Journal of the Neurological Sciences 169 (1999) 69–75
www.elsevier.com / locate / jns
Can amyotrophic lateral sclerosis patients with respiratory insufficiency
exercise?
a,
b
a
b
˜ Carvalho a ,
´
Anabela C. Pinto *, Manuela Alves , Antonio
Nogueira , Teresinha Evangelista , Joao
´
´ b
Antonio
Coelho a , Mamede de Carvalho b , Maria Lurdes Sales-Luıs
b
a
Department of Medical Rehabilitation, Hospital de Santa Maria, Av. Prof. Egas Moniz, 1600 Lisboa, Portugal
Department of Neurology, Centro de Estudos Egas Moniz, Faculty of Medicine, Hospital de Santa Maria, Lisboa, Portugal
Abstract
The authors have shown in a recent paper that survival with amyotrophic lateral sclerosis (ALS) can be increased by the use of
non-invasive methods of assisted ventilation (Bipap  ). However, the progression of muscle weakness was not affected and the quality of
life was not positively enhanced. In ALS, reduced physical activity may partially be secondary to alveolar hypoventilation syndrome. This
leads to deconditioning of ALS / motor neuron disease (ALS / MND) patients. The authors decided to investigate the possibility of reducing
motor decline by exercising these patients to the anaerobic threshold, but simultaneously compensating the respiratory insufficiency with
the Bipap STD  . We conducted a controlled single blind study, exercising eight consecutive ALS / MND patients and used a control group
of 12 ALS / MND patients. The patients were all evaluated during a 1 year period. Respiratory function tests (RFT) were performed at
entry and then at 6 month intervals. Barthel, Functional Independent Mobility scale (FIM) and Spinal and Bulbar Norris scores were
recorded every 3 months. There was a significant difference between the two groups with respect to FIM scores (P , 0.03), but not
Barthel scores (P , 0.8). A slower clinical course (Spinal Norris score P , 0.02) and a significant difference in the slope of the RFT
(P , 0.008) were observed in the treated group, suggesting that exercise may be beneficial in ALS patients once Bipap  is used to control
peripheral and muscle oxygenation.  1999 Elsevier Science B.V. All rights reserved.
Keywords: Amyotrophic lateral sclerosis / motor neuron disease; Respiratory insufficiency; Non-invasive ventilation (NIV); Respiratory function tests;
Endurance exercise under non-invasive ventilation; Anaerobic threshold; Quality of life; Functional Independent Mobility scale (FIM)
1. Introduction
Amyotrophic lateral sclerosis / motor neuron disease
(ALS / MND) is a progressive and fatal disease in which
the most common terminal event is respiratory insufficiency. Treatment of this terminal phase using various
methods of non-invasive ventilation is advised by many
different authors [1–3], and has finally been accepted as
standard care for ALS / MND patients [4,5]. However, all
patients progress to quadriplegia with substantially reduced
quality of life. Prolonging survival with independence in
activities of daily living is certainly a major goal in the
rehabilitation setting of ALS / MND patients.
Reduced physical activity may partially be secondary to
*Corresponding author. Tel.: 1351-1-797-7782; fax: 1351-1-7957474.
E-mail address: jsanches.apinto@mail.telepac.pt (A.C. Pinto)
the hypoventilation syndrome and responsible for the
deconditioning of MND/ALS patients. We decided to
investigate the possibility of reducing motor decline by
exercising these patients to the anaerobic threshold, while
at the same time compensating the respiratory insufficiency
with the Bipap STD  .
2. Material and methods
To test the effects of an exercise program on ALS /
MND patients, we conducted a prospective, single blind
controlled clinical trial of 20 consecutive patients. All
patients gave their formal informed consent. Group 1
(treated group) included eight patients, six male and two
female, with a mean age of 62614 years (mean6SD).
Group 2 included 12 patients, four female and eight male,
aged 64616 years (mean6SD). All patients were evalu-
0022-510X / 99 / $ – see front matter  1999 Elsevier Science B.V. All rights reserved.
PII: S0022-510X( 99 )00218-X
70
A.C. Pinto et al. / Journal of the Neurological Sciences 169 (1999) 69 – 75
ated at their visit following diagnosis and followed-up
during 1 year. Respiratory Function Tests (RFT) were
performed three times at 6 month intervals and Functional
Independent Mobility scale (FIM), Barthel, and Spinal and
Bulbar Norris scores were each recorded at 3 month
intervals.
Patients in group 1 were submitted to an exercise
program according to a ramp protocol in a treadmill, with
the Bruce or Naughton protocol [6–8] according to their
initial endurance tests. All the patients in this group
breathed with the assistance of a Bipap STD  , with
continuous monitoring of end-tidal volumes, heart rate
(HR) and oxygen saturation using a pulse oximeter (sPO 2 )
(Figs. 1 and 2). Exercise continued with increased inspiratory positive air pressure (Ipap ) when necessary and limited
by lowering of end-tidal volumes or sustained drops of
sPO 2 below 90%. All patients in group 1, with partial or
global respiratory insufficiency, started exercise after a
period of about 0.5 h of non-invasive ventilation with the
Bipap STD  at rest, in order to re-establish normality of
blood gases.
The assessed clinical parameters were as follows. Previous evolution (time between onset of symptoms and first
referral); RFT at initial observation and at 6 and 12
months, including evaluation of volumes, output, input,
and blood gases; FIM and Barthel scales at 3 month
intervals; Norris Spinal and Bulbar scores also at 3 month
intervals; sPO 2 at rest, during exercise and during the
recovery period for the initial endurance test with and
without the Bipap  , and also weekly to evaluate the
possibility of increasing the resistance of the treadmill.
Exercise was applied with the goal of attaining anaerobic threshold in 10–15 min. Exercise ceased when
there was subjective fatigue using the clinical scale of
Borg [6], leg pain, HR above 75% of rest values or
desaturation not correctable with increased Ipap parameter.
The slopes of the different clinical evolution parameters
were evaluated (the ratio of the initial score minus the final
score by the number of months of evolution). Data were
analysed to assess differences in clinical parameters between the two groups using the T-test, assuming unequal
variances with a confidence interval of 0.95.
3. Results
Clinical data, including respiratory function parameters,
are presented in Tables 1–4, and the respective means,
standard deviations and t-tests with the P values are
presented in Table 5. Data from Barthel scores and
respective slopes are omitted because they were not found
to be relevant, in fact we did not find any statistical
significance between the two groups during the period of
this study (Table 6).
In group 1, at initial observation, two patients (2 and 4)
had global respiratory insufficiency (RI) at rest with PCO 2
over 50 mmHg and PO 2 below 80 mmHg. The remaining
Fig. 1. A graphical representation of patient No. 4 with global respiratory insufficiency, starting with a period of rest under non-invasive ventilation with
Bipap STD  . Exercise started at 12:35 h and ended at 12:38 h, with substantially reduced sPO 2 .
A.C. Pinto et al. / Journal of the Neurological Sciences 169 (1999) 69 – 75
71
Fig. 2. A graphical representation of the same patient, 2 months later, exercising for a longer period of 12 min without any substantial reduced sPO 2 and, of
course, under non-invasive ventilation with Bipap STD  .
Table 1
Demographic characteristics and clinical evolution data for patients in group 1: Pre Ev, previous evolution time in months; FVC i, 2, 3, forced vital
capacity at the initial observation and at 6 and 12 months; ScB i, 3, 6, 9, 12, Bulbar Norris scores at the initial observation and at 3 month intervals during a
1 year period; SlB 6, 9 and 12, Norris Bulbar slope at 6, 9 and 12 months
Pat.
No.
Sex
Pre
Ev
FVC (%)
Sl
FVC
ScB
SlB
i
2
3
i
3
6
9
12
6
9
12
1
2
3
4
5
6
7
M
M
M
M
F
F
M
20
6
27
18
6
6
12
78
66
88
62
99
78
40
35
61
70
40
96
88
40
39
63
70
40
95
68
3.25
0.50
1.50
1.83
0.75
0.83
0.00
11
14
15
15
12
17
13
11
11
13
15
12
17
13
11
11
13
16
11
17
13
11
11
13
15
9
17
13
11
9
13
14
9
17
13
0.00
0.50
0.33
0.00
0.17
0.00
0.00
0.00
0.33
0.22
0.00
0.25
0.00
0.00
0.00
0.42
0.17
0.08
0.25
0.00
0.00
8
M
10
89
63
45
2.83
12
9
9
9
6
1.50
1.00
0.75
Table 2
Clinical evolution data for patients in group 1: Sp i, 3, 6, 9, 12, Norris Spinal scores at initial observation and at 3 month intervals; FIM i, 3, 6, 9, 12, initial
Functional Independent Mobility Scale and at 3 month interval observations; SlSp and SlFIM i, 3, 6, 9, 12, Norris Spinal and FIM slopes at initial
observation and at 3 month intervals during a 1 year period
Pat.
No.
Sp
SlSp
FIM
SlFIM
i
3
6
9
12
6
9
12
i
3
6
9
12
6
9
12
1
2
3
4
5
6
7
45
36
45
39
42
40
41
42
36
45
42
41
40
41
42
27
45
43
39
36
41
42
28
45
39
39
33
41
43
29
45
37
39
33
41
0.50
1.50
0.00
0.00
0.50
0.67
0.00
0.33
0.88
0
0
0.33
0.77
0
0.16
0.58
0.00
0.16
0.25
0.58
0.00
123
112
124
108
122
122
123
123
123
123
114
116
122
120
118
117
122
114
112
114
120
108
96
121
110
112
112
120
106
85
117
108
109
108
120
0.83
0.00
0.33
0.00
1.67
1.33
0.50
1.67
1.78
0.33
0.00
1.11
1.11
0.33
1.42
2.25
0.58
0.00
1.08
1.17
0.25
8
42
37
26
26
26
2.67
1.7
1.33
113
106
95
89
64
4.67
3.78
4.92
A.C. Pinto et al. / Journal of the Neurological Sciences 169 (1999) 69 – 75
72
Table 3
Demographic characteristics and clinical evolution data for patients in group 2. See Table 1 for abbreviations
Pat.
No.
Sex
Pre
Ev
FVC (%)
Sl
FVC
i
2
3
1
2
3
4
5
6
7
8
9
10
11
M
M
M
M
F
F
F
M
M
F
M
18
19
8
24
12
12
24
15
12
10
8
108
111
89
77
120
125
87
94
95
96
87
97
76
83
49
61
104
45
76
84
80
60
85
42
51
44
62
39
62
80
60
33
1.92
5.50
3.17
2.75
4.92
5.25
4.00
2.83
1.25
3.00
4.50
12
M
6
106
77
76
2.50
ScB
patients had normal blood gases or partial RI with PO 2
lower than 90 mmHg and normal, or even lower than
normal, PCO 2 . Patient 5 had completely normal RFT and
blood gases. All the patients in group 1 had a decreased
tolerance to exercise on the treadmill compared with the
established tolerance limits in an otherwise normal population matched for age and sex. These patients, in the
beginning, could not exercise within the Bruce or Naughton protocols. Only one patient attained stage 3, two
patients attained stage 2 in the Naughton protocol and
patients 2, 4, and 7 could not go beyond stage 1 (1.4 km / h
with a ramp of 58). After adapting the Bipap STD  , the
latter patients attained stage 2 (2 km / h with a ramp of 108)
offering the possibility of being independent in daily
activities. Six months later these three patients could work
in the Bruce protocol. The remaining patients improved in
the Naughton protocol with the exception of patient 8
because of an uncontrolled spasticity in the legs. Twelve
months later the same patients in the Bruce and in the
Naughton protocol remained stable and patient 8 was
wheelchair-bound, for the same reasons. The limiting
factors for progress in exercise resistance were essentially
SlB
i
3
6
9
12
6
9
12
16
16
17
18
16
14
13
18
18
18
18
17
13
18
18
11
14
12
17
18
18
13
12
12
17
18
11
14
9
17
18
18
13
10
13
17
14
11
17
9
17
17
18
12
10
13
17
14
11
12
7
14
12
15
9
0.67
0.67
0.00
0.00
1.25
0.00
0.67
0.17
0.00
0.00
0.83
0.67
0.33
0.00
0.44
0.56
0.00
0.11
0.11
0.11
0.00
0.67
0.50
0.25
0.00
0.33
0.42
0.17
0.50
0.33
0.50
0.25
0.75
17
15
15
16
13
0.33
0.11
0.33
due to fatigue, with an inadequate response to exercise,
with desaturation (sPO 2 ) below 90% because of a small
inspiratory reserve with lowering of end-tidal volumes, but
other reasons were also noted (Table 7).
Patients in group 2 were not submitted to the endurance
test on the treadmill. Concerning inspiratory volumes (vital
capacity) the two groups showed a significant difference
(P , 0.001) in the same direction to that observed for
FVC.
4. Discussion
Non-invasive ventilation in neuromuscular diseases and
in MND/ALS patients is a well established technique
[9–14]. There are many advantages of Bipap over
invasive methods: it is less expensive, prolongs survival,
and improves quality of life, sleep and exercise tolerance.
But some questions about non-invasive ventilation remain;
particularly, when should this therapy be started? It is
accepted that non-invasive ventilation should be started
Table 4
Clinical evolution data for patients in group 2. See Table 2 for abbreviations
Pat.
No.
Sp
SlSp
FIM
SlFIM
i
3
6
9
12
6
9
12
i
3
6
9
12
6
9
12
1
2
3
4
5
6
7
8
9
10
11
45
28
39
22
37
34
45
37
41
41
37
33
18
40
19
29
34
45
37
41
35
34
35
17
37
21
29
31
45
33
41
27
30
35
11
35
13
29
17
45
29
41
29
27
35
11
35
13
29
14
30
29
39
19
26
1.67
2.83
0.33
0.17
1.33
0.67
0.00
0.67
0.00
2.33
1.17
1.11
1.89
0.44
1.00
0.89
1.89
0.00
0.89
0.00
1.33
1.11
0.83
1.40
0.33
1.00
0.88
1.66
1.25
0.66
0.41
1.83
0.90
120
60
90
70
94
119
125
115
122
115
124
120
53
86
69
89
116
125
111
120
113
124
106
38
79
66
89
94
101
111
120
101
113
104
37
67
58
89
88
87
98
117
92
100
102
34
59
59
89
66
54
80
117
76
89
2.33
3.67
1.83
0.67
0.83
4.17
4.00
0.67
0.33
2.33
1.83
1.78
2.56
2.56
1.33
0.56
3.44
4.22
1.89
0.56
2.56
1.22
1.50
2.17
2.58
0.92
0.42
4.42
5.92
2.92
0.42
3.25
2.92
12
45
45
35
45
45
0.00
0.00
0
127
123
123
121
120
0.33
0.44
0.42
A.C. Pinto et al. / Journal of the Neurological Sciences 169 (1999) 69 – 75
Table 5
Differences between the two groups
Group 1
Age
Pre Ev
FVC i
FVC 6
FVC 12
Sl FVC
ScB i
ScSp i
FIM i
ScB 6
ScSp 6
FIM 6
ScB 9
ScSp 9
FIM 9
ScB 12
ScSp 12
FIM 12
SlSp 6
SlB 6
SlFIM 6
SlSp 9
SlB 9
SlFIM 9
SlSp 12
SlB 12
SlFIM 12
Group 2
t-Test
P values
Mean
6SD
Mean
6SD
62
12
76%
66%
60%
1.44
13.63
41.25
118.4
12.63
37.38
114.00
12.25
36.63
108.5
11.5
36.6
102.1
0.73
0.31
1.17
0.50
0.23
1.26
0.38
0.21
1.46
14
8
0.20
0.24
0.20
1.14
2.00
3.01
6.30
2.72
7.23
8.37
2.82
6.86
11.3
3.46
6.8
18.59
0.93
0.52
1.54
0.59
0.34
1.20
0.44
0.26
1.57
64
14
99%
74%
58%
3.47
16.58
37.58
106.6
14.50
32.58
95.08
14.25
29.67
88.17
12.25
26.83
78.8
0.93
0.68
1.92
0.88
0.26
1.93
0.93
0.36
2.32
16
7
0.15
0.18
0.17
1.36
1.68
7.00
22.64
3.12
8.71
24.43
3.17
11.48
24.10
2.73
10.60
26.0
0.95
0.42
1.42
0.67
0.26
1.19
0.54
0.19
1.72
0.78
0.74
0.01*
0.43
0.81
0.002*
0.004*
0.13
0.11
0.17
0.20
0.03*
0.16
0.11
0.02*
0.62
0.02*
0.03*
0.65
0.76
0.29
0.20
0.82
0.24
0.02*
0.18
0.26
Table 6
Differences between groups with respect to initial Barthel scores and at 3,
6, 9 and 12 months
Group 1
Barthel i
Barthel 3
Barthel 6
Barthel 9
Barthel 12
Group 2
t-Test
P values
Mean
6SD
Mean
6SD
13.9
11.78
10.60
9.67
7.62
2.50
3.12
4.62
6.62
6.95
13.91
12.0
10.7
9.01
6.00
2.96
3.36
4.01
3.9
3.33
0.98
0.74
0.73
0.81
0.61
73
when its advantages are clear to the patient. This usually
occurs when diurnal gas exchange is clearly disturbed.
Some authors [15–17] believe that nocturnal desaturation is the first sign of RI and has to be carefully evaluated
to implement compensation when detected. Nevertheless, a
controlled clinical trial with survival rates has not yet been
reported. Gay and Daube, in 1991 [18], showed that only
two-thirds of these patients had nocturnal desaturation and
only one-third RI. They also found that the best correlation
with survival was involvement of the inspiratory muscles,
evaluated by inspiratory and expiratory maximal pressures.
However, these are unreliable respiratory function parameters since they are dependent on patient collaboration.
We observed that, in five of eight patients in group 1,
the limiting factor for exercising, when first tested (Table
7), was a definite desaturation with substantially reduced
end-tidal volumes. Progressively increasing the Ipap parameter allowed patients to continue exercising to secondary
limiting factors such as leg pain, heart rate or generalised
fatigue. The poor exercise tolerance at the beginning of
this study, improved by the Bipap STD  , implies that
non-invasive ventilation can be useful even sooner that
once believed.
As far as exercise in ALS / MND patients is concerned, it
is accepted [19–21] that exercise is useful when the
muscle strength is above 3 (MRC scale). We consider that
part of the rate of motor decline is due to deconditioning
and diminished respiratory reserve and have tested this
hypothesis through exercise with simultaneous compensation of respiratory symptoms using the Bipap STD  . This
device monitors the end-tidal volumes allowing us to
increase the Ipap parameter as necessary to the limit of
pressure and patient comfort.
Reconditioning exercise up to anaerobic threshold in a
normal population as well as in athletes, cardiac patients,
COPD patients, paediatric patients and even in some
neuromuscular diseases is well tried [22–24]. The use of
this protocol in ALS patients has not previously been
described. Exercising patients to anaerobic threshold
means exercising to the point of the exponential increase
of blood lactate concentration [7,25] or to the point of
Table 7
Clinical evolution data for patients in group 1 exercising on a treadmill. Progression in stages of the Bruce (B) or Naughton (N) protocol, without and with
Bipap STD  assistance initially and at 3, 6 and 12 months later. sPO 2 is the percentage oxygen saturation measured with a pulse oximeter at the end of the
first exercising test (ET) without non-invasive assistance. 18 and 28Lim are the limiting factors to exercise without and with non-invasive ventilation
Pat.
No.
1
2
3
4
5
6
7
8
Initial observation and exercise without Bipap
Exercise with Bipap
Pa O 2
Pa CO 2
sPO 2
ET
18Lim
ET i
28Lim
ET 3
ET 6
ET 12
95
79
88
75
95
95
84
96
38
52
41
56
41
40
36
38
97
80
85
70
70
95
85
87
3(N)
1(N)
3(N)
1(N)
1(N)
2(N)
1(N)
2(N)
HR
Dessat
Dessat
Dessat
Dessat
Fatigue
Dessat
HR
3(N)
2(N)
3(N)
2(N)
2(N)
3(N)
2(N)
2(N)
HR
RI
Leg pain
RI
Dessat
HR
Fatigue
Spastic
3(B)
3(N)
4(N)
3(N)
3(N)
4(N)
4(N)
3(N)
4(B)
4(N)
3(B)
3(N)
3(N)
3(B)
4(N)
2(N)
4(B)
4(N)
3(B)
2(N)
3(N)
3(B)
3(N)
74
A.C. Pinto et al. / Journal of the Neurological Sciences 169 (1999) 69 – 75
maximal oxygen uptake (VO 2 max.). The relationship of
this point to fatigue and the beginning of muscle overuse is
also known. Froelicher [6] demonstrated a linear correlation between VO 2 max. and heart rate.
Since VO 2 max. is equal to the product HR 3 A 2Vdiff. ,
we considered it to be safe working within these limits,
controlling simultaneously the pulse rate and the percentage of saturated O 2 (sPO 2 ) with a simple pulse
oximeter (Vitalograph  , Respironics). Exercising up to
anaerobic threshold is also the most efficient and least time
consuming way of reconditioning, which we considered
critical in these patients.
When considering our results and the differences between the two groups (Table 5) significant differences
between groups at initial observation in Norris Bulbar
score (P , 0.004) and FVC (P , 0.01) were found. There
was far more bulbar involvement in group 1 patients than
in group 2. For this reason we did not analyse survival
between the groups. Nevertheless, at the end of the trial
there was a positive trend towards reduced bulbar slope
(P , 0.18) and a significant reduction in the rate of decline
of the FVC (P , 0.002) These results also suggest that
exercise under non-invasive ventilation does not cause
deleterious effects in respiratory muscle function. The
progressive decline in Bulbar Norris scores, related to
neuronal loss, may be modulated, in part, by the progressive disturbance of gas exchange in ALS patients.
When considering the parameters related to muscle force
(Spinal Norris score) and quality of life (Barthel scores
and FIM scores), both groups did not show significant
differences at initial observation. Spinal Norris score
detected significant differences at the end of the period of
observation (12 months), both in absolute values and in the
rate of decline (P , 0.02 and P , 0.02, respectively).
The FIM scale was the first to detect changes with
significance in absolute values at 6, 9 and 12 months
(P , 0.03, P , 0.02 and P , 0.03, respectively). The
poorer statistical meaning of this scale at the slopes (rate of
decline) might be due to its reduced specificity, but if one
compares the percentage of the number of patients independent in activities of daily living at the end of the
study in both groups we can clearly see that, in group 1,
only 25% of the patients lost independence (FIM score
,90) and, in group 2, 43% of the patients lost independence in activities of daily living during the same period of
observation.
In summary, in this small sample of ALS patients our
results suggest that exercise should be recommended, even
when there is respiratory insufficiency, using Bipap assistance to control tissue oxygenation. Exercise testing is
apparently a provocative method to anticipate disturbed
gas exchanges that otherwise would only be apparent at the
end stage of the disease [3]. We believe this signifies that
the prescription of non-invasive ventilation should be made
at an earlier stage. However, exercise testing was not
applied to patients in group 2 and further studies should
confirm this possibility. This may be particularly important
in bulbar forms of ALS patients, where it is often said that
non-invasive ventilation is less efficient because of the
excessive amount of secretions in advanced stages of the
disease [3,26].
Acknowledgements
The authors are indebted to ‘Gasin Co, Medical Division
of Portugal’, for cooperating with us with patient assistance, and to Margarida Fernandes for secretarial support.
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