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PubMed1998

The evidence for exercise-induced inflammation in intermittent claudication: should we encourage patients to stop walking?

OBJECTIVES: To review clinical and experimental evidence that exercise to the onset of calf pain in patients with intermittent claudication results in an inflammatory response, and to consider whether repeated inflammatory events induced by therapeutic exercise training may lead to progression of atherosclerosis. METHODS: A literature search was performed to identify studies measuring biochemical markers of exercise-induced ischaemia-reperfusion injury in patients with intermittent claudication. Current theories of atherogenesis were reviewed and the use of acute-phase proteins as potential markers of vascular disease explored. RESULTS: Exercise to the onset of calf pain results in an inflammatory response with free radical formation, neutrophil activation and systemic vascular endothelial damage. Acute-phase proteins such as C-reactive protein and serum amyloid A protein have exciting potential use as stable biochemical markers of disease in claudication. CONCLUSIONS: Further studies are needed to determine the effect of long-term exercise training on exercise-induced inflammation in claudication. Early work suggests, in fact, that exercise attenuates this inflammatory response. If this were confirmed then it would support the clinical impression that exercise training is beneficial in terms of symptomatic improvement and cardiovascular health in patients with intermittent claudication.

Acute-Phase Proteins↗
PubMed1998

Exercise-induced neutrophil activation in claudicants: a physiological or pathological response to exhaustive exercise?

OBJECTIVES: To assess the effect of exhaustive exercise on neutrophil activation and degranulation in claudicants and controls. We investigated the hypothesis that neutrophil activation and degranulation are normal responses to exhaustive exercise in healthy patients. DESIGN: This was a controlled experimental two-group study. MATERIALS: Exercise was performed using a fixed workload treadmill test. Neutrophil activation was assessed by flow cytometry of whole blood labelled with anti-CD11b mouse IgG, and neutrophil degranulation in terms of plasma elastase measured by enzyme-linked immunosorbent assay. METHODS: Twenty-eight claudicants with stage 1 chronic leg ischaemia, and 22 healthy controls were recruited. Blood and urine samples were collected before and after treadmill exercise. Claudicants exercised to their maximum walking distance, and controls at a higher "fatigue" workload for a maximum of 20 min. RESULTS: Exercise produced a brief but significant neutrophilia in both groups. Neutrophil CD11b expression increased significantly after exercise only in the claudicants, and was associated with a significant rise in plasma neutrophil elastase. These indices remained unchanged in the control group at all time points despite exercise at a fatigue level. CONCLUSION: The inflammatory response associated with exercise in claudicants is not simply a physiological response to exhaustive exercise.

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PubMed2003

Pharmacological prevention of cardiac risk in claudicants with ischaemic heart disease.

BACKGROUND: Claudicants rarely progress to critical limb ischaemia but have a threefold increase in mortality, mainly due to cardiac disease. Antithrombotic therapy, beta blockers, ACE inhibitors and statins have been shown to reduce mortality and cardiovascular morbidity in patients with ischaemic heart disease. AIM: To investigate secondary pharmacological prevention of ischaemic heart disease in claudicants. MATERIALS AND METHODS: We prospectively recorded comorbidity and drug treatment in 89 patients (67 men and 22 women) with a history of ischaemic heart disease recruited in a supervised exercise and lifestyle modification programme to improve claudication distance and prognosis. RESULTS: Of the 89 cases, 40 had a history of angina only and 49 of myocardial infarction. Sixteen (18%) had diabetes, 47 (53%) had hypercholesterolaemia and 52 (58%) were hypertensive. Antithrombotic therapy was prescribed to 61 patients (68.5%), 64 (72%) with a history of myocardial infarction and 27 (67.5%) with angina only (p = 1). Beta-blockers were prescribed to 12 (13.5%) patients only, seven (15%) with a history of myocardial infarction and five (12.5%) with angina only (p = 1). Of the 47 patients with hypercholesterolaemia, 29 (62%) were on a statin. CONCLUSION: Secondary pharmacological prevention of ischaemic heart disease in claudicants remains suboptimal, with only two thirds of patients receiving antithrombotic therapy and a small minority receiving beta blockers. Pharmacological prevention in claudicants should improve to reduce cardiac morbidity and mortality.

Adrenergic beta-Antagonists↗
PubMed2006

Established and evolving medical therapies for claudication in patients with peripheral arterial disease.

Claudication resulting from peripheral arterial disease causes substantial impairment in the ability to carry out normal daily activities. The medical treatments for claudication that are currently available are exercise rehabilitation and one drug, cilostazol. Pentoxifylline, which improves red cell deformability, lowers fibrinogen levels and decreases platelet aggregation, has been used historically, but frequency of use has declined because of limited effectiveness. Exercise rehabilitation, while efficacious, has been underused in the past. This therapy is, however, currently the subject of several large research projects. These studies are investigating mechanisms by which exercise therapy could benefit people with claudication and are also directly comparing it with other therapies. Concurrently, several new drug therapies for claudication are in the process of being evaluated. These research efforts might increase the available armamentarium and thereby help to alleviate the impairments associated with this symptom. The aim of this article is to discuss the current medical treatments being developed for use in patients with claudication resulting from peripheral arterial disease.

Ankle↗
PubMed1996

Haemostatic and rheological factors in intermittent claudication: the influence of smoking and extent of arterial disease.

Patients with intermittent claudication have been reported to have disturbances in blood rheology and haemostasis. Whether these disturbances are a result of, or largely independent of, smoking history and arterial narrowing has not yet been established. The levels of whole blood and plasma viscosity, haematocrit, von Willebrand factor antigen, fibrin D-dimer antigen and urinary fibrinopeptide A antigen were compared in 617 claudicants and 722 controls from two epidemiological studies in Edinburgh. After adjustment for age and sex, all factors, except whole blood viscosity and haematocrit, were significantly higher in the claudicants compared to controls (P < or = 0.001). The risk of intermittent claudication was significantly raised for unit change in each factor, except for whole blood viscosity and haematocrit. Adjustment for lifetime smoking had little effect on the odds ratios. After further adjustment for the ankle brachial pressure index (as a measure of the extent of peripheral arterial disease), haematocrit, von Willebrand factor and urinary fibrinopeptide A showed a significant independent relationship with the risk of intermittent claudication. We conclude that the association between selected rheological and haemostatic factors and leg ischaemia is largely independent of both smoking history and the extent of arterial narrowing, and may be directly related to microvascular ischaemia.

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PubMed1999

Peripheral thrombolysis for acute-onset claudication. Thrombolysis Study Group.

BACKGROUND: The aim of this study was to determine the outcome of patients who presented with sudden onset of incapacitating claudication of less than 2 weeks' duration and who were treated with peripheral arterial thrombolysis. METHODS: The database of the Thrombolysis Study Group was searched retrospectively for patients who received thrombolysis for acute-onset claudication. Some 108 patients (65 men, median age 69 (range 29-94) years) were treated with intra-arterial tissue plasminogen activator at 14 hospitals. The median duration of symptoms was 72 h (range from 2 h to 2 weeks). There were 52 graft and 56 native vessel arterial occlusions. RESULTS: The immediate outcome of thrombolysis for native vessel arterial occlusion was thrombus clearance in 50 patients (89 per cent) and failed lysis in six (11 per cent). Thirty-six patients (64 per cent) had a secondary radiological or surgical procedure carried out after lysis. After 30 days four patients (7 per cent) had a major amputation, eight (14 per cent) had died, 38 (68 per cent) were symptom free and seven (12 per cent) continued to have claudication. Three patients (5 per cent) suffered a major haemorrhage. The immediate outcome of thrombolysis for graft occlusion was thrombus clearance in 48 patients (92 per cent) and failed lysis in four (8 per cent); 27 patients (52 per cent) had a secondary procedure. After 30 days four patients (8 per cent) had a major amputation, seven (13 per cent) had died, 32 (62 per cent) were symptom free and nine (17 per cent) had persistent claudication. Three patients (6 per cent) suffered a major haemorrhage. CONCLUSION: Patients who presented with acute onset of incapacitating claudication had an outcome similar to that after thrombolysis for critical ischaemia. It is recommended that patients who present in this way should be observed and treated with thrombolysis only if they progress to critical ischaemia. Presented to the Association of Surgeons of Great Britain and Ireland, Edinburgh, UK, May 1998, and published in abstract form as Br J Surg 1998; 85(Suppl 1): 24

Adult↗
PubMed2001

A new device for the measurement of disease severity in patients with intermittent claudication.

OBJECTIVES: To assess a new method of determining functional impairment in patients with intermittent claudication, the Double Physiological Walking Test (DPWT) using the PADHOC (Peripheral Arterial Disease Holter Control) device, against a standard treadmill test. DESIGN: Patients with intermittent claudication presenting to the department were considered for both the DPWT and a standard treadmill test. METHODS: initial claudicating distance, maximal walking distance and speed of walking were determined for both parts of the DPWT. Initial claudicating distance and maximal walking distance were determined from the treadmill test. Comparisons were made between the treadmill test and the DPWT. RESULTS: The treadmill test was unable to be performed in 22% of patients due to defined contraindications. There were strong correlations in both walking distances and disease severity when comparing the DPWT and the treadmill test. Patients in whom the treadmill test was contraindicated had significantly shorter walking distances on the DPWT than those who were able to complete a treadmill walking test. CONCLUSIONS: The DPWT correlates strongly with walking distances obtained from a standard treadmill test. However, the PADHOC can be used in a number of differing locations and settings as well as in patients in whom a treadmill test is contraindicated. It therefore has a role to play in the initial assessment of patients presenting with intermittent claudication.

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PubMed2002

A randomised, double blind, placebo-controlled study to determine the efficacy of immune modulation therapy in the treatment of patients suffering from peripheral arterial occlusive disease with intermittent claudication.

OBJECTIVES: this study examined the effect of immune modulation therapy (IMT) on claudication distances. MATERIALS AND METHODS: a double-blind placebo controlled trial was performed on patients with disabling intermittent claudication with randomisation stratified for short and long distance IC. For IMT, following exposure to UV light, oxidisation and 42.5 degrees C, 10 ml of citrated autologous blood was administered by intra-muscular injection. One course consisted of 6 injections in 3-weeks followed by 3-weeks rest. Patients received 2, 3 or 4 courses depending on response. The primary end-point was the number of responders (>50% increase in initial claudication distance (ICD)) in each group. Secondary end-points included percentage changes in ICD and change in quality of life. RESULTS: at week 24, there were more responders in the IMT group (20/31, 65%) compared to placebo (16/39, 41%) (p=0.06). In the subgroup of short distance claudicants this difference reached significance (IMT 17/26, 65%) (Placebo 12/33, 36%) (p=0.04). The median increase in ICD was significantly greater in the IMT group (81%) compared to placebo (44%, p=0.04). These results were supported by quality of life measurements. CONCLUSIONS; IMT is a safe and apparently effective treatment for patients with short distance claudication.

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PubMed2003

Exercise in claudicants is accompanied by excessive thrombin generation.

BACKGROUND: exercise in IC leads to ischaemia-reperfusion injury of leg muscles and a systemic inflammatory response, but the effect of on coagulation is unknown. OBJECTIVE: to compare the effect of exercise on thrombin formation and fibrin turnover in patients with IC (n = 10), and age and sex matched smokers ([S] n = 5) and non-smokers ([NS] n = 5) without peripheral vascular disease. METHODS: blood was taken from subjects 60 and 30 min before, and 1, 5, 20, 40, 60 and 120 min after, treadmill exercise. Markers of thrombin generation (thrombin-antithrombin complexes [TAT] and prothrombin fragments 1 + 2 [PF1 + 2]) and fibrin turnover (D-dimer and fibrin degradation products [FbDP]) were assayed at each time point. RESULTS: following exercise, thrombin generation was significantly greater in the claudicant group compared to the control groups (Area Under Curve [AUC] post exercise IC vs S vs NS; TAT 3960 vs 1623 vs 1476 vs = 0.007 Kruskal-Wallis [KW]; PF1 + 2 163 vs 107 vs 123 p = 0.024 KW). Pre and post-exercise, fibrin turnover in claudicants was similar to smoking controls, but higher than non-smoking controls. (AUC post exercise IC vs NS; D-dimer 6340 vs 2754 p = 0.055 Mann-Whitney U[MW]; FbDP 45113 vs 21511 p = 0.009 MW). CONCLUSION: when compared to non-claudicants, exercise in IC is associated with excessive production of thrombin. Despite this, claudicants have a similar level of fibrin turnover suggesting a possible defect in fibrinolysis. This prothrombotic state may contribute to the excess thrombotic morbidity and mortality suffered by claudicants.

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PubMed2000

Intestinal permeability is increased in patients with intermittent claudication.

PURPOSE: Intermittent claudication can be regarded as repeated ischemia reperfusion injury, which can induce a generalized increase in vascular permeability, including in intestine. The lactulose mannitol test (L/M test) was performed in patients with intermittent claudication to evaluate the change in intestinal permeability when they were forced to walk. METHODS: The L/M test was performed in 11 patients with intermittent claudication and 11 control subjects without intermittent claudication. The test was performed at rest and after exercise. Patients walked on a treadmill until they stopped because of pain. The control subjects were forced to walk as far as 200 m on a treadmill. The L/M test was repeated in the patients after successful arterial reconstruction. Then the patients were instructed to walk the same distance at the same speed as they had before surgery. RESULTS: In patients, the mean L/M ratio after exercise was significantly higher than the mean L/M ratio when they were at rest (0.068 +/- 0.053 vs 0.022 +/- 0.009, P <.05). In control subjects, however, no significant difference was observed between the mean L/M ratios after exercise and at rest. The mean L/M ratio after exercise, decreased from 0.068 +/- 0.053 to 0.018 +/- 0. 016 after successful arterial reconstruction (P <.05) in patients. CONCLUSION: Intestinal permeability, determined by means of the L/M test, significantly increased in patients with intermittent claudication after exercise, and it diminished after arterial reconstruction. The L/M test is, consequently, a new noninvasive method to reflect ischemia in lower limbs during exercise.

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PubMed2001

Outcome events in patients with claudication: a 15-year study in 2777 patients.

OBJECTIVE: The purpose of this study was to delineate the natural history of claudication and determine risk factors for death. METHODS: We reviewed the key outcomes (death, revascularization, amputation) in 2777 male patients with claudication identified over 15 years at a Veterans Administration hospital with both clinical and noninvasive criteria. Patients with rest pain or ulcers were excluded. Data were analyzed with life-table and Cox hazard models. RESULTS: The mean follow-up was 47 months. The cohort exhibited a mortality rate of 12% per year, which was significantly (P <.05) more than the age-adjusted US male population. Among the deaths in which the cause was known, 66% were due to heart disease. We examined several baseline risk factors in a multivariate Cox model. Four were significant (P <.01) independent predictors of death: older age (relative risk [RR] = 1.3 per decade), lower ankle-brachial index (RR = 1.2 for 0.2 change), diabetes requiring medication (RR = 1.4), and stroke (RR = 1.4). The model can be used to estimate the mortality rate for specific patients. Surprisingly, a history of angina and myocardial infarction was not a significant predictor. Major and minor amputations had a 10-year cumulative rate less than 10%. Revascularization procedures occurred with a 10-year cumulative rate of 18%. CONCLUSIONS: We found a high mortality rate in this large cohort and four independent risk factors that have a large impact on survival. Risk stratification with our model may be useful in determining an overall therapeutic plan for claudicants. A history of angina and myocardial infarction was not a useful predictor of death, suggesting that many patients in our cohort presented with claudication before having coronary artery symptoms. Our data also indicate that claudicants have a low risk of major amputation at 10-year follow-up.

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PubMed2003

Treating patients with peripheral arterial disease and claudication.

The vascular nurse plays an important role in the treatment of patients with peripheral arterial disease (PAD), a prevalent atherosclerotic occlusive disease that affects approximately 8 to 12 million people in the United States. Approximately 4 to 5 million individuals with PAD experience claudication, the exercise-induced ischemic pain in the lower extremities that is relieved upon rest. Both PAD and claudication are associated with increased morbidity and mortality, limitations in functional capacity, and a decreased quality of life. Despite its prevalence, PAD is often undiagnosed and, therefore, increases the risk for cardiovascular ischemic events, disease progression, functional disability, amputation, and death. Risk factors for PAD and claudication are similar to those for other atherosclerotic diseases, including age, cigarette smoking, diabetes mellitus, hypertension, dyslipidemia, and hyperhomocysteinemia. Effective treatment to normalize these risk factors can reduce disease progression and the incidence of cardiovascular ischemic events. Claudication symptoms can be improved most effectively through exercise training, which may be used in conjunction with medications specifically indicated to improve these symptoms. Vascular nurses, practicing in a multitude of inpatient and outpatient settings, can assist patients with risk-factor modifications and behavioral changes to help them stop smoking, maintain glycemic control, normalize high blood pressure and lipid levels, and ensure initiation of lifelong antiplatelet therapy and participation in exercise rehabilitation programs, thus, promoting positive outcomes for patients with claudication.

Algorithms↗
PubMedDate not supplied

Controlled trial of suloctidil in intermittent claudication.

Forty-five patients with intermittent claudication were first treated with placebo tablets for 3 months and then randomly allocated to double-blind therapy with either suloctidil or placebo for 6 months. Walking distance improved significantly in both groups during the 3 months of placebo treatment. During the 6 months of double-blind treatment with a further significant improvement occurred only in the placebo group when all patients were analyzed. However, when patients who stopped for reasons unrelated to claudication such as angina and exhaustion during repeated walking tests were eliminated, only suloctidil-treated patients improved significantly. The evolution of leg flow and distal pressure was similar in the two treatment groups whether all legs or only legs with abnormal flow and pressure values were considered. By contrast, when the analysis was limited to legs with claudication pain, a significant improvement occurred only in the suloctidil-treated group. These findings suggest that suloctidil may improve the claudication symptoms of patients with chronic arterial obstructive disease and in particular the perfusion of legs experiencing claudication pain. However, the clinical significance of this improvement appears limited.

Clinical Trials as Topic↗
PubMed1986

Jaw claudication in primary systemic amyloidosis.

Amyloid deposits in the temporal artery were observed 40 years ago, but the presence of vascular ischemic symptoms in patients with amyloidosis has been infrequently recognized. We examined 22 patients who had typical jaw claudication with biopsy-proven primary amyloidosis. In none was vasculitis a contributing cause of the claudication. However, two patients were misdiagnosed initially as having temporal arteritis and polymyalgia rheumatica and were treated with corticosteroids, which resulted in significant toxicity. Subsequent temporal artery biopsy revealed extensive amyloid deposits in both patients. Jaw claudication was associated with other ischemic vascular symptoms, such as arm or calf claudication. The median survival for the subset of patients with amyloidosis and jaw claudication was 42 months, and that for the entire group of patients with amyloidosis was 12 months. Appropriate staining of temporal artery biopsy specimens is necessary for the correct diagnosis in such cases.

Aged↗
PubMed1994

Jean-François Bouley (Bouley jeune). Pioneer investigator in intermittent claudication.

Reports of pathologic investigations as to the cause of intermittent claudication in horses were made in France in October, 1831, by veterinarian Jean-François Bouley. Obstructive clots in the femoral arteries were found to be responsible for the muscular changes causing limping. Bouley's work in the horse was used by Charcot in 1858 to understand the mechanism of claudication in the case of a soldier with gunshot wound in whom a traumatic aneurysm, clotting, and ischemia of the legs developed. This was not, however, the first medically reported case of human claudication from vascular occlusive disease; the one reported by Barth in 1835 seems to be the first. According to Dejerine in 1911, the disease in the horse appeared to be due to invasion of the vessels by a parasitic round worm; earlier he had ascribed some cases of human claudication to impaired circulation of the spinal cord. It was not until 1949, however, that Verbiest elaborated the concept of spinal stenosis to explain one type of human claudication.

Animals↗
PubMedDate not supplied

Effects of long-term exercise rehabilitation on claudication distances in patients with peripheral arterial disease: a randomized controlled trial.

PURPOSE: To determine if improvements in physical function and peripheral circulation after 6 months of exercise rehabilitation could be sustained over a subsequent 12-month maintenance exercise program in older patients with intermittent claudication. METHODS: Seventeen patients randomized to exercise rehabilitation and 14 patients randomized to usual care control completed this 18-month study. Patients exercised three times per week during the first 6 months of a progressive exercise program, followed by two times per week during the final 12 months of a maintenance program. Patients were studied at baseline, 6 months, and 18 months during the study. RESULTS: Eighteen months of exercise rehabilitation increased the initial claudication distance by 373 meters (189%) (P <.001), the absolute claudication distance by 358 meters (80%) (P <.001), walking economy by 11% (P <.001), 6-minute walk distance by 10% (P <.001), daily physical activity by 31%, and maximal calf blood flow by 18% (P <.001). These changes were similar to those found after 6 months of exercise rehabilitation (P = NS), and were significantly greater than the changes in the control group throughout the study (P <.05). CONCLUSION: Improvements in claudication distances, walking economy, 6-minute walk distance, physical activity level, and peripheral circulation after 6 months of exercise rehabilitation are sustained for an additional 12 months in older patients with intermittent claudication using a less frequent exercise maintenance program.

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PubMed1980

Capillary supply and muscle fibre types in patients with intermittent claudication: relationships between morphology and metabolism.

There have been previous reports on an increased oxidative capacity in muscle tissue from the diseased legs of patients with intermittent claudication. The present study was designed to correlate metabolic and morphological data and to investigate whether the metabolic adaptive changes in muscle tissue of claudicating legs were also reflected in morphological variables such as capillary supply, fibre type distribution, and fibre area. The activity of cytochrome-c-oxidase in gastrocnemius muscle was determined and the insulin and glucose uptakes were measured across the leg in the basal state and 10 min following intravenous administration of 25 g glucose. The finding of a reduced relative number of Type II B fibres and a reduced ratio Type II B/II A fibre area, as well as an increased capillary supply to Type II A, indicated that the most extensive morphologic changes in muscle tissue of claudicating legs had occurred in Type II fibres. The increased number of capillaries in contact with Type II A fibres in muscle tissue from claudicating legs, compared with muscle tissue from control legs, suggested that the most apparent metabolic changes occurred in this fibre type in the adaptation process of these patients. The more pronounced morphologic and metabolic changes in Type II fibres suggest that these fibres are more intensely activated than Type I fibres during physical activity in claudicating legs. The insulin uptake correlated positively with the number of capillaries per fibre, suggesting that the endothelial surface area is one of the determining factors for insulin uptake. The percentage of Type II B fibres reflected to a certain extent the metabolic adaptation in muscle tissue.

Aged↗
PubMed1993

The impact of intermittent claudication on quality of life evaluated by the Sickness Impact Profile technique.

Unselected patients suffering from intermittent claudication (n = 148) were invited to take part in a prospective study. Physical examination and several circulatory investigations were performed including a treadmill walking test, bicycle ergometry and a quality of life examination (Sickness Impact Profile, SIP, technique). The SIP has been reported to be sensitive enough to identify specific dysfunction profiles in several clinical conditions, but it has not been used on patients with intermittent claudication. The aim of this study was to determine to what extent quality of life was influenced by reduced walking ability in patients with intermittent claudication. If so, the SIP technique should then be a useful tool for determination of the degree of reduced exercise capacity in patients who may benefit from surgery instead of conservative treatment. A majority of the SIP categories, Sleep and rest, Emotional behaviour, Body care and movement, Home management, Mobility, Social interaction, Ambulation and Overall SIP were shown to be useful in confirming objective dysfunctions in our patients. The correlation between maximum walking ability and SIP scores indicated an approximate cut-off limit at 70 W walking capacity. Thus, significant reductions in everyday life function were demonstrated in patients with maximum walking ability below 70 W. Patients with intermittent claudication also suffered from several other dysfunctions in addition to walking disability. These factors may, as well, impact on quality of life without walking disability. Our results demonstrated that quality of life assessment by the SIP technique was a sensitive method for evaluation of overall dysfunction in patients with intermittent claudication.(ABSTRACT TRUNCATED AT 250 WORDS)

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