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 < or = 15 cm2 and wound ages of < or = 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.

Is routine use of the intensive care unit after elective infrarenal abdominal aortic aneurysm repair necessary?

INTRODUCTION: Postoperative care after infrarenal abdominal aortic aneurysm (AAA) repair has traditionally involved admission to the intensive care unit (ICU). With the advent of endovascular AAA repair, the management of open procedures has received increased scrutiny. We recently modified our AAA clinical pathway to include selective use of the ICU. METHODS: Consecutive elective infrarenal AAA repairs performed by members of the vascular surgery division at a university medical center from 1994 to 1999 were analyzed retrospectively with a computerized database, the Medical Archival Retrieval System. Group I consisted of 245 patients who were treated in the ICU for 1 or more days, and Group II included 69 patients admitted directly to the floor. Ruptured, symptomatic, suprarenal, endovascular, and reoperative repairs were excluded. Outcome variables were compared over the 6-year period. RESULTS: Floor admissions increased over the study period with 0%, 0%, 3.3%, 16.3%, 48.6%, and 43.6% of patients admitted directly to the surgery ward from 1994 to 1999. The average ICU length of stay declined from 4.6 to 1.2 days, whereas the hospital length of stay decreased from 12.5 to 6.8 days from 1994 to 1999. The change in ICU use had no effect on death (2.4% in Group I vs 0% in Group II). Major and minor morbidity was comparable. Hospital charges were significantly lower for patients in Group II. CONCLUSION: A policy of selective utilization of the ICU after elective infrarenal AAA repair is safe. It can reduce resource use without a negative impact on the quality of care.

Wound healing trajectories as predictors of effectiveness of therapeutic agents.

BACKGROUND: One goal of wound healing research is to discover agents to accelerate healing. Regulatory agencies have suggested stringent criteria to determine efficacy, that of 100% wound closure. Data analysis at a single point such as 100% closure does not provide detailed information about agent effectiveness over the entire span of healing. HYPOTHESIS: Wound healing trajectories can provide such information and can be used to demonstrate utility as alternative end points for wound healing trials. DESIGN: Data from 160 patients in 11 clinical trials of diabetic foot ulcers conducted at 2 centers were evaluated. Wound healing trajectories were constructed for patients whose wounds healed (100% closure) and those whose did not (<100% closure) over a 20-week period. The percentage of patients achieving total healing vs time of treatment was plotted and divided into patients receiving a test agent or placebo. RESULTS: The healing trajectories were almost identical for patients achieving complete healing at the 2 centers, as were the trajectories for patients with less than 100% closure. However, the trajectories of patients achieving total healing were significantly different from those not achieving 100% closure. Fifty-two percent of all patients achieved 100% healing by 20 weeks; 61% of patients receiving an experimental agent had total healing compared with 39% of placebo-treated patients. Linear regression suggested that all patients would achieve total healing by 37 weeks. CONCLUSIONS: Since wound healing trajectories for diabetic foot ulcers treated at 2 centers so closely mimic one another, trajectories might be useful efficacy end points, and used to compare significant points along a continuum rather than a single static end point. Shifting of the wound healing trajectory from an impaired to a more ideal course may be considered when determining efficacy of new wound treatments.

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.

Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: a combined analysis of four randomized studies.

The results of a combined analysis and separate analyses of four multicenter, randomized, parallel group studies that evaluated the effects of once-daily topical administration of becaplermin gel for the treatment of chronic, full thickness, lower extremity diabetic ulcers are presented. The four studies included a total of 922 patients with nonhealing lower extremity diabetic ulcers of at least 8 weeks' duration. Following initial complete sharp debridement of the ulcer, patients were randomized to receive a standardized regimen of good ulcer care alone, good ulcer care plus placebo gel, or good ulcer care plus becaplermin gel-30 microg/g, or good ulcer care plus becaplermin gel-100 microg/g, with various combinations of regimens used in the four studies. Safety was assessed by monitoring adverse events and by clinical laboratory evaluations. Meta-analytic statistical techniques were used in the combined analysis to establish homogeneity of treatment comparisons across studies. Based on an analysis of patients with baseline ulcer area common to all trials (

Oxygen-dependent chronic obstructive pulmonary disease does not prohibit aortic aneurysm repair.

BACKGROUND: Severe oxygen-dependent chronic obstructive pulmonary disease (COPD) is considered by many to be a contraindication to open abdominal aortic aneurysm (AAA) repair. We reviewed our own experience with this patient population. METHODS: From July 1995 to March 1999, 14 consecutive patients limited by home oxygen-dependent COPD underwent elective open infrarenal AAA repair. Their medical records were reviewed. RESULTS: The mean aortic aneurysm size was 6.3 cm. The mean PaO2 = 70 mm Hg, PaCO2 = 45 mm Hg, forced expiratory volume in 1 second (FEV1) = 34% of predicted, and forced vital capacity (FVC) = 67% of predicted. All 14 patients were extubated within 24 hours, mean length of hospital stay was 5.9 days, and there were no perioperative deaths. CONCLUSIONS: Severe home oxygen-dependent COPD is not a contraindication to safe elective open AAA repair.

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.

Foundations of good ulcer care.

Diabetic foot ulcers are a significant healthcare problem affecting more than 1 million patients at some point in their lifetime. Good ulcer care begins with thorough assessment of the ulcer, which includes determining whether the ulcer is infected and whether neuropathy or peripheral vascular disease is present. The principles of good wound care include use of proper footwear, non-weight-bearing limb support, use of appropriate antibiotics, debridement, aggressive revascularization, control of serum glucose levels, and careful monitoring of the ulcer. For refractory ulcers, new therapies, such as the use of exogenous recombinant growth factors, are being developed that may have a significant benefit in treating these ulcers and lowering the amputation rate.

Modifying the wound healing response with exogenous growth factors.

Growth factors exert a powerful influence over wound healing. They control the growth, differentiation, and metabolism of cells. Although their influence on wound repair has been studied, there are only a few reports in which growth factors applied topically exerted a positive influence on wound repair. However, there is no doubt that they do control the wound environment. It is likely that their actions will be defined further, and the wound environment will be able to be controlled to achieve complete and durable wound healing in patients.

Reversal of impaired wound repair in iNOS-deficient mice by topical adenoviral-mediated iNOS gene transfer.

Most evidence indicates that nitric oxide plays a role in normal wound repair; however, involvement of inducible nitric oxide synthase (iNOS) has not been established. Experiments were carried out to determine the requirement for iNOS in closing excisional wounds. Wound closure was delayed by 31% in iNOS knockout mice compared with wild-type animals. An identical delay in wound closure was observed in wild-type mice given a continuous infusion of the partially selective iNOS inhibitor N6-(iminoethyl)-L-lysine. Delayed wound healing in iNOS-deficient mice was completely reversed by a single application of an adenoviral vector containing human iNOS cDNA (AdiNOS) at the time of wounding. Reverse transcription PCR identified iNOS mRNA expression in wild-type mice peaking 4-6 d after wounding, and confirmed expression of human iNOS in the adenoviral vector containing human iNOS cDNA-treated animals. These results establish the key role of iNOS in wound closure, and suggest a gene therapy strategy to improve wound healing in iNOS-deficient states such as diabetes, and during steroid treatment.

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.

The factor V Leiden mutation: spectrum of thrombotic events and laboratory evaluation.

PURPOSE: This study aims to describe the spectrum of clinical thrombotic events and to compare the methods of laboratory evaluation for the newly described prothrombotic factor V Leiden mutation. METHODS: Specimens from 1376 patients with thrombotic events or their relatives were tested for the factor V Leiden mutation by polymerase chain reaction plus restriction digest from Jan. 1, 1995, to Mar. 31, 1996. Activated protein C (APC) resistance test data was available for 554 of these patients. Clinical information was available for 166 patients with the mutation. RESULTS: Of 1376 patients tested for factor V Leiden mutation, 270 (19.6%) were positive, with 12 homozygotes and 258 heterozygotes. Of 554 patients for whom APC resistance data was available, 221 (39.9%) had low APC resistance ratios (< or = 2.4); of these only 97 (43.9%) were factor V Leiden-positive. Among 333 samples with normal or elevated APC resistance ratios, 19 (5.7%) were later identified with the factor V Leiden mutation, despite the normal screening test. One hundred fourteen of 166 patients (68.7%) with the mutation had at least one thrombotic event, most commonly deep venous thrombosis and pulmonary embolus. Arterial cerebrovascular thrombotic events occurred in 11 patients (10%), and myocardial infarctions in eight (7%). The mean age of all patients with arterial thrombotic events was 45.4 years. CONCLUSIONS: The factor V mutation is a common cause of venous thromboses but may also be associated with the early presentation of arterial thrombotic events. The APC resistance test is a sensitive screening assay but has limitations of its specificity in clinical practice.

Utility of clinical pathway and prospective case management to achieve cost and hospital stay reduction for aortic aneurysm surgery at a tertiary care hospital.

PURPOSE: We reviewed our experience with a clinical pathway instituted in December 1993 for all nonurgent abdominal aortic aneurysm (AAA) surgery. METHODS: We analyzed a reference group of 49 consecutive pre-pathway AAA patients (group I) and the 44 patients enrolled in the first year of the pathway (group II). On the basis of the interim review of data collected during the first year, pathway modifications were made, and 34 patients enrolled after these modifications (group III) were also analyzed. RESULTS: Comparison of groups I and II showed that institution of the pathway resulted in a marginally significant reduction in mean charges of 14.7% (p = 0.09), and a slight fall in mean length of stay (LOS) (13.8 vs 13.1 days, NS) and mortality rate (4.1% vs 2.3%, NS). For group II, a significant correlate (p < 0.05) of increased charges was fluid overload as diagnosed by chest radiograph. This recognition led to active efforts to reduce perioperative fluid administration. Comparison of groups II and III revealed that the practice modifications led to marked reduction in the incidence of fluid overload (73% vs 24%; p < 0.01), mean charges (30.4% reduction; p < 0.05), mean LOS (13.1 vs 10.2 days; p < 0.05), and median LOS (11 vs 8 days). Multiple regression analysis of all pathway patients showed that preoperative renal insufficiency is a significant predictor of both increased LOS (p < 0.01) and charges (p < 0.01), but that age, sex, and coronary disease were not predictive. Of the postoperative parameters analyzed, important correlates of increased charges were acute renal failure (p < 0.01) and fluid overload (p < 0.01). CONCLUSIONS: Institution of a clinical pathway for AAA repair resulted in significant charge reduction and a slight reduction in stay. Practice modifications based on interim data analysis yielded further significant reductions in charges and LOS, with overall per-patient charge savings (group I vs III) of 40.6% (p < 0.05) and overall LOS reduction of 3.5 days (p < 0.05). The reduction in actual charges was seen despite an overall increase in the hospital rate structure. Comparing groups I, II, and III, we found no indication of increasing mortality rate. Ongoing analysis has identified correlates of increased charges, potentially permitting identification of high-cost subgroups and more focused cost-control efforts. Rather than restricting management, clinical pathways with periodic data analysis may improve quality of care.

Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Diabetic Ulcer Study Group.

BACKGROUND: There has been a broad interest in the use of growth factors to treat patients with chronic nonischemic diabetic ulcers. STUDY DESIGN: One hundred eighteen patients were studied in a randomized, prospective, double-blind, multicenter trial comparing treatment with topically applied recombinant human platelet-derived growth factor (rhPDGF) or placebo (vehicle) and were treated until completely healed or to 20 weeks. All patients had aggressive sharp debridement of their ulcers before randomization and repeat debridement of callus and necrotic tissue as needed. The influence of debridement was evaluated by reviewing the records of the office visits where debridement was performed. RESULTS: Forty-eight percent of patients treated with rhPDGF healed compared with 25 percent of patients who received placebo (p = 0.01). The mean percentage of office visits where debridement was performed was comparable for the two treatment groups: 46.8 percent (rhPDGF) and 48.0 percent (placebo). In general, a lower rate of healing was observed in those centers that performed less frequent debridement. The improved response rate observed with more frequent debridement was independent of the treatment group. However, for any given center, the percentage of patients who healed was greater with rhPDGF than placebo. CONCLUSIONS: Wound debridement is a vital adjunct in the care of patients with chronic diabetic foot ulcers.

Simultaneous radical nephrectomy and repair of abdominal aortic aneurysm.

OBJECTIVES: The combination of abdominal aortic aneurysm repair with other intra-abdominal surgery is controversial. Most studies have shown that a variety of procedures can be performed at the same time as an aneurysm repair with little change in mortality or complication rates. We conducted a retrospective study to determine if aneurysm repair could be safely and effectively combined with radical nephrectomy. METHODS: We studied 10 patients who underwent combined abdominal aortic aneurysm repair and radical nephrectomy during a 4-year period. Results from this group were compared to a separate control group of 10 patients who underwent radical nephrectomy alone and another of 12 patients underwent abdominal aortic aneurysm repair alone, during the same time period. RESULTS: The overall mortality was 10% and significant complications occurred in an additional 10% of patients. Minor, self-limiting complications occurred in 30% of patients. There were no aortic graft infections that occurred in the entire series of patients at 18 months of mean follow-up. There were no remarkable differences in the entire series of patients and the combined values in a separate group of control patients who had undergone either procedure alone. CONCLUSIONS: Simultaneous radical nephrectomy for presumed renal cell carcinoma can be safely combined with repair of abdominal aortic aneurysm in selected patients.