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Flow-volume loop changes reflecting respiratory muscle weakness in chronic neuromuscular disorders
Flow-Volume Loop Changes Reflecting Respiratory Muscle Weakness in Chronic Neuromuscular Disorders
WALTER G. VINCKEN, M.D.* MURRAY G. ELLEKER, M.D.+ MANUEL G. COSIO, M.D. Montreal,
Canada
From the Desmond N. Stoker Pulmonary Function Laboratory, Respiratory Division, Department of Medicine, Royal Victoria Hospital and Montreal Neurological Institute, McGill University, Montreal, Canada. Manuscript submitted January 27, 1987, and accepted May 25, 1987. * Current address and address for reprint requests: Intensive Care Unit, Academic Hospital, University of Brussels, 101 Laarbeeklaan, B1090 Brussels, Belgium. t Current address: Neurology Unit, University of Alberta, Edmonton, Alberta, Canada.
In order to identify the changes in pulmonary function and in the flowvolume loop due to respiratory muscle weakness, two groups of 10 nonsmokers with stable, chronic neuromuscular disease but without respiratory symptoms were studied: one without (Group 1) and one with (Group 2) respiratory muscle weakness as assessed by measurement of maximal static inspiratory and expiratory pressures. In Group 1, pulmonary function was normal except for increased ratio of onesecond forced expiratory volume to forced vital capacity and forced expiratory flow at 25 to 75 percent forced vital capacity, which may reflect increased elastic lung recoil. Group 2 had mild volume restriction, appropriate for the degree of respiratory muscle weakness, and reduced inspiratory and expiratory flow rates. Pulmonary function was significantly more disturbed in Group 2 than in Group 1, and correlated well with maximal static inspiratory and expiratory pressures. Analysis of the flow-volume loop configuration revealed that four parameters describing effort-dependent portions were significantly related to maximal static inspiratory pressure and maximal static expiratory pressure. These parameters were peak expiratory flow, the slope of the ascending limb of the maximal expiratory curve, a drop of forced expiratory flow near residual volume, and forced inspiratory flow at 50 percent of vital capacity. A flow-volume loop score obtained from these four parameters was significantly higher in Group 2 than in Group 1 (2.8 f 1.03 versus 1.1 f 1.37; p
1987
The American
Journal
of Medicine
Volume
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873
FLOW-VOLUME
TABLE
I
LOOP
IN RESPIRATORY
Anthropometric Disease*
Number Age (years) Height (cm) Weight (kg) GMS index MIPS (percent MEPS (percent RMS (percent
MUSCLE
WEAKNESS-VINCKEN
and Respiratory
predicted) predicted) predicted)
Muscle Strength
ET AL
Data in Patients
All
G~OUD 1.
20 50 f 13 169 f IO 66f 13
10 50f 10 170 f 10 65f 15
78.3 68.9
f f
a 31.8
67.3 67.5
f f
32.2 30.9
a0 96 93.7 94
f f f f
with Stable
Chronic
Neuromuscular
G~OUD 2
Dt
10 50f
10
NS NS
11 9.6
NS NS
168f9
67f 76.5 f 41.7 f
6.1 la.9 17.1 15.5
40.9 f 41 f
11.9 la.5 14.7
* Mean values f standard deviation. t Significance level of comparison GMS = general muscle strength; respiratory muscle strength.
of means MIPS =
of both groups maximal static
(NS = not significant). inspiratory pressure;
ally to the force generated by the respiratory muscles, all other factors (in particular upper aiway resistance) remaining constant. lnspiratory isovolume pressure-flow curves [ 1,151 indeed do not show flow plateaux, indicating that at any lung volume, the highest ,possible flow achievable depends on the pressure (force) generated by the inspiratory muscles. At high lung volumes, expiratory isovolume pressure-flow curves also do not show flow plateaux, so that the maximal flow achievable during the initial 25 percent of forced expiration depends mainly on the pressure (force) generated by the expiratory muscles. The middle half of the maximal expiratoty flow-volume curve by contrast is largely effort-independent in that isovolume pressure-flow curves in this volume range do show flow plateaux, indicating that, beyond a given pressure, additional force generated by the expiratory muscles does not further increase the flow. During the terminal part of forced expiration, i.e., at lung volumes below functional residual capacity, however, sufficient expiratory muscle force is again required to overcome the increasing outward elastic recoil pressure of the chest wall [16]. Accordingly, it may be expected that when weak respiratory muscles fail to generate sufficient pressure, this will be reflected in reduced maximal flow rates over the entire inspiratory volume range as well as during the initial and terminal portions of the expiratory volume range. The few studies that have reported flow-volume loops in neuromuscular diseases only mentioned some changes [11,12] and did not investigate the relationship of these changes to the severity of respiratory muscle weakness. In order to detect the changes in routine pulmonary function test results, especially the flow-volume loop, associated with chronic neuromuscular disease, we studied 20 nonsmokers in a stable stage of their disease and without respiratory symptoms. In half of the patients, the respiratory muscles were spared, as evidenced by normal maximal respiratory pressures, whereas in the other half, the respiratory muscles were involvedas evidehced by moderately to severely reduced maximal respiratory pressures. Comparison of routine pulmonary function test 674
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1987
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Volume
MEPS
=
maximal
static
expiratory
pressure;
RMS
=
results between both groups allowed us to assess specifically the effect of respiratory muscle involvement on pulmonary function, and to describe a profile of routine pulmonary function, and especially flow-volume loops, that should lead to the suspicion of respiratory muscle weakness in patients with known or unknown neuromuscular disease. PATIENTS AND METHODS Twenty patients, eight women and 12 men, aged 24 to 73 years, with chronic but stable neuromuscular disease, not or minimally interfering with daily activities, participated in this study. They were followed at the Montreal Neurological Institute, where the diagnosis of motor neuron disease (five patients), polyneuropathy including Guillain-Barre syndrome (seven patients), myasthenia gravis (three patients), and myopathy (five patients) had been well documented by clinical and complementary electrodiagnostic examination. Only nonsmokers with normal results of chest roentgenography and without respiratory signs or symptoms were included. The patients were consecutively referred for pulmonary function testing, including spirometry with flow-volume loops, lung volumes by body plethysmography, singlebreath diffusion capacity for carbon monoxide, and maximal inspiratory and expiratory static mouth pressures. All tests were performed according to recommended standard procedures [ 1,6,17]. Maximal inspiratory and expiratory static mouth pressures were expressed as percent of predicted values obtained in our laboratory [18]. From these measurements, respiratory muscle strength was calculated as the arithmetical mean of maximal static inspiratory pressure and maximal static expiratory pressure. According to their
respiratory
muscle
strength,
the 20 patients
were
separated into Group 1, containing 10 patients with preserved respiratory muscle strength (range 76 to 122 percent predicted), and Group 2, containing 10 patients with moderate to severe respiratory muscle weakness (respiratory muscle strength ranging from 19 to 61 percent predicted). Apart from their separation on the basis of respiratory muscle strength, both patient groups were completely comparable (Table I). The contour of the flow-volume loop was inspected and 93
FLOW-VOLUME
LOOP
IN RESPIRATORY
TABLE II
FEF(
I/s)
MUSCLE
WEAKNESS-VINCKEN
Signlflcant Linear Correlations between Respiratory Pressures and Pulmonary Function Test Results MIPS (percent predicted) r P
TLC (percent predicted) VC (percent predicted) IC (percent predicted) FRC/TLC (percent) RV/TLC (percent) FIFsO (liters/second) PEF (percent predicted) nA-slope (percent predicted/percent vital capacity) FV loop score
PEF
ET AL
+0.48 +0.61 +0.71 -0.66
<0.05
+0.44
<0.05
-0.62
MEPS(percent predicted) I
P
f0.60
-0.76 -0.49
i-O.63 f0.48
-0.57
MIPS = maximal static inspiratory pressure; MEPS = maximal static expiratory pressure; TLC = total lung capacity; VC = vital capacity: IC = inspiratory capacity; FRC = functional residual capacity; RV = residual volume; FIFsO = forced mid-inspiratory flow; PEF = peak expiratory flow; nA-slope = chord slope of the ascending limb of the maximal expiratory flow-volume curve; FV = flow volume. Note: None of the other pulmonary function test results obtained were significantly correlated to maximal static inspiratory pressure or maximal static expiratory pressure.
UME
FIF 50
FIF(l/s) Vgure 1. Representative flow-volume loop of a patien tt with chronic neuromuscular disease showing how the different flow-volume loop parameters describing its configuration were obtained.
quantitated by means of four parameters (Figure 1). Each of these four parameters had been selected out of a number of other parameters because they referred to an effort-dependent portion of the flow-volume loop and correlated well with maximal static inspiratory pressure or maximal static expiratory pressure (Table II). They were thus expected to quantitate the effects of changes in respiratory muscle strength on the effort-dependent portions of the flow-volume loop. These four parameters were: (1) peak expiratory flow, describing the height of the initial part of the maximal expiratory flow-volume curve: (2) the ratio of peak expiratory flow (expressed as percent predicted) to the exhaled volume at which peak expiratory flow was reached (expressed as percent vital capacity), describing the (normalized) chord slope of the ascending limb of the maximal expiratory flow-volume curve (nA-slope); (3) an abrupt vertical drop of forced expiratory flow near residual volume, describing the configuration of the terminal part of the maximal expiratory flow-volume curve (FEF drop): and (4) forced mid-inspiratory flow, characterizing the maximal inspiratory flow-volume curve. From these four parameters, a
October
flow-volume loop score (ranging from 0 to 4) was obtained by attributing one point to each abnormal variable, i.e., a peak expiratory flow less than 70 percent predicted; a nAslope less than 4.09 in men and 2.97 in women; the presence of an FEF drop; and a forced mid-inspiratory flow less than 3 liters/second. These limits of normality correspond to the 95 percent confidence limits obtained by subtracting 1.65 SD from the mean value obtained in 65 normal subjects (35 male and 30 female) in our laboratory. Because thls analysis is entirely based on effort-dependent parts of the flow-volume loop, it was critical to differentiate between flow-volume loops rendered abnormal by virtue of respiratory muscle weakness and flow-volume loops from noncooperating patients who failed to make a maximum effort. Therefore, a series,of three or more flow-volume loops was obtained from each patient until the peak expiratory flow, peak inspiratory flow, and forced expired volume in one second of the two best trials agreed within 5 percent. Furthermore, both these trials had to produce satisfactory flow-volume loop tracings free from artifacts on the x-y recorder. Calculations were performed on the loop with the highest sum of one-second forced expiratory volume and forced vital capacity. General muscle strength was assessed by clinical examination of the strength of 17 limb and girdle muscle groups, yielding a general muscle strength index ranging from 0 (completely paralyzed) to 85 (no detectable weakness)
[191.
Statistical analysis included linear regression analysis for significant relationships between pulmonary function variables, and two-tailed Mann-Whitney test for comparison of mean values of both groups. Statistical significance was inferred for p values below 0.05.
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875
FLOW-VOLUME
LOOP
IN RESPIRATORY
MUSCLE
WEAKNESS-VINCKEN
ET AL
% Pred MIPS
MEPS
TLC
VC
RV
Figure 2
Comparison of mean values (bars, with whiskers indicating standard deviations) of maximal respiratory pre.+ sores and lung volumes of 10 patients with preserved ( 7) and 10 patients with reduced (2) respiratory muscle strength. Asterisks indicate significance levels. A/i test results expressed as percent predicted except residual volume/total lung capacity (N/TLC) and functional residual capacity/total lung capacity (F/X/TLC), which are expressed as percent.
RESULTS Routine Pulmonary Function Tests and Relationship to Maximal Respiratory Pressures. Compared with expected values, total lung capacity, vital capacity, inspiratory capacity, and peak expiratory flow were significantly reduced, whereas the one-second forced expiratory volume/forced vital capacity and functional residual capacity/total lung capacity ratios were significantly increased in the whole study group. Significant direct linear correlations were found between maximal static inspiratoty pressure and total lung capacity, vital capacity, inspiratory capacity, and forced mid-inspiratory flow each, and between maximal static expiratory pressure and vital capacity and peak expiratory flow each. Significant indirect linear correlations were found between maximal static inspiratory pressure and the ratio of functional residual capacity to total lung capacity, and between maximal static expiratory pressure and the ratio of residual volume to total lung capacity and the ratio of functional residual capacity to total lung capacity each (Table II). All other routine pulmonary function test results were normal and not significantly related to the maximal respiratory pressures. Separation of the patients into two groups according to respiratory muscle strength revealed that, except for an increased forced expiratory flow at 25 to 75 percent forced vital capacity (FEF2s-r5) and one-second forced expiratoty volume/forced vital capacity ratio, Group 1 had normal pulmonary function, whereas most test results were abnormal in Group 2. In Group 2, vital capacity, inspiratory capacity, one-second forced expiratory volume, half-second forced expiratory volume, peak expiratory flow, forced mid-expiratory flow, forced expiratory
flow at 25 percent forced vital capacity (FEF&, peak inspiratory flow, and forced mid-inspiratory flow were significantly lower, and residual volume, residual volume/ total lung capacity ratio, and functional residual capacity/ total lung capacity ratio significantly higher than in Group 1 (Figures 2 and 3). Flow-Volume Loop Configuration. Inspection of the flow-volume loop contour revealed frequent abnormalities, the most striking being a reduced and delayed expiratory peak, a sudden and sharp drop of end-expiratory flow, and a flattened inspiratory curve (Figure 1). As indicated in the Patients and Methods section, these configurational abnormalities were quantitatively expressed by means of four variables (peak expiratory flow, nA-slope, FEF drop, and forced mid-inspiratory flow) constituting the flowvolume loop score. The most prevalent abnormality was a reduced nA-slope (15 of 20 patients, 75 percent), the three other variables being abnormal in 35 to 45 percent of patients (Table Ill). The nA-slope, peak expiratory flow, and forced mid-inspiratory flow were significantly related to maximal respiratory pressures (Table II), and maximal static expiratory pressure was lower in the eight patients with an FEF drop than in the 12 patients without FEF drop (52 f 34 percent predicted versus 77 f 28 percent predicted, p <0.05). In Group 2, mean values of peak expiratory flow, nAslope, and forced mid-inspiratory flow were reduced (as compared with expected) and significantly lower than in Group 1 (Table IV). Also, the prevalence of abnormality of the flow-volume loop variables was higher in Group 2 than in Group 1 (Table Ill). Accordingly, the flow-volume loop score was higher in Group 2 than in Group 1 (2.8 f 1.03 versus 1.1 f 1.37, respectively; p
676
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1967
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FLOW-VOLUME
LOOP
IN RESPIRATORY
MUSCLE
WEAKNESS-VINCKEN
Figure 3. Comparison of mean values (bars, with whiskers indicating standard deviations) of expiratov and inspiratoty flow rates derived from maximal-effort flow-volume loops of 10 patients with preserved ( 7) and 10 with reduced (2) respiratory muscle strength. All tests expressed as percent predicted except peak inspiratoty flow (P/F) and forced mid-inspira toty f/o w (F/FSO)(expressed in liters/second) and one-second forced expiratoty volume/forced vital capacity (FEVJFVC) ratio (expressed as percent). Asterisks indicate significance levels.
TABLE III
Prevalence
of Abnormal
PIF FIF
70 60 50 40 30 20 10 0
Flow-Volume
Loop Parameters PEF
FEF-Drop
3 13 16 14 4 5 19 10 2 18 20 11 1 7 8 17 6 9 12 15
2 2 2 1 2 2 2 1 2 2 2 2 1 1 1 1 1 1 1 1
A A A A A A A A A A A A A A A N N N N N
A A A A N A A A N A A N N N N N N N N N
A A A A A A N A N N N N N N N A N N N N
A A A A A N A N A N N N N N N N N N N N
15 (75) 5 (50) 10 (100) 50 100
9 (45)
8 (40) 3 (30) 5 (50) 70 80
7 (35) 1(10)
result;
N = normal
FEVl Fyc
60
nA-Slope
A = abnormal
‘x,
90
Group
test
50
100
Patient Number
Number (percent) abnormal All (n = 20) Group 1 (n = IO) Group 2 (n = 10) Specificity (percent) Sensitivity (percent)
ET AL
FV Loop Score
Fho
4 4 4 4 3 3 3 3 2 2 2 1 1 1 1 1 0 0 0 0
results
result;
FEF drop
defined
2 WY 7 (70) 80 70 in Patients
whole study group, this score was significantly related to both maximal static inspiratory pressure (r = -0.62, p
and Methods
section;
6 (60) 90 60 other
abbreviations
as in Table
II.
loop scores (0 to 1) (Figure 4). The between-subject variability of the flow-volume loop parameters and score (Table IV) was of the same order of magnitude as that of the maximal respiratory pressures (Table I) and probably reflects their interrelationships (Table II). Within-subject variability of flow-volume loop parameters and score was low (coefficients of variation typically ranging from 2.7 to 1987
The American
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FLOW-VOLUME
TABLE
LOOP
IV
IN RESPIRATORY
Flow-Volume
ioop
MUSCLE
WEAKNESS-VINCKEN
Parameters
and
ET AL
Score
All 81 f 3.0 f
PEF (percent predicted) nA-slope (percent predicted/ percent vital capacity) FIFsO (liters/second) FEF drop (number abnormal) FV loop score
Group 1
27.5’ 1.8
95.4 f 3.9 f
3.9 f 1.8 8120 1.9 f 1.5%
Values expressed as mean f standard as in Tables II and Ill. * Significance level of comparison of 7 p
deviation,
except
for FEF drop
This report describes routine pulmonary function tests, in particular flow-volume loop characteristics, in patients with neuromuscular disease, with the aim of defining
MIPS
MEPS
l
l **
% Pred 100
GMS 8580 -
90
i-O-
70
60-
60
50 -
50
40 -
40
30 -
30
20 -
20
lo-
10
O._
80
-
-
-
.
._
0 .~.
..
c;omparison of mean values (bars, With wnla kers indicating standard deviations) of maximal static inspiratoty pressure (MIPS), maximal static expiratoty pressure (MEPS) and general muscle strength (GMS) between patients with flow-volume loop score of 0 to 1 (A) andpatients with flow-volume loop score of 2 to 4 (S). MIPS and MEPS expressed as percent predicted, GMS score ranging from 0 to85. ***p
676
4.
October
1967
The American
66.6 f 2.2 f
(where
numbers
are fraction
P”
21.65 0.95
3.0 f I.17 5110 2.8 f 1.039
of abnormal
test results).
Abbreviations
means of both groups. predicted value. predicted value. predicted value.
COMMENTS
**
25.9 2.1
4.8 f 2.0 3110 1.1 f 1.37x
7.4 percent), indicating good reproducibility and excluding poor cooperation as a factor rendering the flow-volume loop abnormal.
GMS
Group 2
Journal
of Medicine
Volume
those variables that might reflect the presence of respiratory muscle involvement. The results suggest that some changes in the flow-volume loop configuration, expressed in a flow-volume loop score, might be particularly helpful in suspecting respiratory muscle weakness in the (not infrequent) event that maximal respiratory pressures are not available. Unlike most previous studies on pulmonary function in neuromuscular disease [ l-4,7- 141, our patient population was homogeneous, containing only nonsmokers free from respiratory symptoms or complications and in a stable stage of their disease. Furthermore, on the basis of maximal respiratory pressures, our patients were divided into two groups, one with normal respiratory muscle strength and one with weak respiratory muscles. This allowed us to specifically assess the effects of respiratory muscle involvement on routine pulmonary function. An increased one-second forced expiratory volume/forced vital capacity ratio and FEFgSmT5 were the only changes found in patients with preserved respiratory muscle strength. These changes, which may reflect increased elastic lung recoil, have been noted previously in patients with asymptomatic neuromuscular disease, but these patients had a 50 percent reduction in maximal respiratory pressures [2]. Patients with weak respiratory muscles had a pattern of lung volume restriction with normal lung diffusion capacity, and inspiratory and expiratory flow limitation. The observed 25 percent reduction in vital capacity was appropriate for the 60 percent decrement in respiratory muscle strength [ 1,2,20]. In other studies, not excluding smokers or patients with respiratory complications, lung volume restriction exceeding that expected for the degree of respiratory muscle weakness has been noted [4,11,12,14] and attributed to secondary changes in lung and chest wall mechanics [ 11,141. Comparison of our data with previous reports on moderate [1,2] and severe neuromuscular disease [4,11,12,14] suggests that lung volume changes might follow the following sequence of events: with preserved respiratory muscle strength, an increased one-second forced expiratory 83
FLOW-VOLUME
volume/forced vital capacity ratio and FEF2se75 might indicate some increased elastic lung recoil, but lung volume remains normal; when respiratory muscle weakness develops, an “appropriate” loss of lung volume results from the inability to pull up the respiratory system to total lung capacity and to push it down to residual volume; in more advanced or complicated stages of the disease, “disproportionate” lung volume restriction occurs as a result of further advancing secondary changes in lung and chest wall elastic recoil. In previous studies, changes in flow rates and flowvolume loops occurring in neuromuscular disease have received little attention, Yet, isovolume pressure-flow curves [ 151 indicate that all inspiratory flow rates as well as expiratory flow rates at high lung volume depend to a large extent on effort, i.e., respiratory muscle strength. The terminal portion of forced expiration is alSO effortdependent, since at lung volumes below functional residual capacity, sufficient force is required to overcome the outward elastic recoil of the chest wall [ 161. Therefore, respiratory muscle weakness may be expected to affect inspiratory flow rates as well as expiratory flow rates at high and low lung volume. Accordingly, we found normal flow rates in patients with preserved respiratory muscle strength and reduced inspiratory and expiratory flow rates in patients with weak respiratory muscles (Figure 3). Maximal respiratory pressures correlated directly with the effort-dependent flow rates peak expiratory flow and forced mid-inspiratory flow (Table II). The flow-volume loop contour, which integrates all flow data in one visual image, was frequently abnormal (Figure 1): at its onset, the maximal expiratory flowvolume curve rises sluggishly towards a delayed, reduced and rounded peak; at end-expiration, a sudden drop in forced expiratory flow may occur, thus setting residual volume; and instead of the normal hemispherical or conical shape, the maximal inspiratory flow-volume curve is often characterized by a flattened shape. Some of these maximal expiratory flow-volume curve abnormalities have been previously reported: Kreitzer et al [12] found that in 15 patients with motor neuron disease, forced expiratory flow “decreased with concavity towards the volume-axis, giving the impression that forced expiratory flow has dropped off the maximal expiratory flow-volume curve envelope as residual volume was approached.” In seven patients with severe respiratory muscle weakness, Gibson et al [ 1 l] noted “some reduction in peak expiratory flow which developed at a lower than normal percentage of the (restricted) vital capacity.” These authors did not correlate these changes to the degree of respiratory muscle weakness; neither did they study the maximal inspiratory flow-volume curve. In order to examine the relationship between the degree of respiratory muscle weakness and the observed configurational changes of the flow-volume loop, we selected four parameters that were significantly related to maximal static inspiratory or October
LOOP
IN RESPIRATORY
MUSCLE
WEAKNESS-VINGKEN
ET AL
expiratory pressure (Table II), referred each to an effortdependent part of the flow-volume loop, and could each be visually observed on the loop (Figure 1). These parameters were the peak expiratory flow, nA-slope, FEF drop, and forced mid-inspiratory flow. As shown in the results, these variables were more frequently and to a greater degree abnormal in patients with weak respiratory muscles than in patients with preserved respiratory muscle strength (Tables Ill and IV). The parameters peak expiratory flow and forced mid-inspiratory flow are both entirely effort-dependent, in that they are limited only by the available force of the expiratory and inspiratory muscles, respectively [ 1,151. Respiratory muscle weakness, hence, may be expected to result in reduced peak expiratory flow and forced mid-inspiratory flow. The parameter nA-slope is the ratio of peak expiratory flow to the exhaled volume at which the peak expiratory flow occurs, and as such has the units of s- I: it is the reciprocal of the time constant of lung emptying at the start of forced expiration. Reduced (less steep) nA-slope, hence, reflects a longer time constant, i.e., a slower rate of lung emptying at high lung volume. Since maximal expiratory flow in this volume range is in part determined by the velocity of shottening and recruitment of expiratoty muscles [21], we assume that expiratory muscle weakness may delay the rate of rise of maximal expiratory flow, resulting in a less steep slope of the ascending limb of the maximal expiratory flow-volume curve, hence, in a reduced nA-slope. Finally, the parameter FEF drop was also attributed to expiratory muscle weakness, since patients with an FEF drop had lower maximal static expiratory pressure than those without. Furthermore, prolonged expiration reaching the breath-holding limits with premature inspiration truncating the maximal expiratory flow-volume curve was not observed and considered unlikely in view of the increased one-second forced expiratory volume/forced vital capacity ratio (indicating fast, rather than slow, emptying of the available entire vital capacity). Combining the four flow-volume loop variables in a flow-volume loop score enhanced their ability to predict respiratory muscle involvement in our patients. The flowvolume loop score was significantly higher (more abnormal) in patients with respiratory muscle weakness than in those without. When a flow-volume loop score of 4 was considered abnormal, the test was a 90 percent specific but only a 30 percent sensitive predictor of respiratory muscle weakness in patients with neuromuscular disease (Table V). Reducing the limits of abnormality of the test improved its sensitivity with only a minimal loss of specificity. Thus, arbitrarily accepting only scores of 0 or 1 as normal enabled the test to predict respiratory muscle involvement in our patients with a 90 percent sensitivity, an 80 percent specificity, and an 85 percent efficiency. Setting the limits of abnormality for the test that low seems justified, since its purpose is to detect respiratory muscle weakness in patients with that condition, i.e., 1987
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FLOW-VOLUME
TABLE
V
LOOP
IN RESPIRATORY
Sensitivity and Specificity Volume Loop Score’
Group 1 (n = 10) Number of positive (false-positives) Number of negative Group 2 (n = 10) Number of positive Number of negative (false-negatives) Sensitivity (percent) Specificity (percent) Efficiency (percent) * As a predictor neuromuscular
MUSCLE
WEAKNESS-VINCKEN
of the FlowLimit of Abnormality 4 3
2
1
2
2
results
9
8
a
test results test results
3 7
6 4
9 1
30 90 60
60
90 80 85
test results test
of respiratory disease.
muscle
weakness
80 70
in uncomplicated
avoid false-negative results. The flow-volume loop score, indeed, was not designed to replace the measurement of maximal static inspiratory and expiratory pressures. Rather, when these measurements are lacking, an increased flow-volume loop score should alert the physician to the possible presence of respiratory muscle weakness in patients undergoing routine pulmonary function studies. False-positive results will then be easily identified by
ET AL
complementary measurements of maximal static inspiratory and expiratory pressures, which are not routinely performed in most pulmonary function laboratories. The scoring system as applied weighs expiratory muscle performance out of proportion to inspiratory muscle performance. However, this is not critical, since an excellent linear relationship was found between maximal static inspiratory pressure and maximal static expiratory pressure (r = 0.87, p
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WALTER G. VINCKEN, M.D.* MURRAY G. ELLEKER, M.D.+ MANUEL G. COSIO, M.D. Montreal,
Canada
From the Desmond N. Stoker Pulmonary Function Laboratory, Respiratory Division, Department of Medicine, Royal Victoria Hospital and Montreal Neurological Institute, McGill University, Montreal, Canada. Manuscript submitted January 27, 1987, and accepted May 25, 1987. * Current address and address for reprint requests: Intensive Care Unit, Academic Hospital, University of Brussels, 101 Laarbeeklaan, B1090 Brussels, Belgium. t Current address: Neurology Unit, University of Alberta, Edmonton, Alberta, Canada.
In order to identify the changes in pulmonary function and in the flowvolume loop due to respiratory muscle weakness, two groups of 10 nonsmokers with stable, chronic neuromuscular disease but without respiratory symptoms were studied: one without (Group 1) and one with (Group 2) respiratory muscle weakness as assessed by measurement of maximal static inspiratory and expiratory pressures. In Group 1, pulmonary function was normal except for increased ratio of onesecond forced expiratory volume to forced vital capacity and forced expiratory flow at 25 to 75 percent forced vital capacity, which may reflect increased elastic lung recoil. Group 2 had mild volume restriction, appropriate for the degree of respiratory muscle weakness, and reduced inspiratory and expiratory flow rates. Pulmonary function was significantly more disturbed in Group 2 than in Group 1, and correlated well with maximal static inspiratory and expiratory pressures. Analysis of the flow-volume loop configuration revealed that four parameters describing effort-dependent portions were significantly related to maximal static inspiratory pressure and maximal static expiratory pressure. These parameters were peak expiratory flow, the slope of the ascending limb of the maximal expiratory curve, a drop of forced expiratory flow near residual volume, and forced inspiratory flow at 50 percent of vital capacity. A flow-volume loop score obtained from these four parameters was significantly higher in Group 2 than in Group 1 (2.8 f 1.03 versus 1.1 f 1.37; p
1987
The American
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Volume
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873
FLOW-VOLUME
TABLE
I
LOOP
IN RESPIRATORY
Anthropometric Disease*
Number Age (years) Height (cm) Weight (kg) GMS index MIPS (percent MEPS (percent RMS (percent
MUSCLE
WEAKNESS-VINCKEN
and Respiratory
predicted) predicted) predicted)
Muscle Strength
ET AL
Data in Patients
All
G~OUD 1.
20 50 f 13 169 f IO 66f 13
10 50f 10 170 f 10 65f 15
78.3 68.9
f f
a 31.8
67.3 67.5
f f
32.2 30.9
a0 96 93.7 94
f f f f
with Stable
Chronic
Neuromuscular
G~OUD 2
Dt
10 50f
10
NS NS
11 9.6
NS NS
168f9
67f 76.5 f 41.7 f
6.1 la.9 17.1 15.5
40.9 f 41 f
11.9 la.5 14.7
* Mean values f standard deviation. t Significance level of comparison GMS = general muscle strength; respiratory muscle strength.
of means MIPS =
of both groups maximal static
(NS = not significant). inspiratory pressure;
ally to the force generated by the respiratory muscles, all other factors (in particular upper aiway resistance) remaining constant. lnspiratory isovolume pressure-flow curves [ 1,151 indeed do not show flow plateaux, indicating that at any lung volume, the highest ,possible flow achievable depends on the pressure (force) generated by the inspiratory muscles. At high lung volumes, expiratory isovolume pressure-flow curves also do not show flow plateaux, so that the maximal flow achievable during the initial 25 percent of forced expiration depends mainly on the pressure (force) generated by the expiratory muscles. The middle half of the maximal expiratoty flow-volume curve by contrast is largely effort-independent in that isovolume pressure-flow curves in this volume range do show flow plateaux, indicating that, beyond a given pressure, additional force generated by the expiratory muscles does not further increase the flow. During the terminal part of forced expiration, i.e., at lung volumes below functional residual capacity, however, sufficient expiratory muscle force is again required to overcome the increasing outward elastic recoil pressure of the chest wall [16]. Accordingly, it may be expected that when weak respiratory muscles fail to generate sufficient pressure, this will be reflected in reduced maximal flow rates over the entire inspiratory volume range as well as during the initial and terminal portions of the expiratory volume range. The few studies that have reported flow-volume loops in neuromuscular diseases only mentioned some changes [11,12] and did not investigate the relationship of these changes to the severity of respiratory muscle weakness. In order to detect the changes in routine pulmonary function test results, especially the flow-volume loop, associated with chronic neuromuscular disease, we studied 20 nonsmokers in a stable stage of their disease and without respiratory symptoms. In half of the patients, the respiratory muscles were spared, as evidenced by normal maximal respiratory pressures, whereas in the other half, the respiratory muscles were involvedas evidehced by moderately to severely reduced maximal respiratory pressures. Comparison of routine pulmonary function test 674
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1987
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MEPS
=
maximal
static
expiratory
pressure;
RMS
=
results between both groups allowed us to assess specifically the effect of respiratory muscle involvement on pulmonary function, and to describe a profile of routine pulmonary function, and especially flow-volume loops, that should lead to the suspicion of respiratory muscle weakness in patients with known or unknown neuromuscular disease. PATIENTS AND METHODS Twenty patients, eight women and 12 men, aged 24 to 73 years, with chronic but stable neuromuscular disease, not or minimally interfering with daily activities, participated in this study. They were followed at the Montreal Neurological Institute, where the diagnosis of motor neuron disease (five patients), polyneuropathy including Guillain-Barre syndrome (seven patients), myasthenia gravis (three patients), and myopathy (five patients) had been well documented by clinical and complementary electrodiagnostic examination. Only nonsmokers with normal results of chest roentgenography and without respiratory signs or symptoms were included. The patients were consecutively referred for pulmonary function testing, including spirometry with flow-volume loops, lung volumes by body plethysmography, singlebreath diffusion capacity for carbon monoxide, and maximal inspiratory and expiratory static mouth pressures. All tests were performed according to recommended standard procedures [ 1,6,17]. Maximal inspiratory and expiratory static mouth pressures were expressed as percent of predicted values obtained in our laboratory [18]. From these measurements, respiratory muscle strength was calculated as the arithmetical mean of maximal static inspiratory pressure and maximal static expiratory pressure. According to their
respiratory
muscle
strength,
the 20 patients
were
separated into Group 1, containing 10 patients with preserved respiratory muscle strength (range 76 to 122 percent predicted), and Group 2, containing 10 patients with moderate to severe respiratory muscle weakness (respiratory muscle strength ranging from 19 to 61 percent predicted). Apart from their separation on the basis of respiratory muscle strength, both patient groups were completely comparable (Table I). The contour of the flow-volume loop was inspected and 93
FLOW-VOLUME
LOOP
IN RESPIRATORY
TABLE II
FEF(
I/s)
MUSCLE
WEAKNESS-VINCKEN
Signlflcant Linear Correlations between Respiratory Pressures and Pulmonary Function Test Results MIPS (percent predicted) r P
TLC (percent predicted) VC (percent predicted) IC (percent predicted) FRC/TLC (percent) RV/TLC (percent) FIFsO (liters/second) PEF (percent predicted) nA-slope (percent predicted/percent vital capacity) FV loop score
PEF
ET AL
+0.48 +0.61 +0.71 -0.66
<0.05
+0.44
<0.05
-0.62
MEPS(percent predicted) I
P
f0.60
-0.76 -0.49
i-O.63 f0.48
-0.57
MIPS = maximal static inspiratory pressure; MEPS = maximal static expiratory pressure; TLC = total lung capacity; VC = vital capacity: IC = inspiratory capacity; FRC = functional residual capacity; RV = residual volume; FIFsO = forced mid-inspiratory flow; PEF = peak expiratory flow; nA-slope = chord slope of the ascending limb of the maximal expiratory flow-volume curve; FV = flow volume. Note: None of the other pulmonary function test results obtained were significantly correlated to maximal static inspiratory pressure or maximal static expiratory pressure.
UME
FIF 50
FIF(l/s) Vgure 1. Representative flow-volume loop of a patien tt with chronic neuromuscular disease showing how the different flow-volume loop parameters describing its configuration were obtained.
quantitated by means of four parameters (Figure 1). Each of these four parameters had been selected out of a number of other parameters because they referred to an effort-dependent portion of the flow-volume loop and correlated well with maximal static inspiratory pressure or maximal static expiratory pressure (Table II). They were thus expected to quantitate the effects of changes in respiratory muscle strength on the effort-dependent portions of the flow-volume loop. These four parameters were: (1) peak expiratory flow, describing the height of the initial part of the maximal expiratory flow-volume curve: (2) the ratio of peak expiratory flow (expressed as percent predicted) to the exhaled volume at which peak expiratory flow was reached (expressed as percent vital capacity), describing the (normalized) chord slope of the ascending limb of the maximal expiratory flow-volume curve (nA-slope); (3) an abrupt vertical drop of forced expiratory flow near residual volume, describing the configuration of the terminal part of the maximal expiratory flow-volume curve (FEF drop): and (4) forced mid-inspiratory flow, characterizing the maximal inspiratory flow-volume curve. From these four parameters, a
October
flow-volume loop score (ranging from 0 to 4) was obtained by attributing one point to each abnormal variable, i.e., a peak expiratory flow less than 70 percent predicted; a nAslope less than 4.09 in men and 2.97 in women; the presence of an FEF drop; and a forced mid-inspiratory flow less than 3 liters/second. These limits of normality correspond to the 95 percent confidence limits obtained by subtracting 1.65 SD from the mean value obtained in 65 normal subjects (35 male and 30 female) in our laboratory. Because thls analysis is entirely based on effort-dependent parts of the flow-volume loop, it was critical to differentiate between flow-volume loops rendered abnormal by virtue of respiratory muscle weakness and flow-volume loops from noncooperating patients who failed to make a maximum effort. Therefore, a series,of three or more flow-volume loops was obtained from each patient until the peak expiratory flow, peak inspiratory flow, and forced expired volume in one second of the two best trials agreed within 5 percent. Furthermore, both these trials had to produce satisfactory flow-volume loop tracings free from artifacts on the x-y recorder. Calculations were performed on the loop with the highest sum of one-second forced expiratory volume and forced vital capacity. General muscle strength was assessed by clinical examination of the strength of 17 limb and girdle muscle groups, yielding a general muscle strength index ranging from 0 (completely paralyzed) to 85 (no detectable weakness)
[191.
Statistical analysis included linear regression analysis for significant relationships between pulmonary function variables, and two-tailed Mann-Whitney test for comparison of mean values of both groups. Statistical significance was inferred for p values below 0.05.
1987
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875
FLOW-VOLUME
LOOP
IN RESPIRATORY
MUSCLE
WEAKNESS-VINCKEN
ET AL
% Pred MIPS
MEPS
TLC
VC
RV
Figure 2
Comparison of mean values (bars, with whiskers indicating standard deviations) of maximal respiratory pre.+ sores and lung volumes of 10 patients with preserved ( 7) and 10 patients with reduced (2) respiratory muscle strength. Asterisks indicate significance levels. A/i test results expressed as percent predicted except residual volume/total lung capacity (N/TLC) and functional residual capacity/total lung capacity (F/X/TLC), which are expressed as percent.
RESULTS Routine Pulmonary Function Tests and Relationship to Maximal Respiratory Pressures. Compared with expected values, total lung capacity, vital capacity, inspiratory capacity, and peak expiratory flow were significantly reduced, whereas the one-second forced expiratory volume/forced vital capacity and functional residual capacity/total lung capacity ratios were significantly increased in the whole study group. Significant direct linear correlations were found between maximal static inspiratoty pressure and total lung capacity, vital capacity, inspiratory capacity, and forced mid-inspiratory flow each, and between maximal static expiratory pressure and vital capacity and peak expiratory flow each. Significant indirect linear correlations were found between maximal static inspiratory pressure and the ratio of functional residual capacity to total lung capacity, and between maximal static expiratory pressure and the ratio of residual volume to total lung capacity and the ratio of functional residual capacity to total lung capacity each (Table II). All other routine pulmonary function test results were normal and not significantly related to the maximal respiratory pressures. Separation of the patients into two groups according to respiratory muscle strength revealed that, except for an increased forced expiratory flow at 25 to 75 percent forced vital capacity (FEF2s-r5) and one-second forced expiratoty volume/forced vital capacity ratio, Group 1 had normal pulmonary function, whereas most test results were abnormal in Group 2. In Group 2, vital capacity, inspiratory capacity, one-second forced expiratory volume, half-second forced expiratory volume, peak expiratory flow, forced mid-expiratory flow, forced expiratory
flow at 25 percent forced vital capacity (FEF&, peak inspiratory flow, and forced mid-inspiratory flow were significantly lower, and residual volume, residual volume/ total lung capacity ratio, and functional residual capacity/ total lung capacity ratio significantly higher than in Group 1 (Figures 2 and 3). Flow-Volume Loop Configuration. Inspection of the flow-volume loop contour revealed frequent abnormalities, the most striking being a reduced and delayed expiratory peak, a sudden and sharp drop of end-expiratory flow, and a flattened inspiratory curve (Figure 1). As indicated in the Patients and Methods section, these configurational abnormalities were quantitatively expressed by means of four variables (peak expiratory flow, nA-slope, FEF drop, and forced mid-inspiratory flow) constituting the flowvolume loop score. The most prevalent abnormality was a reduced nA-slope (15 of 20 patients, 75 percent), the three other variables being abnormal in 35 to 45 percent of patients (Table Ill). The nA-slope, peak expiratory flow, and forced mid-inspiratory flow were significantly related to maximal respiratory pressures (Table II), and maximal static expiratory pressure was lower in the eight patients with an FEF drop than in the 12 patients without FEF drop (52 f 34 percent predicted versus 77 f 28 percent predicted, p <0.05). In Group 2, mean values of peak expiratory flow, nAslope, and forced mid-inspiratory flow were reduced (as compared with expected) and significantly lower than in Group 1 (Table IV). Also, the prevalence of abnormality of the flow-volume loop variables was higher in Group 2 than in Group 1 (Table Ill). Accordingly, the flow-volume loop score was higher in Group 2 than in Group 1 (2.8 f 1.03 versus 1.1 f 1.37, respectively; p
676
63
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1967
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FLOW-VOLUME
LOOP
IN RESPIRATORY
MUSCLE
WEAKNESS-VINCKEN
Figure 3. Comparison of mean values (bars, with whiskers indicating standard deviations) of expiratov and inspiratoty flow rates derived from maximal-effort flow-volume loops of 10 patients with preserved ( 7) and 10 with reduced (2) respiratory muscle strength. All tests expressed as percent predicted except peak inspiratoty flow (P/F) and forced mid-inspira toty f/o w (F/FSO)(expressed in liters/second) and one-second forced expiratoty volume/forced vital capacity (FEVJFVC) ratio (expressed as percent). Asterisks indicate significance levels.
TABLE III
Prevalence
of Abnormal
PIF FIF
70 60 50 40 30 20 10 0
Flow-Volume
Loop Parameters PEF
FEF-Drop
3 13 16 14 4 5 19 10 2 18 20 11 1 7 8 17 6 9 12 15
2 2 2 1 2 2 2 1 2 2 2 2 1 1 1 1 1 1 1 1
A A A A A A A A A A A A A A A N N N N N
A A A A N A A A N A A N N N N N N N N N
A A A A A A N A N N N N N N N A N N N N
A A A A A N A N A N N N N N N N N N N N
15 (75) 5 (50) 10 (100) 50 100
9 (45)
8 (40) 3 (30) 5 (50) 70 80
7 (35) 1(10)
result;
N = normal
FEVl Fyc
60
nA-Slope
A = abnormal
‘x,
90
Group
test
50
100
Patient Number
Number (percent) abnormal All (n = 20) Group 1 (n = IO) Group 2 (n = 10) Specificity (percent) Sensitivity (percent)
ET AL
FV Loop Score
Fho
4 4 4 4 3 3 3 3 2 2 2 1 1 1 1 1 0 0 0 0
results
result;
FEF drop
defined
2 WY 7 (70) 80 70 in Patients
whole study group, this score was significantly related to both maximal static inspiratory pressure (r = -0.62, p
and Methods
section;
6 (60) 90 60 other
abbreviations
as in Table
II.
loop scores (0 to 1) (Figure 4). The between-subject variability of the flow-volume loop parameters and score (Table IV) was of the same order of magnitude as that of the maximal respiratory pressures (Table I) and probably reflects their interrelationships (Table II). Within-subject variability of flow-volume loop parameters and score was low (coefficients of variation typically ranging from 2.7 to 1987
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FLOW-VOLUME
TABLE
LOOP
IV
IN RESPIRATORY
Flow-Volume
ioop
MUSCLE
WEAKNESS-VINCKEN
Parameters
and
ET AL
Score
All 81 f 3.0 f
PEF (percent predicted) nA-slope (percent predicted/ percent vital capacity) FIFsO (liters/second) FEF drop (number abnormal) FV loop score
Group 1
27.5’ 1.8
95.4 f 3.9 f
3.9 f 1.8 8120 1.9 f 1.5%
Values expressed as mean f standard as in Tables II and Ill. * Significance level of comparison of 7 p
deviation,
except
for FEF drop
This report describes routine pulmonary function tests, in particular flow-volume loop characteristics, in patients with neuromuscular disease, with the aim of defining
MIPS
MEPS
l
l **
% Pred 100
GMS 8580 -
90
i-O-
70
60-
60
50 -
50
40 -
40
30 -
30
20 -
20
lo-
10
O._
80
-
-
-
.
._
0 .~.
..
c;omparison of mean values (bars, With wnla kers indicating standard deviations) of maximal static inspiratoty pressure (MIPS), maximal static expiratoty pressure (MEPS) and general muscle strength (GMS) between patients with flow-volume loop score of 0 to 1 (A) andpatients with flow-volume loop score of 2 to 4 (S). MIPS and MEPS expressed as percent predicted, GMS score ranging from 0 to85. ***p
676
4.
October
1967
The American
66.6 f 2.2 f
(where
numbers
are fraction
P”
21.65 0.95
3.0 f I.17 5110 2.8 f 1.039
of abnormal
test results).
Abbreviations
means of both groups. predicted value. predicted value. predicted value.
COMMENTS
**
25.9 2.1
4.8 f 2.0 3110 1.1 f 1.37x
7.4 percent), indicating good reproducibility and excluding poor cooperation as a factor rendering the flow-volume loop abnormal.
GMS
Group 2
Journal
of Medicine
Volume
those variables that might reflect the presence of respiratory muscle involvement. The results suggest that some changes in the flow-volume loop configuration, expressed in a flow-volume loop score, might be particularly helpful in suspecting respiratory muscle weakness in the (not infrequent) event that maximal respiratory pressures are not available. Unlike most previous studies on pulmonary function in neuromuscular disease [ l-4,7- 141, our patient population was homogeneous, containing only nonsmokers free from respiratory symptoms or complications and in a stable stage of their disease. Furthermore, on the basis of maximal respiratory pressures, our patients were divided into two groups, one with normal respiratory muscle strength and one with weak respiratory muscles. This allowed us to specifically assess the effects of respiratory muscle involvement on routine pulmonary function. An increased one-second forced expiratory volume/forced vital capacity ratio and FEFgSmT5 were the only changes found in patients with preserved respiratory muscle strength. These changes, which may reflect increased elastic lung recoil, have been noted previously in patients with asymptomatic neuromuscular disease, but these patients had a 50 percent reduction in maximal respiratory pressures [2]. Patients with weak respiratory muscles had a pattern of lung volume restriction with normal lung diffusion capacity, and inspiratory and expiratory flow limitation. The observed 25 percent reduction in vital capacity was appropriate for the 60 percent decrement in respiratory muscle strength [ 1,2,20]. In other studies, not excluding smokers or patients with respiratory complications, lung volume restriction exceeding that expected for the degree of respiratory muscle weakness has been noted [4,11,12,14] and attributed to secondary changes in lung and chest wall mechanics [ 11,141. Comparison of our data with previous reports on moderate [1,2] and severe neuromuscular disease [4,11,12,14] suggests that lung volume changes might follow the following sequence of events: with preserved respiratory muscle strength, an increased one-second forced expiratory 83
FLOW-VOLUME
volume/forced vital capacity ratio and FEF2se75 might indicate some increased elastic lung recoil, but lung volume remains normal; when respiratory muscle weakness develops, an “appropriate” loss of lung volume results from the inability to pull up the respiratory system to total lung capacity and to push it down to residual volume; in more advanced or complicated stages of the disease, “disproportionate” lung volume restriction occurs as a result of further advancing secondary changes in lung and chest wall elastic recoil. In previous studies, changes in flow rates and flowvolume loops occurring in neuromuscular disease have received little attention, Yet, isovolume pressure-flow curves [ 151 indicate that all inspiratory flow rates as well as expiratory flow rates at high lung volume depend to a large extent on effort, i.e., respiratory muscle strength. The terminal portion of forced expiration is alSO effortdependent, since at lung volumes below functional residual capacity, sufficient force is required to overcome the outward elastic recoil of the chest wall [ 161. Therefore, respiratory muscle weakness may be expected to affect inspiratory flow rates as well as expiratory flow rates at high and low lung volume. Accordingly, we found normal flow rates in patients with preserved respiratory muscle strength and reduced inspiratory and expiratory flow rates in patients with weak respiratory muscles (Figure 3). Maximal respiratory pressures correlated directly with the effort-dependent flow rates peak expiratory flow and forced mid-inspiratory flow (Table II). The flow-volume loop contour, which integrates all flow data in one visual image, was frequently abnormal (Figure 1): at its onset, the maximal expiratory flowvolume curve rises sluggishly towards a delayed, reduced and rounded peak; at end-expiration, a sudden drop in forced expiratory flow may occur, thus setting residual volume; and instead of the normal hemispherical or conical shape, the maximal inspiratory flow-volume curve is often characterized by a flattened shape. Some of these maximal expiratory flow-volume curve abnormalities have been previously reported: Kreitzer et al [12] found that in 15 patients with motor neuron disease, forced expiratory flow “decreased with concavity towards the volume-axis, giving the impression that forced expiratory flow has dropped off the maximal expiratory flow-volume curve envelope as residual volume was approached.” In seven patients with severe respiratory muscle weakness, Gibson et al [ 1 l] noted “some reduction in peak expiratory flow which developed at a lower than normal percentage of the (restricted) vital capacity.” These authors did not correlate these changes to the degree of respiratory muscle weakness; neither did they study the maximal inspiratory flow-volume curve. In order to examine the relationship between the degree of respiratory muscle weakness and the observed configurational changes of the flow-volume loop, we selected four parameters that were significantly related to maximal static inspiratory or October
LOOP
IN RESPIRATORY
MUSCLE
WEAKNESS-VINGKEN
ET AL
expiratory pressure (Table II), referred each to an effortdependent part of the flow-volume loop, and could each be visually observed on the loop (Figure 1). These parameters were the peak expiratory flow, nA-slope, FEF drop, and forced mid-inspiratory flow. As shown in the results, these variables were more frequently and to a greater degree abnormal in patients with weak respiratory muscles than in patients with preserved respiratory muscle strength (Tables Ill and IV). The parameters peak expiratory flow and forced mid-inspiratory flow are both entirely effort-dependent, in that they are limited only by the available force of the expiratory and inspiratory muscles, respectively [ 1,151. Respiratory muscle weakness, hence, may be expected to result in reduced peak expiratory flow and forced mid-inspiratory flow. The parameter nA-slope is the ratio of peak expiratory flow to the exhaled volume at which the peak expiratory flow occurs, and as such has the units of s- I: it is the reciprocal of the time constant of lung emptying at the start of forced expiration. Reduced (less steep) nA-slope, hence, reflects a longer time constant, i.e., a slower rate of lung emptying at high lung volume. Since maximal expiratory flow in this volume range is in part determined by the velocity of shottening and recruitment of expiratoty muscles [21], we assume that expiratory muscle weakness may delay the rate of rise of maximal expiratory flow, resulting in a less steep slope of the ascending limb of the maximal expiratory flow-volume curve, hence, in a reduced nA-slope. Finally, the parameter FEF drop was also attributed to expiratory muscle weakness, since patients with an FEF drop had lower maximal static expiratory pressure than those without. Furthermore, prolonged expiration reaching the breath-holding limits with premature inspiration truncating the maximal expiratory flow-volume curve was not observed and considered unlikely in view of the increased one-second forced expiratory volume/forced vital capacity ratio (indicating fast, rather than slow, emptying of the available entire vital capacity). Combining the four flow-volume loop variables in a flow-volume loop score enhanced their ability to predict respiratory muscle involvement in our patients. The flowvolume loop score was significantly higher (more abnormal) in patients with respiratory muscle weakness than in those without. When a flow-volume loop score of 4 was considered abnormal, the test was a 90 percent specific but only a 30 percent sensitive predictor of respiratory muscle weakness in patients with neuromuscular disease (Table V). Reducing the limits of abnormality of the test improved its sensitivity with only a minimal loss of specificity. Thus, arbitrarily accepting only scores of 0 or 1 as normal enabled the test to predict respiratory muscle involvement in our patients with a 90 percent sensitivity, an 80 percent specificity, and an 85 percent efficiency. Setting the limits of abnormality for the test that low seems justified, since its purpose is to detect respiratory muscle weakness in patients with that condition, i.e., 1987
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FLOW-VOLUME
TABLE
V
LOOP
IN RESPIRATORY
Sensitivity and Specificity Volume Loop Score’
Group 1 (n = 10) Number of positive (false-positives) Number of negative Group 2 (n = 10) Number of positive Number of negative (false-negatives) Sensitivity (percent) Specificity (percent) Efficiency (percent) * As a predictor neuromuscular
MUSCLE
WEAKNESS-VINCKEN
of the FlowLimit of Abnormality 4 3
2
1
2
2
results
9
8
a
test results test results
3 7
6 4
9 1
30 90 60
60
90 80 85
test results test
of respiratory disease.
muscle
weakness
80 70
in uncomplicated
avoid false-negative results. The flow-volume loop score, indeed, was not designed to replace the measurement of maximal static inspiratory and expiratory pressures. Rather, when these measurements are lacking, an increased flow-volume loop score should alert the physician to the possible presence of respiratory muscle weakness in patients undergoing routine pulmonary function studies. False-positive results will then be easily identified by
ET AL
complementary measurements of maximal static inspiratory and expiratory pressures, which are not routinely performed in most pulmonary function laboratories. The scoring system as applied weighs expiratory muscle performance out of proportion to inspiratory muscle performance. However, this is not critical, since an excellent linear relationship was found between maximal static inspiratory pressure and maximal static expiratory pressure (r = 0.87, p
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Black LF, Hyatt RE: Maximal static respiratory pressures in generalized neuromuscular disease. Am Rev Respir Dis 1971; 103: 641-650. Demedts M, Beckers J, Rochette F, Bulcke J: Pulmonary function in moderate neuromuscular disease without respiratory complaints. Eur J Respir Dis 1982; 63: 6267. Keltz H: The effect of respiratory muscle dysfunction on pulmonary function. Studies in patients with neuromuscular disease. Am Rev Respir Dis 1965; 91: 934-938. Braun NMT, Arora NS, Rochester DF: Respiratory muscle and pulmonary function in polymyositis and other proximal myopathies. Thorax 1983; 38: 616-623. Vincken W, Elleker MG, Cosio MG: Determinants of respiratory muscle weakness in stable chronic neuromuscular disorders. Am J Med 1987; 82: 53-58. Black LF, Hyatt RE: Maximal respiratory pressures: normal values and relationship to age and sex. Am Rev Respir Dis 1966; 99: 696-702. Ferris BG, Whittenberger JL, Affeldt JE: Pulmonary function in convalescent poliomyelitic patients. I. Pulmonary subdivisions and maximal breathing capacity. N Engl J Med 1952; 246: 919-923. Ringqvist I, Ringqvist T: Respiratory mechanics in untreated myasthenia gravis with special reference to the respiratory forces. Acta Med Stand 1971; 190: 499-508. Hapke EJ, Meek JC, Jacobs J: Pulmonary function in progressive muscular dystrophy. Chest 1972; 61: 41-47. lnkley SR, Oldenbrug FC, Vignos PJ: Pulmonary function in Duchenne muscular dystrophy related to stage of disease. Am J Med 1974; 56: 297-306. Gibson GJ, Pride NB, Newsom-Davis J, Loh LC: Pulmonary mechanics in patients with respiratory muscle weakness.
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