David L. Steed

Guidelines for the treatment of diabetic ulcers

1. Chaired this panel2. University of Pittsburgh/UPMC, Pittsburgh, PA3. Georgetown University Hospital, Washington, DC4. Colaizzi Pedorthic Center, Pittsburgh, PA5. HCA Richmond Retreat Hospital, Richmond, VA6. University of Michigan Hospital, Ann Arbor, MI7. University of Texas Health Science Center, San Antonio, TX8. Covance, Princeton, NJ9. St Joseph’s Hospital, Belleville, IL10. University of South Florida, Tampa, FL11. Penn North Centers for Advanced Wound Care, Warren, PA12. Cabrini Medical Center, NY, NY13. Beth Israel Deaconess Medical Center, Boston, MA, and14. Barnes-Jewish Hospital at Washington University Medical Center, St Louis, MO

Compromised cerebral blood flow reactivity is a predictor of stroke in patients with symptomatic carotid artery occlusive disease

PURPOSE The purpose of this study was to determine whether the hemodynamic consequences of extracranial carotid disease correlate with the risk of subsequent cerebral infarction. METHODS In 95 patients with symptoms who had greater than or equal to 70% stenosis (31 patients) or who had occlusion (64 patients) of the ipsilateral carotid artery, cerebral blood flow was measured by the stable xenon/computed tomography technique both at baseline and after vasodilatory challenge with intravenous acetazolamide. Patients were stratified into group 1, 43 patients with no more than a 5% decrease in flow in any vascular territory, and group 2, 52 patients with greater than a 5% decrease in one or more vascular territories after an acetazolamide challenge. RESULTS In group 2, 15 (28.9%) of 52 patients had a new stroke, but only one (2.3%) of 43 patients in group 1 did (p = 0.0005). Of patients with total carotid occlusion 10 (26%) of 38 in group 2 and none (0%) of 26 in group 1 had a new stroke (p = 0.003). Of patients with greater than or equal to 70% stenosis, five (36%) of 14 in group 2 and only one (6%) of 17 in group 1 had a stroke (p = 0.067). CONCLUSION The loss of cerebral reactivity in patients with symptoms who had greater than or equal to 70% carotid stenosis or occlusion is an important predictor of impending cerebral infarction.

THE ROLE OF GROWTH FACTORS IN WOUND HEALING

Growth factors applied topically to wounds can accelerate healing by stimulating granulation tissue formation and enhancing epithelialization. This has been suggested by several different studies of topically applied growth factors. It is clear, however, that topical growth factor therapy should not be considered as a substitute for good wound care, including surgical debridement or revascularization.

Cellular content and permeability of intraluminal thrombus in abdominal aortic aneurysm

PURPOSE A pathologic feature commonly associated with abdominal aortic aneurysms is the presence of variably sized and shaped intraluminal thrombus, which may be fundamental to the disease process. However, the precise role of the intraluminal thrombus in the formation, enlargement, and rupture of abdominal aortic aneurysms is unknown. The hypothesis tested in this study was whether there were structural features of aortic thrombi to suggest that it may be involved in the pathogenesis of abdominal aortic aneurysms. We have investigated this hypothesis using a variety of structural and biochemical techniques. METHODS Tests performed were light, transmission, and scanning electron microscopy; fluid permeability measurements; and Western blots. RESULTS Intraluminal thrombus found in abdominal aortic aneurysms is structurally complex and is traversed from the luminal to abluminal surface by a continuous network of interconnected canaliculi. Quantitative microscopic analysis of the thrombus shows cellular penetration for at least 1 cm from the luminal surface of the thrombus. Macro-molecular penetration may be unrestricted throughout the entire thickness of the thrombus. Fibrin deposition occurred throughout the thrombus, whereas fibrin degradation occurred principally at the abluminal surface. CONCLUSIONS These principally structural studies support the hypothesis that the thrombus is a self-sustaining entity that may have significance in the pathophysiologic mechanism of abdominal aortic aneurysms.

Guidelines for the treatment of venous ulcers

1. Co-chaired this panel2. University of South Florida, Tampa, FL3. Healthpoint Ltd., Fort Worth, TX4. University of California, San Francisco, CA5. University of Texas Medical Branch, Galveston, TX6. University of Cardiff, Cardiff, Wales, UK7. University of Pennsylvania, Philadelphia, PA8. Private practice, Warren, PA9. Private practice, Tamarac, FL10. University of Pittsburgh, Pittsburgh, PA11. St. Louis University, St. Louis, MO, and12. Washington University, St. Louis, MO

Randomized trial of topically applied repifermin (recombinant human keratinocyte growth factor-2) to accelerate wound healing in venous ulcers.

About 600,000 people in the United States are estimated to be affected by venous ulcers. The cornerstone of care of chronic venous ulcers involves the application of compression bandages. Other therapies include treatment of associated infection, treatment for edema and inflammation, and debridement when necessary. Repifermin, a recombinant human KGF‐2 (fibroblast growth factor‐10), exerts a proliferative effect on epithelial cells, in vitro and in vivo, and has been shown to accelerate wound healing in several experimental animal models. A randomized, double‐blind, parallel‐group, placebo‐controlled, multicenter study was conducted to evaluate the safety and efficacy of topical repifermin treatment, for 12 weeks, in the healing of chronic venous ulcers in 94 patients. Repifermin was shown to accelerate wound healing, with significantly more patients achieving 75% wound closure with repifermin than with placebo. The treatment effect appeared more marked for a subgroup of patients with initial wound areas ≤ 15 cm2 and wound ages of ≤ 18 months. A longer duration of treatment (e.g., 26 weeks) may allow better differentiation of the benefit of repifermin compared with placebo, particularly with respect to complete wound closure. The safety assessment showed that repifermin was well tolerated.

Agent-based model of inflammation and wound healing : insights into diabetic foot ulcer pathology and the role of transforming growth factor-β1

Inflammation and wound healing are inextricably linked and complex processes, and are deranged in the setting of chronic, nonhealing diabetic foot ulcers (DFU). An ideal therapy for DFU should both suppress excessive inflammation while enhancing healing. We reasoned that biological simulation would clarify mechanisms and help refine therapeutic approaches to DFU. We developed an agent‐based model (ABM) capable of reproducing qualitatively much of the literature data on skin wound healing, including changes in relevant cell populations (macrophages, neutrophils, fibroblasts) and their key effector cytokines (tumor necrosis factor‐α [TNF], interleukin [IL]‐1β, IL‐10, and transforming growth factor [TGF]‐β1). In this simulation, a normal healing response results in tissue damage that first increases (due to wound‐induced inflammation) and then decreases as the collagen levels increase. Studies by others suggest that diabetes and DFU are characterized by elevated TNF and reduced TGF‐β1, although which of these changes is a cause and which one is an effect is unclear. Accordingly, we simulated the genesis of DFU in two ways, either by (1) increasing the rate of TNF production fourfold or (2) by decreasing the rate of TGF‐β1 production 67% based on prior literature. Both manipulations resulted in increased inflammation (elevated neutrophils, TNF, and tissue damage) and delayed healing (reduced TGF‐β1 and collagen). Our ABM reproduced the therapeutic effect of platelet‐derived growth factor/platelet releasate treatment as well as DFU debridement. We next simulated the expected effect of administering (1) a neutralizing anti‐TNF antibody, (2) an agent that would increase the activation of endogenous latent TGF‐β1, or (3) latent TGF‐β1 (which has a longer half‐life than active TGF‐β1), and found that these therapies would have similar effects regardless of the initial assumption of the derangement that underlies DFU (elevated TNF vs. reduced TGF‐β1). In silico methods may elucidate mechanisms of and suggest therapies for aberrant skin healing.

Thrombin injection versus compression of femoral artery pseudoaneurysms

OBJECTIVE The compression of femoral artery pseudoaneurysms is a time consuming, painful, and sometimes unsuccessful procedure. Thrombin injection has been advocated as a superior alternative. In this study, we compare our experiences with both techniques. METHODS All the records of femoral artery false aneurysms that were treated in the vascular laboratory from January 1996 to April 1999 were retrospectively reviewed. Treatment with ultrasound scan-guided compression was compared with treatment with dilute thrombin injection (100 U/mL). RESULTS Both groups had similar demographics and aneurysm sizes (P >.2). Of the pseudoaneursyms, 88% were caused by cardiac catheterization and the others were the results of femoral artery access for cardiac surgery (6%), arteriography (5%), and renal dialysis (1%). Compression was successful in 25 of 40 patients (63%). Nine persistent aneurysms necessitated operation, and six were treated successfully with thrombin injection. Primary thrombin injection successfully obliterated 21 pseudoaneurysms in 23 patients. Overall, 27 of 29 pseudoaneurysms were treated successfully with thrombin injection (93%). Thrombosis occurred within seconds of the thrombin injection and required, on average, 300 units of thrombin (100 to 600 units). The patients who underwent successful compression required an average of 37 minutes of compression (range, 5 to 70 minutes) and required analgesia on several occasions. No patients in the thrombin group required analgesia or sedation. Neither group had complications. A cost analysis shows that thrombin treatment results in considerable savings in vascular laboratory resource use but not in overall hospital expenditures. CONCLUSION Ultrasound scan-guided thrombin injection is a safe, fast, and painless procedure that completely obliterates femoral artery pseudoaneurysms. The shift from compressive therapy to thrombin injection reduces vascular laboratory use and is less expensive, although it does not significantly impact hospital costs.

Changing etiology of iliopsoas abscess

Over a 5-year period, iliopsoas abscesses were found in 11 patients. Although the most common underlying condition was Crohns disease (3 of 11 patients), 5 abscesses resulted from hematogenous spread from a distant site. Each of these five patients was elderly, severely malnourished, or had an underlying chronic disease. Fever was a presenting sign in 8 of 11 patients, whereas all 4 patients who presented with back pain had nontuberculous lumbar osteomyelitis or disk space infections. No patient presented with the classic triad of fever, back pain, and anterior thigh or groin pain. Computed tomographic (CT) scans accurately established the clinical diagnosis in 10 of 11 patients. Two of the patients died. One patient was an intravenous drug abuser, whereas the other patient was being treated with steroids for systemic lupus erythematosus. Elderly patients, diabetics, and patients with chronic disease are susceptible to this kind of occult infection and may present with minimal clinical findings. Aggressive diagnosis using CT scanning and treatment with resection of involved bowel, complete drainage of the abscess, and prolonged antibiotics are required to salvage these patients.

Progression of asymptomatic carotid stenosis: A natural history study in 1004 patients ☆ ☆☆

PURPOSE The purpose of this study was to delineate the natural history of the progression of asymptomatic carotid stenosis. METHODS In a 10-year period, 1701 carotid arteries in 1004 patients who were asymptomatic were studied with serial duplex scans (mean follow-up period, 28 months; mean number of scans, 2.9/patient). At each visit, stenoses of the internal carotid artery (ICA) and the external carotid artery (ECA) were categorized as none (0 to 14%), mild (15% to 49%), moderate (50% to 79%), severe (80% to 99%), preocclusive, or occluded. Progression was defined as an increase in ICA stenosis to >/=50% for carotid arteries with a baseline of <50% or as an increase to a higher category of stenosis if the baseline stenosis was >/=50%. The Cox proportional hazards model was used for data analysis. RESULTS The risk of progression of ICA stenosis increased steadily with time (annualized risk of progression, 9.3%). With multivariate modeling, the four most important variables that affected the progression (P <.02) were baseline ipsilateral ICA stenosis >/=50% (relative risk [RR], 3.34), baseline ipsilateral ECA stenosis >/=50% (RR, 1.51), baseline contralateral ICA stenosis >/=50% (RR, 1.41), and systolic pressure more than 160 mm Hg (RR, 1. 37). Ipsilateral neurologic ischemic events (stroke/transient ischemic attack) occurred in association with 14.0% of the carotid arteries that were studied. The progression of ICA stenosis correlated with these events (P <.001), but baseline ICA stenosis was not a significant predictor. CONCLUSION In contrast to recently published studies, we found that the risk of progression of carotid stenosis is substantial and increases steadily with time. Baseline ICA stenosis was the most important predictor of the progression, but baseline ECA stenosis also was identified as an important independent predictor. Contralateral ICA stenosis and systolic hypertension were additional significant predictors. We found further that the progression of ICA stenosis correlated with ischemic neurologic events but not baseline stenosis. The data provide justification for the use of serial duplex scans to follow carotid stenosis and suggest that different follow-up intervals may be appropriate for different patient subgroups.