Influence of secondary infection on amputation in chronic critical limb ischemia.

OBJECTIVES: To evaluate the influence of secondary infection on major amputation in chronic critical leg ischemia (CLI). DESIGN: Prospective, controlled observational study. MATERIALS AND METHODS: Sixty-seven patients with CLI and ischemic lesions participated in the study. Presence of infection was defined by clinical, laboratory and radiological criteria. Patients were categorized as having no local infection, soft tissue infection or osteomyelitis treated without antibiotics, amoxicillin/clavulanacid for 1 month or ciprofloxacin and clindamycin for 3 months, respectively. Clinical outcome was assessed at 2, 6 and 12 months. Study endpoints were major amputation and mortality. Analyses were performed using the Kaplan-Meier method. RESULTS: Forty-seven of 67 patients had a local infection. Major amputation was lower in patients with successful revascularization as compared to patients unsuitable for or with failed (without) revascularization (0% vs 26%, p<0.01). In patients with successful revascularization the probability of complete healing was lower with secondary infection (23% vs 71%, p=0.03). In patients without revascularization complete healing was rare (<10%), but secondary infection did not influenced major amputation, mortality or serious adverse events. CONCLUSION: Secondary infection reduces the likelihood of successful healing following revascularisation of CLI.

Venous thromboembolism prophylaxis in acutely ill medical patients: definite need for improvement.

AIM OF THE STUDY: To examine the frequency and adequacy of thromboprophylaxis in acutely ill medical patients hospitalized in eight Swiss medical hospitals. METHODS: A cross-sectional study of 1372 patients from eight Swiss hospitals was carried out. After exclusion of patients (275) given therapeutic anticoagulation, 1097 patients were audited. The adequacy of thromboprophylaxis was assessed by comparison with predefined explicit criteria. RESULTS: Of 1097 patients, 542 (49.4%) received thromboprophylaxis. According to the explicit criteria, 644 (58.7%) should have been on prophylaxis (P < 0.001, when compared with the rate observed). The rate of prevention differed widely between hospitals (from 29.4 to 88.6%) with no difference between teaching and nonteaching hospitals. According to the explicit criteria, a substantial proportion (44.9%) of the patients who should have been treated were not. Conversely, 41.3% of the patients were unnecessarily treated. CONCLUSIONS: Even though the appropriateness of the explicit criteria used could be challenged, our data suggest that the current practice is associated with important uncertainty leading to both overuse and underuse of thromboprophylaxis in patients hospitalized in medical wards. More efforts are urgently needed to develop new or endorse existing explicit, evidence-based criteria and guidelines for thromboprophylaxis in this population of patients.

Antiplatelet and anticoagulant drugs for prevention of restenosis/reocclusion following peripheral endovascular treatment.

BACKGROUND: Peripheral arterial disease (PAD) is frequently treated by balloon angioplasty. Restenosis/reocclusion of the dilated segments occurs often depending on length of occlusion, lower leg outflow, stage of disease and presence of cardiovascular risk factors. To prevent reocclusion, patients are treated with antithrombotic agents. OBJECTIVES: To determine whether any antithrombotic drug is more effective in preventing reocclusion after peripheral endovascular treatment, compared to another antithrombotic drug, no treatment, placebo, or other vasoactive drugs. SEARCH STRATEGY: We searched the Cochrane Peripheral Vascular Diseases Group's trials register (last searched April 2004), the Cochrane Central Register of Controlled trials (CENTRAL Issue 2, 2004), MEDLINE and EMBASE (last searched June 2004). SELECTION CRITERIA: Randomised trials were categorised as A (double or single blinded) or B (not blinded). Participants included patients with symptomatic PAD treated by endovascular revascularisation of the pelvic or femoropopliteal arteries. Interventions were anticoagulant, antiplatelet or other vasoactive drug therapy compared with no treatment, placebo, or any other vasoactive drug. Clinical endpoints were re-obstruction, amputation, death, myocardial infarction, stroke and major bleeding. DATA COLLECTION AND ANALYSIS: Details of the number of randomised patients, treatment, study design, study category, allocation concealment and patient characteristics were extracted. Analysis was based on intention-to-treat data. To examine the effects of binary outcomes such as amputation and major bleeding, odds ratios were computed using a fixed effect model. The 95% confidence intervals of the effect sizes were calculated. MAIN RESULTS: A 60% reduction of recurrent obstruction was found with aspirin (ASA) 330 mg combined with dipyridamol (DIP) as compared to placebo at 12 months follow-up. At six months following endovascular treatment, a positive effect on patency was found with 50 to 100 mg ASA combined with DIP (n = 356). However, this was not significant. ASA/DIP tended towards showing a superior effect on patency after femoropopliteal angioplasty compared with VKA at three, six, and twelve months. Periinterventional treatment with LMWH in femoropopliteal obstructions resulted in significantly lower restenosis/reocclusion rates than with unfractionated heparin. AUTHORS' CONCLUSIONS: Aspirin 50 to 300 mg started prior to femoropopliteal endovascular treatment appears to be the most effective and is safe. Clopidogrel might be an alternative, but data are lacking. Abciximab might be a useful adjunctive for high risk patients with long segmental femoropopliteal interventions. Low molecular weight heparin seems to be more effective in preventing reocclusion or restenosis than unfractionated heparin.

Antithrombotic agents for preventing thrombosis after infrainguinal arterial bypass surgery.

BACKGROUND: Chronic peripheral arterial disease (PAD) is frequently treated by implantation of either an infrainguinal autologous venous or artificial graft. One-year occlusion rates for infrainguinal bypasses vary between 15 and 75%, depending on the site of distal anastomosis, length, quality, and material of the graft, but also on other factors such as proximal inflow and distal outflow conditions. To prevent graft occlusion, patients are usually treated with either an antiplatelet or antithrombotic drug, or a combination of both. Little is known about which drug is optimal to prevent infrainguinal graft occlusion. OBJECTIVES: To evaluate whether antithrombotic treatment in patients with chronic PAD undergoing infrainguinal bypass surgery improves graft patency, limb salvage and survival by performing a meta-analysis of performed RCTs. SEARCH STRATEGY: The search strategy was that adopted by the Cochrane Review Group on Peripheral Vascular Diseases. Additional data bases were reviewed (Reference lists of papers resulting from this search, MEDLINE from 1966-onwards and EMBASE from 1980-onwards using the terms 'anticoagulant' and 'arterial surgery'. SELECTION CRITERIA: The methodological quality of each trial was assessed independently by at least two reviewers using the checklist provided by the Peripheral Vascular Diseases Collaborative Review Group, with emphasis on concealment of randomisation. Each trial was given an allocation score of A (clearly concealed), B (unclear if concealed), or C (clearly not concealed) and a summary score of A (low risk of bias), B (moderate risk), or C (high risk). Trials scoring A were included and those scoring C were excluded. For a trial scoring B, an attempt was made to obtain more information by contacting the author. DATA COLLECTION AND ANALYSIS: For each trial, the number of patients originally allocated to each treatment group was extracted from the data and an 'intention to treat' analysis performed. Data collection on each trial included inclusion and exclusion criteria, patient details, type of graft, type and dose of antithrombotic therapy used, outcome, and side effects. The treatment and control groups were compared for important prognostic factors and differences described. If any of the above data was not available, further information was sought from the author. However, the heterogeneity between trials could not be tested due to inaccessible data. Data were synthesized by comparing group results. MAIN RESULTS: The analysis including four trials which evaluated vitamin K antagonists (VKA) versus no VKA indicate, that oral anticoagulation tendentially favours venous but not artificial graft patency as well as limb salvage and survival. Two other studies comparing VKA with aspirin or aspirin/dipyridamole supported evidence for a positive effect of VKA on the patency of venous but not artificial grafts. Subgroup analysis for artificial grafts as performed in one trial showed a favourable effect of antiplatelet agents on synthetic bypasses. In two trials with a relatively small number of patients low molecular weight heparin treatment was associated with a lower incidence of early postoperative graft thrombosis compared to treatment with unfractionated heparin. In one trial infusion of antithrombin concentrate was reported to have a negative effect on intraoperative graft thrombosis necessitating the study to be stopped before termination. Perioperative administration of ancrod was compared to unfractionated heparin showing no benefit of one drug compared to the other. REVIEWER'S CONCLUSIONS: Patients operated for an infrainguinal venous graft might benefit from treatment with VKA, whereas patients receiving an artificial graft might profit more from platelet inhibitors (aspirin). However, the evidence is not conclusive. Randomised controlled trials with larger patient numbers comparing antithrombotic therapies with either placebo or antiplatelet therapies are called for in the future.

Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery.

BACKGROUND: Peripheral arterial disease (PAD) may cause occlusions (blockages) in the main arteries of the lower limbs. It is frequently treated by implantation of either an infrainguinal autologous (using the patient's own tissue) venous or artificial graft. A number of factors influence occlusion rates, including the material used. To prevent graft occlusion, patients are usually treated with either an antiplatelet or antithrombotic drug, or a combination of both. OBJECTIVES: To evaluate whether antiplatelet treatment in patients with symptomatic PAD undergoing infrainguinal bypass surgery improves graft patency, limb salvage and survival. SEARCH STRATEGY: The reviewers searched the Cochrane Peripheral Vascular Diseases Group Specialised Register, (last searched April 2003), and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 1, 2003). Additional trials were sought through reference lists of papers and by reviewing proceedings from the vascular surgical society meetings. SELECTION CRITERIA: The methodological quality of each trial was assessed independently by two reviewers (JD, MMK), with emphasis on concealment of randomisation. DATA COLLECTION AND ANALYSIS: Details of the studies selected were extracted independently by two reviewers (JD, MMK), and an 'intention-to-treat' analysis performed. The treatment and control groups were compared for important prognostic factors and differences described. If any data were not available, further information was sought from the author. Data were synthesized by comparing group results. MAIN RESULTS: The administration of a variety of platelet-inhibitors resulted in improved venous and artificial graft patency compared to no treatment. However, analysing patients for graft-type indicated that patients receiving a prosthetic graft were more likely to profit from administration of platelet-inhibitors than those treated with a venous graft. REVIEWER'S CONCLUSIONS: Antiplatelet therapy with aspirin had a slight beneficial effect on the patency of peripheral bypasses, but seemed to have an inferior effect on venous graft patency compared with artificial grafts. The effect of aspirin on cardiovascular outcomes and survival was mild and not statistically significant; this might be due to the fact that the majority of patients receiving a peripheral graft have an advanced stage of PAD with critical ischemia. These patients are usually seriously ill with respect to cardiovascular diseases with high mortality rates of 20% per year. Additionally, the number of patients included in this analysis might still be too small to reach a statistically significant effect for mortality and cardiovascular morbidity.

[Anticoagulation and antiaggregation in patients with peripheral arterial occlusive diseases]. / Antikoagulation und Antiaggregation beim Patienten mit PAVK.

Peripheral vascular occlusive disease (PAOD) is frequently seen in patients suffering from coronary heart or cerebrovascular disease and is, considered as a prognostic predictor for the morbidity and mortality of this patient group. Thus, secondary antithrombotic and antiplatelet prophylaxis in these patients is not limited to achievement of long-term patency of the revascularized or recanalized arterial segment, but plays as well a pivotal role for the prevention of myocardial infarction and stroke. Generally, claudicants as well as patients undergoing percutaneous transluminal angioplasty (PTA), supragenicular femoro-popliteal artificial bypass surgery, aortofemoral, iliaco-femoral unilateral bypass, or aortobifemoral Y-graft implantation with unimpaired arterial outflow are treated life-long with low dose acetylsalicylic acid (ASA) 75-250 mg. On the other hand, those undergoing axillo-femoral, femoro-femoral crossover, aorto-profundal or femoro-popliteal infragenicular and femoro-distal venous bypass surgery should be treated with vitamin K antagonists. The role of Clopidogrel in secondary prevention after peripheral revascularization and recanalization still needs to be defined.

Mouse models of focal arterial and venous thrombosis.

Mouse models of arterial and venous thrombosis have gained increasing interest over the last 15 years, due to direct availability of a growing number of genetically modified mice, improved technical feasibility, standardization of new models of local thrombosis, and low maintenance costs. In order to provide an overview of suitable models for the study of arterial and venous thrombosis in mice, we have systematically searched MEDLINE electronic databases for publications reporting on murine thrombo-embolic models from 1966-1999. We found that the variety of murine thromboembolic models through 1995 was rather limited, as most methods used intravenous injections of strong coagulation triggers such as thrombin, thromboplastin and collagen, causing lethal thromboembolism. Between 1996 and the end of 1999, a number of more sophisticated murine models of local acute or chronic thrombosis have been established. They seem to be more suitable for mimicking the natural scenario of thrombosis and, therefore, are preferable models for pathophysiological or drug evaluation studies. In this paper various models are described and their advantages and limitations discussed.

Diurnal and long-term variations of lymph capillary pressure in healthy subjects.

The variability of pressure in the cutaneous lymph capillaries on the forefoot was determined in 2 groups of healthy volunteers. In group A, including 12 healthy subjects (8 men, 4 women; mean age 28 years, range 22 to 37 years), measurements were performed in the morning and late afternoon of the same day. In group B (12 healthy subjects, 5 women, 7 men; mean age 53 years, range 23 to 72 years), measurements of lymph capillary pressure were repeated with an interval of 7 weeks. The superficial microlymphatics were visualized by intravital fluorescence microlymphography, cannulated with glass micropipettes, and the lymph capillary pressure was measured using a servonulling pressure system. In group A, lymph capillary pressure measured in the morning (mean 7.5 +/- 4.4 mmHg; range -4 to 16 mmHg) did not differ (p > 0.05) from the pressure in the late afternoon (mean value 5.6 +/- 3.4 mmHg; range-1 to 13 mmHg). In group B, initial lymph capillary pressure (mean 3.9 +/- 2.9 mmHg, range -1.1 to 9.7 mmHg) was not different (p > 0.05) compared with the pressure after 7 weeks (2.9 +/- 2.7 mmHg, range -1.0 to 6.8 mmHg). We conclude that lymph capillary pressure in healthy subjects does not exhibit significant changes during the daytime or over the long term.

Effects of subcutaneous insulin-like growth factor-I infusion on skin microcirculation.

When healthy volunteers were treated with human insulin-like growth factor-I (IGF-I), mild generalized edema often developed. In the present study, the effect of IGF-I on cutaneous capillary permeability and microvascular skin blood flow was investigated using fluorescence videomicroscopy and laser Doppler fluxmetry. Transcapillary diffusion of intravenously injected sodium fluorescein (NaF) was quantitated by videodensitometry in terms of fluorescent light intensities (FLIs) 5, 10, 20, 30, 60, 120, 180 and 300 s after the first appearance of the dye. Laser Doppler fluxmetry was performed at rest (LDFrest) and during postocclusive reactive hyperemia (LDFpeak). Eight healthy subjects (3 women, 5 men; mean age 28 years, range 24-30 years) were investigated. The sensing site was the skin on the right dorsal wrist. Measurements were performed after 4 days of subcutaneous infusion of 0.9% saline (control) and of IGF-I. Mean values for the FLI were significantly higher after IGF-I than after saline infusion (p < 0.05), when the FLIs were expressed in arbitrary units. As percentages of their individual maxima, the differences were significant (p = 0.05) after 60 s (23.6 +/- 6.6% with NaCl and 31.9 +/- 7.6% with IGF-I). LDFrest and LDFpeak tended to be higher after IGF-I treatment without achieving statistical significance (p = 0.176). The mean appearance time of the dye after injection was significantly shorter (p = 0.016) in the IGF-I group than in the control group (32.0 +/- 8.4 s with IGF-I, 42.4 +/- 8.3 s with NaCl).(ABSTRACT TRUNCATED AT 250 WORDS)

Fluctuation of skin lymphatic capillary pressure in controls and in patients with primary lymphedema.

The microlymphatic pressure was monitored by using the servo-nulling technique at the forefoot skin in 24 healthy volunteers (number of capillaries studied: 97) and in 27 patients with primary lymphedema (capillary number: 67). The lymphatic capillaries were stained by fluorescence microlymphography with fluorescein isothiocyanate-dextran 150 and cannulated using glass needles with a diameter between 7 and 9 microns. The lymphatic capillary hypertension described recently in primary lymphedema was confirmed in this series (mean pressure of controls 6.7 +/- 3.8 and, of patients 12.8 +/- 5.9 mm Hg; p < 0.001). Two patterns of pressure fluctuation were observed: rhythmic low-amplitude (mean value 3.7 mm Hg) waves with a frequency identical to respiration (respiratory movements of the thorax recorded simultaneously by a photo cell) and spontaneous nonrhythmic, low-frequency waves with a higher amplitude (mean value 5.5 mm Hg). The prevalence of waves synchronous with respiration was identical in patients and controls, whereas the low-frequency waves exhibited a significantly (p < 0.05) higher prevalence in the patients (41.7%) than in the controls (70.4%). The hypothesis is advanced that in primary lymphedema a considerable amount of lymphatic fluid is removed by lymphatic pathways with small calibre and high resistance, resulting in microvascular hypertension, and that contractions of the few preserved large proximal lymphatic collectors are enhanced. The latter mechanism could explain the increased prevalence of spontaneous microlymphatic pressure fluctuations with high amplitude and low frequency.

Lymphatic capillary pressure in patients with primary lymphedema.

Flow and pressure dynamics in minute human lymphatics are unexplored. Lymphatic capillary pressure was measured by the servo-nulling technique at the foot dorsum of 14 patients with primary lymphedema and 15 healthy controls. Glass micropipettes (7-9 microns) were inserted under microscopic control into lymphatic microvessels previously stained by fluorescence microlymphography (FITC-Dextran 150,000). Mean lymphatic capillary pressure was 7.9 +/- 3.4 mm Hg in the controls and 15.0 +/- 5.1 mm Hg in the patients. The difference was significant at the P < 0.001 level. In about half of the patients and control subjects studied pressure fluctuated by more than 3 mm Hg. The mean intralymphatic pressure of lymphedema patients was slightly below mean interstitial pressure measured by J. T. Christensen, N. J. Shaw, M. M. Hamas and H. K. Al Hassan (1985, Microcirc., Endothelium, Lymphatics 2, 267-384) (17.9 mm Hg) in lower leg lymphedema. Microlymphatic hypertension present in patients with primary lymphedema is probably an important factor for edema formation.