Cardiopulmonary Exercise Testing Using the Modified Balke Protocol in Fully Ambulatory People With Multiple Sclerosis

Abstract

Purpose:

This study examined the application, outcomes, and validity of cardiopulmonary exercise test (CPET) outcomes using a modified Balke protocol on a motor-driven treadmill in fully ambulatory people with multiple sclerosis (MS).

Methods:

Fully ambulatory people with MS (N = 20) underwent assessments of disability (Expanded Disability Status Scale, EDSS), walking endurance (6-minute walk distance, 6MWD), and cognition (Symbol Digit Modalities Test, SDMT), and completed a maximal CPET (modified Balke protocol) on a motor-driven treadmill while expired gases were collected with indirect calorimetry. Serious adverse events (AEs) and AEs, defined by National Institutes of Health guidelines, and provision of a “maximal” effort test using standard criteria for a maximal effort were documented. The physiological outcomes derived from the CPET included oxygen uptake (V̇o₂), carbon dioxide production, ventilation (VE), respiratory exchange ratio, and heart rate (HR). Other outcomes were calculated using standard guidelines, including V̇o₂/HR slope and oxygen uptake efficiency slope (V̇o₂/log10VE). Descriptive statistics were summarized with mean ± SD and descriptively compared with normative data from apparently healthy individuals using a similar CPET protocol. Spearman’s rho rank-order correlations (ρ) were performed among peak V̇o₂ and SDMT, 6MWD, and EDSS scores.

Results:

There were no AEs, and 17 of 20 tests were characterized as yielding a maximal effort and therefore interpretable. V̇o₂ peak derived from the modified Balke protocol was predictably different in MS (25.8 ± 6.3) than normative values for healthy samples men (43.4 ± 9.3) and women (35.0 ± 7.2). V̇o₂ peak positively correlated with SDMT (ρ = 0.53, P = .01) and 6MWD (ρ = 0.73, P = .0003), and negatively correlated with disability (ρ = −0.51, P = .02).

Conclusions:

Cardiopulmonary exercise test using a modified Balke protocol on a motorized treadmill is safe, feasible, and valid for the measurement of aerobic power in fully ambulatory people with MS.

INTRODUCTION

Multiple sclerosis (MS) is an immune-mediated disease resulting in axo-neuronal damage in the brain, brain stem, and spinal cord¹ with a prevalence approaching 1 million adults in the United States.² Multiple sclerosis and the underlying disease processes result in multiple consequences including disability, cognitive and ambulatory dysfunction, symptoms of depression, fatigue, and pain, and reduced quality of life and participation.³ Another important consequence of MS is physiological deconditioning, particularly lower aerobic power reflecting reduced exercise tolerance.⁴ Aerobic power has been identified as a correlate of the aforementioned consequences of MS and a target of exercise training programs for restoration of function and management of symptoms.^3,5

Aerobic power is typically measured using cardiopulmonary exercise testing (CPET). The application of CPET provides a comprehensive assessment of the integrative exercise response involving the pulmonary, cardiovascular, hematopoietic, neural, and skeletal muscle systems.⁶ The application of CPET further permits evaluations of exercise tolerance and prescription as well as dysfunction and disability. The delivery of CPET involves exercise equipment such as a cycle ergometer or treadmill for the administration of an exercise testing protocol, typically of incremental or graded maximal cycling or walking, and a system of airflow/volumetric transducers, gas analyzers, and gas exchange measurements. This system provides measurement of oxygen uptake (V̇o₂), carbon dioxide production (V̇co₂), and ventilation (VE) during the CPET. Those measurements permit the derivation of other standard CPET outcomes, and Appendix 1 provides a description of CPET outcomes and the typical responses observed during a maximal CPET in healthy people without chronic, disabling disease conditions.

There are 2 prominent articles that have described the application of CPET in people with MS.^4,7 One of those articles provided a comprehensive report of CPET outcomes based on an incremental, maximal cycle-ergometer protocol with a large sample of people with MS (n = 162) and a comparison group of healthy controls (n = 80). The sample of people with MS was predominantly female (87%) with a relapsing-remitting clinical disease course (96.4%) and a range of disability from mild through severe (Patient Determined Disease Steps scores of 0–6). The authors reported on a comprehensive set of CPET outcomes, including V̇o₂ peak (L/min), relative V̇o₂ peak (mL/kg/min), and peak respiratory exchange ratio (RER) (V̇co₂ [L/min]/V̇o₂ [L/min]).⁴ The authors notably reported a lower mean V̇o₂ peak among those with MS compared with apparently healthy controls. Persons with MS who had worse ambulatory disability based on Patient-Determined Disease Steps scores demonstrated significantly lower mean V̇o₂ peak (F = 39.2, P < .05). The suggestions stated by the authors in this article present a framework for application and interpretation of CPET using a cycle-ergometry protocol among people with MS for future investigation.⁴

The authors are unaware of published research that provides a comprehensive description of CPET and its outcomes on a motor-driven treadmill for people with MS in a manner that is consistent with previous research using cycle ergometry.⁴ Yet, this is despite the applications of the modified Balke and modified Naughton CPET protocols performed on a motorized treadmill as endpoints of exercise training trials in MS.^8,9 Those studies both reported an increase in aerobic power after exercise training and no adverse events (AEs) before, during, or after the CPET protocols. This supports the successful application of CPET on a motor-driven treadmill in fully ambulatory people with MS, yet does not provide a comprehensive description of CPET safety, outcomes, and validity.

There may be several reasons for a void in the literature describing and validating a treadmill-delivered CPET protocol among persons with MS. one reason may be the belief that CPET on a treadmill will provide a similar outcome profile compared with CPET on a cycle ergometer in people with MS. There may be further safety concerns associated with performing a CPET on a treadmill for people with MS, such as foot-drop and spasticity that could increase the risk of falling. Nevertheless, the lack of a well-established treadmill-based CPET protocol represents a mismatch between the mode of aerobic exercise that is commonly completed during trials (ie, walking) and the mode adopted for CPET (ie, cycling) in MS.^10,11 This discrepancy may result in underestimating adaptations with exercise training that involves walking and/or underestimating CPET outcomes for understanding disability and impairment in MS. Such a discrepancy further might be a source of response heterogeneity in CPET outcomes after exercise training.^10,11 Indeed, a mismatch between the modality of exercise training and exercise testing presumably increases the chance for error in appropriately interpreting the efficacy of interventions, particularly those that involve treadmill or overground walking training as a primary stimulus. To reduce this error, an appropriate treadmill CPET protocol should be developed and comprehensively demonstrated in this population. Such an investigation would allow researchers to confidently adopt the treadmill CPET protocol for prescriptive purposes, as well as for evaluating the efficacy of exercise training interventions that apply treadmill walking or overground walking for increasing aerobic power in MS.

The current research study described the application, outcomes, and validity of a modified Balke protocol performed on a motor-driven treadmill in fully ambulatory people with MS.

METHOD

The current study is consistent with the STRoBE guidelines in reporting for observational studies.¹² The data collection for this study was conducted during the calendar year between the dates of January 2015 and July 2019.

Participants

The sample of persons with MS was recruited through advertisements among members of local chapters of the National Multiple Sclerosis Society, word of mouth, and direct contact with patients in the offices of collaborating neurologists. The inclusion criteria were: (1) 18 to 59 years of age; (2) definite MS diagnosis¹³; (3) relapse-free for the past 30 days; (4) independently ambulatory; and (5) low risk for contraindications for maximal exercise testing based on the Physical Activity Readiness Questionnaire (ie, no more than one self-reported “yes” response).¹⁴ Importantly, this study did not involve an a priori power analysis, but rather the sample size was based on convenience predicated on the time and budget constraints for this research project. Overall, 33 participants were contacted, 29 underwent screening for eligibility, and 21 participants met inclusion criteria and subsequently completed the CPET.

Procedures

The procedures were approved by a university institutional review board, and all participants provided written informed consent. Participants initially provided demographic information and completed the SDMT (Symbol Digit Modalities Test), underwent a neurological examination, and performed the 6-minute walk distance (6MWD). After a 15-minute break, the participants completed the CPET; the CPET was administered over the course of the working hours of the day (ie, 8 am–5 pm). All participants were remunerated with a gift card for completing testing.

Cardiopulmonary Exercise Test

All participants completed a “maximal exertion” graded CPET on a motor-driven treadmill (Trackmaster TMX425C, Lawrence, KS) using a modified Balke protocol and an open-circuit spirometry system (TrueOne, ParvoMedics, Sandy, UT) for collecting and analyzing expired gases; the CPET was performed in a temperature- and humidity-controlled research laboratory. The O₂ and CO₂ analyzers of the spirometry system were calibrated using verified concentrations of gases, and flow volume was calibrated using a 3-L syringe. The speed for the modified Balke protocol was determined from the average walking speed (mph) measured during a test of 6MWD¹⁵ completed at least 15 minutes before the CPET. Standardized instructions were provided when explaining the CPET and ratings of perceived exertion (RPE) scale.¹⁶ The personnel administering the CPET were certified in cardiopulmonary resuscitation and automated external defibrillator use, received extensive training for delivering the CPET protocol, and further were within an arm’s reach of the participant throughout the entire test. Temporary use of handrails was further permitted, as needed, for preventing falls and injury during the CPET. The CPET began with a 3-minute warm-up at 2.5 mph unless the participant’s average speed from the test of 6MWD was lower than 2.5 mph. During the final minute of the warm-up, the treadmill speed was increased so that the speed from the test of 6MWD (ie, the speed used for the actual CPET) was reached within the last 30 seconds. The CPET speed was then kept constant for the remainder of the graded exercise test, as per the modified Balke protocol.¹⁷ The first 2 minutes of the CPET was performed at 0% grade, and the grade increased 2% every 2-minute period until the participant reached maximal exertion and volitionally terminated the test. Expired respiratory gases were collected as 20-second averages, and recorded HR (heart rate) using a Polar HR monitor (Oy, Finland). Participants provided RPE every minute. After termination of the CPET, participants completed a cool-down for 3 minutes. The CPET was interpreted as involving maximal exertion (ie, successful test administration for interpretation of outcomes) based on ascertainment of 2 of the 4 criteria: (1) plateau of V̇o₂ despite continued increase in grade; (2) peak values of RER ≥1.10; (3) RPE ≥17; and (4) HR within 10 bpm of age-predicted maximum (ie, 220–age). Such criteria are important for judging participant effort as “maximal” and therefore allowing for appropriate interpretation of the resulting CPET data; this is particularly relevant in a sample such as MS wherein exercise capacity is reduced by the disease and its manifestations.⁶

Six-Minute Walk Distance

The 6MWD was included as a valid and reliable measure of walking endurance performance in persons with MS.¹⁵ Briefly, participants were instructed to walk as fast and as far as possible within the limits of safety and stability for 6 minutes along an oval course that was free of obstructions. As per standardized instructions, no motivation was provided throughout the 6MWD.¹⁵ The total distance traveled in feet was recorded as the main outcome using a measuring wheel (Uline, H-3757). Walking speed in miles per hour (mph) was then calculated for the CPET based on total 6MWD traveled in miles (ie, feet divided by 5280) divided by the walking time in hours (ie, 6 minutes divided by 60).

Symbol Digit Modalities Test

The oral version of the SDMT was included as a neuropsychological measure of cognitive processing speed.^18,19 This test is considered the best-characterized measure of generalized MS-related cognitive impairment.²⁰ The SDMT is a sensitive, reliable, and valid measure of cognitive processing speed for people with MS,²⁰ and scores on the SDMT have been associated with meaningful outcomes such as employment status in MS.²¹ Participants are presented with a page displaying 9 abstract geometric symbols that corresponded with 9 single-digit numbers in a key. A series of 110 unpaired symbols are presented under the key, and participants are required to report the digit that correctly corresponds with each consecutive symbol verbally, as quickly as possible. The primary SDMT outcome is the total number of correct responses provided in 90 seconds with the possible range of scores between 0 and 110.

Neurological Examination–Expanded Disability Status Scale

All participants underwent a neurological examination administered by a Neurostatus-certified Level-C examiner for generation of an Expanded Disability Status Scale (EDSS; Kurtzke, 1983) score. The neurological examination covers 8 functional systems and ambulation, and the scores are converted into an EDSS value that ranges between 0 and 10. The EDSS score is presented in 0.5-unit increments with higher scores representing greater disability associated with MS. Expanded Disability Status Scale scores between 0 and 4.0 described persons with MS who ambulate without using an assistive device, and was the working definition of “fully ambulatory” in this study. The EDSS range between 0 and 3.5 is further interpreted as mild disability, whereas the score between 4.0 and 5.5 is commonly interpreted as moderate neurological disability.²²

Calculated Cardiopulmonary Exercise Test Outcomes

The CPET variables (ie, V̇o₂, V̇co₂, VE, and HR) were exported into a Microsoft Excel file for processing into V̇o₂/HR (O₂ pulse) slope and oxygen uptake efficiency slope (OUES) (log₁₀ [VE])/(V̇o₂ [mL/min]). All the calculated variables were derived using standard guidelines⁶ as previously applied in MS.⁴

Data Analysis

The primary outcomes of interest from the CPET included safety (ie, adverse and serious events defined using National Institutes of Health [NIH] guidelines during the CPET) and interpretability (ie, number of tests wherein participants met criteria for determining maximal exertion). Adverse event is defined by the NIH as “any untoward or unfavorable medical occurrence in a human study participant, including any abnormal sign (eg, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participants’ involvement in the research, whether or not considered related to participation in the research.” Serious AE (SAE) is defined by the NIH as resulting in death or a life-threatening situation, prolonged hospitalization, significant disability, or a significant hazard to the participant judged by the investigators.²³ Cardiometabolic variables included oxygen uptake [V̇o₂], carbon dioxide production [V̇co₂], ventilation [VE], RER and HR, V̇o₂/HR slope, oxygen uptake efficiency slope [V̇o₂/log₁₀VE], and time to exhaustion [TTE]. Other outcomes include preliminary evidence of validity, based on the pattern of correlations between peak V̇o₂ and neurological disability, walking performance, and cognitive processing speed.

All analyses were conducted using SPSS Statistics 25 (SPSS Inc., Chicago, IL). Descriptive statistics were presented in text and tables as minimum, maximum, mean, and SD, unless otherwise noted. The descriptive statistics for the CPET outcomes in this study were nonstatistically compared with published normative data for healthy adults.²⁴ Spearman’s rho rank-order correlation coefficients (ρ) were performed between peak V̇o₂ and SDMT, 6MWD, and EDSS scores; this approach was undertaken because neither does it rely on assumptions of normality nor is it influenced by possible outliers.²⁵

RESULTS

Cardiopulmonary Exercise Test Procedural Complications

Of the 21 participants who underwent CPET, only 20 were included in the primary data analyses. One participant was excluded from the analyses based on device error whereby the metabolic cart did not adequately collect the respiratory gases. Of the 20 participants included in the primary data analyses, aberrant HR data were removed for one participant based on the HR monitor inaccurately recording HR during the CPET. Data from 2 participants were removed from the analysis of V̇o₂-HR slope because the HR monitor did not record the HR accurately during the middle portion of the CPET.

Demographics and Clinical Characteristics

The demographic and clinical characteristics of the 20 persons included in the analyses are included in Table 1. The mean age was 42.5 ± 9.1 years. Of the 20 participants included in the study, 16 were females and 4 were males. Regarding race/ethnicity, the sample included 16 Caucasians, 1 American Indian, 2 Black/African American, and 1 Latino/a. All participants presented with relapsing-remitting MS (RRMS). The median (interquartile range [IQR]) EDSS score was 3.0 (2.0), and the mean 6MWD distance in feet was 1807.6 (SD = 364.3). Collectively, this indicates that the sample presented with mild to moderate neurological disability. Regarding cognitive processing speed, the mean SDMT score was 55.5 (SD = 13.8), reflecting an MS sample that did not present with major processing speed impairment.²⁶

TABLE 1.

Demographics and Clinical Characteristics in 20 Fully Ambulatory People With Relapsing-Remitting Multiple Sclerosis

Variable	Mean	SD	Minimum	Maximum
Age	42.5	9.1	23.0	56.0
Height (cm)	166.0	8.5	154.0	188
Weight (kg)	79.0	26.7	51.2	147.9
MS duration (yr)	12.3	7.2	1.0	26
EDSS	2.9	0.9	1.5	4
6MWD (feet)	1807.6	364.3	1182.7	2461.0
SDMT	55.5	13.8	40.0	86.0

EDSS, Expanded Disability Status Scale; MS, Multiple Sclerosis; SDMT, Symbol Digit Modalities Test; 6MWD, 6-minute walk distance.

Cardiopulmonary Exercise Test Protocol Safety and Delivery

There were no AEs for any of the participants before, during, or after the administration of the CPET. Of the 20 tests, 17 were interpreted as consistent with “maximal exertion” based on meeting 2 of the 4 criteria for a successful CPET administration (Table 2). The 4 criteria for maximal exertion and therefore interpretable test were examined to identify the number of participants who met each criterion: V̇o₂ plateau with an increase in grade (14/20), peak RER ≥1.10 (5/20), HR within 10 bpm of age-predicted maximum (11/19), and peak RPE ≥17 (19/20).

TABLE 2.

Summary for CPET Criteria for an Interpretable Test as Resulting From Maximal Exertion Per Participant

Participant	V̇o2 Plateau	RER	HR	RPE	Interpretable Test
1	✓		✓	✓	✓
2	✓		✓	✓	✓
3	✓		✓	✓	✓
5			✓	✓	✓
6	✓	✓	✓	✓	✓
7	✓			✓	✓
8	✓
9	✓			✓	✓
10				✓
11	✓	✓	✓	✓	✓
12		✓	✓	✓	✓
13			✓	✓	✓
14			✓	✓	✓
15	✓		✓	✓	✓
17	✓			✓	✓
18	✓			✓	✓
19	✓			✓	✓
20	✓	✓	✓	✓	✓
21	✓	✓	*	✓	✓
Total	14/20 (70%)	5/20 (25%)	11/19 (58%)	19/20 (95%)	17/20 (85%)

^*Participant 21 did not have accurate HR data.

CPET, Cardiopulmonary Exercise Testing; ✓, achievement of criterion; V̇o₂ Plateau, plateau in volume of oxygen consumed; RER, respiratory exchange ratio ≥1.10; HR, peak heart rate within 10 bpm of age-predicted max; RPE, rating of perceived exertion ≥17; Interpretable Test, determined if at least 2 of the 4 criteria indicating maximal exertion were satisfied.

Cardiopulmonary Exercise Test Outcomes

Table 3 includes descriptive statistics (mean, SD, minimum, and maximum) for CPET outcome variables. The observed mean V̇o₂ peak was 25.8 (6.3) mL/kg/min and the mean HR peak was 168 (23) bpm. Table 4 includes a comparison of CPET outcomes from the modified Balke protocol in the current sample with those reported for a cycle ergometer protocol in people with MS⁴ and reference values for apparently healthy men and woman with the modified Balke protocol.²⁴ Overall, peak V̇o₂ from the current sample is higher than values reported for people with MS who had mild to moderate neurological disability when performing cycle-ergometry derived CPET,⁴ but lower than reference values reported for healthy men and women using the modified Balke protocol.²⁴

TABLE 3.

Modified Balke Protocol Cardiopulmonary Exercise Test Variables in 20 People With Mild to Moderate Multiple Sclerosis-Related Disability

Variable	Mean	SD	Minimum	Maximum
V̇o2 Peak (L/min)	2.0	0.6	1.1	3.4
V̇o2 Peak (mL/kg/min)	25.8	6.3	17.7	34.3
V̇co2 Peak (L/min)	2.0	0.6	0.9	3.3
VE peak (L/min)	64.4	17.6	28.9	103.2
Heart rate peak (bpm) [N = 19]	167.9	23.2	120.0	194.0
RER peak (V̇co2 [L/min]/V̇o2 [L/min])	1.0	0.08	0.9	1.3
OUES (Log10 [VE]/V̇o2/[mL/min])	2126.7	668.0	1170.1	3805.1
V̇o2/HR slope ([mL/min]/[bpm]) [N = 19]	18.0	8.2	6.2	41.3
TTE (s)	646.7	237.7	300.0	1029.0

bpm, beats per minute; HR, heart rate; MS, multiple sclerosis; OUES, oxygen uptake efficiency slope; V̇o₂ peak, peak volume of oxygen; RER peak, peak respiratory exchange ratio; TTE, time to exhaustion; V̇co₂ peak, peak volume of carbon; VE peak, ventilation peak.

TABLE 4.

Comparison of CPET Outcomes Between Cycle and Treadmill Protocols in Multiple Sclerosis, and Apparently Healthy People Reference Values Derived From the Modified Balke Protocol

Participants Protocol Sample (N = X)	MS		Healthy Sample–Treadmillb
	Treadmill N = 20	Cyclea N = 162	Male N = 242	Female N = 223
V̇o2 peak (L/min)	2.0 (0.6)	1.6 (0.5)	3.6 (0.6)	2.41 (0.4)
V̇o2 peak (mL/kg/min)	25.8 (6.3)	21.4 (6.6)	43.4 (9.3)	35. (7.2)
V̇co2 peak (L/min)	2.0 (0.6)
VE peak (L/min)	64.4 (17.6)	62.4 (20.2)
Heart rate peak (bpm)	158.0 (19)	155.0 (20.1)
RER peak (V̇co2 [L/min]/V̇o2 [L/min])	1.0 (0.08)	1.2 (0.1)	1.23 (0.1)	1.21 (0.1)
OUES Log10 (VE)/V̇o2/(mL/min)	2126.7 (668.0)	1884.5 (496.7)
V̇o2/HR slope (mL/min)/(bpm)	17.1 (5.1)	16.5 (4.6)
TTE (s)	646.7 (237.7)	502.0 (144.7)	918 (144)	786 (144)

^aKlaren et al., 2016.

^bAadland et al., 2017.

Reported as mean (SD); bpm, beats per minute; HR, heart rate; MBP, modified Balke protocol; MS, multiple sclerosis; OUES, oxygen uptake efficiency slope; RER peak, peak respiratory exchange ratio; TTE, time to exhaustion; V̇o₂ peak, peak volume of oxygen uptake; V̇co₂ peak, peak volume of carbon; VE peak, ventilation peak.

Correlation With Clinical Endpoints

There were positive correlations between peak V̇o₂ (mL/kg/min) and total 6MWD (ρ = 0.73, P = .0003) and SDMT score (ρ = 0.53, P = .01), whereby greater aerobic power was strongly associated with greater walking endurance and faster cognitive processing speed. There was a negative correlation between peak V̇o₂ (mL/kg/min) and EDSS score (ρ = −0.51, P = .02), whereby greater aerobic power was moderately-to-strongly associated with lower neurological disability.

DISCUSSION AND CONCLUSIONS

The current study described and characterized the application of the modified Balke protocol for performing CPET on a motor-driven treadmill in a sample of fully ambulatory people with MS. Overall, this study demonstrated that the modified Balke protocol was safe and feasible for assessing aerobic power in fully ambulatory people with MS. The CPET yielded metrics that were compared with published normative data collected from healthy controls in the general population using the modified Balke protocol.²⁴ Of note, the main CPET outcome (ie, V̇o₂ peak) among fully ambulatory persons with MS was lower than the published normative data and further correlated with clinical endpoints measuring disability, cognition, and walking endurance. Collectively, the results support the application of the modified Balke protocol for performing CPET on a motor-driven treadmill in a sample of fully ambulatory people with MS.

Demographic and Clinical Characteristics

Our sample consisted of persons with mild or moderate neurological disability (EDSS median [IQR], 3 [1.5–4.0]), who presented with the most common MS phenotype (RRMS). The sample demographics generally match the reported sample composition within a scoping review of broader exercise training studies in MS²⁷ and prevalence data for MS.² Collectively, a typical sample of people with MS who have mild or moderate disability within exercise training research was included in this study.

Safety and Interpretability

There were no SAEs or AEs before, during, or after participants performed the modified Balke protocol in our study. This is consistent with other published research that has reported no AEs during CPET using cycle ergometry in people with MS.⁴ This supports the fact that the application of CPET is safe when performed on a cycle ergometer or motorized treadmill, if appropriate safety guidelines are followed for prescreening, monitoring, and terminating the test.¹⁷ Collectively, the data indicate that this CPET protocol is safe for delivery in people with MS who have minimal disability, and typically yields a maximal effort necessary for subsequent interpretation.

Maximal exertion or effort during CPET was defined for the study based on a participant reaching 2 of the 4 criteria, and this is consistent with previous research⁴ and accepted protocols for CPET.^17,28 The application of those criteria resulted in 17 of the 20 (85%) CPETs providing interpretable data. The relatively low percentage of persons demonstrating a V̇o₂ plateau is consistent with CPET cycle protocols in MS.^4,29 The lack of a V̇o₂ plateau suggests that CPET in MS likely provided a measure of peak V̇o₂, and consequently would not expect a plateau of oxygen uptake because participants may volitionally end the CPET based on peripheral fatigue (ie, muscular endurance in the legs).

The primary criterion for a maximal effort that was not satisfied in the current sample involved RER values. Indeed, our sample had peak RER values that were lower than values reported for RER with cycle ergometry CPET in MS.^4,9,29,30 This could be explained by our protocol that allowed temporary use of handrails, as needed, for preventing falls and injury during the CPET. The discrepancy in RER may further be explained by a reduced drive in ventilation due to respiratory muscle weakness or damage within the respiratory center located in the medulla oblongata and pons.³¹ The percentage of individuals who reached 10 bpm of age-predicted HR-max for our sample was 58%; this is relatively consistent with other published data derived from cycle CPET.^4,29 A similar percentage (95%) of participants who attained an RPE ≥17 before volitionally ending the test was observed compared with previous research using cycle ergometry in MS.^4,29 Overall, there were observed similar percentages of satisfied criteria for an interpretable CPET, with the exception of our lower RER values, when compared with previous research.

Cardiopulmonary Exercise Test Outcomes–V̇o₂ (Aerobic Power)

The mean (SD) V̇o₂ peak was 25.8 (6.3) mL/kg/min in the current study and this is higher than values published using cycle CPET in people with MS.³⁰ There was a similar pattern for treadmill CPET outcomes across disability levels as observed with cycle CPET, such that as disability increased (ie, mild vs moderate), there was a decrease in aerobic power (mean peak V̇o₂) in the sample of people with MS. The mean peak V̇o₂ of 26.6 ([6.6] n = 15) mL/kg/min elicited by treadmill CPET in persons with mild disability was slightly higher than the value of 23.7 ([6.8] n = 82) mL/kg/min elicited by cycle ergometry with mild disability. For individuals with moderate disability, the mean peak V̇o₂ of 22.4 ([6.3] n = 5) mL/kg/min elicited by the treadmill CPET was slightly higher than the value of 21.2 ([5.1] n = 31) mL/kg/min elicited by cycle ergometry.⁴ In other words, as disability increases, aerobic power decreases, demonstrating the inverse correlation between disability and aerobic power when performed through treadmill CPET. When the peak V̇o₂ of our sample was compared with peak V̇o₂ values derived from apparently healthy populations using a similar protocol (male, n = 242 = 43.4 mL/kg/min and female, n = 223 = 35.0 mL/kg/min),²⁴ our data still support the notion that people with MS are deconditioned based on a markedly reduced V̇o₂ peak.

Furthermore, CPET outcomes were compared with the values reported in an article of CPET on a cycle ergometer in MS.⁴ The peak volume oxygen consumption, HR, oxygen uptake efficiency slope, and TTE derived from the modified Balke treadmill protocol were seemingly higher than values reported for cycle ergometry.⁴ This is an expected pattern for V̇o₂, HR, and OUES because treadmill CPETs are typically more metabolically demanding than cycle ergometry CPET.²⁸ By comparison, the RER and the volume of oxygen consumption-HR (ie, oxygen pulse) slope were seemingly lower than values collected using cycle ergometry CPET in previous MS research.⁴

Correlates of Aerobic Power

Significant bivariate correlations were observed between peak V̇o₂ and common clinical endpoints associated with aerobic power in MS. Those with a higher V̇o₂ peak had a longer 6MWD, scored higher on the SDMT, and had lower EDSS scores. This observation is consistent with published research among persons with MS who have mild to moderate disability.^4,8 Such results are important for demonstrating that the main outcome from the Balke protocol for performing CPET on a motor-driven treadmill, namely peak V̇o₂, is associated with clinical endpoints in a manner that supports this modality of CPET as yielding valid and meaningful outcomes for clinical research involving MS.

Limitations

The limitations of this study include a relatively small sample when compared with previous CPET articles.⁴ The research study included only fully ambulatory people with MS. Blood lactate was not collected from our participants, and this is a common fifth criterion for determining a maximal effort and therefore interpretable CPET. Temporary holding of the handrails as needed for balance during the CPET was permitted, as mandated for safety by the local Institutional Review Board. This may limit the interpretation of some calculable variables that involved ventilation, namely RER. This along with peripheral fatigue and/or reduced ventilatory drive commonly exhibited in untrained participants are likely causes for the low RER. There was not a focal follow-up 24 or 48 hours after completion of CPET for capturing AE/SAE and this limits our interpretation regarding safety.

CONCLUSION

The results of this current study support the safety and feasibility of implementing the modified Balke protocol for the valid measurement of aerobic fitness and secondary CPET outcomes in ambulatory persons with MS. This was demonstrated by 17 of 20 tests defined as “successful” and bivariate correlations among V̇o₂ peak and the 6MWD, SDMT, and EDSS in this sample of people with MS. The V̇o₂ peak derived from treadmill CPET in fully ambulatory people with MS was lower than normative data from healthy controls.²⁴

Future Research

The results of this article support the adoption of the protocol to measure aerobic fitness for larger aerobic exercise training trials. Furthermore, the adoption of this protocol may be used to investigate correlation between aerobic fitness and outcomes in people living with MS. Of note, future CPET research using treadmill-based protocols in MS might consider controlling for time of day (ie, fatigue) and seasonality as possible factors that can influence the interpretability of CPET outcomes in this population.

APPENDIX 1. Description of Essential CPET Outcomes

CPET Outcome	Description and Response in Apparently Healthy Individuals
V̇o2 (L/min & mL/kg/min)	Volume of oxygen consumed during exercise. V̇o2 increases in linearly fashion with work rate until plateau (V̇o2 max/peak) and is typically expressed as absolute and relative to bodyweight.
V̇co2 (L/min)	Volume of carbon dioxide production; V̇co2 is modulated by cardiac output (Q), buffering capacity of the blood and tissue exchange; V̇co2 typically increases linearly as metabolic stress increases.
VE (L/min)	Ventilation is the volume of air breathed in and out in a minute. VE regulates the acid–base environment in the blood to match the needed metabolic demands; VE increases in linear fashion as metabolic demand increases and then plateaus.
RER (V̇co2/V̇o2 L/min)	Respiratory exchange ratio is the gas exchange ratio between expired CO2 and inhaled O2. This concerns substrate utilization being used for energy formation processes. RER of 1.10 is typically adopted for a V̇o2 max criterion.
V̇o2/HR (O2 pulse) (mL/min)/(bpm)	O2 pulse represents the relationship between oxygen consumption and heart rate. O2 pulse increases linearly with stroke volume. Also reported as V̇o2-HR slope.
Heart Rate (Bpm)	The HR is the amount of times the heart beats per minute. HR increases in linear fashion during exercise to meet the metabolic demands (i.e., as metabolic demands increase, so does HR).
OUES Log10 (VE)/V̇o2/(mL/min)	Oxygen uptake efficiency slope is a graphical representation of oxygen usage relative to ventilation. OUES is calculated as a linear slope of the log10 VE (Y axis) over V̇o2 (X axis).

ATS/ACCP Statement on Cardiopulmonary Exercise Testing, 2003; VO₂, oxygen uptake; VCO₂, carbon dioxide produce; VE, total air breathed; RER, respiratory exchange ratio; OUES, oxygen uptake efficiency slope.