Feasibility and Safety of Cardiopulmonary Exercise Testing in Multiple Sclerosis: A Systematic Review

Archives of Physical Medicine and Rehabilitation journal homepage: www.archives-pmr.org Archives of Physical Medicine and Rehabilitation 2015;-:-------

REVIEW ARTICLE

Feasibility and Safety of Cardiopulmonary Exercise Testing in Multiple Sclerosis: A Systematic Review Lizanne Eva van den Akker, MSc,a,b Martin Heine, MSc,c Nikki van der Veldt, MSc,a,d Joost Dekker, PhD,a,b Vincent de Groot, MD, PhD,a,b Heleen Beckerman, PhD, PTa,b From the aDepartment of Rehabilitation Medicine, Vrije Universiteit University Medical Center, Amsterdam; bEMGO Institute for Health and Care Research, Vrije Universiteit University Medical Center, Amsterdam; cRudolf Magnus Institute of Neuroscience and Center of Excellence for Rehabilitation Medicine, University Medical Center Utrecht and Rehabilitation Center De Hoogstraat, Utrecht; and dFaculty of Medicine, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands.

Abstract Objective: To investigate the feasibility and safety of cardiopulmonary exercise testing (CPET) in patients with multiple sclerosis (MS). Data Sources: PubMed, EMBASE, CINAHL, SPORTDiscus, PsycINFO, ERIC, and the Psychology and Behavioral Sciences Collection were searched up to October 2014. References from retrieved articles were examined to identify additional relevant studies. Study Selection: Inclusion of original studies was on the basis of performance of maximal CPET, description of the protocol, and participants with definite MS aged
18 years. No language restrictions were applied. Data Extraction: The quality of CPET reporting in included studies was scored according to a structured checklist considering 10 feasibility (eg, test abnormalities) and 12 safety quality criteria (eg, adverse events). Structured data extraction was performed for these feasibility and safety features of CPET. Data Synthesis: Forty-six studies were included, comprising 1483 patients with MS, with a mean age  SD of 42.05.8 years and a median Expanded Disability Status Scale (EDSS) score of 2.8 (first quartileZ2.1; third quartileZ3.9; range of average EDSS scores, .75e5.8). Quality of reporting on CPET varied from 3 to 13 out of a possible 22 quality points. The percentage of test abnormalities (feasibility) was 10.0%, primarily because of an inability to maintain pedaling at a specific resistance. The percentage of adverse events (safety) was 2.1%. All adverse events were temporary. Conclusions: Based on the available data, we conclude that CPET is feasible provided that the CPET modality is tailored to the physical abilities of the patient. Furthermore, CPET is safe when recommended precautions and safety measures are implemented. However, future optimization of CPET will require protocolized testing and the implementation of standard reporting procedures. Archives of Physical Medicine and Rehabilitation 2015;-:------ª 2015 by the American Congress of Rehabilitation Medicine

Multiple sclerosis (MS) is a neurodegenerative disease of the central nervous system that results in damage to myelin and axons. The estimated prevalence of MS in Europe is 80 cases per 10,000 people, and the average age of onset ranges from 25 to 32 years, with women twice as likely to be affected as men.1 MS is an unpredictable disease, with symptoms that can develop acutely, remain stable for a certain period, and then recede.2 MS symptoms include muscle weakness, poor balance, spasms, pain and fatigue, cognitive impairment, and depression.2 These impairments are

Supported by the Fonds NutsOhra (grant no. ZonMW 89000005). This article is performed on behalf of the Treating Fatigue in Multiple Sclerosis, Aerobic Training, Cognitive Behavioral Therapy and Energy Management study. Disclosures: none.

common and often explain the reduction in physical activity and decrease in physical fitness and deconditioning. In general, patients with MS tend to be less physically active than healthy persons.3,4 Physical inactivity is now a pandemic health problem, particularly in people with disabilities, which recently led to a worldwide campaign to promote physical activity.5 General attitudes toward physical activity in patients with MS have changed considerably over time.6 In 1889, Uhthoff7 advised patients with MS to avoid physical activity on the grounds that symptoms can be exacerbated by elevated body temperatures. This led health care specialists to advise patients with MS to avoid physical activity. By contrast, modern views are based on the wellestablished positive effects of physical activity and aerobic exercise in patients with MS in terms of physical fitness,

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comorbidities, and quality of life.8-11 Unresolved questions mainly involve determining the most beneficial type, intensity, and duration of exercise interventions.8,12 Prescribing the optimal intensity of aerobic training requires objective measurement of each patient’s physical fitness. The American College of Sports Medicine defines physical fitness as a combination of cardiovascular fitness, muscular strength, muscular endurance, body composition, and flexibility.13 Cardiovascular fitness can be determined by measurement of maximal oxygen uptake (V_ O2max), which is defined as the ability of the cardiopulmonary system to deliver oxygen to skeletal muscles and the efficiency of muscles in using oxygen.14,15 In clinical practice, the measurement of cardiopulmonary fitness in patients with MS is aimed at (1) evaluating aerobic capacity, (2) defining an appropriate exercise intensity, and (3) monitoring the effects of exercise training and other interventions on physical fitness. In healthy participants, the criterion standard for determining cardiopulmonary fitness is the cardiopulmonary exercise test.16 The cardiopulmonary exercise test is a graded exercise test until voluntary exhaustion, and it is usually conducted on a bicycle ergometer or treadmill. The American Thoracic Society/American College of Chest Physicians (ATS/ACCP) described cardiopulmonary exercise testing (CPET) as “an assessment of the integrative exercise responses involving the pulmonary, cardiovascular, hematopoietic, neuropsychological and skeletal muscle systems, which are not adequately reflected through the measurement of individual organ system function.”17(p212) The so-called primary criterion for attainment of maximum aerobic capacity (V_ O2max) in adults is an oxygen consumption (V_ O2) plateau, despite a further increase in work rate.18,19 Since this plateau will not be reached often in practice, the ATS/ACCP recommends that V_ O2 should be derived from the highest V_ O2 value obtained during an incremental exercise test.17 The highest attainable V_ O2 is referred to as peak oxygen uptake (VO2peak). In practice, only about a third of healthy subjects will reach a V_ O2 plateau under maximal effort because most participants cannot endure the discomfort long enough to sustain a plateau in V_ O2.19 Because of various forms of discomfort such as shortness of breath, leg or chest pain, these individuals are said to reach symptom-limited exhaustion.19 Although VO2peak will not satisfy the definition of V_ O2max in such cases, V_ O2max and VO2peak are often used interchangeably in the current literature.14,16 We therefore chose to use the term V_ O2max in this review to indicate both V_ O2max and VO2peak. Although the role of physical fitness in the clinical management of MS now receives greater attention and the use of CPET is increasing, during a recent multicenter research program on MS fatigue we encountered widely differing responses from medical ethics committees, with some committees stipulating strict standard operating procedures for CPET. However, a brief literature

List of abbreviations: ATS/ACCP American Thoracic Society/American College of Chest Physicians CPET cardiopulmonary exercise testing ECG electrocardiogram EDSS Expanded Disability Status Scale MS multiple sclerosis V_ O2 oxygen consumption V_ O2max maximal oxygen uptake VO2peak peak oxygen uptake

search revealed that there is no solid evidence on appropriate procedures for CPET in patients with MS, and there is also no data available on safety. Comparable comprehensive reviews have been recently published on CPET in cancer rehabilitation.20,21 The goal of the present systematic review was to synthesize the available evidence regarding the feasibility and safety of CPET in determining the aerobic fitness of patients with MS. The adherence of studies to international CPET guidelines was also assessed.17 Features of feasibility that should be considered in patients with MS include which patients to select with respect to, for example, age, severity of disease or comorbidities, and determining how CPET should be performed (ie, the most appropriate CPET modalities and protocols). Moreover, the occurrence of test abnormalities has to be considered. Safety features that should be considered include preparation for performance of CPETand of the patient, the safety measures required during CPET, and when to end CPET. Furthermore, diseaseassociated or CPET-associated adverse events should be registered.

Methods Review methods and reporting were in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The database-specific search strategies, data extraction, data synthesis, and analysis were performed according to a prespecified protocol (available on request from the corresponding author).

Literature search Conclusions on the feasibility and safety of CPET were based on articles published up to October 2014. The electronic databases PubMed (MEDLINE), EMBASE, CINAHL, SPORTDiscus, PsycINFO, ERIC, and Psychology and Behavioral Sciences Collection were searched using the following keywords: cardiopulmonary exercise test, exercise test, V_ O2max, VO2peak, oxygen uptake, fitness, and physical exertion. These keywords were combined with multiple sclerosis and MS. There were no language restrictions or restrictions on the design of the studies. Two reviewers (L.A., H.B.) implemented the search strategy independently. Selection was based first on title and abstract, followed by screening of the full-text articles for inclusion. References from retrieved articles were then examined to identify additional studies that met the inclusion criteria.

Study selection Articles were included if they met the following inclusion criteria: (1) they were original studies; (2) participants were aged
18 years and had received a diagnosis of definite MS; (3) maximal CPET was performed; and (4) the CPET protocol was reported. Maximal CPET was defined as a test to determine aerobic capacity by means of a graded exercise protocol until voluntary exhaustion. A reported CPET protocol was considered acceptable when it included a description of the manner in which the work rate was applied: (1) continuous progressive; (2) multistage progressive; (3) or discontinuous multistage (with rest between stages).

Data extraction All articles were systematically scrutinized for qualityddefined as reported adherence to aspects of CPET feasibility and safety as www.archives-pmr.org

Aerobic exercise tests in multiple sclerosis

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described in the international ATS/ACCP guidelines.17 These guidelines were preferred because they contain specific directives on CPET and cover every aspect of CPETdfor example, absolute and relative contraindications (cardiovascular, pulmonary, and other), and how CPET should be performed. To determine the quality of reporting on CPET in the included studies, 22 items were checked and 1 point was given for each of the fulfilled criteria, yielding a maximum score of 22, with higher scores indicating better adherence to ATS/ACCP guidelines. A point was only awarded for an item when an article explicitly reported the item. The data extraction form detailing feasibility and safety items was based on a standardized checklist developed and used by Jones,20 Steins Bisschop,21 Church,22 and colleagues. Criteria related to disease characteristics were adjusted for characteristics relevant to MS. The following 10 feasibility items were checked: age range, Expanded Disability Status Scale (EDSS) range, comorbidities, recent exacerbations, ability to perform CPET, whether permission was obtained from a physician, warming up, resistance raise, definition of V_ O2max, and whether test abnormalities occurred. Adherence to safety guidelines was checked for the following 12 items: comorbidities, equipment calibration, room temperature and pressure, room humidity, patient preparation, physician monitoring, 12-lead electrocardiogram (ECG), heart rate, blood pressure, pulse oximetry, whether a predefined endpoint for CPET was used, and whether adverse events were described.

In total, 376 male (25.4%) and 1033 female (69.7%) participants with MS underwent CPET. The sex of 74 participants (5.0%) was not described. The mean age  SD of the participants was 42.05.8 years. A total of 595 patients (40.1%) were diagnosed with relapsing remitting MS, 59 (4.0%) were diagnosed with primary progressive MS, and 46 (2.9%) with secondary progressive MS. The type of MS was not described for 783 patients (52.8%). The median EDSS score was 2.8 (first quartileZ2.1; third quartileZ3.9), with a range of average EDSS scores between .75 and 5.8. The modality used for CPET was a bicycle ergometer in 37 (80.4%) studies,23-33,35-38,40-47,49-52,54-58,61,64-66,68 an arm crank ergometer in 4 (8.7%) studies,34,39,62,63 a treadmill in 2 (4.4%) studies,48,60 a combined arm-leg ergometer in 2 (4.4%) studies,53,67 and a stepper in 1 (2.2%) study.59 The ranges of V_ O2max outcomes per modality are summarized in table 1. Mean V_ O2max was lowest when using an arm crank, while the bicycle ergometer resulted in the highest V_ O2max. Thirty-one studies (67.4%) reported V_ O2max values in milliliters per kilogram per minute, ranging from 10.1 to 57.3ml/kg/ min, while 17 studies (37.0%) reported V_ O2max values in liters per minute, ranging from 1.0 to 3.0L/min. One study56 reported a value of 81.77V_ O2/kg, with no description of exact units. Based on the studies that included a healthy control group, patients with MS were able to achieve a VO2max ranging from 70% to 91.7% of healthy controls (see table 1). Overall, quality was estimated using 22 items, with scores varying between 3 and 13 points, with a median of 8 (table 2).

Data synthesis

Feasibility

In this review, inferences regarding feasibility were primarily based on the percentage of test abnormalities described in the studies that reported the occurrence of abnormalities. Safety was primarily summarized by the number of adverse events reported in the studies that reported the occurrence of adverse events. The cardiopulmonary fitness of patients with MS was compared with the cardiopulmonary fitness of healthy controls reported in studies in which both groups were described. Between-group comparisons within the same study can be reliably analyzed since V_ O2max results are comparable for many factors, such as equipment quality assurance, the CPET protocol, data validation, and the determination of V_ O2max.

Quality estimates for feasibility ranged from 1 to 7 points (out of a possible 10 points), with a median of 5 points. Test abnormalities were described in 15 studies (32.6%), comprising 502 patients. Abnormalities during CPET were described in 50 (10.0%) of the 502 patients, with most occurring because of an inability to maintain pedaling at the required resistance (nZ45), but also because of failure to achieve a corresponding increase in heart rate (nZ4). In 1 patient, a knee joint contracture disrupted performance of the test. Criteria to perform CPET were defined for age (12 studies [26.1%]) and EDSS (21 studies [45.7%]). Exclusion criteria in 23 studies (50%) were comorbidities that affected feasibility, such as cognitive impairment, disability resulting from other diseases, a cognitive or psychiatric impairment, or a condition other than MS affecting the central nervous system. A recent exacerbation led to the exclusion of patients from CPET in 25 studies (54.3%), and a physician’s permission was obligatory in 4 studies (8.7%). Forty-one studies (89.1%) described a warming-up period. All included studies described an increase in resistance (this was an inclusion criterion). Thirteen studies (28.3%) used specific definitions for determining whether V_ O2max was reached, including the following criteria: a respiratory exchange ratio >1.0 during CPET, a peak heart rate within 10 beats of the calculated maximal heart rate, and a Borg score of perceived exertion >8.5 on a 10-point scale (2 studies23,39) and a score
17 (5 studies29,43,45,46,58) or
18 (1 study54) on a 20-point scale.

Results Literature search and study selection Forty-six23-68 studies describing CPET in patients with MS were included, comprising 1483 patients. The flowchart depicting the search strategy is shown in figure 1. Included studies and study characteristics are shown in table 1, ordered by CPET modality and year of publication. The aim of CPET was to measure cardiopulmonary fitness in 25 (54.3%) studies,29-32,36-38,40,41,43,45,46,48,53,54,56-59,62-66,68 to define the appropriate exercise level in 10 (21.7%) studies,23,25,28,33,35,47,51,52,61,67 and to determine the effects of exercise training or other interventions in 19 (41.3%) studies.23-28,33-35,39,42,44,49-52,55,60,61 In 8 (17.4%) studies,23,25,28,33,35,51,52,61 CPET was used both to determine the appropriate exercise level and as an outcome measure. www.archives-pmr.org

Safety Regarding safety, study quality ranged from 0 to 7 points, with a median score of 3.5 out of 12 points.

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Fig 1

L.E. van den Akker et al

Flowchart depicting the search strategy. Abbreviations: 2MWT, 2-minute walk test; 6MWT, 6-minute walk test; T25FW, timed 25-ft walk.

Fourteen studies (30.4%), comprising 467 patients, reported on the occurrence of adverse events during CPET. Adverse events occurred in 339,44,57 of these 14 studies and affected 10 patients (2.1%). These adverse events were ST-segment changes (nZ2), dizziness (nZ1), dyspnea (nZ2), an abnormal increase in blood pressure (nZ1), and symptom exacerbations in the form of vertigo, elevated spasticity, or abnormal physical sensations (nZ4). Table 3 shows the occurrence of adverse events and test abnormalities per CPET modality, together with the number of participants in the studies that reported these features. Cardiopulmonary comorbidities, an important safety issue, were an exclusion criterion in 25 studies (54.3%). Test equipment preparation was described in 5 studies (10.9%), and room temperature and room pressure were described in 2 studies (4.3%). Controls on room humidity were not reported in any of the included studies. Patient preparation, reported in 6 studies (13.0%), involved participants being asked to abstain from behaviors on the day of CPET that might affect CPEToutcomes, such as alcohol use, caffeine, exercise, and smoking.

Two studies described the presence of a physician to monitor CPET (4.3%). Safety measures during the test were as follows: a 12-lead ECG was reported in 16 studies (34.8%), heart rate monitoring was described in 39 studies (84.8%), blood pressure measurement was described in 18 studies (39.1%), and continuous pulse oximetry was performed in 5 studies (10.9%). Forty studies (87.0%) defined criteria for CPET endpointsdfor example, volitional fatigue or a drop in heart rate.

Discussion The present systematic review of the feasibility and safety of cardiopulmonary fitness testing in patients with MS was based on 46 studies, including 1483 patients with MS. Test abnormalities occurred in 10% of the patients, and adverse events occurred in 2.1% of patients. The reported adherence to the ATS/ACCP quality guidelines17 varied widely.

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Study characteristics of 46 studies ordered according to CPET modality and year of publication

Study First Author, Year of Publication

N

Bicycle Bjuro26 (1975)

MS 13 HC 15 65 Vaz Fragoso (1995) MS 1 Petajan50 (1996) MS 46 Tantucci64 (1996)

MS 10 HC 10

PonichteraMulcare52 (1997)

MS 23

Mulcare47 (2001)

MS 20 HC 8 MS 26 HC 26

Mostert44 (2002)

V_ O2max

Type MS

EDSS  SD

RR (n)

PP (n)

SP (n)

M/F

Age  SD (y)

MS 0/15 HC 0/15 MS 0/1 MS E 6/15 MS C 9/16 MS 5/5 HC 5/5

MS 47.010.3 HC 43.510.5 MS 38.0 MS E 41.12.0 MS C 39.01.7 MS 32.65.4 HC 31.14.8

MS AMB 3/8 MS SEMI 2/6 MS C 3/1 MS 9/11 HC 3/5 MS E3/10 MS C 2/11 HC E 3/10 HC C 11/2

MS AMB 41.05.0 MS SEMI 46.014.0 MS C 40.05.0 MS 50.18.6 HC 49.811.4 MS E 45.28.7 MS C 43.913.9 HC E 44.710.0 HC C 41.711.2

MS MS MS MS

MS G1 4/11 MS G2 5/8 HC 6/14 MS 33/59

MS G1 39.82 MS G2 41.04 HC 40.52 MS M 44.46.8 MS F 43.56.6

MS 2.30.2

21

MS M 3.01.2 MS F 2.20.9

M 22 M 7 M 5 MS M 27.05.2 F 51 F 4 F 4 MS F 21.75.5

mL/kg/min

Adverse Events (n þ Reason)

Test Abnormalities (n þ Reason)

Other Reported CPET Outcomes Watts, V_ O2, HR, BP

MS 17.0 MS E 24.21.1 MS C 25.81.3

MS E 3.80.3 MS C 2.90.3 MS 0.80.3

AMB 1.9 SEMI 5.8 C 3.3 3.62.1

84.0

Watts, V_ O2, HR, V_ O2/HR, V_ E, VT, respiratory rate, VDS/VT HR, watts

80.2

V_ CO2, V_ E, BP, HR

MS AMB 1.7 MS SEMI 1.3 MS C 1.6 MS 23.56.0 HC 29.38.0 MS E 22.7 MS C 22.3

MS E 4.61.2 MS C 4.51.9

MS 28 HC 20

Romberg57 (2004)

MS 92

Schulz61 (2004)

MS 28

MS E 4/11 MS C 5/8

MS E 39.09.0 MS C 40.011.0

MS E 2.01.4 MS C 2.50.8

19

2

5

MS E 33.17.1 MS C 28.97.8

Rasova56 (2006)

MS 112

MS 29/83

MS 36.49.5

MS 3.11.7

79

24

9

MS 81.8*

White68 (2005)

MS 1y

MS 0/1

MS 52.3

MS 57.3

Pariser49 (2006)

MS G1 1 MS G2 1

MS G1 0/1 MS G2 0/1

MS G1 40 MS G2 51

MS G1 23.4 MS G2 17.6

Bjarnadottir25 (2007) Konecny38 (2007)

MS 16

MS E 3/3 MS C 2/8 MS 7/28

MS E 38.7 MS C 36.1 MS 49.110

MS E 2.1 MS C 1.8 MS 3.01.2

RER, V_ E, SaO2 HR

MS 1.0

MS 1.90.5 HC 2.20.6

Heesen35 (2003)

MS 35

L/min

%V_ O2 max of Healthy Controls

1

2

2 ST-segment change 2 elevated spasticity 2 symptom exacerbation

Watts, AT

5

16 17

70.0

Aerobic exercise tests in multiple sclerosis

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Table 1

16

MS E 27.3 MS C 23.4 MS 20.65.9

MS M 2.20.5 MS F 1.50.4

MS 3.0

MS E 1.9 MS C 1.7

1 dizziness

Watts, HR, Borg 1 inability to RPE maintain pedaling 1 knee joint contracture 8 inability to reach Watts, cytokines, 100W neurotropins, hormones, La, HR HR, watts, V_ E/kg, RER, V_ O2/kg, V_ O2/HR, V_ E, HR, V_ O2/HR, RER, La V_ O2, HR, watts, Spasticity interfered with Borg RPE, La ability to ride bike V_ O2, V_ CO2, Borg RPE, AT, watts Watts, HR, V_ O2, V_ E, RER (continued on next page)

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Table 1 (continued ) Study First Author, Year of Publication

N

M/F

Age  SD (y)

EDSS  SD

RR (n)

MS 24

MS 0/24

MS 44.77.1

MS 2.61.8

24

MS 5/14 MS 3/8 HC 3/8 MS 2/10 HC 2/10 MS G1 3/10 MS G2 3/14

MS 41.08.0 MS 40.010.0 HC 40.010.0 MS 38.34.9 HC 37.94.9 MS G1 33.66.1 MS G2 40.512.7

MS 3.5 (1e6) MS 3.4

11

McCullagh42 (2008)

MS 19 MS 11 HC 11 MS 12 HC 12 MS 30

Kuspinar40 (2010) Collett30 (2011) Motl46 (2011)

MS 59 MS 55 MS 49

Petruzzello51 (2009)

MS 25

MS MS MS MS MS

MS MS MS MS MS

Bansi23 (2013)

MS 52

Motl45 (2012)

MS 32 HC 16

Prakash

V_ O2max

Type MS

54

(2007)

Rampello55 (2007) Castellano28 (2008) Morrisson43 (2008)

MS 31 HC 31 Waschbisch (2012) MS G1 MS G2 Briken27 (2014) MS G1 MS G2 MS G3 Dawes31 (2014) MS 58 HC 15 Feltham33 (2013) MS 21 Larson41 (2013)

D’hooghe32 (2014) Heine36 (2014)

MS 9 MS 56

21 21 10 11 11

MS 4/27 HC 4/27 MS G1 4/17 MS G2 3/18 MS G1 5/5 MS G2 4/7 MS G3 5/6

MS MS MS MS

MS 43.47.7 HC 42.47.5 MS G1 39.08.3 MS G2 36.00.9 MS G1 49.18.5 MS G2 50.99.2 MS G3 48.86.8 MS 52.011.0 HC 49.06.0 MS G1 52.32.1 MS G2 49.33.5 MS 51.69.2 HC 49.414.3 G1 3/22 MS G1 44.610.9 G2 13/44 MS G2 47.79.9 3/6 MS 42 (28e49) 19/37 MS 44.810.7

SP (n)

49 25 MS G1 4.7 (4.1 e5.3) MS G2 4.6 (4.0 e5.2)

29 G1 G2 G1 G2 G3

MS 22.96.2 HC 25.75.3

MS 2.20.4 HC 2.41.0 MS 1.50.5 HC 1.80.6

MS 27.67.3

MS 1.90.6

MS G1 21.46.2 MS G2 21.75.9 MS 21.76.0

MS 1.60.4

MS G1 17.1 (14.6 e19.6) MS G2 18.1 (15.7 e20.5) MS 22.15.8 MS 1.60.4 HC 25.05.0 HC 1.80.3

32

2

91.7 83.3

MS 23.56.4 HC 29.38.8

Watts, V_ O2/HR, HR V_ O2 VT, watts, HR, Borg RPE, V_ CO2, La HR, Borg RPE, watts, Exercise time HR, RER, Borg RPE Watts

88.0

Watts, RER, HR, Borg RPE, V_ CO2, V_ E

80.2

Borg RPE, RER, watts, HR Watts, HR HR, Borg RPE, La

21 8 58 MS 3 (1e4) MS 2.81.6

Other Reported CPET Outcomes

V_ CO2, V_ E, RER, HR, Borg RPE HR, RER, Borg RPE, watts

1.41.0 1.20.9 5.20.9 4.70.8 5.00.8

MS 2.61.6

Test Abnormalities (n þ Reason)

V_ E, V_ O2, V_ CO2, RER, HR, Borg RPE

7

MS 1.5

MS MS MS MS MS

L/min

High fit (nZ12): 25.44.8 Low fit (nZ12): 16.72.1 MS 17.17.0

MS 2.8 (0e3) 17

mL/kg/min

Adverse Events (n þ Reason)

12

MS 20.16.4 HC 27.86.8 MS G1 20.21.6 MS G2 22.91.8 MS 13.73.2 HC 18.15.8

72.3 MS G1 1.50.1 MS G2 1.70.1

MS 21.77.2

MS 1.650.5

75.6

12

Watts, HR, Borg RPE, La, RER BP, V_ O2, RER, HR, watts HR, Watts, Borg RPE, La Exercise time V_ E, watts, exercise time, RER, Borg RPE, HR (continued on next page)

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Beier24 (2014)

MS 8 HC 7 MS 82

39.08.8 52.09 G1 429.4 G2 44.17.4 41.89.7

MS G1 10/18 MS G1 52.0 (46.7 MS G2 8/16 e56.3) MS G2 50.0 (44.6 e55.1) MS 0/32 MS 43.67.8 HC 0/16 HC 45.77.9

Sandroff58 (2012) 66

20/39 16/39 G1 0/25 G2 0/24 0/25

PP (n)

%V_ O2 max of Healthy Controls

First Author, Year of Publication

N

M/F

Age  SD (y)

EDSS  SD

RR (n)

PP (n)

MS 20 HC 20

MS 9/11 HC 9/11

MS 399 HC 408

MS 2.61.6

19

1

MS 60 HC 48

MS 16/44 HC 10/28

MS 44.010.4 HC 40.031.7

MS 10 HC 10 MS 6

MS 4/6 HC 4/6 MS 3/3

MS 39.06.0 HC 39.05.0 MS 46.07.0

MS 24 HC 20 MS 60

MS 14/10 HC 11/9 MS 14/64

MS 38.012.5 HC 36.312.5 MS 38.38.4

MS 21 HC 20

MS 8/13 HC 9/11

MS 40.0 HC 37.8

Foglio34 (1994)

MS 24

MS 7/17

MS 48.09.0

Koseoglu39 (2006)

MS 25 HC 15

MS 12/13 HC 6/9

MS 36.99.5 HC 31.57.4

Skjerbaek63 (2014)

MS 11

MS 3/8

MS E 62.05.9 MS C 55.28.2

MS 62

MS 17/45

MS 52.47.3

LangeskovChristensen29 (2014) Kerling37 (2014) Combined arm þ leg PonichteraMulcare53 (1995) White67(2000) Treadmill Olgiati48 (1986) Schmidt60 (2014) Arm crank Senaratne62 (1984)

Stepper Sandroff59 (2015)

V_ O2max

Type MS SP (n)

%V_ O2 max of Healthy Controls

Adverse Events (n þ Reason)

Test Abnormalities (n þ Reason)

Other Reported CPET Outcomes

mL/kg/min

L/min

MS 32.08.6 HC 38.46.8

MS 2.40.6 HC 2.80.6

83.3

V_ O2, La, HR, RER, Borg RPE, V_ E

MS 23.78.2 HC 32.510.5

MS 1.60.6 HC 2.40.9

72.9

BP, HR, V_ O2, watts, Borg RPE, La, VT

MS 1.7

MS 2.76

MS 3.10.9

MS 30.44.0

MS 1.90.6

MS 22.53.9z HC 14.71.5x MS 27.66.8

60

MS 11.22.0

MS 4.42.6

HR

MS 0.70.2

MS 10.14.7 HC 14.31.6

X

48

13

X

70.5

MS E 0.60.2 MS C 0.90.4 MS 19.37.3

2 dyspnea 1 abnormal BP response

21 inability to reach 100W

HR

7 failed to achieve the minimum increase in systolic BP; 4 failed to achieve the corresponding increase in HR 8 not enough upper limb coordination

HR, BP, watts

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Table 1 (continued ) Study

V_ CO2, HR, RER, watts

Watts, respiratory rate, V_ E, HR HR, V_ E, respiratory rate, RER, SaO2, VDS/VT, watts, exercise time, BP HR V_ O2

Abbreviations: AMB, ambulatory patients; AT, aerobic threshold; BP, blood pressure; C, control group; E, experimental group; F, female; G1, group 1; G2, group 2; G3, group 3; HC, healthy controls; HR, heart rate; La, lactate; M, male; PP, primary progressive; RER, respiratory exchange ratio; RPE, rate of perceived exertion; RR, relapsing-remitting; SaO2, arterial oxygen saturation; SEMI, semiambulatory patients; SP, secondary progressive; V_ CO2, carbon dioxide production; VDS/VT, ratio of physiologic dead space to tidal volume; V_ E, ventilation (L/min); VT, ventilatory threshold; X, type MS included. * Exact outcome measures unknown. y Measured V_ O2max per left/right leg, highest V_ O2max is displayed in table. z Only 3 patients reached maximum speed (5.0km/h) compared with 20 healthy controls. x Healthy participants had not reached their V_ O2max by end of test.

7

8

Castellano28 ð2008Þ

Collett30 ð2011Þ

Dawes31 ð2014Þ

D’hooghe32 ð2014Þ

Feltham33 ð2013Þ

Foglio34 ð1994Þ

Vaz Fragoso65 ð1995Þ

Heesen35 ð2003Þ

Heine36 ð2014Þ

Kerling37 ð2014Þ

Konecny38 ð2007Þ

Koseoglu39 ð2006Þ

Kuspinar40 ð2010Þ

Langeskov-Christensen29 ð2014Þ

Larson41 ð2013Þ

McCullagh42 ð2008Þ

Morrisson43 ð2008Þ

Mostert44 ð2002Þ

Motl46 ð2011Þ

Motl45 ð2012Þ

Mulcare47 ð2001Þ

Olgiati48 ð1986Þ

Pariser49 ð2006Þ

Petajan50 ð1996Þ

Petruzzello51 ð2009Þ

Ponichtera-Mulcare53 ð1995Þ

Ponichtera Mulcare52 ð1997Þ

Prakash54 ð2007Þ

Rampello55 ð2007Þ

Rasova56 ð2006Þ

Romberg57 ð2004Þ

Sandroff 58 ð2012Þ

Sandroff 59 ð2015Þ

Schmidt60 ð2014Þ

Schulz61 ð2004Þ

Senaratne62 ð1984Þ

Skjerbaek63 ð2014Þ

Tantucci64 ð1996Þ

Waschbisch66 ð2012Þ

White67 ð2000Þ

White68 ð2005Þ

D D D D D L 5

L L L L L L 0

L D D D L L 3

L D L D L L 2

D L D D D L 4

L L D L D L 2

L L L L L L 0

L L D D D D 4

L L D D L L 2

L L L L L L 0

L D D D L L 3

L D D L L L 2

D D D L L L 3

L L D D L L 2

L L D L D L 2

L L D D L L 2

D D D D L L 4

L D L D L L 2

L L D D L L 2

L L D D L L 2

L L L D D L 2

L L L D L L 1

L L L D L L 1

L D L L L L 1

L L L L L L 0

L L L L L L 0

L D D L L L 2

L L L D L D 2

L D D L L L 2

L D L L L L 1

L L D L L D 2

D D L D L L 3

L L L L L L 0

D D D D L L 4

D L D D D L 4

D L L D L D 3

D D L L L L 2

L D D D L L 3

L L L D L L 1

D D L L L L 2

D D L L L L 2

L D D L L L 2

L L L D L L 1

L L L L L L 0

D D D 3

D D L 2

L D L 1

L D L 1

D D L 2

D D D 3

D D L 2

D D L 2

D D L 2

D D L 2

D D L 2

L D L 1

D D L 2

D D D 3

D D L 2

D D L 2

D D D 3

D D L 2

D D D 3

D D L 2

D D L 2

D D D 3

D D L 2

D D D 3

D D D 3

D D L 2

D D L 2

D D L 2

D D L 2

L D L 1

D D L 2

D D D 3

D D D 3

D D L 2

D D L 2

D D L 2

D D D 3

D D D 3

L D L 1

D D L 2

D D L 2

D D L 2

D D D 3

D D L 2

D D L 2

D 41 89.1 D 46 100 L 13 28.3 2

No. of Studies (NZ46)

Briken27 ð2014Þ

D D D D L L 4

%

Bjarnadottir25 ð2007Þ

Bjuro26 ð1975Þ

L D L L L L 1

12 21 23 25 7 4

26.1 45.7 50.0 54.3 15.2 8.7

L L D L L L D D L L D D L L L L D D L L L L D L L L D D L L L L L L L D L L D D D D L L L L 15 32.6 4 6 7 1 5 5 7 5 2 6 5 2 5 5 5 4 6 5 7 4 4 5 5 4 4 3 3 3 4 3 4 4 5 5 2 7 7 6 4 6 4 5 5 4 3 2

D L D L D D D D L L L L L L L L D D D D L D D D D D D L D L D D L D L L D D D L D L L D L L 25 54.3 L 5 L 2 L 0 0

10.9 4.3 0

L D L L L D D L L D L L L L L L L L D L L L L L L L L L L L L L L D L L L L L L L L L L L L 6

13.0

L L L 1

L L D D L D 3

L L L 0

L e L L L D 2

L L L 1

D D D D L L 4

L L L 0

L D D D L D 4

L L L 1

L L D L L D 2

L L L 1

L L D L L D 3

L L L 1

L L D D L D 4

L L L 1

L L D D L D 3

L L L 0

L D D L L D 3

D L L 1

L L D D D D 5

L L L 0

L L D D L D 3

L L L 0

L D L L L L 1

L L L 0

L L D L L D 2

L L L 0

L L D L L D 2

L L L 0

L L D D L D 3

L L L 0

L L D D L D 3

L L L 1

L D D L D L 3

L L L 1

L L D D L D 3

D D L 3

L L D L L D 3

L L L 1

L L D L D D 3

L L L 0

L L D L L D 2

L D L 2

L D D D L D 4

L L L 1

D D D L L D 4

L L L 1

L L D L L D 2

L L L 1

L L D L L D 2

L L L 1

L D D D L D 4

L L L 1

L D D D L D 4

D L L 1

L D D L L D 3

D L L 2

L D D D L D 4

L L L 0

L L L L L L 0

L L L 1

L D D D L D 4

L L L 1

L L D D L D 3

L L L 0

L L D L L D 2

D L L 2

L D D D D L 5

L L L 0

L D D L L D 3

L L L 0

L L D L L D 2

L L L 1

L L L L L D 1

L L L 1

L L D L L D 2

L L L 1

L L D L L L 1

L L L 0

L L D L L D 2

L L L 1

L D D D L D 4

L L L 0

L L D L L D 2

L L L 0

L D D L D D 4

L L L 1

L L L L L D 1

L L L 0

L L L L L D 1

L L L L L D 1

2 16 39 18 5 40

4.3 34.8 84.8 39.1 10.9 87.0

L L D L L L D D D L L D L L L L D D L L L L D L L L D L L L L D L L L D L L D L D D L L L L 14 30.4 4 2 6 4 3 4 6 5 4 6 3 2 2 2 3 3 5 5 6 4 2 6 6 3 3 5 6 4 6 0 5 5 2 7 3 3 2 3 3 2 6 3 4 2 1 1 8 8 13 5 8 9 13 10 6 12 8 4 7 7 8 7 11 10 13 8 6 11 11 7 7 8 9 7 10 3 9 9 7 12 5 10 9 9 7 8 10 8 9 6 4 3

Abbreviations: AE, adverse event; þ, item was reported; , item was not reported. * Comorbidities concerning feasibility: a cognitive impairment; disability due to other diseases; a cognitive or psychiatric impairment or a condition other than MS affecting the central nervous system. y Comorbidities concerning safety: a certain score on the Physical Activity Readiness Questionnaire (PAR-Q) and a history of cardiac, pulmonary, or other medical conditions.

L.E. van den Akker et al

www.archives-pmr.org

Feasibility Patient-related Ageerange EDSSerange Comorbidities* Recent exacerbation Ability to perform CPET Permission of physician Subtotal patient-related Conduct of CPET Warming up described Resistance raise Definition V_ O2max Subtotal conduct of CPET Reported test abnormalities Test abnormalities Total feasibility Safety Patient-related Comorbiditiesy CPET preparation Equipment calibration Room temperature and pressure Room humidity Subtotal CPET preparation Patient preparation Patient preparation Conduct of CPET Physician monitoring 12-lead ECG Heart rate Blood pressure Pulse oximetry Definition of when to end CPET Subtotal conduct of CPET Reported AEs AEs Total safety Total

Bansi23 ð2013Þ

Reported adherence to ATS/ACCP recommendations in the CPET protocol

Beier24 ð2014Þ

Table 2

Aerobic exercise tests in multiple sclerosis Table 3

9

Number of adverse events and test abnormalities in patients with MS, per CPET modality

CPET Modality

No. of AEs/No. of Participants (N)

%

Participants With No AEs Reported (N)

No. of TAs/No. of Participants (N)

%

Participants With No TAs Reported (N)

Bicycle Combined arm-leg Treadmill Arm crank Stepper

7/321 0/10 0/84 3/52 NR

2.2 0.0 0.0 5.8 NR

919 6 0 29 62

11/342 NR 21/84 19/76 NR

3.2 NR 25.0 25.0 NR

898 16 0 5 62

Abbreviations: AE, adverse event; NR, not reported; TA, test abnormality.

Feasibility In most patients with MS, a bicycle ergometer is the recommended method of testing aerobic fitness, as this CPET modality requires less of patients in terms of balance and coordination compared with walking on a treadmill. Moreover, the lowest percentage of adverse events and test abnormalities and the highest range of V_ O2max were reported while using a bicycle ergometer (see table 3). Even so, a bicycle ergometer requires selectivity of leg movements and sufficient leg muscle force, and most reported test abnormalities were due to an inability to maintain pedaling at the required resistance during warming up. We therefore strongly recommend that a patient’s physical abilities are taken into account when choosing the appropriate CPET modality. In patients who are unable to cycle, an arm-crank ergometer might be a reasonable alternative. A disadvantage of the armcrank ergometer is that rapid arm muscle fatigue will often limit or prevent maximal exhaustion of the cardiopulmonary system. Further research concerning the criterion validity of the CPET modalities is warranted53 to make CPET part of clinical practice. Thirteen (28.3%) studies23,28,29,36,39,43,45,46,53,54,58,59,64 used the so-called secondary validity criteriadthe Borg rate of perceived exertion, respiratory exchange ratio, or a minimal heart ratedto determine whether subjects performed at their maximum. It was shown recently that with use of additional V_ O2max validity criteria, up to 95% of patients with MS (with an EDSS <6 and age >18y) were able to perform a maximum exercise test.29 In the studies reviewed here, it was often unclear whether the results presented were from only those patients who successfully met the criteria. This is important because exclusion of unsuccessful test results from the analyses might have given a distorted and overly optimistic view of the feasibility features summarized here.

Safety Adverse events were reported in 14 studies and affected 10 (2.1%) of 467 patients. The percentage of adverse events was consistent with results for cancer patients before a physical exercise program (1% adverse events in 843 patients).20 None of the studies reported the occurrence of MS-specific adverse events, such as acute heat sensitivity during CPET or the occurrence of relapses after completion of CPET. All reported adverse events were temporary, which suggests that CPET can be used safely, assuming that the recommended safety precautions are taken.17 The most notable adverse events were ST-segment changes in 2 of the 109 patients in whom ECG monitoring was used. The lack of ECG monitoring in 65% of the studies might be largely explained by the added costs and required expertise and personnel.

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In the field of cardiology and lung diseases, CPET with monitoring of gas exchange, ECG, blood pressure, and blood oxygen saturation is primarily used for diagnostic purposes. None of the studies included in the present review reported all of these measurements, and limited evidence is available for several procedures such as ECG monitoring or the presence of a supervising physician.69 This has also been pointed out in the review by Jones.20 Of the studies included in the present review, 87.0% described these precautions and carried out pretest screening for cardiopulmonary comorbidities and other risk factors. Based on these findings, and assuming prescreening for risk factors, in our opinion ECG monitoring during CPET is advisable but may not be strictly necessary. This review showed that the V_ O2max of patients with MS was reduced compared with age and sex-matched healthy controls, with MS patients able to achieve a V_ O2max ranging from 70% to 91.7% of healthy controls.28,44 Limitations in aerobic fitness can influence a patient’s ability to be physically active and to participate in societal activities.8,9 Reduced aerobic fitness and sedentary behavior may also lead to higher risks for other health problems. Effective aerobic exercise programs could improve aerobic fitness in patients with MS, and should be tailored to the patient’s individual cardiopulmonary fitness level.70 Despite the considerable number of research studies reviewed here, CPET in patients with MS has not yet been routinely implemented in clinical practice. Besides uncertainties about feasibility and safety, other factors may hamper clinical implementation such as the lack of exercise laboratory facilities, appropriate equipment, testing time (including preparation for and performance of CPET and analyzing test results), and the availability of experienced clinicians or physiotherapists. The scientific challenges of CPET in MS center on validity and reliability. A recent study36 showed that in patients with mild disability (EDSS, 0e4), CPET is a valid measure of cardiopulmonary fitness. Furthermore, excellent test-retest reliability in mild to moderately disabled patients with MS (EDSS, 0e6) has been reported.29 Day-to-day variation implied that a change of >10% in V_ O2max could be considered a real change. Further studies of the reliability of the various sources of measurement variation (eg, exercise laboratory, equipment, CPET modality, interraters, time intervals) and the magnitude of measurement error of maximal CPET in patients with MS are warranted.

Quality of reporting on CPET In this type of systematic review, a common methodological quality assessment of the risk of bias of individual studies was not applicable. To address this issue, the quality of reporting on CPET in the included studies was defined as the adherence to the international guidelines17 for CPET methods.

10 Regarding future research, the importance of protocolized testing and the implementation of standard reporting procedures for CPET cannot be overemphaised.20,21 We suggest that the following feasibility aspects should be described for patients with MS: patientrelated inclusion and exclusion criteria for CPET, the CPET modality, how CPET is performed (complete CPET protocol, whether a definition of V_ O2max is used), and whether test abnormalities occurred. With respect to safety, the following aspects should be reported: comorbidities as exclusion criteria, the preparation of patient and CPET equipment, the safety measures taken during the conduct of CPET, and whether MS-related or CPET-related adverse events occurred. Separate guidelines for reporting adverse events are available.71 Finally, the data analysis and results section should clearly describe the eligibility rate, the acceptance rate, the determination of V_ O2max, and the number of excluded unsuccessful tests and the reasons for exclusion from analyses. Complete reporting contributes to further insights into the feasibility, safety, and validity of the various CPET modalities in patients with MS.

Study limitations Our review assessed the safety and feasibility of CPET in patients with MS only in an indirect way, since direct evidence from a large cohort study is not available. Only a meta-analysis of the individual patient records (assuming a complete set of data) could provide specific recommendations regarding inclusion or exclusion of patients with MS from CPET, and identify patients able to successfully complete testing without CPET-induced complications. Ideally, a large cohort study should aim to investigate the safety, feasibility, and validity of CPET in a heterogeneous patient population with MS (eg, with regard to age, EDSS, time since diagnosis), and should compare various CPET modalities (eg, bicycle, arm crank, combined arm-leg, stepper). Regarding adverse events, in the other 70% of the studies in which information was lacking concerning test abnormalities and adverse events, it is presently unclear whether the low reported percentage of adverse events (and test abnormalities) in patients with MS reflects true safety or is simply due to a lack of reporting.

Conclusions Based on the aggregated data of 1483 patients with MS and the low reported occurrence of MS-related adverse events, we conclude that CPET is feasible in patients with MS when physical limitations are taken into consideration and the CPET modality is adjusted appropriately. Furthermore, we conclude that CPET is safe when the right precautions are taken (ie, screening patients beforehand to exclude patients at risk of adverse events). We urge that all future research should recognize the importance of protocolized testing and standard reporting of CPET.

Keywords Cardiopulmonary exercise test; Multiple sclerosis; Physical fitness; Rehabilitation; Safety

Corresponding author Lizanne Eva van den Akker, MSc, Department of Rehabilitation Medicine, Vrije Universiteit University Medical Center, PO Box

L.E. van den Akker et al 7057, 1007 MB Amsterdam, The Netherlands. E-mail address: l. [email protected].

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