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* From the Fondazione Don C. Gnocchi, ONLUS, Pozzolatico (Firenze), Italy.
Correspondence to: Giorgio Scano MD, FCCP, Section of Respiratory Disease, Fondazione Don C. Gnocchi, ONLUS, Pozzolatico, Via Imprunetana, Pozzolatico (Firenze) 50020 Italy; e-mail: g.scano{at}dfc.unifi.it
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Abstract |
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 TOP Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Material: Eleven patients with NMD (mean ± SD age, 44 ± 11.8 years; 5 men) of different etiology and a group of normal subjects matched for age and sex (control subjects).
Methods: While patients were breathing room
air, lung volumes, arterial blood gases, the pattern of breathing
(minute ventilation [
E], tidal volume
[VT], respiratory frequency, inspiratory time), and
maximal (less negative) esophageal pressure during a sniff maneuver
(Pessn), as an index of inspiratory muscle strength, were measured.
Then we evaluated the response to hypercapnic-hyperoxic stimulation
(hypercapnic-hyperoxic rebreathing test [RT]) in terms of breathing
pattern, inspiratory swing of pleural pressure (Pessw), and inspiratory
effort (Pessw[%Pessn]). During the RT, dyspnea was assessed every
30 s using a modified Borg scale (0 to 10).
Results: Pulmonary volumes were reduced in seven
patients, and PCO2 was out of proportion to
E in four patients. Group Pessn was 42.8 ± 23.6
cm H2O in patients and 107 ± 20.4 cm H2O in
control subjects (p < 0.001). Dynamic elastance (Eldyn)
[p = 0.0016] and Pessw(%Pessn) [p < 0.0005] were higher in
patients. During the RT, Borg/CO2,
Pessw(%Pessn)/CO2, and Borg/Pessw(%Pessn) were similar in
the two groups, while E/CO2 and
VT/CO2 were lower in patients (p < 0.0002
for both). As a consequence, for unit change in VT
(percentage of predicted vital capacity [%VC]), greater changes in
Pessw(%Pessn) were associated with greater Borg scores in patients.
Baseline Eldyn related to Pessw(%Pessn)/VT(%VC)
during hypercapnia (r2 = 0.85), an index
of neuroventilatory coupling of the ventilatory pump (NVC). NVC
predicted a good amount of the variability in Borg/E
(r2 = 0.46, p < 0.02).
Conclusions: In this subset of NMD patients during hypercapnic stimulation, a normal inspiratory motor output per unit change in PCO2 results in a shallow breathing pattern. The consequent impairment of NVC underlies the higher scoring of dyspnea in these patients.
Key Words: breathing pattern • dyspnea • neuromuscular coupling • neuromuscular disease • respiratory drive • respiratory muscles
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Patients with respiratory muscle weakness exhibit an increased central motor output and rapid shallow breathing (RSB).8 9 10 11 As weakness progresses, the bellows action of the chest decreases and tidal volume (VT) decreases further. This results in a decreased peripheral afferent input to supraspinal centers, likely to amplify the perception of breathlessness throughout the mismatching mechanism.2 3 We speculate that this mechanism is involved in the perception of dyspnea in patients with NMD.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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None of the patients had a scoliosis or any abnormalities shown on
chest radiography or obvious abnormalities in diaphragm
placement. Five patients were current mild smokers (
5 pack-years).
Seventeen healthy normal subjects matched for age (range, 26 to 62
years; mean, 41.5 years) and sex (8 men) were studied as a control
group. The study was approved by the local ethics committee, and
subjects gave their informed consent. The anthropometric
characteristics of the patients are shown in Table 1
.
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For mechanical studies, an esophageal latex balloon (length, 10 cm; air volume, 0.5 mL) was introduced via the nose. A marker was placed on the polyethylene tubing 40 cm from the balloon tip.15 The catheter was connected to a differential pressure transducer (Validyne; Northridge, CA). Total lung resistance (RL) and dynamic lung elastance (Eldyn) were measured during resting breathing.16 RL was obtained using the isovolume method17 ; predicted values are those proposed by the European Community for Coal and Steel.14 Eldyn was determined by dividing the difference in esophageal pressure (Pes) between points of zero flow by VT.
The highest (most negative in sign) Pes during a sniff maneuver (Pessn) was evaluated at FRC16 and was repeated until three measurements with < 5% variability were recorded. The highest value of Pessn was used for subsequent analysis.
During room-air breathing, the ventilatory pattern was evaluated by a
Fleisch type 3 pneumotachograph with subjects sitting comfortably in an
armchair. The flow signal was integrated into volume. From the
spirogram, we derived inspiratory time (TI), expiratory
time, total respiratory cycle breathing time, and VT.
Respiratory frequency (1/total respiratory cycle breathing
time x 60) and minute ventilation (E)
[VT x respiratory frequency] were also calculated.
Expired CO2 (PCO2) was sampled continuously at the mouth by an infrared CO2 meter (Normocap 200 Datex; Helsinki, Finland). The output of the CO2 meter, flow signal, integrated flow signal, and mouth pressure were recorded on a personal computer hard-disk using an eight-channel analog/digital board at 50-Hz sampling rate. After a 10-min adaptation period, evaluation began. Signals were recorded over a 10-min time period. Average values for each subject are presented.
Hypercapnic-Hyperoxic Rebreathing Test
A hypercapnic-hyperoxic rebreathing test (RT) was performed
following the procedure recommended by Read,18
a clinical
method for assessing the ventilatory response to
CO2. Rebreathing was terminated when the
PCO2 reached 72 to 74 mm Hg. Changes
in arterial oxygen saturation, volume and time components of breathing
pattern, and Pessw were recorded continuously. Details of the
procedures have been described elsewhere.8
16
19
Dyspnea
Under control conditions and every 30 s during RTs,
subjects were asked to quantify the sensation of dyspnea, which was
described to the patients as a nonspecific discomfort associated with
the act of breathing.20
Patients quantified dyspnea by
pointing to a score on a large Borg scale from 0 (none) to 10
(maximal).21
Specifically, the subjects were asked to
quantify the intensity of the symptom by relating it to their common
experience. The scale was a continuous vertical linear display
associated with 10 verbal descriptors of the extent of the symptom,
which corresponded to those of the 10-point Borg category scale. The
subjects were instructed to indicate with a hand-controlled
potentiometer how dyspneic they felt with reference to the category
descriptors.
Protocol
All subjects were tested in the morning. Before the experiment,
the subjects were well acquainted with the laboratory and
equipment. An arterial blood sample and lung function tests were
performed, and then changes in volume, flow, and Pes were
recorded. Finally, the respiratory muscle strength tests were performed
in each patient.
Data Analysis
Volume and time components of the respiratory cycle, RL, and
Eldyn were averaged in each patient over 30 consecutive breaths. Single
linear regression analysis by the least-squares method using data point
at 30-s intervals and stepwise multiple regression analyses were
performed to assess relationships between variables.22
The
statistical analysis we carried out considers the dependency of a
variable (eg, the Borg score) on a series of independent
variables. The effect of each variable on the Borg score was evaluated
independent of the effect of all other variables. In a multivariate
analysis, a rule of thumb is to limit the number of variables as a
function of the number of patients. Thus, multiple regression analysis
with stepwise selection of the independent variables was carried out
relating the Borg score to functional variables. The proportion of
total variance in the dependent variable, accounted for by the
predicted variables, is reported as the square of the correlation
coefficient (r2). Single regression
analysis was performed using Pearson’s single correlation coefficient.
Comparisons between groups were made using the Mann-Whitney test. A
value of p < 0.05 was considered as the threshold of statistical
significance. Data are presented as means and SDs unless otherwise
specified.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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E. Group Pessn was lower while inspiratory effort
(Pessw[%Pessn]) and Eldyn were significantly greater in patients
compared to control subjects (Table 2
). During the RT, Borg/PCO2,
Pessw(%Pessn)/PCO2, and both slope
and intercept of the relationship between changes in Borg vs changes in
Pessw(%Pessn) were similar in the two groups, while
VT/PCO2 and
E/PCO2 were lower
(p < 0.001 for both) in patients (Table 3
).
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E was greater in patients than in control subjects
(Fig 2 ). Change in Borg score per unit change in
E was also greater in patients, so that at
any given level of E from 15 to 30 L/min,
patients experienced a greater perception of dyspnea than control
subjects (Fig 3
).
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E (Fig 4
,
5
). In a multivariate analysis with Borg/E
as dependent variables and other variables (Eldyn, Pessw[%Pessn],
Pessw(%Pessn)/VT[%VC],
PCO2) as independent,
Pessw(%Pessn)/VT(%VC) was selected as the
unique predictor of a part of the variance in
Borg/E (p < 0.02,
r2 = 0.41). Figure 6
shows the schematic increase in Borg with increasing respiratory effort
for any given VT(%VC) in patients as compared to
control subjects.
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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First of all, we decided to give patients a global definition of the sensation of dyspnea avoiding specific definitions like the most commonly used "respiratory effort." This was due to three different reasons: (1) dyspnea is a sensation that almost everyone will have experienced and so intuitively understands, (2) we did not want to bias or confuse subjects with a specific definition, and (3) the perception of respiratory effort arises from a corollary discharge transmitted from a motor center to a sensory center at the same time as the outgoing motor command is sent to the ventilatory muscles.23 The sensation of effort, however, may decrease during hypercapnia as the origin of the outgoing motor command to the respiratory muscles starts from the brainstem and the resulting corollary discharge diminishes.2 3
The present study indicates that both the central motor output and the Borg score for unit change in PCO2 were similar in patients and control subjects (Table 3) . Thus, a central effect was not thought to be primarily involved in the different perception of dyspnea between groups.
More recently, the emphasis has been on the central mismatching between
respiratory muscle effort and instantaneous feedback from sensory
receptors throughout the respiratory system.23
24
When
sensory feedback from a change in volume and flow does not match the
degree of effort, dyspnea results.2
3
4
In healthy subjects
under conditions of stimulated breathing, an increase in respiratory
muscle effort promotes a proportional increase in VT,
whereas an increase in respiratory muscle load, either resistive or
elastic or both, may affect the coupling between respiratory effort and
volume.2
3
4
According to this hypothesis, central
mismatching plays a pivotal role in contributing to the sensation of
dyspnea in patients with COPD,4
asthma,25
or
interstitial lung disease.26
In the present study, we have
found a good relationship between the impairment of neuroventilatory
coupling and the perception of dyspnea as assessed in terms of Borg
score (Fig 4
, 5)
. Importantly, Eldyn, a parameter that reflects elastic
load of the lung, related to both Pessw(%Pessn)/VT(%VC)
[r2 = 0.85, p < 0.0000] and
Borg/E during chemical stimulation.
Increase in elastic load in patients with NMD has been reported to be
due to either pulmonary microatelectasis10
or
abnormalities in the rib cage or both.27
As an indirect
confirmation of the role of mechanical lung abnormalities, in an
article by Clague et al,28
a normal perception of
respiratory effort was found in patients with myotonic dystrophy in
whom muscle weakness was associated with normal respiratory impedance
and respiratory drive by applying mouth occlusion pressure.
Nevertheless, in patients with NMD, the employment of mouth occlusion
pressure may be criticized as an index of respiratory motor
output.29
30
Although this does not detract validity to
the data by Clague et al,28
we believe that a more
invasive but more accurate method is needed to assess respiratory motor
output and its relationships to ventilatory response in these patients.
|
Our study16
and others4
25
26
raise the
possibility that NMD, COPD, asthma, interstitial lung disease, and
airway involvement in multisystem disease share some common mechanism
underlying the discomfort associated with the act of breathing, a
nonspecific global expression to define dyspnea. Finally, although
PCO2 was not an independent predictor
of the variability of Borg/E, we cannot exclude that
a brainstem reflex stimulation of ventilation with
CO22
3
modulating mechanical factors
might be involved in the perception of dyspnea.
In conclusion, the present study shows that in patients with NMD, the association of muscle weakness and elastic load is responsible for the modulation of a normal central respiratory output into a shallow pattern of breathing. The consequent impairment of NVC underlies the greater scoring of dyspnea in these patients.
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Footnotes |
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E = minute ventilation; VT = tidal
volume This study was supported by a grant from Fondazione Don C. Gnocchi, ONLUS, Pozzolatico (Firenze), and from the Ministero dell’Università e della Ricerca Scientifica e Tecnologica of Italy.
Received for publication October 31, 2000. Accepted for publication February 12, 2001.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This article has been cited by other articles:
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  N Ambrosino and M Serradori Determining the cause of dyspnoea: linguistic and biological descriptors Chronic Respiratory Disease, July 1, 2006; 3(3): 117 - 122. [PDF]
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 G. Scano, L. Stendardi, and M. Grazzini Understanding dyspnoea by its language Eur. Respir. J., February 1, 2005; 25(2): 380 - 385. [Abstract] [Full Text] [PDF]
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