Pharmacotherapy as Adjunctive Treatment for Serious Foot Wounds in the Patient with Diabetes: A Case Study

Literature Review

   Nonhealing foot ulcers, characterized by a lack of self-repair over time, are prevalent among individuals with diabetes mellitus.¹ Although surveillance reports of diabetic foot ulcers are fraught with limitations, primarily due to the number of ulcers managed in the outpatient setting, the prevalence ranges from 5.3 to 10.5 per 100 people, depending on the type of diabetes and age of the patient.²

The diabetic population represents 4% of the total US population; however, nearly 50% of all lower-limb amputations are performed in these individuals, underscoring the high risk for foot ulcers associated with diabetes.³ Diabetes is strongly and independently associated with peripheral arterial disease (PAD) and its most frequent symptom, intermittent claudication. In one population-based study (N = 6,450), patients with PAD were twice as likely to have diabetes as healthy controls (odds ratio 2.0, 95% confidence interval, 1.6 to 2.5).⁴ Peripheral arterial disease is an independent risk factor for foot ulcers.⁵ Impaired blood flow of both the macrovascular and microvascular circulations secondary to vascular occlusion and ischemia promote the development and exacerbation of foot ulceration and impair the healing process by impeding delivery of oxygen and nutrients to the wound.

   Foot ulcers are resistant to many forms of therapy. Even when the basic tenets of chronic wound care such as offloading, debridement, and maintenance of a moist wound base are employed, healing these wounds remains difficult at best. Indeed, the lack of a uniformly effective regimen utilized in the general medical population to treat foot wounds is reflected in the high amputation rate among patients with diabetes. Recently, anecdotal reports suggest that cilostazol, which was approved in Japan in 1988 for the treatment of PAD-associated ulcerations, pain, and coldness and is FDA-approved for the treatment of intermittent claudication in the US, appears to increase the rate of wound healing in patients with diabetes. This report describes the clinical experience of one such patient who presented with a nonhealing wound of the left great toe and a second ulceration at the medial plantar aspect of the left foot.

Case Study

   A 54-year-old woman with type 2 diabetes and PAD presented at the wound-care clinic for evaluation of an open foot wound that had not healed over approximately 6 months. The woman's diabetes was non-insulin dependent for 24 years, but glycemic control was managed by insulin for 1 year before presentation. The patient had several cardiovascular risk factors: her father had a history of coronary artery disease and myocardial infarction; she smoked cigarettes for 20 years but had quit 17 years before presentation; and she had a history of hypercholesterolemia.

   For the 5 months immediately following the wound's development, the patient received chloramine-T whirlpools (Chlorazene® Whirlpool Antiseptic, Lake Erie Medical, Hinckley, Oh.) and collagenase (Santyl®; Smith and Nephew, Largo, Fla.) treatment at the direction of her primary care physician. One month before she came to the wound clinic, she underwent femoral-popliteal bypass surgery, at which time the wounds were debrided. Following surgery, the patient developed a systemic infection, extending her hospital stay and mandating the use of intravenous antibiotics. Subsequent treatment consisted of the chloramine-T whirlpools with some additional debridement around the wound. Local treatment to the wound consisted of collagenase applied twice daily. She was fully weight-bearing with ambulation. The patient had been advised that below-knee amputation was imminent if the wounds failed to heal.

   When the wound failed to respond to this treatment regimen, she was referred to the Wound Healing Center. Initial evaluation revealed a superficial wound on the left great toe. A second wound on the left medial plantar aspect demonstrated significant tunneling distal toward the heel, proximal toward the toes, and medial up over the top of the foot (see Figure 1). Additionally, Charcot's deformity was noted. An ankle-brachial index (ABI) could not be obtained because of medial calcification, but angiography demonstrated significant stenosis at the superficial femoral artery. The greatest concern for the patient was the significant tunneling of the foot wound, which placed her at high risk for infection and subsequent amputation. Whirlpools offer no demonstrated efficacy for chronic wound care and, indeed, may even have detrimental effects from osmotic effects on the granulation tissue and maceration of the adjacent wound epithelium, making it more prone to injury. Similarly, collagenase treatment does not promote granulation tissue formation for final healing. The patient was referred for aggressive surgical debridement. The goal was to open the tunnels of the left medial aspect wound, because most likely they had epithelialized, resulting in continual draining and lack of healing. Aggressive debridement with removal of the epithelium, coupled with excellent wound care, could prevent amputation. The great left toe was also aggressively debrided, and primary closure was attempted (see Figure 2). The patient was told to minimize weight-bearing on the left foot and was given a special offloading shoe and crutches. Because of the arteriography findings of macrovascular disease, and recognizing that she likely had diabetes-associated microvascular disease, she was started on cilostazol (Pletal®; Otsuka America Pharmaceuticals, Inc., Rockville, Md.) 100 mg bid to improve both the macro- and microvascular circulation.

   Following surgery, the patient was advised to apply growth factor-stimulant ointment (Regranex® Gel; Ortho-McNeil Pharmaceutical, Raritan, NJ) to the plantar foot wound daily. Shortly thereafter, the toe wound was dehiscent with the presence of nonviable tissue. Treatment was initiated using a papain-urea debriding ointment (Accuzyme Debriding Ointment; Healthpoint, San Antonio, Tex.) with a simple dressing (a small adhesive bandage with a semi-absorbent center) changed every other day. Two months after the initial visit, the wound on the left plantar foot was healing well, demonstrating only minimal serous drainage. The patient was told to continue applying dressings, making sure to cover the entire wound with the growth factor-stimulant ointment, continue taking cilostazol, and return for a follow-up examination in approximately 2 weeks.

   Two weeks later, both wounds demonstrated dramatic improvement, with significant increase in granulation tissue and a concurrent decrease in the length and width. The patient was advised to continue dressing the wounds with the growth factor-stimulant ointment, cover it with hydrogel, and continue taking cilostazol. Expectations were that the wounds would heal satisfactorily within the next 4 to 6 weeks.

   Four weeks later, the left plantar foot wound and the great toe wound had healed almost completely (see Figure 3), and the patient was given permission to begin weight-bearing activity. Over the next 3 months, the patient developed no further wounds and experienced no complications from the other earlier wounds other than the development of a noninfectious blister over the previous wound site. The patient is fully ambulatory and has returned to work.

Discussion

   Patients with diabetes are at significantly increased risk for foot ulceration and subsequent amputation. They commonly have systemic atherosclerosis, frequently including PAD. Impaired blood flow secondary to vascular occlusion can lead to nonhealing foot ulceration because delivery of oxygen, nutrients, and antibiotics to the site of the wound is impeded.⁵ Not infrequently, chronic wounds progress to such a degree that amputation becomes necessary.

   Effective wound care consists of numerous components, each of which contributes to healing. Special attention must be given to assessment of any severe ulceration in which tunneling may have occurred, as in this case. Adequate debridement to healthy tissue is mandatory. Additionally, application of ointments such as a growth factor-stimulant, the use of dressings that provide a moist environment, and avoidance of exacerbating factors such as weight-bearing activity are critical to ensure effective healing. Because the underlying cause of poor healing is impaired blood flow to the wound site, improving the macro- and microvascular circulation to enhance delivery of nutritive blood flow is important. Administering a systemic agent such as cilostazol that improves peripheral circulation in addition to providing optimal wound care, may contribute to wound healing.

   Cilostazol is a phosphodiesterase type III (PDE III) inhibitor whose mechanisms of action include platelet aggregation and vasodilation. The PDE III inhibitor function leads to increased levels of cyclic adenosine monophosphate (cAMP). Studies have shown that the agent inhibits proliferation of vascular smooth-muscle cells in vitro, increases peripheral blood flow in patients with arteriosclerosis obliterans, and prevents reocclusion following coronary artery thrombolysis.^6-8 More recently, investigators have reported that cilostazol increases nitric oxide synthesis in rat vascular smooth-muscle cells and human neuroblastoma cells.^9,10 Nitric oxide, the active constituent of the potent vasorelaxation endothelium-derived relaxing factor, exerts inhibitory effects on platelet activation, aggregation, and adhesion, thus playing an important role in vascular homeostasis. Cellular deficiencies of cAMP and nitric oxide are thought to be involved in the pathogenesis of diabetic neuropathy and it is believed that cilostazol may exert positive effects in such cases through the increased production of these compounds. Such a beneficial effect has, in fact, been demonstrated in patients with diabetic neuropathy.^11,12

Conclusion

   Two chronic wounds, one on the great toe and the second on the medial plantar aspect, in a patient with diabetes healed approximately 3 months after application of growth-factor stimulant ointment and administration of cilostazol. The cilostazol was well tolerated with no specific adverse events. At this time, no further wounds have developed.

   Chronic foot ulcers present significant management challenges to the clinician. To prevent the serious complications of such wounds, including amputation and impact on patient quality of life, a comprehensive program that addresses the wound itself, as well as impaired macro- and microvascular circulation, must be implemented and monitored. Controlled clinical trials on the role of cilostazol in the treatment of chronic foot ulcers seem warranted. One trial (HEAL-IT) is currently underway through Yale and Emory Universities. With an expected enrollment of 300 patients, it is the largest clinical trial of its kind yet to be conducted. - OWM

Acknowledgment

This manuscript was supported by an unrestricted educational grant from Otsuka Pharmaceuticals.

This case study was presented at the 5th Annual Wound Care Congress, October 25 to 27, 2001, Providence, Rhode Island.

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