Patients with peripheral artery disease (PAD) may be asymptomatic, have intermittent claudication (IC), or have critical limb ischemia (CLI). In general, patients with claudication have improved walking performance following supervised exercise therapy, which focuses on a walking program. However, the benefits of a walking program in patients with CLI are more challenging and not as well described.
There are limitations for walking programs for patients with CLI. Available exercise regimens are structured for patients with claudication, but are not necessarily specific for those with CLI. Additionally, the functional goals vary for claudicants when compared with patients with CLI. Among claudicants, the main objective is to improve walking performance, but for patients with CLI, the major goals are to prevent or limit amputation, heal wounds, and improve rest pain. Walking may be a successful outcome in a CLI patient.
Currently prescribed supervised exercise for PAD patients with claudication may not be practical for CLI patients. Alternative exercise regimens (cycling, strength training, and upper-arm ergometry) might be considered for patients with CLI.
Key words: critical limb ischemia, claudication, peripheral artery disease
PAD is caused by progressive atherosclerosis and affects more than 200 million people globally.1,2 Several epidemiological studies have used objective testing to evaluate total disease prevalence and have found that it ranges from 3% to 10%, increasing to 15% to 20% in persons over 70 years.3 Approximately 1% to 3% of patients with PAD may present with CLI; however, with increasing life expectancy and the prevalence of diabetes, obesity, and sedentary lifestyles, these estimates are likely to increase.4
A common clinical presentation of PAD is intermittent claudication, which often affects walking performance, but may also decrease quality of life.3 Supervised exercise has been shown to improve walking performance in this patient population.5 In contrast to claudicants, patients with CLI present with ischemic rest pain, tissue loss, or gangrene.4,6 Patients with CLI have a significant compromise in quality of life when compared with patients with non-CLI PAD.4,7 With claudication, a person must be ambulatory to experience symptoms, whereas the goal in CLI may be simply to be ambulatory. Despite the fundamental differences between CLI and claudication, the limited evidence in patients with PAD means they are often grouped together. In other words, supervised exercise programs traditionally prescribed for patients with claudication may be impractical for those with CLI.8,9 This article will address the need for exercise therapies specific to the CLI population.
Supervised Exercise Therapy in PAD
Ten randomized, controlled trials examining walking outcomes in 558 PAD patients demonstrated that supervised exercise programs were more effective than community walking.8 However, in a meta-analysis of 30 studies, any exercise program was overall superior to control for walking performance.10 As such, supervised exercise therapy is a Class I recommendation for the patient with PAD. Supervised exercise programs for PAD occur in a hospital or outpatient setting and implement an intermittent walking program as the treatment modality (either standalone or within the cardiac rehabilitation program). The programs are overseen by a qualified health care provider. Sessions are typically performed for a duration of 30 to 45 minutes at least 3 times per week for a minimum of 12 weeks. Sessions involve intermittent bouts of walking until moderate to maximum claudication, alternating with periods of rest. A warm-up and cool-down period precede and follow each session of walking. A structured community or home-based exercise program is a Class II recommendation in the management of patients with PAD. The exercise regimen prescribed is similar to that of a supervised program. It may incorporate behavioral change techniques, such as health coaching or the use of activity monitors.9
Mechanism of Clinical Benefit of Walking Programs for PAD
The exact physiologic mechanisms leading to the improvement of walking capacity in PAD patients remains unclear. The improved walking capacity may be due to skeletal muscle adaptation, improvement in walking economy, increased angiogenesis, decrease in blood viscosity, improvement in endothelial function, decrease in atherosclerosis, and/or increase in pain tolerance.8 Some of the mechanisms associated with exercise therapy and outcomes among patients with PAD are summarized below. The data largely involve patients with claudication. Research has yet to reveal whether the same mechanistic benefits apply to patients with CLI.
I. Impact on inflammatory markers. Repeated episodes of calf or buttock pain can cause ischemia-reperfusion injuries, resulting in an inflammatory response. In a case-control study, several inflammatory markers, including plasma fibrinogen, serum amyloid A protein, C-reactive protein, and urinary albumin-creatinine ratio, were measured in 67 patients with claudication and 15 matched controls.11 In a randomized portion of this study, 22 patients were randomized to supervised exercise training and 17 to observation. Follow-up was out to 12 months. Exercise training reduced inflammatory markers, with no similar changes in controls.11 It remains unclear whether the clinical benefit of supervised exercise in those with PAD is related to a reduction in an inflammatory state.
II. Improved endothelium function. Patients with claudication often demonstrate endothelial dysfunction.12 It has been shown that supervised exercise training can improve brachial flow-mediated vasodilation, a measurement of endothelial function. The mechanism may involve a reduction in an inflammatory state or ischemic preconditioning.12
III. Increased capillary density: The hypothesis that supervised exercise training in PAD patients increases capillary density (CD) has been studied. For example, in a randomized trial of 35 patients with PAD, patients undergoing 12 weeks of supervised or home-based exercise training underwent peak VO2 testing and gastrocnemius muscle biopsies before and after training. CD (endothelial cells/mm2) as assessed by immunofluorescence imaging from muscle biopsy specimens increased at 3 weeks compared with baseline, which preceded increases in peak VO2.13
IV. Altered skeletal muscle metabolism. There are adaptations in skeletal muscle tissue following exercise training. In 7 adult men who underwent training with knee-extension exercises of one leg but not the other, the trained leg showed improvements in the efficiency of lipid and fatty acid metabolism compared with the non-trained leg.14
V. Improvement in walking economy. Walking economy might be defined as the rate of oxygen consumption per unit distance by an individual who walks at a submaximal level. Walking economy can be adversely affected by cardiopulmonary disorders, PAD, and biomechanical disturbances. To assess effects of supervised exercise on walking economy, 16 participants with PAD were randomized to a control group or a supervised exercise group. Oxygen consumption was measured at baseline and after 6 months. There were no differences in oxygen consumption at baseline, but following exercise training, the treatment group had lower oxygen consumption during graded treadmill testing as compared with the control group.15 These results suggest that supervised walking programs may improve physiologic efficiency and walking economy.
VI. Improvements in blood rheology. Whether training can ameliorate the flow properties of blood was tested in patients with IC. Forty-two patients with claudication were assigned to 2 groups. Participants in Group I (n=22) underwent standardized treadmill exercise for 2 months. The control Group II (n=20) patients did not exercise over the same period of time, Not surprisingly, walking performance improved in Group I, but not Group II. However, interestingly, the rheology of blood, as measured by blood and plasma viscosity, hematocrit, blood filterability, and red cell aggregation, was initially abnormal in patients with PAD when compared with that of matched controls. The measurements normalized after 2 months of exercise in Group I, however, while the measurements remained abnormal in Group II.16 These results suggest that supervised exercise may improve blood rheology, which may be linked to a mechanism of clinical benefit.
Functional Goals in Patients With Claudication vs CLI
The functional goals vary for claudicants when compared with patients with CLI, as the major objective is to improve walking performance among claudicants vs to prevent or limit amputation, heal wounds, and improve rest pain among CLI patients. The ability to walk is often limited among patients with CLI as a result of non-healing wounds that require offloading, as well as the lower functional status in this population. Alternatives to a walking program should be considered.
Alternative modes of exercise therapy include cycling, strength training, and upper-arm ergometry. A Cochrane systematic review and meta-analysis assessed 5 clinical trials (n=135) that compared supervised walking to alternative modes of exercise in patients with PAD.17 No statistical difference was found between supervised walking exercise and alternative modes of exercise in maximum walking distance on a treadmill with no incline and an average speed of 3.2 km/h, which is comparable with walking in daily life. Similarly, there was no difference between supervised walking exercise and alternative modes of exercise in pain-free walking distance. Quality of life measures showed similar and significant improvements in both groups.17
Barriers to Supervised Exercise Therapy
Within a social cognitive framework, there are multidimensional factors influencing walking in patients with PAD. That is, there are patient-level factors (eg, co-morbid health concerns), walking-related factors (eg, claudication pain), and environmental factors (eg, support systems).5 There are often transportation and time barriers that limit the ability of patients to travel frequently to a center and participate in a supervised walking program. In addition, patients with CLI have additional barriers such as a painful foot wound, need for offloading, multiple comorbidities, and competing health care appointments. Given the nature of CLI, alternatives to a walking program should be made available, and a rehabiltation program specific to this population is needed.
Supervised exercise is a proven therapy for claudication, but may not be practical for patients with CLI. Furthermore, treatment goals differ for patients with CLI as compared to those with claudication. As such, a CLI-specific rehabilitation program that incorporates alternative exercise options and prescriptions is needed.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest and report no conflicts of interest regarding the content herein.
Manuscript submitted February 21, 2019; Accepted on February 25, 2019
Address for correspondence: R. Kevin Rogers, MD, MSc, RPVI, Associate Professor and Program Director, University of Colorado, Mail Stop B132, Leprino Building, 12401 East 17th Avenue, Room 560, Aurora, Colorado, 80045; Phone: (720) 848-6506; Email: email@example.com
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