Interventions for treating leg ulcers in people with sickle cell disease

Martí‐Carvajal, Arturo J; Knight‐Madden, Jennifer; Martinez-Zapata, María José

doi:10.1002/14651858.cd008394.pub2

Cited by 15 publications

(10 citation statements)

References 102 publications

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“…We summarize our approach to patients with SCD and ulcers, with recommendations based on our experience in the clinic as well as a critical review of the literature. Unfortunately, as a rare complication of a rare disease, there are few therapeutic trials of any kind and even fewer randomized controlled studies to provide clear evidence to guide practice in the clinic [7,8].…”

Section: Introductionmentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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The past five decades have seen an improvement in the mortality and morbidity of sickle cell disease (SCD) because of prophylaxis against infectious complications, improved and expanded red cell transfusions, implementation of hydroxyurea therapy, and advances in supportive care. Now that the majority of patients in the western hemisphere reaches adulthood, end organ diseases are frequent, which include vasculopathic complications such as chronic leg ulcers. The management of patients with leg ulcers requires the hematologist to lead a team of health care professionals, and investigates the presence of associated, but potentially still occult signs of vasculopathy, such as pulmonary hypertension, renal disease, priapism and retinopathy. These complications may be asynchronous, and long term careful screening is indicated, in order to ensure early diagnosis and intervention. It is crucial to address both the immediate consequences of pain, infection and disability, and long term effects on quality of life, employment and stigma associated with chronic ulceration. Recent insights into their pathophysiology may have practical implications. We propose a holistic approach to the management of patients' physical and emotional problems and mechanisms of ulcers formation and delayed healing. An overview of topical and systemic therapies for chronic ulcers is given, with the understanding that wound care therapy is best left to the wound specialists, medical and surgical, with whom the hematologist must keep an open line of communication. In the absence of evidence-based guidelines, our opinion is based on both a critical review of the literature and our personal clinical and research experience. Am. J. Hematol. 91:22-30, 2016. V C 2015 Wiley Periodicals, Inc. Clinical CasesCase 1. A 49 year old African American woman with sickle cell anemia, bilateral hip replacements for avascular necrosis of the femoral head, pulmonary arterial hypertension documented by pulmonary artery catheterization, and history of laser treatment and vitrectomy for proliferative retinopathy and vitreous hemorrhage, presented with a very painful ulcer at the right malleolus. She has had three previous ulcers, on both legs, the first at age 32 years, attributed to excessive standing at her job, no trauma, which had responded to topical care and healed within few months of presentation. At that time she was not taking hydroxyurea, but has been taking it now for longer than 10 years with good fetal hemoglobin response: 17%. This current ulcer developed while she was experiencing high personal stress but no physical trauma. She rarely experiences vaso-occlusive pain crisis and has very infrequent hospitalizations. She was referred to the wound care service and after 7 months of unfruitful therapies, including surgical debridement, MIST ultrasound therapy, antibiotics, and compressions, she was started on monthly transfusions and her ulcer healed 5 months later. She has had consistently elevated serum lactate dehydrogenase (LDH) (>600 IU/L), serum dire...

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Section: Introductionmentioning

confidence: 99%

Critical Reviews: How we treat sickle cell patients with leg ulcers

Minniti

Kato

2015

American J Hematol

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“…Existing therapeutic approaches for sickle cell disease ulcers are unsatisfactory, and are mostly based on treatments for venous and arterial ulcers in the general population. A recent Cochrane review 2 identified only six prospective, randomised therapeutic trials in sickle cell disease leg ulcers in the past 30 years—four in Jamaica 3–6 and two in the USA. 7,8 The results were mixed, with statistically significant increases in wound closure reported with topical Arg-Gly-Asp (RGD) peptide 7 and intravenous arginine butyrate.…”

Section: Introductionmentioning

confidence: 99%

Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial

Minniti

Gorbach

et al. 2014

The Lancet Haematology

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Summary Background Well-tolerated and effective treatments are needed for chronic leg ulcers in sickle cell anaemia. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects. We aimed to assess the safety, tolerability, and pharmacokinetics of topical sodium nitrite in patients with sickle cell disease and chronic leg ulcers. Methods We enrolled adult patients from an ambulatory clinic at the National Institutes of Health (Bethesda, MD, USA) with sickle cell anaemia with leg ulcers (with a surface area of 2.5–100 cm2) persisting for at least 4 weeks into a safety and tolerability phase 1 dose-escalation trial of topical sodium nitrite. Increasing concentrations of sodium nitrite cream were applied twice weekly for 4 weeks to one ulcer per patient at five dose levels (0.5%, 1%, 1.5%, 1.8%, and 2%). The primary endpoints were safety and tolerability, with secondary endpoints of pharmacokinetics, blood flow, and wound healing. Pain relief was analysed post hoc. Endpoints were analysed over time for the whole study population and according to dose level. This study is registered with ClinicalTrials.gov, number NCT01316796. Findings Between April 4, 2011, and March 19, 2013, we enrolled 18 adult patients with sickle cell anaemia and leg ulcers into our trial. We assigned three patients into each cohort, and each cohort was treated with a different concentration of sodium nitrite cream (cohort 1: 0.5%, cohort 2: 1.0%, cohort 3: 1.5%, and cohort 4: 2.0%). Patients were not enrolled into the next cohort dose until we were able to establish that no dose-limiting toxicities were observed. An additional six patients were enrolled to cohort 3a: 1.8%, after two patients in cohort 4 had asymptomatic drops in diastolic blood pressure. No grade 3–4 adverse events were observed, and there were no serious adverse events or dose-limiting side-effects. Pharmacokinetic analysis showed that systemic absorption of sodium nitrite was very low. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging (p=0.0002), corroborated by increased peri-wound skin temperature by infrared thermography (p=0.0119). We recorded a dose-dependent decrease in leg ulcer size (p=0.0012) and pain (p<0.0001). Ulcers healed completely in three patients who received the highest concentrations of topical sodium nitrite (the 1.8% and 2% cream). In our post-hoc analysis of pain, brief pain inventory scores improved in pain severity (p=0.0048) and pain interference (p=0.0013). Interpretation Our results indicate that topical sodium nitrite 2% cream is suitable for additional clinical trials in adults with sickle cell anaemia to promote healing of leg ulcers. Funding National Heart, Lung and Blood Institute Division of Intramural Research (National Institutes of Health).

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“…In a Cochrane review (1982 to August 2012) to assess the clinical effectiveness and safety of interventions used in the treatment of patients with SCD, 6 randomized clinical trials (198 patients and 250 ulcers) were found. 11 The authors concluded that the evidence of efficacy of either systemic pharmaceutical interventions (l-carnitine, oral zinc zulfate, arginine butyrate, isoxsuprine) and topical pharmaceutical agents (topical antibiotics, RGD [arginineglycine-aspartic acid] peptide dressing, Solcosery cream) managements are limited. 11 Because of huge heterogeneity and high risk of bias, conclusion is difficult.…”

Section: Managementmentioning

confidence: 99%

Hemoglobinopathies and Leg Ulcers

Alavi

Kirsner

2015

The International Journal of Lower Extremity Wounds

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Major hemoglobinopathies, including sickle cell anemia, are becoming a global health issue. Leg ulcers are the most common cutaneous manifestation of sickle cell disease and an important contributor to morbidity burden in this population. Leg ulcers following sickling disorders are extremely painful, and hard to heal. The clinical evidence for the optimal management of these ulcers is limited. Treating the cause and the strategies to prevent sickling are the mainstay of treatment. The basic principles of wound bed preparation and compression therapy is beneficial in these patients.

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Interventions for treating leg ulcers in people with sickle cell disease

Cited by 15 publications

References 102 publications

Critical Reviews: How we treat sickle cell patients with leg ulcers

Critical Reviews: How we treat sickle cell patients with leg ulcers

Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial

Hemoglobinopathies and Leg Ulcers

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