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Pentoxifylline As Adjunctive Therapy in Leg Ulcer Management

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Pentoxifylline As Adjunctive Therapy in Leg Ulcer Management • Pentoxifylline as adjunctive therapy in leg ulcer management STEVEN A. BRENMAN, DO Refractory or recurring leg ul- (Key words: Leg ulcers, pentoxifylline, cers typically signify the presence of im- wound care, microcirculation, venous ul- paired venous or arterial microcirculation cers, arterial ulcers) (or both). A current hypothesis suggests that local oxygen and nutrient deficits oc- Leg ulcers are a frequent cause of patient cur because capillary lumens narrow and discomfort and morbidity. Of more signifi- become permeable to fibrinogen and pro- cance, inadequate healing can lead to ulcer re- teins by activated white blood cells and currence, infection, and partial limb amputa- inadequate fibrinolysis. As a result, the tion. Leg ulcers are associated with ischemic deposition of a relatively impermeable per- disease and occur most frequently in the eld- ivascular fibrin sheath occurs, prevent- erly; the obese; and the diabetic; and in pa- ing adequate delivery of oxygen and nutri- tients with peripheral vascular disease, a his- ents. Therapy should therefore aim at re- tory of deep vein thrombosis, or vasculitis.1-4 versing these deficits and improving Ulcers also occur secondary to infection, ma- wound healing. Pentoxifylline (Trental), lignant disease, anemia, and trauma. A par- used in combination with local wound ticularly refractory type of ulcer develops in care and appropriate antibiotic therapy, patients with chronic venous insufficiency or has been successful in significantly im- venous hypertension and inadequate arterial proving the healing of refractory leg ul- circulation.5 cers. Pentoxifylline can reverse the abnor- Each year in the United States, 35,000 or mal function of white and red blood cells more diabetic patients require lower limb am- and platelets, as well as reduce blood vis- putation because of leg ulcers, a rate 15 times cosity and vascular permeability. The that of the nondiabetic population. Lower ex- mechanisms of action of pentoxifylline are tremity ulcers occur in patients with diabetes described in light of current hypotheses of long-standing duration (for example, 20 pertaining to leg ulcer development. Also years) as a consequence of the extensive pe- discussed are nine cases in which pentoxi- ripheral vascular, immunologic, and neuropa- fylline, when added to previously unsuc- thic diseases that become complications of dia- cessful local wound care, either improved betes.4,6 or healed the refractory ulcers. Leg ulcers develop as a result of inadequate oxygen and substrate delivery to, and removal The author has no commercial or proprietary interest in pentoxifylline, nor does he have any financial inter- of waste from, the skin and deeper tissues. How- est (as consultant, reviewer, or evaluator) in pentoxifyl- ever, the precise cause of, and optimal treat- line. ment for, many leg ulcers remains elusive. Em- Reprint requests to Steven Brenman, DO, West Side Skin Clinic, 2465 S Downing St, Suite 107, Denver, CO piric approaches that typically include local 80210-5886. debridement, topical modes of therapy, and an- Clinical practice • Brenman JAOA • Vol 91 • No 7 • July 1991 • 677 tibiotics have not been universally effective.7 tension and preexisting arterial occlusive dis- Pentoxifylline (Trental), with its ability to ease. In an epidemiologic study that evaluated reduce hypercoagulability and blood viscosity, leg ulcers in 357 patients in England, 38% of has been used successfully in leg ulcer man- the patients had evidence of deep vein involve- agement.8-1° Treatment regimens incorporat- ment, 43% had superficial vein incompetence, ing pentoxifylline with local wound manage- and 10% had no venous or arterial disease, as ment produced ulcer healing rates of 60% to measured by ultrasound and refilling time.2 88% in a total of 850 patients who participated Ischemia was present in 70% of the patients in several open-labeled studies. 3-11 In addition, with intermittent claudication and in 31% of the results of two double-blind, placebo-con- the patients overall. trolled studies demonstrated that pentoxifyl- A recent theory suggests that white blood line, added to previously unsuccessful local cells (WBCs) (including neutrophils and to a care, healed or significantly improved 86% and lesser extent monocytes, lymphocytes, and baso- 75% of the ulcers, respectively. 8,10 In this arti- phils) may account for at least part of the tro- cle, I discuss various causes of leg ulcers, as phic skin and vascular flow changes associated well as the role of pentoxifylline in leg ulcer with venous ulcers (Figure ).5,13'14 Venous hy- management, by relating my experience in pertension may reduce capillary flow, allow- treating nine patients with therapy-resistant ing WBCs to accumulate at the border of the leg ulcers. capillary lumen. Because most WBCs, such as neutrophils and monocytes, are significantly Hypothesis regarding the causes of leg larger than red blood cells (RBCs) and 1000 ulcers times stiffer, lumen resistance and blood vis- The pathophysiology of leg ulcers has been of cosity increase.5 interest for at least 2000 years. 12 In that time, Moreover, when the patient stands, arterial various theories have emphasized the role and venous hydrostatic pressures, as well as played in the evolution of leg ulcers by arte- capillary resistance, continue to increase, fur- rial insufficiency or hypercoagulability versus ther reducing capillary flow. The vessel endo- venous stasis, elevated venous pressure, ex- thelium becomes more permeable as aggre- cessive capillary permeability, and inflamma- gated WBCs release their toxic oxygen tion. Consequently, lower limb ulcers have metabolites and proteolytic enzymes such as been broadly categorized as either arterial or peroxiddse. Fluid, WBCs, fibrinogen, throm- venous, although many elderly and diabetic boxane, and other proteins leak through the patients, as well as patients with refractory capillary walls, causing edema, local tissue dam- leg ulcers, experience a combination of arte- age, and fibrin deposition. 5,12 Platelet aggre- rial and venous abnormalities. Recent hypothe- gation, RBC and WBC aggregation, and blood ses for ulcer development have evolved based viscosity continue to increase, along with the on these two categories. size of the pericapillary fibrin sheath and in- tracapillary resistance. Blood is shunted away Venous ulcers from the capillaries with high resistance, and Venous ulcers account for 81% or more of all ischemic tissue changes are exacerbated. As leg ulcers. 1,2 These ulcers are typically found the rigid fibrin sheath thickens, diffusion of over the medial malleolus with a margin that oxygen and nutrients becomes impaired and is usually less well defined than that of arte- the surrounding tissues undergo fibrosis. Ne- rial ulcers. Necrotic and eczematous changes crotic regions also form and may eventually may be present, and the lower leg may be ede- develop into an ulcer. matous with a papillomatous appearance. Four recent studies lend support to the hy- Patients with venous ulcers may have a his- pothesis that WBCs are intimately involved tory of deep vein thrombosis, familial venous with venous ulceration. In 1982, Browse and valve incompetence, ischemic vascular disease, Bernard12 reported the accumulation of peri- peripheral vascular disease, or venous hyper- capillary fibrin deposition in ulcerated regions 678 • JAOA • Vol 91 • No 7 • July 1991 Clinical practice • Brenman in patients with postphlebitic venous insuffi- ciency. Soon afterward, Schmalzer and Chien15 found that one polymorphonuclear cell blocked Insult capillary blood flow as effectively as 700 RBCs • Thrombosis in vitro. Recent work by Thomas and col- • Venous obstruction leagues 15 demonstrated that 24% more WBCs • Familial incompetent values became trapped in the interstitial fluid of the • Immune complex/vasospastic disorder feet of ten sitting patients with venous hyper- tension as compared with ten sitting normal 1 subjects. Red blood cells did not become trapped to the same degree in either group. 1, Capillary flow rate T Venous pressure (with standing) Once the leg was elevated, WBCs were no longer trapped. Nash and colleagues 14 provided additional support to this hypothesis when they observed T White blood cell capillary adherence that WBCs from the arms of nine patients who T Hypercoagulable state required leg amputation had a significantly T Blood viscosity slower flow rate, or lower deformability rate, than WBCs isolated from ten control patients (P < .01). Moreover, the unfractionated WBCs obtained from the legs of the patients requir- T Endothelial damage ing amputation were significantly slower than those from the arms of the same patients. Once the amputation was completed, WBC flow rates increased and were not significantly dif- T Vascular permeability ferent from those of control subjects. 14 These studies therefore suggest that poor capillary V perfusion leads to the trapping of WBCs in in- Perivascular and intravascular terstitial fluid. This causes endothelial dam- fibrin/protein sheath forms age and the leakage of fluid and fibrinogen as well as proteolytic enzymes and inflam- matory proteins. As an edematous, fibrous peri- capillary sheath forms, tissue perfusion is re- Oxygen/nutrient delivery duced and venous ulcers form. Waste removal Venous ulcers may also occur in patients with occlusive arterial disease. These types of ulcers are frequently refractory to local treat- ments because of the added reduction in blood Tissue ischemia
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