving the bladder that was Stage IV at time of diagnosis. He is bedridden and unable to endure transport to clinic. Cadexomer iodine has been continued as a palliative wound dressing, controlling both exudate and smell, mitigating infection, and preserving the patient’s sense of well being. At last visit with the patient in his home, he was in good spirits, denied pain, and proximal amputation had been postponed for more than 18 months in a now terminally ill patient.

Discussion

     In this cohort, no ischemic wounds treated with CI converted to wet gangrene. Oral and systemic antibiotics were used at the discretion of the clinician to treat suspected or confirmed local soft tissue infection. With this approach, even wounds that had exposed or infected bone did not worsen to the point of causing systemic symptoms of infection. To date, the use of CI has successfully delayed major amputations of wounded and chronically ischemic limbs for months, even years. While gratifying to accomplish the goal of palliative limb salvage in this group with presumably intractable wounds, it was unexpected to see these wounds first stabilize and later begin to heal. These findings might not surprise those who participated in an investigatory committee sponsored by the European Tissue Repair Society whose report was published in 1997. ²⁰ Their conclusion was not only is CI safe to use on living tissue, but the observed response of wounds to CI appears to be greater than can be explained by the product’s antimicrobial properties alone. ²⁰ This observation led the participants to speculate that CI might have additional wound healing enhancing properties.      Aside from preventing microbes from overwhelming an ischemic wound, the observed healing reported in our cohort is probably related to the ability of CI to further mitigate inflammation. The level of perfusion necessary to maintain homeostasis in intact viable tissue appears to be substantially less than is needed when that same tissue is inflamed. The difference in perfusion required when tissue is inflamed has been projected to be as much as 20 fold. ¹ The significance of this difference is frequently observed in patients with CCLI. Although symptomatic with claudication, patients typically have no wounds until minor trauma such as stubbing a toe causing localized inflammation that culminates in necrosis of the injured toe, and results in a wound whose size and severity is out of proportion with the original insult. Another similar scenario is observed in a patient with CCLI who has a foot or toe wound that becomes infected. The increased localized inflammation results in neighboring intact tissue subsequently and rapidly necrosing. Modulation of inflammation in limbs with CCLI prevents the increased oxygen demand that would exceed the blood supply leading to compromise of additional tissue and ensuring healing failure of the original wound.      It is interesting to theorize how CI might mitigate inflammation beyond fighting infection. Iodine binds nonspecifically to proteins and deactivates them. Inflammatory proteins, such as metallomatrix proteases (MMP) floating in the wound milieu are likely susceptible to binding and deactivation by iodine. Inactivating excess MMPs would certainly be expected to help mitigate inflammation. Since wounds of varying etiologies do close in the presence of CI, it seems reasonable to postulate that the CI does not eliminate all MMP’s from the wound bed. Iodine has also been demonstrated to affect white blood cell function. The above noted consensus meeting convening more than a decade ago, reported iodine has a dose-dependent modulating effect on macrophage production of TNF-α. ²⁰      However, there appears to be more to the story regarding how CI decreases inflammation. A related product composed of the same starch polymer of cadexomer beads but without iodine known as Cadesorb™ (Smith & Nephew, London) is marketed in Europe as a “protease modulating ointment.” This product has been demonstrated to modulate activity of MMPs and serine proteases by altering the pH of wound fluid. ^38,39 It has since been demonstrated that an ion exchange occurs as exudate is absorbed by cadexomer beads. Chemical bonds of the starch polymer are broken as the matrix absorbs moisture and swells. This ion exchange causes a local decrease in pH.⁴⁰ A slightly acidic environment has previously been demonstrated to facilitate hydrolysis of inflammatory proteins.⁴¹ Whether by iodination or acidic facilitation of hydrolysis, the modulation of MMP’s appears to facilitate a chronic wound progressing from the inflammatory phase to the proliferative phase of healing.      It is this author’s experience that enzymatic debridement of ischemic wounds frequently elicits a localized inflammatory response. As a result of that inflammation, the underlying tissue necroses and forms more necrotic tissue at virtually the same rate it is being hydrolyzed by these enzymes. This process results in wounds that are slightly larger than when enzyme debridement was initiated but are still necrotic. When CI is used on wounds associated with CCLI that are necrotic, the necrotic tissue first desiccates and hardens but does not remain firmly adherent to underlying tissue. Instead, the necrotic tissue softens at the necrotic-viable tissue interface, and necrotic tissue slowly separates from viable tissue. Cadexomer iodine appears to facilitate debridement of wounds in a slow and limited degree consistent with an autolytic process. It has been previously noted in clinical trials studying venostasis ulcers or pressure ulcers that CI facilitated removal of exudate, slough, and debris. ^30,31,42 The debridement observed with CI is not quite as fast as enzymatic debridement would be under ideal conditions in nonischemic wounds, but CI does appear to be a more effective debriding agent in profoundly ischemic wounds. It is possible that autolytic debridement is facilitated by the exchange of ions occurring as exudate is absorbed by the starch matrix and chemical bonds are broken. The ion exchange or subsequent reduction in pH may activate autolytic enzymes directly, deactivate their inhibitors, or merely stabilize protein structure and enhance autolytic function. Another possible explanation is that iodine plays a role in activating and modulating function of macrophages and neutrophils, and that this halide is an essential cofactor in phagocytosis. ^43–46      Wound bed preparation of ischemic wounds can be enhanced by occasional, conservative, and preferably bloodless, sharp debridement. This approach also helps to ensure that the wound bed derives the intended antimicrobial and anti-inflammatory benefits of CI rather than allowing necrotic tissue, dried exudate, and old dressing material to form a barrier that negates the desired effect of subsequent product applications. Care must be taken not to disrupt the fragile, yet viable tissue within the wound bed. Aggressive sharp debridement of an ischemic wound can elicit an inflammatory response that might result in further necrosis.      Cadexomer iodine does not desiccate the bed of an ischemic wound as the author had originally anticipated. Instead, the product actually optimizes the moisture of the wound environment. Only necrotic tissue dries out; viable tissue does not appear to become dry or compromised. While cadexomer molecules have tremendous absorptive capacity, it appears that these molecules only absorb fluid that is passively released from tissue. The starch matrix does not appear to actively draw moisture out of the interstitial matrix or intact cells. In retrospect, there is no risk of desiccating viable tissue with this product, even in the face of end-stage occlusive peripheral artery disease.      Cadexomer iodine is useful in stabilizing an ischemic wound. First, CI reduces a wound’s inherent bioburden and then acts as a barrier to subsequent microbial invasion. Nonviable tissue is desiccated by the absorptive qualities of cadexomer, making the environment even less conducive to microbial growth. The CI mitigates the body’s local inflammatory response, thereby shifting tissue demand for oxygen to a level that the impaired circulatory system may actually be able to provide. Cadexomer iodine facilitates autolytic debridement while optimizing the moisture of a viable wound bed. At this point, wound healing may ensue as is evident by the formation of granulation tissue and epithelial migration observed in the above discussed cases and as has been previously demonstrated in many other wounds of nonischemic etiology. ^{27,31,35,42,47}

Conclusion

     Our experience suggests that if the inherent bioburden of a wound is controlled, if inflammation is adequately mitigated, if the moisture of the wound bed is balanced, and given an appropriate amount of time, a wound with a cutaneous oxygen tension much lower than predicted necessary for healing can close. The rate of wound closure with CCLI using CI is slow, but more important than temporarily closing wounds in these terminally diseased limbs is successfully averting, or at least delaying, major amputations among elderly and frail patients. The palliative use of CI in limb salvage can potentially prolong life and maintain certain aspects of quality of life.      Cadexomer iodine does not reverse the endovascular disease process of atherosclerosis, but it can stabilize ischemic wounds by treating and preventing infection, minimizing inflammation, facilitating autolytic debridement of necrotic tissue, and surprisingly, by encouraging granulation and epithelialization, even in the face of terminal peripheral artery disease. This palliative approach can serve as adjunctive therapy to invasive revascularizing procedures. Stabilizing ischemic wounds in the peri-procedure time period improves wound healing outcomes following successful reperfusion.      Healing these recalcitrant ulcers is not a reliably predictable outcome, but clinicians should realize that CI is an effective palliative dressing that not only buys time in terms of limb salvage but also can shift the balance of nature toward healing. Since the usual clinical course for these chronic ischemic wounds is fraught with potentially sudden and rapid deterioration, close monitoring is imperative. Systemic antibiotics should be initiated if clinical signs or symptoms of infection arise if the limb is considered salvageable.      Cadexomer iodine facilitates wound bed preparation in the following 3 ways: 1) encourages autolytic debridement (removes exudate and necrotic tissue); 2) reduces inflammation (decreases bioburden and directly mitigates inflammatory pathways); 3) optimizes a moist wound environment (absorbs excess fluid without desiccating viable tissue).      Our experience demonstrates that even a hypoperfused wound can granulate and eventually epithelialize if the wound is freed of necrotic tissue, has negligible bioburden, is not inflamed, and has a balanced moist environment. Cadexomer iodine is a safe and effective way to buy time for wounds with low healing potential due to CCLI, and can be used to delay major limb amputation with associated morbidity and mortality.