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Hydroxyurea Associated Leg Ulcer Succesfully Treated
with Hyperbaric Oxygen in a Diabetic Patient

B. Akinci 1 , S. Yesil 1 , A. Atabey 2 , S. Ilgezdi 3
Affi liations
1 Dokuz Eylul University, Endocrinology and Metabolism, Izmir, Turkey 2 Dokuz Eylul University, Plastic and Reconstructive Surgery, Izmir, Turkey 3 Yesilyurt Ataturk Education and Research Hospital, Undersea and Hyperbaric Medicine Key words
Abstract
this agent for a long time and at higher cumu- lative doses. Here we describe a diabetic patient Oxygen tension in healing tissues is hetero- with foot ulcer associated with HU treatment for geneous. Increased oxygen mostly stimulates polycythemia vera, who was treated successfully repair mechanisms and enhances tissue heal- with hyperbaric oxygen and general wound care ing. Hyperbaric oxygen therapy increases blood after discontinuation of HU. Faster improvement and tissue oxygen content and may help main- of leg ulcer in our patient compared to literature tain cellular integrity and function. Hydroxyurea regarding HU withdrawal as single therapy sug- (HU) is a cytotoxic agent, which leads to inacti- gests that hyperbaric oxygen may be helpful in vation of ribonucleotide reductase, inhibition of the management of HU associated leg ulcers, cellular DNA synthesis, and cell death in the S phase. HU induced leg ulcers occur after use of Introduction
of autologous bone marrow cells [6] may also promote wound healing in diabetic foot ulcers. Hydroxyurea (HU) is an antineoplastic agent, Hyperbaric oxygen therapy is designed to greatly which is indicated in the treatment of various increase tissue oxygen tension. It involves breath- hematological disorders and solid tumors. HU ing 100 % oxygen at pressures greater than one inhibits DNA synthesis via inactivation of ribo- atmosphere by using a pressurized treatment nucleotide reductase in actively dividing cells, chamber. It is used as an adjuvant therapy in Downloaded by: University of Michigan. Copyrighted material.
and causes cell death in the S phase [1] . patients with certain types of wounds including Systemic side effects of HU are rare, dose depend- ent, and mostly reversible. However, dermato- benefi cial for diabetic ulcers, where the regional logical side effects of HU are relatively common. vascular system is intact or only partly damaged, received
Hyperpigmentation, photosensitivity, partial but the tissue needs nutritive fl ow and oxygen fi rst decision 28. 9. 2006
alopecia, scaling, brown discoloration of the supply because of local factors such as injury or accepted
nails, erythema and desquamation of the face and hands, oral ulceration, and stomatitis may be Here we report a HU associated leg ulcer in a dia- Bibiliography
seen in the course of treatment with HU [1, 2] . betic man, which was successfully treated with DOI 10.1055/s-2007-956164
Leg ulcers due to HU are seen less frequently and are less well described than other dermatologi- 2007; 115: 143 – 145 Georg Thieme Verlag KG cal side effects of the drug. HU associated leg ulcers are commonly located near the malleoli, are painful, and usually resolve after cessation of the drug [2] . There are reports suggesting that A 63 year old male was referred in 2001 to Correspondence
various therapies such as prostaglandin E1 [3] , department of hematology at our hospital for the B. Akinci
topical basic fi broblast growth factor therapy [4] , evaluation of polycythemia. Investigation lead to and topical granulocyte-macrophage colony the diagnosis of polycythemia vera and he was stimulating factor [5] may be helpful in the man- treated with HU. His blood cell count was con- sity · Dokuz Eylul University Hospital · Ineiralti · 35340 agement of HU associated ulcers when they are trolled between target values by a total daily dose added to standard wound care. Local application Akinci B et al. Hydroxyurea Associated Leg Ulcer … Exp Clin Endocrinol Diabetes 2007; 115: 143 – 145 Ulcer on the right lateral malleolus of the patient The ulcer resolved almost completely with hyperbaric oxygen and general wound care after discontinuation of HU of 1.5 g. The cumulative dose of HU used for this patient was 0.91 g / kg. of proliferation of capillaries, fi broplasia and fat necrosis. It did He reported to an outpatient clinic 7 months ago with com- not reveal evidence of vasculitis or malignancy. plaints of pain, erythma, and ulcer over right lateral malleolus. HU treatment was discontinued, when considered as the etio- He did not recall any trauma. He was given various topical wound logical factor of leg ulcer in the patient. Hyperbaric oxygen ther- dressing including mupirocin and oral antibiotics but the lesion apy was initiated two days after withdrawal of HU. He underwent failed to heal. Despite local debridment and wound care, no 90 minutes daily sessions of 100 % O 2 breathing in a multiplace improvement was observed. Skin grafting of the area over the hyperbaric chamber pressured at 2.5 absolute atmosphere air lateral tibia was performed. Although the wound from graft for 30 days. Wound care and surgical debridement were also region on the tibia healed well, the malleolar wound did not performed. Systemic antibiotics were given empirically until improved. Repeated debridement, oral antibiotics, and local blood and tissue culture results were obtained. After cultures wound care failed to promote healing. He was referred to us for indicated that there was no evidence of infection, antibiotics hospitalization and further investigation. were discontinued. The ulcer resolved almost completely within He had an 8 year history of type-2 diabetes. He was treated with 35 days ( ᭹ ᭤ Fig. 2 ). Phlebotomy was performed to control eryth-
oral antidiabetics for 3 years, and thereafter with insulin. His rocytosis due to polycythemia vera. Since extreme thrombocy- HbA 1C was 5.8 % , controlled on a basal-bolus regime of regular tosis developed, the treatment was continued with anegrelide. insulin and NPH. He had mild proliferative diabetic retinopathy. No ulcer episode was observed after treatment with anegrelide He didn ’ t have any other microvascular complications of diabe- tes. There was no history of ischemic heart disease and other macrovascular complications of diabetes. The patient was a non-smoker, and he did not consume alcohol. Discussion
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ulceration on the right lateral malleolus. Skin atrophy and mini- The mechanisms underlying the pathogenesis of the HU associ- mal edema were seen around the lesion as well as elsewhere on ated leg ulcer are not clearly defi ned. Defective DNA repair the foot ( ᭹ ᭤ Fig. 1 ). The dorsalis pedis and posterior tibial pulses
mechanisms and cytotoxicity may be responsible for the leg were easily palpable. Monofi lament (10 g) testing revealed no ulcer. Keratinocytes having high proliferation rates are the most peripheral neuropathy. No gross foot deformities were apparent. sensitive cell type in the skin to be damaged due to cytotoxic There was no radiological evidence of vascular insuffi ciency and agents [1] . Some authors argued that pathogenesis of HU associ- no culture evidence of infection. A plain radiograph showed no ated leg ulcers are related to ischemia due to intravascular evidence of osteomyelitis. Venous Doppler ultrasound was not thrombosis [9] . It has been speculated that HU may induce pro- coagulation in the malleolar vessels and cause cutaneous atro- Blood examination revealed a red blood cell count of phy. Velez et al. [10] also considered macroerythrocytosis as a 3.05 × 10 12 L − 1 (normal: 4.0 – 5.77 × 10 12 L − 1 ), hemoglobin concen- pathogenic factor and hypothesized that the circulating red cell tration: 12.3 g / dl (normal: 13.5 – 17.5 g / dl), mean corpuscular vol- survival coincides with the duration required for healing after ume of 125.9 (normal: 80.7 – 95.59, white cell count of 4.9 × 10 9 L − 1 HU withdrawal. The megaloblastic changes of the erythrocytes (normal: 4 – 10.3 × 10 9 L − 1 ) with a differential of 71 % segmented due to HU may prohibit these cells from easily traversing the cap- neutrophils, 18 % lymphocytes, 8 % monocytes, 2 % eosinophils, illaries. This may impair blood fl ow in the microcirculation and × 10 9 L − 1 (normal: 156 – 373 × 10 9 L − 1 ). cause relative ischemia in the basal layer of the skin, which Peripheral blood smear revealed macrocytosis. Serum C-reactive requires more oxygen for proliferation. Engstrom et al. protein, erythrocyte sedimentation rate, kidney and liver func- reported that HU causes changes in red cell geometry and deform- tion tests, and urinalysis were within normal limits. Biopsy of ability, and may impair blood fl ow in the microcirculation. the ulcer showed pseudoepithelial hyperplasia in the epidermis, Another possible factor leading to risk for leg ulcer is hyperviscos- acantolysis and granulomatous changes in the dermis consisting ity associated with blood dyscrasia in polycythemia vera [1] . Akinci B et al. Hydroxyurea Associated Leg Ulcer … Exp Clin Endocrinol Diabetes 2007; 115: 143 – 145 The presence of coexisting disease, like diabetes in our case, ulcer. Discontinuation of HU is essential. Hyperbaric oxygen makes the differential diagnosis of HU associated ulcer more treatment may be benefi cial to accelerate wound healing. Fur- diffi cult. The most frequent location of HU associated ulcers on ther studies are required to determine clinical benefi t of hyper- lower extremities and especially near the malleoli suggests that baric oxygen treatment in the treatment of HU associated leg trauma may be an initiating factor. Best et al. [2] reported that of the 18 ulcers in 14 patients, 10 (55.6 % ) were over the medial malleolus and 8 (44.4) were over the lateral malleolus. References
Collagen synthesis by fi broblasts is critical in the healing of soft 1 Sirieix ME , Debure C , Baudot N et al. : Leg ulcers and hydroxyurea: tissue wounds. It is dependent on effi cient oxygen supply. forty-one cases . Arch Dermatol 1999 ; 135 (7) : 818 – 820 Hyperbaric oxygen stimulates fi broblast proliferation and differ- 2 Best PJ , Daoud MS , Pittelkow MR , Petitt RM : Hydroxyurea-induced leg ulceration in 14 patients . Ann Intern Med 1998 ; 128 (1) : 29 – 32 entiation, increases collagen formation and cross-linking, aug- 3 Kido M , Tago O , Fujiwara H , Ito M , Niwano H : Leg ulcer associated with ments neovascularization, and ameliorates leukocyte functions hydroxyurea treatment in a patient with chronic myelogenous leu- [8] . Hyperoxia can trigger the onset of signal transduction path- kaemia: successful treatment with prostagladin E1 and pentoxifylline . Br J Dermatol 1998 ; 139 (6) : 1124 – 1126 ways regulating the gene expression of growth factors. Oxygen 4 Aragane Y , Okamoto T , Yajima A , Isogai R , Kawada A , Tezuka T : Hydrox- has direct activity against anaerobic organisms and can enhance yurea-induced foot ulcer successfully treated with a topical basic fi brob- microbiocidal capacity of endogenous defense mechanisms. last growth factor product . Br J Dermatol 2003 ; 148 (3) : 599 – 600 Other possible benefi cial effects of hyperbaric oxygen are 5 Stagno F , Guglielmo P , Consoli U , Fiumara P , Russo M , Giustolisi R : Suc- cessful healing of hydroxyurea-related leg ulcers with topical granu- improved preservation of energy metabolism and reduction of locyte-macrophage colony-stimulating factor . Blood 1999 ; 94 edema [7, 8] . Controlled clinical trials suggest that hyperbaric oxygen treatment is associated with improvement outcomes 6 Humpert PM , Bartsch U , Konrade I et al. : Locally applied mononuclear when used as an adjunctive treatment for diabetic foot ulcers bone marrow cells restore angiogenesis and promote wound healing in a type 2 diabetic patient . Exp Clin Endocrinol Diabetes 2005 ; 113 [7, 12] . It has been reported that hyperbaric oxygen treatment reduces the incidence of major amputation in diabetic patients 7 Niinikoski JH : Clinical hyperbaric oxygen therapy, wound perfusion, with gangrenous foot [13] . In a randomized prospective study, and transcutaneous oximetry . World J Surg 2004 ; 28 (3) : 307 – 311 8 Roeckl-Wiedmann I , Bennett M , Kranke P : Systematic review of hyper- Kessler et al. [14] documented that hyperbaric oxygen, in addi- baric oxygen in the management of chronic wounds . Br J Surg 2005 ; tion to standard multidisciplinary management, doubles the mean healing rate of nonischemic foot ulcers in selected dia- 9 Weinlich G , Schuler G , Greil R , Kofl er H , Fritsch P : Leg ulcers associated betic patients. The long-term follow-up study results of Kalani with long-term hydroxyurea therapy . J Am Acad Dermatol 1998 ; 39 (2 Pt 2) : 372 – 374 et al. [15] indicate that hyperbaric oxygen therapy accelerates 10 Velez A , Garcia-Aranda JM , Moreno JC : Hydroxyurea-induced leg the rate of healing, and reduces the need for amputation. ulcers: is macroerythrocytosis a pathogenic factor? J Eur Acad Der- Healing times can be predicted in various types of wounds such matol Venereol 1999 ; 12 (3) : 243 – 244 as neuropathic diabetic foot ulcers [16] . HU associated leg ulcers 11 Engstrom KG , Lofvenberg E : Treatment of myeloproliferative disorders with hydroxyurea: effects on red blood cell geometry and deformabil- usually resolve after cessation of the drug. Montefusco et al. [17] ity . Blood 1998 ; 91 (10) : 3986 – 3991 found complete resolution in 14 patients and marked improve- 12 Faglia E , Favales F , Aldeghi A et al. : Adjunctive systemic hyperbaric oxy- ment in 3 patients after discontinuation of HU in their study gen therapy in treatment of severe prevalently ischemic diabetic foot including 17 patients with HU associated leg ulcer. Best et al. [2] ulcer. A randomized study . Diabetes Care 1996 ; 19 (12) : 1338 – 1343 13 Baroni G , Porro T , Faglia E et al. : Hyperbaric oxygen in diabetic gan- reported that the leg ulcers completely resolved in 12 patients of grene treatment . Diabetes Care 1987 ; 10 (1) : 81 – 86 14 after cessation of HU. The mean healing duration of the HU 14 Kessler L , Bilbault P , Ortega F et al. : Hyperbaric oxygenation accelerates associated leg ulcers was reported as 4.3 months in the study of the healing rate of nonischemic chronic diabetic foot ulcers: a pro-spective randomized study . Diabetes Care 2003 ; 26 (3) : 2378 – 2382 Montefesco et al. [17] . Sirieix et al. [1] reported that 80 % of 15 Kalani M , Jorneskog G , Naderi N , Lind F , Brismar K : Hyperbaric oxygen Downloaded by: University of Michigan. Copyrighted material.
patients recovered completely after discontinuation of HU in a (HBO) therapy in treatment of diabetic foot ulcers. Long-term follow- mean duration of 3 months (range: 1 – 24 months). The shorter up . J Diabetes Complications 2002 ; 16 (2) : 153 – 158 duration of healing in our patient (35 days) compared to mean 16 Zimny S , Pfohl M : Healing times and prediction of wound healing in neuropathic diabetic foot ulcers: a prospective study . Exp Clin Endo- values from both studies suggest that hyperbaric oxygen treat- crinol Diabetes 2005 ; 113 (2) : 90 – 93 ment may have benefi cial effects in the management of HU 17 Montefusco E , Alimena G , Gastaldi R , Carlesimo OA , Valesini G , Mandelli F : Unusual dermatologic toxicity of long-term therapy with hydroxyu- In conclusion, we suggest that meticulous wound care and anti- rea in chronic myelogenous leukemia . Tumori 1986 ; 72 (3) : 317 – 321 biotics are not enough for the resolution of the HU associated leg Akinci B et al. Hydroxyurea Associated Leg Ulcer … Exp Clin Endocrinol Diabetes 2007; 115: 143 – 145

Source: http://oxfordhbot.com/library/diabetes/221.009.pdf

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