I often find topics for this blog in a sideways fashion. Recently while searching for something else I ran across an article about the minimum clinically important difference (MCID) of the Residual Volume (RV) in patients with emphysema. I’ve come across the MCID concept before but I had never really followed up on it. This time I started researching MCID and immediately ran across a number of articles about the MCID of the 6-minute walk test (6MWT). This got me to review the articles I have on hand and I found that since I last wrote about the 6MWT I’ve accumulated quite a few new (or at least new to me) reference equations as well as a number of articles about performance issues. Given all this how could I not re-visit the 6MWT?

In addition to the 6 reference equations I had previously I’ve found another 13 female and 14 male reference equations for the 6MWT (total 19 female, 20 male) which is an opportunity to re-visit the selection process. This immediately raises the question about what factors should be used to calculate the predicted 6-minute walk distance (6MWD). Because the 6MWT is essentially an exercise test age has an obvious effect on exercise capacity so it is no surprise that with the exception of one set all of the reference equations consider age to be a factor. It should be noted however, that many of the reference equations are intended to be only applied over a limited range of ages and this may limit their utility.

Given the fact that stride length and therefore walking speed are directly related to height it is somewhat surprising to find that only twelve of the male and eleven of the female reference equations consider height to be a factor. When height is a factor, the predicted 6MWD is usually affected something like this:

Weight also affects exercise capacity but an interesting question is whether the observed 6MWD should be compared to a predicted 6MWD based on a “normal” weight or whether the 6MWD should be adjusted to the individual’s actual weight and assessed accordingly. To some extent this is already an issue in current PFT predicted equations. For example, weight is not a factor in any of the FVC or TLC reference equations and when lung volumes are decreased in the presence of obesity they are considered to be abnormal. On the other hand, the reference equations I use for maximum oxygen consumption during a CPET include weight as a factor and for a number of reasons this is likely the correct approach. For this last reason I would think that weight should be a factor and ten of the reference equation sets consider weight (or BMI) to be a factor. When weight is a factor, the predicted 6MWD is usually affected like this:

Interestingly two sets of equations consider the maximum heart rate attained during the 6MWT (as a percent of predicted) to be a factor. When a closer look is taken at these equations what can be seen is that the higher the maximum heart rate is during the 6MWT, the higher the 6MWD is expected to be. This could be because a higher heart rate could be seen as the result of a greater patient effort but a known effect of deconditioning is a higher heart rate for a given work load and conversely, fit individuals have a lower heart rate for the same workload. There seems to be a bit of disconnect between the heart rate and the 6MWD and for this reason I have trouble seeing how including heart rate as a factor improves the accuracy of a predicted 6MWD.

Finally, one set of equations uses an individual’s observed FEV1 as a factor. This is the same set of equations that does not use age as a factor and is therefore using FEV1 as substitute. This is an interesting notion since a reduced FEV1 occurs with both age and lung disease and both will have an effect on exercise capacity but it also means the formula is equating age and lung disease and this may be a bit too simplistic. It also means that the predicted 6MWD is being adjusted for an individual’s lung disease and I don’t think this is appropriate.

As usual I’ve graphed the predicted values for individuals with an average height and weight (and where needed a normal max HR and FEV1). Also as usual, there is a large scatter among the predicted 6-minute walk distances which makes deciding which reference equation to use more than a little difficult.

To some extent I am bothered more by the higher predicted 6-minute walk distances than I am by the low ones. My lab has used Enright et al’s 1998 reference equations ([I] on both graphs) for over 15 years and the results seem to correlate with the functional capacity of our patients quite well. In particular however, it is very rare for us to get anybody with a 6MWD that is above 100% of predicted. As a comparison we get more CPET patients with a max VO2 above 100% of predicted than patients with a 6MWD above 100% of predicted and every year we perform 3-4 times as many 6MWTs as we do CPETs. Despite this the predicted 6MWD’s from Enright’s 1998 reference equations are mostly below the average of the predicted 6MWD’s and around 20% below the highest predicted 6MWD’s.

Because these high predicted 6MWD’s bothered me I did a quick search and found that when walking speeds reach 1.9 to 2.1 meters/second most individuals transition to a jog or a slow run. I’m not a kinesthesiologist but it seems to me that for an individual to be able to walk faster than about 2 meters/sec (7.2 km/hour, 4.4 MPH) they would have to adopt an exaggerated walking pattern which may not be a jog but is also probably not a “normal” walk either. A number of the reference equations would require an individual to walk faster than the usual walk-to-jog transition speed (although this applies more to males than to females) in order to attain a “normal” 6-minute walk distance and this makes me a bit skeptical of these specific reference equations.

Having said all that, more than one investigator has noted significant ethnic differences in 6MWD’s and that reference equations should be selected accordingly. It may well be that Enright’s 1998 equations have hit a “sweet spot” for my lab (even though we service an ethnically diverse population). It may also be that we aren’t expecting enough from our patients and they should be doing better than we think they should.

The physical layout of the 6-minute walk test will also have an effect on the 6MWD. The ATS/ERS standards specify a 30 meter (or 100 foot) track length (distance between turnaround points) but this distance may not always be available. At least one study has shown that a shorter track distance (10 meters) led to a lower 6-minute walk distance (not really surprising given that the time and distance spent during turnaround don’t count towards the 6MWD). Conversely, another study showed that a completely circular track (no turnaround points) led to slightly longer 6MWD’s. This may be important because a number of the studies that generated reference equations used track lengths different than the ATS/ERS standards (10-20 and 40-50 meters). It’s worth mentioning that several (not all) of the equations that predict the highest 6-minute distance were performed on tracks longer than what the ATS/ERS specifies. For these reasons whatever 6MWT track layout is available to a lab should have some affect on either the selection or the interpretation of the 6MWD.

When selecting a 6MWD reference equation it seems to me that the most relevant ones are those that include height and weight (or BMI) as factors. Ethnicity (or at least a similarity in location) of the study population may also be important and should be considered as well. An ideal situation would be to have a record of previous 6MWD’s and the relative disability of the patient’s performing them, and to use these when comparing different reference equation. Regardless of how a 6MWD reference equation is selected, once put to use it should be monitored for a while. If too many patients have either an elevated or overly reduced 6MWD (factoring in relative disability, of course), then it may be necessary to look at a different reference equation.

Even when the correct reference equation has been selected one of the primary uses of the 6MWT is to assess changes in functional capacity after an intervention of one kind or another (rehabilitation, drug changes, surgery, therapy). This is where the minimum clinically important difference (MCID) comes into play.

MCID has been defined as “the smallest difference in score in the domain of interest which patients perceive as beneficial and which would mandate, in the absence of troublesome side effects and excessive cost, a change in the patients management”. The MCID is not the same as a statistically significant change since what is being measured is clinical and not statistical relevance. There appear to be two different approaches towards measuring the MCID (Anchor and SEM) but it’s not clear that either one generates values that are significantly different from each other. One important point however, is that the MCID is a change in 6MWD distance and not a percent change.

The MCID for the 6MWD has been determined for a number of conditions:

MCID (meters):	Condition:	Reference:
25	CAD	Gremeaux et al.
25-33	Chronic Resp. Dis.	Singh et al
30	COPD	Polkey et al
31	COPD	Puhan et al
54-80	COPD	Wise et al
54	COPD	Laviolette et al
42	COPD	Hernandes et al
24-45	IPF	du Bois et al
28	IPF	Swigris et al
30.5	IPF	Holland et al
33	PAH	Mathai et al

It would be nice if there was more of a consensus on the 6MWD MCID, but given the diversity of the underlying conditions and of their severity among the study populations this isn’t surprising. In addition the MCID values do not really take the baseline condition of an individual patient into consideration and are applied to their study populations as a whole. It’s also important to note that Hernandes et al showed there is a learning effect and that on average patients with COPD improved by 27 meters from their first to their second 6MWT test.

MCID analysis should therefore not be performed when comparing a patient’s first and second tests. In addition when a post-intervention MCID comparison is made, some allowance should be made for the patient’s baseline condition, with a lower number used for more severe conditions and a higher for less severe. Even so, the most recent ERS/ATS statement on the 6MWT (Singh et al) indicates that the MCID is 25-33 meters for patients with chronic respiratory diseases and this is likely to be what most labs use as a standard.

The 6-minute walk test is widely used as an assessment of functional status. It requires a minimum amount of equipment but an attention to detail is still necessary and the ERS/ATS standards should be closely followed whenever possible. The results of a 6MWT are non-specific but they relate well to a patient’s exercise capacity. The 6MWD reference equations are useful as a yardstick when assessing of the severity of any functional limitations but there are limitations to their accuracy and it is the changes that occur in an individual’s 6MWD that are more significant. Although there is a lack of consensus on the values for the minimally clinically important difference, when assessing increases or decreases in the 6MWD the MCID remains a more appropriate tool than a percent change.

6MWD Reference Equation Demographics:

Reference:	Age Range:	Number:	Distance (meters)	Ethnicity:
[A]	18-50	127	30	Arab
[B]	40-90	181	10	Caucasian
[C]	40+	229	40	North African
[D]	29-67	617	30	Brazilian
[E]	55-75	70	45	Australian
[F]	20-60	323	30	Caucasian, Obese
[G]	40-80	238	30	Caucasian
[H]	20-50	48	30	Caucasian
[I]	43-77	117	30.5	Caucasian
[J]	77 +/- 4	2117	30.5	Caucasian
[K]	20-80	79	20	Canadian
[L]	45-85	70	30	Canadian
[M]	14-84	61	30	Brazilian
[N]	45-85	109	45	Australian
[O]	40-80	155	30	Tunisian
[P]	20-80	175	30	Chilian
[Q]	45-85	35	45	Chinese
[R]	20-80	132	30	Brazilian
[S]	50-85	29	50	Caucasian
[T]	40-60	101	30	North India

Male 6MWD Reference Equations:

Reference:
[A]	(2.81 x Ht(cm)) – (age x 0.79) – 28.5
[B]	1266 − (7.8 x age) − (5.92 x BMI)
[C]	720.5 – (5.14 x age) – (2.23 x Wt(kg)) + (2.7198 x Ht(cm))
[D]	890.46 – (6.11 × age) + (0.0345 × age^2) – (4.87 × BMI) + 48.87
[E]	64.69 + (3.12 x Ht(cm)) + (23.29 x FEV1 (L))
[F]	894.2177 − (2.07 x age) – (5.51663 x BMI)
[G]	361 + (2 x Ht(cm)) + ((max hr/pred max hr x 100) x 3) – (4 x age) – (1.5 x Wt(kg))
[H]	518.853 + (1.25 x Ht(cm)) – (age x 2.816)
[I]	(7.57 x Ht(cm)) – (5.02 x age) – (1.76 x Wt(kg)) – 309
[J]	493 + (2.2 * Ht(cm)) – (0.93 x Wt(kg)) – (5.3*age) + 17
[K]	868.8 – (2.99 x age)
[L]	970.7 – (5.5 x age) + 56.3
[M]	622.461 – (age x 1.846)
[N]	867- (5.71 x age) + (1.03 x Ht(cm))
[O]	299.8 – (4.34 x age) + (3.426 x Ht(cm)) – (1.46 x Wt(kg)) + 62.5
[P]	530 – (3.31 x age) + (2.36 x Ht(cm)) – (1.49 x Wt(kg))
[Q]	(5.50 x ((HR max/pred HR max)*100)) + (6.94 x Ht(cm)) – (4.49 x age) – (3.51 x Wt(kg)) – 473.27
[R]	390 + (2.14 x Ht(cm)) – (2.37 x age) – (2.34 x BMI)
[S]	269.31 + (5.14 x Ht(cm)) – (5.78 x age) – (2.29 x Wt(kg))
[T]	127.121 + (3.654 × Ht(cm) − (4.139 × age)

Female 6MWD Reference Equations:

Reference:
[A]	(2.81 x Ht(cm)) – (age x 0.79) – 28.5
[B]	1064 − (5.28 x age) − (6.55 x BMI)
[C]	560.5 – (5.14 x age) – (2.23 x Wt(kg)) + (2.7198 x Ht(cm))
[D]	890.46 – (6.11 × age) + (0.0345 × age^2) – (4.87 × BMI)
[E]	64.69 + (3.12 x Ht(cm)) + (23.29 x FEV1 (L))
[F]	894.2177 − (2.07 x age) – (5.51663 x BMI) – 51.4489
[G]	331 + (2 x Ht(cm)) + ((max hr/pred max hr)*100) x 3) – (4 x age) – (1.5 x Wt (kg))
[H]	479.783 + (1.25 x Ht(cm)) – (age x 2.816)
[I]	(2.11 x Ht(cm)) – (2.29 x Wt(kg)) – (age x 5.78) +611
[J]	493 + (2.2 * Ht(cm)) – (0.93 x Wt(kg)) – (5.3*age)
[K]	794.1 – (2.99 x age)
[L]	970.7 – (5.5* age)
[M]	560.961 – (age x 1.846)
[N]	525 – (2.86 x age) + (2.71 x HT(cm)) – (6.22 x BMI)
[O]	299.8 – (4.34 x age) + (3.426 x Ht(cm)) – (1.46 x Wt(kg))
[P]	457 – (3.46 x age) + (2.61 x Ht(cm)) – (1.57 x Wt(kg)),
[Q]	(5.50 x ((HR max/pred HR max)*100)) + (6.94 x Ht(cm)) – (4.49 x age) – (3.51 x Wt(kg)) – 473.27
[R]	683 + (0.91 x Ht(cm)) – (3.94 x age) – (3.57 x BMI)
[S]	269.31 + (5.14 x Ht(cm)) – (5.78 x age) – (2.29 x Wt(kg)) – 51.31

References:

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ATS Statement: Guidelines for the six-minute walk test. Amer J Respir Crit Care Med 2002; 166: 111-117.

Bansal V, Hill K, Delmage TE, Brooks D, Woon LJ, Goldstein RS. Modifying track layout from straight to circular has a modest effect on the 6-min walk distance. Chest 2008; 133: 1155-1160.

Beekman E, Mesters I, Hendriks EJM, Klaassen MPM, Gosselink R, van Schayck OCP, de Bie RA. Course length of 30 metres versus 10 metres has a significant influence on six-minute walk distance in patients with COPD: an experimental crossover study. J Physiotherapy 2013; 59: 169-176.

[B] Beekman E, Mesters I, Gosselink R, Klaassen MPM, Hendriks EJM, Van Schayck OCP, de Bie RA. The first reference equations for the 6-minute walk distance over a 10 m course. Thorax 2014; 69(9): 867-868

[C] Ben Saad H, Prefaut C, Tabka Z, Hadj Mtir A, Chemit M, Hassasoune R, Ben Abid T, Zara K, Mercier G, Zbidi A, Hayot M. 6-minute walk distance in health North Africans older than 40 years: Influence of parity. Resp Med 2009; 103: 74-84.

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[E] Camarri B, Eastwood PR, Cecins NM, Thompson PJ, Jenkins S (2006) Six minute walk distance in healthy subjects aged 55–75 years. Resp Med 2006; 100: 658–665.

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Cote CG, et al. Validation and comparison of reference equations for the 6-min walk distance test. Eur Respir J 2008; 31: 571-578.

Du bois, RM, Weycker D, Albera C, Bradford WZ, Costabel U, Kartashov A, Lancaster L, Noble PW, Sahn SA, Szwarcberg J, Thomeer M, Valeryre D, King TE, Six-minute walk test in idiopathic pulmonary fibrosis. Test validation and minimally clinically important difference. Am J Respir Crit Care Med 2011; 183(9): 1231-1237.

[I] Enright PL, Sherril DL. Reference Equations for the six-minute walk in healthy adults. Amer J Respir Crit Care Med 1998; 158: 1384-1387.

[J] Enright PL, McBurnie MA, Bittner V, Tracy RP, McNamera R, Arnold A, Newman AB. The 6-min walk test: A quick measure of functional status in elderly adults. Chest 2003; 123: 387-398.

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Gremeaux V, Troisgros O, Benaim S, Hannequin A, Laurent Y, Casillas JM, Benaim C. Determining the minimal clinically important dierence for the six-minute walk test and the 200-meter fast-walk test during cardiac rehabilitation program in coronary artery disease patients after acute coronary syndrome.. Archives of Physical Medicine and Rehabilitation, 2011; 92 (4): pp.611-619.

Hernandes NA, Wouters EFM, Meijer K, Annegarn J, Pitta F, Spruit MA. Reproducibility of 6-minute walking test in patients with COPD. Eur Respir J 2011; 38: 261-267.

[L] Hill K, Wickerson LM, Woon LJ, Abady AH, Overend TJ, Goldstein RS, et al (2011) The 6-min walk test: responses in healthy Canadians aged 45 to 85 years. Applied Physiology, Nutrition, and Metabolism 2011; 36: 643–649.

Holland AE, Hill JC, Conron M, Munro P, McDonals CF. Small changes in six-minute walk distance are important in diffuse parenchymal lung disease. Resp Med 2009; 103: 1430-1435.

Holland AE et al. An official European Respiratory Society/American Thoracic Society technical standard: field walking tests in chronic respiratory disease. Eur Respir J 2014; 44: 1428-1446.

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[N] Jenkins S, Cecins N, Camarri B, Williams C, Thompson P, Eastwood P. Regression equations to predict 6-minute walk distance in middle-aged and elderly adults. Physiotherapy Theory and Practice 2009; 25(7): 516-522.

Larsson UE, Reynisdottir S. The six-minute walk test in outpatients with obesity: reproducibility and known group validity. Physiother Res Int 2008; 13(2): 84-93.

Laviolette L, Bourbeau J, Bernard S, Lacasse Y, Pepin V, Preton M-J, Baltzan M, Rouleau M, Maltais F. Assessing the impact of pulmonary rehabilitation on functional status in COPD. Thorax 2008; 63: 115-121.

[O] Masmoudi K, Aouicha MS, Fki H, Dammak J, Zouari N. The six minute walk test: which predictive values to apply for Tunisian subjects aged between 40 and 80 years? Tunis Med 2008; 86(1): 20–26.

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[P] Osses AR, Yanez VJ, Barria PP, Palacios MS, Dreyse DJ, Diaz PO, et al. Reference values for the 6-minutes walking test in healthy subjects 20–80 years old. Revista Medica de Chile 2010; 138: 1124–1130.

[Q] Poh H, Eastwood PR, Cecins NM, Ho KT, Jenkins SC. Six-minute walk distance in healthy Singaporean adults cannot be predicted using reference equations derived from Caucasian populations. Respirology 2006; 11: 211–216.

Polkey MI, et al. Six-minute-walk test in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2013; 187(4): 382-386.

Puhan MA, Chandra D, Mosenifir Z, Ries A, Make B, Hansel NN, Wise RA, Sciurba F. The minimal important difference of exercise tests in severe COPD. Eur Respir J 2011; 37: 784-790.

Singh SJ et al. An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory diseases. Eur Respir J 2014; 44: 1447-1478

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Swigris JJ, Wamboldt FS, Behr J, du Bois RM, King TE, Raghu G, Brown KK. The 6 minute walk in idiopathic pulmonary fibrosis: longitudinal changes and minimum important difference. Thorax 2010; 65: 173-177.

[S] Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J 1999; 14: 270-274.

[T] Vaish J, Ahmed F, Sinigla R, Shukla DK. Reference equation for the 6-minute walk test in healthy North Indian males. Int J Tuberc Lung Dis 2013; 17(4): 698-703.

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