CALF MUSCLE HEMOGLOBIN OXYGEN SATURATION IN PATIENTS WITH PERIPHERAL ARTERY DISEASE WHO HAVE DIFFERENT TYPES OF EXERTIONAL LEG PAIN

Abstract

Purposes

To compare calf muscle hemoglobin oxygen saturation (StO₂) and exercise performance during standardized treadmill exercise in patients with peripheral artery disease (PAD) who describe different types of exertional leg pain, and to compare secondary outcomes consisting of daily ambulatory activity and exercise performance during a 6-minute walk test.

Methods

One hundred fourteen PAD patients were evaluated on leg pain symptoms using the San Diego claudication questionnaire, which defined patients as having atypical exertional leg pain (n = 31), claudication (n = 37), or leg pain on exertion and rest (n = 46). Patients were evaluated on a standardized, graded treadmill test during which calf muscle StO2 was continuously monitored, 6-minute walk test, walking impairment questionnaire (WIQ), and ambulatory activity monitored during one week.

Results

All patients experienced symptoms during the treadmill test consistent with claudication. The groups were not significantly different on the primary outcomes of time to reach the minimum calf muscle StO₂ (p = 0.350) and peak walking time (p = 0.238) during treadmill exercise. Patients with atypical leg pain had the highest daily ambulatory activity for total strides per day (p = 0.032), average daily cadence (p = 0.010), maximum cadences for durations between 5 min (p = 0.035) and 60 min (p = 0.029), speed score on the WIQ (p = 0.006), and lowest rating of perceived exertion at the end of the 6-minute walk test (p = 0.017).

Conclusion

PAD patients with atypical leg pain have vascular-mediated limitations in exercise performance during standardized treadmill testing similar to patients with claudication and patients with leg pain on exertion and rest, but they have higher levels of daily ambulatory activity in the community setting and higher perceived ambulatory function.

INTRODUCTION

Peripheral artery disease (PAD) is prevalent in more than 12% of the US population aged 65 years and older,¹ and is associated with increased prevalence of cardiovascular disease risk factors,^{1, 2} and increased co-prevalence of disease in the coronary, cerebral, and renal arteries.^{1, 2} More than 60% of those with PAD have concomitant cardiovascular and/or cerebrovascular disease,² thereby contributing to their elevated rates of mortality.^{3, 4} In addition to having high cardiovascular risk, many of those with PAD are physically limited by ambulatory leg pain, resulting in impaired ambulation,^{5, 6} reduced physical function,^{7, 8} and lower daily physical activity.^{9, 10}

On initial clinical presentation, 10–35% of patients with PAD report claudication symptoms, and 30–50% report other leg pain that is atypical of the classic description of claudication.^{1, 2} When comparing PAD patients with different types of exertional leg pain, patients with claudication have worse functional status, self-reported ambulatory function, and health-related quality of life than patients with atypical pain,¹¹ but better values than those reporting leg pain on exertion and rest.^{7, 11} We recently found that regardless of the type of leg pain reported, all patients experienced symptoms during a standardized treadmill test consistent with classic claudication,¹² indicating the limitations associated with descriptions of leg pain during initial clinical presentation. Furthermore, patients with different types of exertional leg pain were remarkably similar on claudication onset time (COT) and peak walking time (PWT) during treadmill exercise, and on ankle/brachial index (ABI) and ischemic window.¹²

Calf muscle hemoglobin oxygen saturation (StO₂), a measure of the microcirculation in the musculature during exercise, is highly associated with COT and PWT,^{13, 14} and this association persists even after adjusting for ABI.¹⁴ As such, differences in the microcirculation may partially explain the different descriptions of leg pain. However, calf muscle StO₂ in PAD patients with different types of exertional leg pain has not been examined.

The primary purpose of this study is to compare calf muscle StO₂ and exercise performance during standardized treadmill exercise in patients with PAD who describe different types of exertional leg pain. An additional aim is to compare secondary outcomes consisting of daily ambulatory activity and exercise performance during a 6-minute walk test among the exertional leg pain groups. We hypothesized that the group with leg pain on exertion and rest have the most impaired calf muscle StO₂ during treadmill exercise, and have the lowest 6-minute walk distance and daily ambulatory activity.

METHODS

PATIENTS

IRB Approval and Informed Consent. The procedures used in this study were approved by the Institutional Review Board at the University of Oklahoma Health Sciences Center (HSC) and by the Research and Development committee at the Oklahoma City VA Medical Center. Written informed consent was obtained from each patient prior to investigation.

Recruitment. Patients were recruited by referrals from vascular and primary care clinics from the University of Oklahoma HSC and the Oklahoma City VA Medical Center, and by newspaper advertisements for possible enrollment into a randomized controlled exercise rehabilitation study for the treatment of leg pain secondary to PAD.¹⁵ The data and analyses for this study were part of the baseline assessments obtained for the exercise study. A consecutive series of 174 individuals were evaluated for study eligibility. Patients were evaluated in the General Clinical Research Center (GCRC), at the University of Oklahoma HSC.

Medical Screening through History, Physical Examination, and Anthropometry. Patients arrived at the GCRC in the morning fasted, but were permitted to take their usual morning medication regimen. Demographic information, height, weight, cardiovascular risk factors, co-morbid conditions, claudication history, blood samples, and a list of current medications were obtained from a medical history and physical examination at the beginning of the study. During the physical examination, arterial oxygen saturation was measured from the index finger using a standard pulse oximeter. Afterwards, subcutaneous fat over the medial gastrocnemius muscle was measured from a skinfold using a Lange skinfold caliper according to standard guidelines,¹⁶ and waist circumference was recorded using a plastic measuring tape.¹⁶

Inclusion and Exclusion Criteria. Patients with PAD were included in this study if they met the following criteria: (a) a history of any type of exertional leg pain, (b) ambulatory leg pain confirmed during a graded treadmill test,⁵ and (c) an ABI ≤ 0.90 at rest¹ or an ABI ≤ 0.73 after exercise because some PAD patients have normal values at rest which only become abnormal following an exercise test.¹⁷ Patients were excluded from this study for the following conditions: (a) absence of PAD (ABI > 0.90 at rest and ABI > 0.73 after exercise), (b) inability to obtain an ABI measure due to non-compressible vessels, (c) asymptomatic PAD determined from the medical history and verified during the graded treadmill test, (d) use of medications indicated for the treatment of intermittent claudication (cilostazol and pentoxifylline) initiated within three months prior to investigation, (e) exercise tolerance limited by any disease process other than PAD, (f) active cancer, (g) kidney failure defined as stage 5 chronic kidney disease, (h) abnormal liver function, (i) calf skin fold > 50 mm because of potential interference with the light path of the near infra-red spectrometer (NIRS) probe from penetrating the subcutaneous tissue, and (j) pulse arterial oxygen saturation of the index finger < 95% because of the potential deleterious effect on calf muscle StO₂ from poor pulmonary gas exchange. A total of 174 patients were evaluated for this study, and 114 patients were deemed eligible.

Exertional Leg Symptom Groups. Leg symptoms were evaluated by administering the San Diego claudication questionnaire,¹⁸ a standardized and validated 11-item questionnaire based on the Rose questionnaire for intermittent claudication.¹⁹ According to the responses from the San Diego claudication questionnaire, PAD patients were placed into one of the following exertional leg symptom groups: (1) atypical exertional leg pain group (n = 31), defined either as leg pain on exertion that does not cause the patient to stop or slow down (9 of the 31 patients), or the pain does cause the patient to stop or slow down but does not fulfill the remaining criteria for claudication (22 of the 31 patients), (2) claudication group (n = 37), defined as leg pain on exertion that causes the patient to stop or slow down, is located in the calves, does not resolve while walking, and goes away within 10 minutes of rest, and (3) leg pain on exertion and rest group (n = 46), defined as leg pain on exertion that sometimes begins at rest.^{7, 11, 20–22}

PRIMARY OUTCOME MEASURES

Calf Muscle StO₂, COT, PWT, and Ischemic Window Obtained During the Graded Treadmill Test. Patients performed a progressive, graded treadmill protocol to determine study eligibility, as well as to obtain outcome measures related to peak exercise performance.⁵ The COT, measured as the walking time at which the patient first experienced pain, and the PWT, measured as the walking time at which ambulation could not continue due to maximal pain, were both recorded to quantify the severity of claudication. Peak oxygen uptake was measured by oxygen uptake obtained during the peak exercise work load with a Medical Graphics VO2000 metabolic system (Medical Graphics Inc, St. Paul, MN). Using these procedures, the test-retest intraclass reliability coefficient is R = 0.89 for COT,⁵ R = 0.93 for PWT,⁵ and R = 0.88 for peak oxygen uptake.²³

Calf muscle StO₂ was measured before, during, and after the treadmill test using a continuous-wave, NIRS unit (InSpectra model 325; Hutchinson Technology, Inc, Hutchinson, MN), an optical cable attached to a 25-mm probe, InSpectra software (version 2.0), and a dedicated laptop computer as previously described.¹³ The probe was attached to the skin over the medial gastrocnemius muscle of the more severely affected leg using a double-sided adhesive light-excluding patch.²⁴ A baseline measure of calf muscle StO₂ was obtained at rest as patients stood on the treadmill for two minutes to allow for equilibration. From the start of treadmill exercise, the minimum StO₂ value, the time taken to reach the minimum value, the absolute and percentage drops in calf muscle StO₂ from rest to the minimum exercise value, the average rate of decline from rest to the minimum exercise value, and the calf muscle StO₂ at PWT were obtained. The recovery times for StO₂ to reach one half of the resting StO₂ value (recovery half-time), to reach the full resting StO₂ value (recovery time), and to reach the maximum StO₂ value were calculated by subtracting the time to end of exercise from the time recovery StO₂ values were observed.

As in our previous investigations,^{13, 14} we attempted to calculate tau using exponential models for StO₂ data.²⁵ However, we found that individual graphs of time course of StO₂ during exercise did not fit this kinetic model for calculating tau. As such, we calculated the parameters described above because they are easily obtained metrics that do not require prior assumptions. In addition to their clinical utility, particularly the strong association between the time to minimum calf muscle StO₂ with COT and PWT,^{13, 14} we also have found that calf muscle StO₂ measures can be reliably obtained during and after exercise. Reliability of these measures was assessed in 110 patients who performed the progressive, graded treadmill protocol twice in our laboratory. The test-retest intraclass reliability coefficient was R = 0.85 for calf muscle StO₂ obtained at rest, R = 0.91 for the minimum value obtained during exercise, R = 0.86 for the time to reach the minimum calf muscle StO₂ value during exercise, and between R = 0.81 and R= 0.91 for the remaining calf muscle StO₂ measures obtained during and after exercise.

ABI measures were obtained from the more severely diseased lower extremity before and 1, 3, 5, and 7 minutes after the treadmill test.^{5, 23} The reduction in ankle systolic blood pressure after treadmill exercise from the resting baseline value was quantified by calculating the area under the curve, referred to as the ischemic window.²⁶ Because the ischemic window is a function of both PAD severity and the amount of exercise performed, the ischemic window was normalized per meter walked.

SECONDARY OUTCOME MEASURES

Walking Impairment Questionnaire (WIQ). Self-reported ambulatory ability was assessed using a validated questionnaire for PAD patients that assesses ability to walk at various speeds and distances, and to climb stairs.²⁷

6-Minute Walk Test. Patients performed an over-the-ground, 6-minute walk test supervised by trained exercise technicians.²⁸ The pain-free and total distance walked during the test was recorded. The test-retest intraclass reliability coefficient is R = 0.75 for distance to onset of claudication pain, and R = 0.94 for total 6-minute walking distance.²⁸

Ambulatory Activity Monitoring. Daily ambulatory activity was assessed using a step activity monitor (StepWatch3™, Orthoinnovations, Inc., Oklahoma City, OK) as previously described.²⁹ Ambulatory activity was measured during seven consecutive days in which patients were instructed to wear the monitor during waking hours and to remove it before retiring to bed and while showering. The step activity monitor was attached to the right ankle above the lateral malleolus using an elastic Velcro strap, and continuously recorded the number of strides taken each day and the number of minutes spent ambulating each day. The daily ambulatory strides and time are further analyzed by the software program, and are quantified into the following variables: maximum cadence for 60, 30, 20, and 5 continuous minutes of ambulation each day, maximum cadence for 1 minute of ambulation each day (i.e., the minute having the single highest cadence value each day), and peak activity index obtained by ranking all minutes of the day according to cadence, and then taking the highest 30 values. These outcome measures are recorded and averaged for each day, and then the daily averages are averaged over the seven-day monitoring period. The accuracy of the step activity monitor exceeds 99% ± 1% in patients with claudication,²⁹ and the test-retest intraclass reliability coefficient for the daily ambulatory activity measures range from R = 0.83 to R = 0.94.²⁹

STATISTICAL ANALYSES

Means of all measurement variables were compared among the three groups using a one way ANOVA, and where significance (p<0.05) was observed, a Tukey-Kramer multicomparison test among the three means was conducted. For the primary outcome variables, 95% confidence intervals were calculated for the difference from the claudication group mean and the mean of each of other two groups. For these sample sizes the power is approximately 95% for effect size .37 and 80% for effect size .29, indicating that this study was more than adequately powered to detect rather small effect size differences among groups for the time to minimum calf muscle StO₂. The proportions for the dichotomous variables were tested for differences using 2 degree of freedom Chi Square test. All calculations and power analysis were made using NCSS 2000 statistical package.

RESULTS

Clinical Characteristics

Patients with PAD were classified into three groups based on their type of exertional leg pain. The clinical characteristics of these groups are displayed in Table I. Groups were significantly different on BMI (p = 0.018), ABI (p = 0.002), prevalence of obesity (p = 0.009), and prevalence of abdominal obesity (p = 0.030), with the leg pain on exertion and rest group having the highest values, and the claudication group having the lowest values. The groups were not significantly different (p > 0.05) on all remaining variables.

Table I.

Clinical characteristics of patients with peripheral artery disease placed in three exertional leg symptom groups. Values are means (SD) and percentages.

Variables	Atypical Leg Pain Group (n = 31)	Claudication Group (n = 37)	Leg Pain on Exertion and Rest Group (n = 46)	P Value
Age (years)	66 (9)	65 (11)	62 (10)	0.218
Weight (kg)	85 (19)	81 (20)	89 (19)	0.142
Body Mass Index (kg/m2)	29.0 (5.9)	28.4 (5.7)	32.0 (6.4) *	0.018
Ankle/Brachial Index	0.69 (0.22)	0.63 (0.20)	0.81 (0.28) *	0.002
Sex (% Men)	55	60	48	0.564
Race (% Caucasian)	45	49	46	0.603
Current Smoking (% yes)	39	50	33	0.277
Hypertension (% yes)	84	89	85	0.785
Medication Use (% yes)	74	87	87	0.277
Number of Medications (n)	2.3 (1.1)	2.6 (1.1)	2.4 (1.0)	0.567
Dyslipidemia (% yes)	71	87	85	0.199
Medication Use (%)	58	84	74	0.058
Number of Medications (n)	1.4 (1.0)	1.3 (0.5)	1.3 (0.5)	0.799
Diabetes (% yes)	39	35	46	0.610
Medication Use (%)	36	35	46	0.540
Number of Medications (n)	1.6 (0.7)	1.7 (0.8)	1.9 (0.9)	0.607
Abdominal Obesity (% yes)	58	47	76	0.030
Metabolic Syndrome (% yes)	74	95	85	0.063
Metabolic Syndrome Components (n)	3.4 (1.5)	3.7 (1.0)	3.8 (1.2)	0.456
Obesity (% yes)	42	30	63	0.009
Lower Extremity Revascularization (% yes)	36	54	30	0.079
Coronary Artery Disease (% yes)	19	35	35	0.276
Myocardial Infarction (% yes)	7	22	22	0.182
Cerebrovascular Disease (% yes)	13	24	15	0.405
Cerebrovascular Accident (% yes)	13	24	13	0.315
Renal Disease (% yes)	10	5	7	0.778
Chronic Obstructive Pulmonary Disease (% yes)	23	30	30	0.726
Dyspnea (% yes)	48	57	70	0.162

^*Different than claudication group (p < 0.05).

Primary Outcome Measures

The exercise measures of each group during the treadmill test are shown in Table II. All patients experienced symptoms during the treadmill test consistent with claudication. The groups were not significantly different (p > 0.05) on any of the exercise performance measures or on any of the calf muscle StO₂ measures. Of particular importance, the time to reach the minimum calf muscle StO₂ value during exercise was remarkably similar among the groups (p = 0.350). The 95% confidence interval comparing the time to minimum calf muscle StO₂ between those with atypical exertional leg pain and those with claudication was −34 to 200 seconds, indicating that the group difference for the populations of inference is within approximately four minutes during the treadmill test (equivalent to two exercise stages). An even smaller 95% confidence interval was noted for the comparison between those with claudication and those with leg pain on exertion and rest (−120 to 77 seconds), indicating that the group difference for the population of inference is within approximately three minutes.

Table II.

Exercise measures during a graded treadmill test in patients with peripheral artery disease placed in three exertional leg symptom groups. Values are means (SD) for each of the three groups, and mean differences (95% CI) for the comparison between groups.

Variables	Group 1: Atypical Leg Pain (n = 31)	Group 2: Claudication (n = 37)	Group 3: Leg Pain on Exertion and Rest (n = 46)	P Value	Group 1 vs 2 Mean Differences (95% CI)	Group 2 vs 3 Mean Differences (95% CI)
Exercise Performance
Claudication Onset Time (sec)	233 (171)	171 (133)	162 (117)	0.074	61 (−12 to 135)	10 (−45 to 64)
Peak Walking Time (sec)	463 (307)	352 (216)	408 (275)	0.238	111 (−16 to 238)	−56 (−166 to 54)
Peak Oxygen Uptake (ml.kg−1.min−1)	13.0 (4.5)	12.6 (3.1)	12.2 (3.2)	0.631	0.4 (−1.5 to 2.2)	0.4 (−1.0 to 1.8)
Ischemic Window (mmHg × min / meter)	−0.52 (0.82)	−0.74 (0.84)	−0.66 (1.68)	0.777	0.21 (−0.19 to0.62)	0.08 (−0.68 to0.52)
Calf Muscle StO2
StO2 at rest (% saturation)	53 (21)	55 (17)	51 (23)	0.646	−2 (−11 to 7)	4 (−5 to 14)
Minimum StO2 (% saturation)	15 (19)	18 (21)	17 (20)	0.817	−3 (−13 to 7)	1 (−8 to 10)
Time to minimum StO2 (sec)	254 (284)	170 (197)	192 (244)	0.350	83 (−34 to 200)	−22 (−120 to 77)
Absolute Drop in StO2 (% saturation)	38 (19)	37 (17)	34 (22)	0.547	1 (−8 to 10)	3 (−5 to 12)
Percentage Drop in StO2 (%)	75 (26)	72 (30)	69 (31)	0.651	4 (−10 to 17)	3 (−11 to 16)
StO2 at Peak Walking Time (% saturation)	19 (19)	22 (23)	22 (22)	0.863	−2 (−13 to 8)	0.1 (−10 to 10)
Average Rate of Decline in StO2 from rest to minimum exercise value (% saturation/sec)	0.52 (0.60)	0.64 (0.62)	0.50 (0.46)	0.471	−0.12 (−0.42 to0.18)	0.15 (−0.09 to0.38)
Recovery Half-Time of StO2 (sec)	138 (155)	174 (157)	132 (124)	0.405	−36 (−114 to 42)	42 (−21 to 105)
Recovery Time of StO2 (sec)	224 (230)	311 (270)	191 (174)	0.058	−87 (−212 to 38)	120 (20 to 219)
Recovery Time to Maximal StO2 (sec)	696 (297)	721 (252)	615 (265)	0.182	−25 (−158 to 108)	106 (−9 to 220)
Maximum recovery StO2 (% saturation)	85 (21)	81 (17)	76 (24)	0.186	4 (−5 to 13)	5 (−4 to 14)

Secondary Outcome Measures

The 6-minute walk performance, daily ambulatory activity, and walking impairment questionnaire measures are displayed in Table III. Patients with atypical exertional leg pain reported the lowest rating of perceived exertion at the end of the 6-minute walk test (p = 0.017). Patients with atypical exertional leg pain also had the highest daily ambulatory activity measures for total strides per day (p = 0.032), peak activity index (p = 0.040), average daily cadence (p = 0.010), and maximum cadences for durations of 5 minutes (p = 0.035), 20 minutes (p = 0.007), 30 minutes (p = 0.020), and 60 minutes (p = 0.029). Patients with atypical exertional leg pain also reported the highest speed score on the walking impairment questionnaire (p = 0.006).

Table III.

6-minute walk performance, daily ambulatory activity recorded during a 7-day monitoring period, and walking impairment questionnaire measures in patients with peripheral artery disease placed in three exertional leg symptom groups. Values are means (SD).

Variables	Atypical Leg Pain Group (n = 31)	Claudication Group (n = 37)	Leg Pain on Exertion and Rest Group (n = 46)	P Value
6-Minute Walk Test
Pain-Free Distance (meters)	202 (117)	148 (79)	151 (118)	0.072
Total Distance (meters)	370 (102)	317 (104)	333 (102)	0.100
Rating of Perceived Exertion (score)	12.5 (2.8)	13.5 (2.0)	14.1 (2.4) *	0.017
Walked Continuously for 6 Minutes (% of subjects)	68 (48)	42 (50)	59 (50)	0.087
Daily Ambulatory Activity
Maximum 1-minute cadence (strides/min)	47.7 (6.0)	44.5 (6.1)	44.8 (5.8)	0.061
Maximum 5-minute cadence (strides/min)	32.4 (8.8)	27.4 (6.7) *	28.9 (7.9)	0.035
Maximum 20-minute cadence (strides/min)	23.4 (16.8)	15.7 (5.3) *	17.4 (6.9) *	0.007
Maximum 30-minute cadence (strides/min)	17.5 (7.4)	13.3 (4.8) *	14.6 (6.1)	0.020
Maximum 60-minute cadence (strides/min)	13.0 (5.8)	9.9 (3.6) *	10.9 (4.7)	0.029
Peak Activity Index (strides/min)	32.2 (8.0)	27.9 (6.3) *	28.9 (7.1)	0.040
Average Cadence (strides/min)	13.0 (3.1)	11.1 (2.2) *	11.6 (2.3)	0.010
Total Strides (strides/day)	4051 (2109)	2901 (1380) *	3386 (1767)	0.032
Total Activity Time (min/day)	309 (124)	254 (92)	283 (110)	0.128
Walking Impairment Questionnaire
Distance Score (%)	42 (28)	26 (27)	37 (35)	0.083
Speed Score (%)	45 (20)	30 (23) *	29 (25) *	0.006
Stair Climbing Score (%)	48 (28)	34 (27)	33 (30)	0.056

^*Different than atypical leg pain group (p < 0.05).

DISCUSSION

Novel Findings – Calf Muscle StO₂

The novel finding to this investigation is that calf muscle StO₂ variables were not significantly different among the exertional leg pain groups during standardized treadmill exercise. A key measure of calf muscle StO₂ during exercise is the observed time to reach the minimum StO₂ value, as this measure is positively associated with COT and PWT,^{13, 14} and this association persists even after adjusting for ABI.¹⁴ No group differences in the time to minimum calf muscle StO₂, as well as the minimum value of calf muscle StO₂, indicates that the microcirculation in the calf musculature during exercise is impaired to a similar extent among groups, and is unlikely to be a reason for different descriptions of exertional leg pain obtained from the San Diego claudication questionnaire.

Atypical leg pain is defined as pain located in the buttocks or thighs, or pain which does not force the patient to slow down or stop exercising. Furthermore, atypical leg pain is characterized by not resolving within 10 minutes following exercise. As such, it might be anticipated that the atypical pain group would have prolonged time to minimum calf muscle StO₂ during exercise, indicating less rapid oxygen desaturation of the calf musculature, and a slower recovery in calf muscle StO₂. The fact that calf muscle StO₂ during and after exercise was similar between those with claudication and those with atypical leg pain suggests that irrespective of the symptoms, patients with PAD have similar declines in microcirculation in the exercising, ischemic leg muscles. Furthermore, when comparing patients with leg pain on exertion that sometimes begins at rest versus patients with claudication, it might be anticipated that the former group should have greater impairment in calf muscle StO₂, particularly while at rest. This was not the case, as the calf muscle StO₂ of the two groups was similar throughout testing.

Exercise Performance Comparisons

Leg Symptoms. All patients experienced symptoms during the treadmill test consistent with claudication. Each patient reported pain in the calf musculature which gradually progressed to maximal tolerable pain to end the test, and each patient reported pain relief within 10 minutes of rest following the treadmill test. Thus, patients who complain of any type of leg pain should be suspected of having claudication secondary to vascular insufficiency until proven otherwise, regardless of whether the pain description exactly matches that of classic claudication. If high-risk patients with atypical leg pain are not further evaluated, many may go under treated. Indeed, in the current study, only 37 out of 114 patients (32%) with confirmed PAD described exertional leg pain consistent with classic claudication according to the San Diego claudication questionnaire. This percentage is at the upper end of the reported range of 10–35% of patients with PAD describing their symptoms consistent with classic claudication.^{1, 2} It may be surmised that the percentage of patients with classic claudication seen in vascular clinics, but who were not referred to the study for evaluation, was even lower than 32%.

Treadmill Exercise. The groups were not significantly different on COT, PWT, peak oxygen uptake, and ischemic window. This finding is in agreement with our earlier results that exercise performance is not different in patients with claudication, atypical leg pain, and leg pain on exertion and rest.¹² Collectively, these results suggest that PAD symptom subtype has little impact on exercise performance during a standardized treadmill test. Thus, patients with varying symptoms have similar pain-mediated exercise limitations and vascular compromise. From an exercise rehabilitation standpoint, all symptomatic patients should be considered for an exercise program to treat symptoms, regardless of leg pain subtype.

6-Minute Walk Test, WIQ, and Daily Ambulatory Activity. Despite no differences among the groups on calf muscle StO₂ and exercise performance during standardized exercise, significant group differences were found for subjective and self-paced exercise tasks, and for monitored daily ambulatory activity. In general, the patients with atypical exertional leg pain had the most favorable measures for the 6-minute walk test, self-reported ambulatory function, and daily ambulatory activity. Patients with atypical leg pain reported the lowest rating of perceived exertion at completion of the 6-minute walk test and the highest walking speed score on the WIQ. This latter result supports previous studies that found those with atypical leg pain have higher WIQ scores than those with claudication.^{7, 11}

Additionally, patients with atypical leg pain had the highest measures of daily ambulatory activity, supporting our previous observation that they had higher levels of monitored daily physical activity than those with leg pain on exertion and rest.¹² The unique aspect of the current activity data is that it provides information regarding daily ambulatory cadences, and thereby the intensity of ambulation. The average daily cadence, the maximum cadences ranging from five continuous minutes to 60 continuous minutes, and the peak activity index were all higher in the patients with atypical leg pain. This data indicates that the total daily activity of patients with atypical claudication pain is higher than that of the other groups, primarily due to ambulating at faster paces throughout a day. It is possible that atypical leg pain is less uncomfortable, enabling patients to ambulate faster.

The findings in the group with leg pain on exertion and rest are also worth noting. Even though this group had the highest ABI, indicating less severe PAD than the other two groups, they also had the highest prevalence of obesity and the highest BMI values. The fact that their calf muscle StO₂ and treadmill exercise performance measures were similar to the other groups, but not better, suggests that obesity exerts a negative influence on the microcirculation and exercise performance that counteracts the potential advantage of having milder PAD. This supports previous studies reporting a negative effect of obesity on COT and PWT,^30–33 and a negative effect of obesity on reactive hyperemia and transcutaneous oxygen tension^{32, 34} through elevated fasting glucose.³² Finally, the fact that no group differences in treadmill exercise performance in the current study corresponds better with the calf muscle StO₂ findings (i.e., no differences among groups) than with the ABI findings (i.e., significant difference among groups) supports our previous work that COT and PWT are more strongly associated with the time to minimum calf muscle StO₂ than with ABI.^{13, 14}

Limitations

There are limitations to this study. Patients who participated in this trial were volunteers and therefore may represent those who were more interested in exercise, who had better access to transportation to the program, and who had relatively better health than PAD patients who did not volunteer. The cross-sectional design comparing patients with different types of exertional leg pain does not allow causality be established, as it is possible that patients in each group were different in daily ambulatory activity and perceived ambulatory function prior to the development of symptoms. The present findings are also limited to PAD patients with a history of leg pain who are limited by their pain during a standardized treadmill test, regardless of whether the leg pain is typical or atypical of claudication. Thus, the current findings cannot be generalized to patients with less severe PAD (i.e., asymptomatic PAD), or more severe symptoms (i.e., critical leg ischemia), or to those who are limited in their exercise performance by other significant co-morbid conditions.

There are limitations associated with the measurement of calf muscle StO₂ as previously described.¹³ Although calf muscle StO₂ reflects a balance between oxygen delivery and utilization, other factors may also contribute to the StO₂ measurement. First, venous blood, which has low oxygen saturation, may mix with capillary blood in the local tissue. Second, myoglobin may partially contribute to the calf muscle StO₂ measurement. Finally, the subcutaneous fat thickness directly under the probe may interfere with the measure of calf muscle StO₂. However, we believe these limitations have minimal influence on calf muscle StO₂ as discussed earlier.¹³ There are limitations associated with the step activity monitor. It is possible that the patients did not wear the step activity monitor during portions of their waking hours, thereby resulting in an underestimate of daily ambulation. We believe this possibility is unlikely because long durations in which no active minutes were recorded during daytime hours were rarely evident from the software graphs. Another limitation is that the step activity monitor does not quantify non-ambulatory physical activity, and therefore it underestimates the total amount of daily physical activity accomplished to some extent.

Summary, Conclusion, and Clinical Significance

In summary, all patients experienced symptoms consistent with classic claudication during a standardized treadmill test, regardless of their pain description. Each exertional leg pain group demonstrated similar impairments in calf muscle StO₂ and exercise performance during standardized treadmill exercise, but those with atypical exertional leg pain were most active in the community setting and viewed their ambulatory function most favorably. In conclusion, PAD patients with atypical leg pain have vascular-mediated limitations in exercise performance during standardized treadmill testing similar to patients with claudication and patients with leg pain on exertion and rest, but they have higher levels of daily ambulatory activity in the community setting and higher perceived ambulatory function. From an exercise standpoint, the clinical significance is that PAD symptom subtype obtained on initial clinical presentation has little correlation with exercise performance during standardized treadmill exercise. Thus, patients who complain of any type of leg pain should be suspected of having claudication secondary to vascular insufficiency until proven otherwise.