Impaired Efficacy of Cough in Patients With Parkinson Disease
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Impaired Efficacy of Cough in Patients
With Parkinson Disease*
Satoru Ebihara, MD, PhD; Hiroshi Saito, MD, PhD, FCCP; Akio Kanda, MD;
Mizue Nakajoh, MD, PhD; Hidenori Takahashi, MD, PhD;
Hiroyuki Arai, MD, PhD; and Hidetada Sasaki, MD, PhD, FCCP
Study objectives: Aspiration pneumonia, a leading cause of death in patients with Parkinson
disease (PD), usually occurs at the advanced stages of the disease. We investigated both motor
and sensory components of cough and induced-sputum substance P (SP) concentrations in
patients with early and advanced stages of PD to assess whether cough efficacy is impaired in PD.
Subjects: Fifteen female patients with early stages of PD (Hoehn and Yahr stage II-III),
10 patients with advanced stages of PD (Hoehn and Yahr stage IV), and 15 age-matched female
control subjects were investigated.
Measurements: The motor component of cough efficacy was assessed by monitoring voluntary
maximal cough peak flow. The sensory component of cough efficacy was assessed by measuring
cough reflex sensitivity to citric acid inhalation. Sputum SP concentrations were measured in
sputum induced by hypertonic saline solution inhalation.
Results: The mean (ⴞ SD) cough peak flow rates in patients with both early PD (230 ⴞ 74 L/min;
p < 0.005) and advanced PD (186 ⴞ 60 L/min; p < 0.0001) were significantly weaker than that in
control subjects (316 ⴞ 70 L/min). Cough reflex sensitivity in patients with advanced PD
(46.7 ⴞ 49.3 g/L) was significantly lower compared to control subjects (14.5 ⴞ 16.6 g/L; p < 0.01)
and patients with early PD (11.2 ⴞ 14.8 g/L; p < 0.005). The sputum SP concentration was
significantly lower in patients with advanced PD (11.2 ⴞ 8.4 pg/mL) compared to that in control
subjects (35.6 ⴞ 15.4 pg/mL) and patients with early PD (28.5 ⴞ 16.4 pg/mL).
Conclusion: In the early stages of the disease, mainly the motor component of cough was
impaired. In advanced stages of the disease, both the motor and sensory components of cough
were impaired. Sputum SP concentration significantly declined in patients with advanced PD.
The results suggest that the combination of impaired motor and sensory components of cough
may play an important role in the development of aspiration pneumonia in PD.
(CHEST 2003; 124:1009 –1015)
Key words: cough; cough peak flow; cough reflex sensitivity; Parkinson disease
Abbreviations: PD ⫽ Parkinson disease; SP ⫽ substance P
D espite the progress in therapy for Parkinson
disease (PD), PD is still associated with signif-
are well-known,2– 4 it has not been established
whether the efficacy of cough in patients with PD is
icant morbidity and mortality.1 Aspiration pneumo- impaired.
nia is a leading cause of death in patients with PD.1 Cough is an important defense mechanism, the
Airway protective mechanisms such as swallowing main function of which is to remove mucus and/or
and cough may play a role in aspiration pneumonia. foreign bodies from the airways by generating a high
Although swallowing disorders in patients with PD expiratory flow. The impairment of cough efficacy
could be due to the dysfunction of either motor
components (ie, cough intensity such as cough peak
*From the Department of Geriatric and Respiratory Medicine
(Drs. Ebihara, Kanda, Nakajoh, Takahashi, Arai, and Sasaki),
flow) or sensory components (ie, cough reflex sensi-
Tohoku University School of Medicine, Sendai, Japan; and the
Department of Neurology (Dr. Saito), National Nishitaga Hos- Reproduction of this article is prohibited without written permis-
pital, Sendai, Japan. sion from the American College of Chest Physicians (e-mail:
This study was supported by Grants-in-Aid for Encouragement of permissions@chestnet.org).
Young Scientists (No. 13770292) to Dr. Ebihara from the Correspondence to: Hidetada Sasaki, MD, PhD, FCCP, Professor
Ministry of Education, Culture, Sports, Science, and Technology and Chairman, Department of Geriatric and Respiratory Medi-
of Japan. cine, Tohoku University School of Medicine, Seiryo-machi 1–1,
Manuscript received May 20, 2003; revision accepted February 5, Aoba-ku, Sendai 980-8574, Japan; e-mail: dept@geriat.med.
2003. tohoku.ac.jp
www.chestjournal.org CHEST / 124 / 3 / SEPTEMBER, 2003 1009
Downloaded From: http://publications.chestnet.org/ on 05/19/2015tivity) of cough. The risk of aspiration pneumonia is dopa and carbidopa. Sixteen healthy volunteers, who were age-
increased in stroke patients with a weak voluntary matched and height-matched, were recruited from the commu-
nity by advertisement. All subjects were nonsmokers and had no
cough peak flow5 and impaired cough reflex sensi- history of chronic respiratory disease or acute respiratory prob-
tivity.6,7 In patients with motor neuron disease, lems during the previous 6 months. Patients taking angiotensin-
declined cough peak flow was related to episodes of converting enzyme inhibitors were excluded from the study.24,25
choking.8 Cough peak flow is also lower in patients The studies were performed on two consecutive days at the same
with muscular dystrophy,9 –12 amyotrophic lateral time of the day (around 2 h after taking the dopaminergic
medication). On the first day, spirometry (model OST 80A; Chest
sclerosis,11–13 and spinal cord injury,14 who are sus- Co; Tokyo, Japan), cough intensity, and cough reflex sensitivity
ceptible to fatal aspiration pneumonia. Cough reflex were measured. On the second day, the sputum for SP measure-
sensitivity is diminished in patients after heart-lung ment was collected. All measurements were performed by a
transplantation,15 also making them highly suscepti- laboratory technician who did not know the purpose of the study.
ble to aspiration pneumonia. The experimental protocol adhered to the Recommendations of
the Declaration of Helsinki for Human Experimentation. The
The impaired motor component of cough in pa- protocol was approved by the Tohoku University Ethics Com-
tients with PD has been shown by monitoring the mittee. Individual informed consent was obtained after a detailed
electromyogram of abdominal muscles and maximal explanation of the procedure, but not of the purposes, of the
expiratory pressure.16 However, cough peak flow has study. Studies were conducted after the patients gave informed
not been measured in patients with PD. In terms of consent, according to the Declaration of Helsinki for Human
Experimentation.
the sensory component of cough, previous stud-
ies16,17 have failed to detect the decline of cough
reflex sensitivity in patients with PD. In these stud- Cough Reflex Sensitivity
ies, however, the level of clinical disability was not Cough reflex sensitivity to citric acid was evaluated with tidal
taken into consideration when estimating cough breathing of a nebulized solution that was delivered by ultrasonic
reflex sensitivity. Since aspiration pneumonia usually nebulizer (model MU-32; Sharp Co Ltd; Osaka, Japan).21 The
occurs in patients in the advanced stages of PD, it is nebulizer generated particles with a mean mass median diameter
of 5.4 m at an output of 2.2 mL/min. Citric acid was dissolved
possible that this finding is not prominent in the in saline solution, providing a twofold incremental concentration
early stages of the disease. Moreover, accumulating from 0.07 to 36%. Cough was recorded on a Fleisch pneumota-
evidence shows that the cough reflex is more sensi- chograph mounted at the expiratory ports of the valve. The cough
tive in women than in men,18 –20 indicating that threshold was defined as the concentration at which the patients
gender should be matched in a comparison of cough coughed at least five times during 1 min of breathing the citric
acid aerosol. Each nebulizer application had a 2-min interval.
reflex sensitivities.
In the present study, we estimate both the motor
and sensory components of cough efficacy by mea- Cough Intensity
suring the cough peak flow and sensitivity of cough Cough intensity was estimated by measuring the cough peak
reflex to citric acid in female patients with PD at flow during voluntary maximal cough. To measure the cough
different stages. In addition, we investigated sputum peak flow, the sitting subjects were instructed to take a full
substance P (SP) concentration, which may play an inspiration and to cough into the face mask connected to a peak
flowmeter (mini-Wright; Clement Clarke International; Harlow,
important role in cough reflex.21 UK) as forcefully as possible. The values obtained by a peak
flowmeter are known to be quite close to the value obtained by
a pneumotachometer.26 The presented values are the mean of
Materials and Methods the three highest values from five attempts.
Subjects Sputum SP Concentration
Because gender differences in the cough peak flow22 and Induced sputum was collected the day after measurements of
cough reflex sensitivity18 –20 are known, we focused on female cough reflex sensitivity, spirometry, and cough peak flow were
subjects in this study. Twenty-five female outpatients with idio- made. Capsaicin-containing meals were not allowed for 12 h
pathic PD were recruited from our neurologic clinics at Tohoku before sputum collection. Around 2 h after the intake of their
University Hospital and National Nishitaga Hospital in Sendai regular dopaminergic medication, the sputum collection was
City. The diagnosis of idiopathic PD was based on the consensus performed. A 3% saline solution was administered via an ultra-
of two neurologists. The age at onset of PD was defined as the sonic nebulizer for 15 to 30 min until the sputum volume was
appearance of the first symptom estimated by medical interview, approximately 1 mL. Because the sample contained saliva, we
and the severity of PD was classified on a scale from I to V, eliminated this contamination by visual inspection and inverted
as stage II (8 patients), stage III (7 patients), and stage IV microscopy examination.27 The SP was quantified using modifi-
(10 patients), according to Hoehn and Yahr.23 Here, we defined cation of a previously described method.28 The collected 1-mL
the patients with stage II or III disease as early PD, and stage IV sputum samples were immediately mixed with 0.5 U/mL apro-
as advanced PD. All patients had a Mini-Mental State Examina- tonin and 3 mmol/L ethylenediaminetetraacetic acid, and was
tion score of ⬎ 24 and had been stable for at least 3 months stored at ⫺70°C until assay. For radioimmunoassay, the samples
before entering the trial. All patients responded to and their were mixed with 2 vol (vol/vol) acetone using a mixer at room
conditions were being maintained with a combination of levo- temperature for 5 min. The precipitate was pelleted by centrif-
1010 Clinical Investigations
Downloaded From: http://publications.chestnet.org/ on 05/19/2015ugation at 2,500g for 5 min. After centrifugation, the superna- sensitivity in patients with advanced PD (46.7 ⫾ 49.3
tants were extracted twice with petroleum ether, and the super- g/L) was significantly lower than that of control
natant then was evaporated in a water bath under N2 gas. After
evaporation, the dried residue was dissolved in a 0.05 mol/L
subject (14.5 ⫾ 16.6 g/L; p ⬍ 0.01) and patients with
Tris-HCl buffer (pH 8.65) containing 0.1% human serum albu- early PD (11.2 ⫾ 14.8 g/L; p ⬍ 0.005), whereas
min, 0.01 mmol/L ethylenediaminetetraacetic acid, 0.15 mmol/L there was no significant difference in cough reflex
NaCl, 0.002% sodium azide, and 0.2 mL samples were incubated sensitivity between control subjects and patients with
with 0.05 mL rabbit anti-SP serum (SRL, Inc; Tokyo, Japan) for mild PD. Figure 3 shows the concentration of SP in
24 h at 4°C. 125I SP, 15,000 counts per minute (NEN Life
Science Products, Inc; Boston, MA) in 0.05 mL, was added, and
sputum among the three groups. There was no
the mixture was incubated for an additional 24 h at 4°C. Bound significant difference in the mean volume of induced
and free ligands were separated by adding 0.05 mol/L Tris-HCl sputum among control subjects (1.3 ⫾ 0.5 mL), pa-
buffer, 1% ␥-globulin, and 25% polyethyleneglycol (6,000 mol/ tients with early PD (1.2 ⫾ 0.6 mL), and patients
L), and were centrifuged at 1,700g for 20 min. The radioactivity with advanced PD (1.2 ⫾ 0.5 mL). The percentage
in the precipitate was counted in a ␥-spectrometer.
of squamous cells in sputum was ⬍ 10% in all
individuals, indicating that almost all of the sputum
Statistical Analysis
samples were from the tracheobronchial tree. Spu-
Values are expressed as the mean ⫾ SD. The comparisons of tum SP concentrations were significantly lower in
the three groups were performed by one-way analysis of variance patients with advanced PD (11.2 ⫾ 8.4 pg/mL) com-
with post hoc application of the Fisher least-significant-difference pared to those in control subjects (35.6 ⫾ 15.4 pg/
test. A p value of ⬍ 0.05 was taken to be significant.
mL) and patients with early PD (28.5 ⫾ 16.4 pg/
mL), whereas there was no significant difference
between control subjects and patients with early PD.
Results
All 41 subjects completed the experiments without
any difficulties or side effects. Table 1 shows the Discussion
characteristics of the subjects. There were no signif-
icant differences in age, height, FVC, and FEV1 Cough is an important defense mechanism func-
among control subjects, patients with early PD, and tioning to remove mucus and foreign bodies from
patients with advanced PD. Patients with advanced the respiratory tract by generating a high expiratory
PD had a tendency to have experienced a longer flow. In our study, we showed impaired efficacy of
duration of the disease than patients with early PD. cough in patients with PD, with more pronounced
The intensity of maximal voluntary cough, ex- impairment in patients with advanced PD compared
pressed as rates of cough peak flow, both in patients to those with early PD. In the early stages of the
with early PD (230 ⫾ 74 L/min; p ⬍ 0.005) and disease, the motor component of cough was im-
advanced PD (186 ⫾ 60 L/min; p ⬍ 0.0001) were paired. In advanced stages of the disease, both motor
significantly weaker than the cough intensity of and sensory components of cough were impaired.
control subjects (316 ⫾ 70 L/min) [Fig 1]. There was Since dysphagia and the risk of aspiration worsen
no significant difference in the value of cough peak with the progression of PD,2– 4 it is of importance to
flow between patients with early PD and those with elucidate the factors involved in the impaired effi-
advanced PD. As shown in Figure 2, cough reflex cacy of cough in the advanced stage of PD.
Several measurements have been reported to be
useful in the assessment of the motor component of
the cough (ie, cough intensity), as follows: cough
Table 1—Characteristics of Control Subjects and noise; electromyogram of abdominal muscles; and
Patients With PD* peak expiratory pressure. These measurements of
the intensity of cough require special equipment and
Patients with PD
skills to measure, whereas it is quite simple to
Control Subjects Early Advanced measure the cough peak flow by flowmeter. Using
Characteristics (n ⫽ 16) (n ⫽ 15) (n ⫽ 10)
electromyogram and peak expiratory pressure, Fon-
H-Y stage 0⫾0 2.6 ⫾ 0.7 4⫾0 tana and colleagues16 showed that the reduced motor
Age, yr 69.8 ⫾ 10.3 67.1 ⫾ 8.4 70.9 ⫾ 8.8 component of cough efficacy started in the early
Duration, yr 0.0 ⫾ 0.0 5.8 ⫾ 5.2 9.7 ⫾ 6.3
stages of PD. This result is consistent with our
Height, cm 145 ⫾ 6 146 ⫾ 5 145 ⫾ 5
FVC % predicted 87.1 ⫾ 12.1 82.1 ⫾ 9.0 75.6 ⫾ 20.0 observation that was assessed by cough peak flow.
FEV1 % predicted 85.8 ⫾ 9.4 84.1 ⫾ 7.2 77.4 ⫾ 16.6 The abnormal flow-volume curve in patients with
*Values given as mean ⫾ SD. There was no significant difference in PD is well-established.29 –31 The decreased or less
age, height, FVC, and FEV1 among the three groups. H-Y ⫽ coordinated respiratory muscle force and/or upper
Hoehn-Yahr. airway obstruction are thought to be causes for the
www.chestjournal.org CHEST / 124 / 3 / SEPTEMBER, 2003 1011
Downloaded From: http://publications.chestnet.org/ on 05/19/2015Figure 1. Comparison of cough peak flow among control subjects and patients with early PD (ie,
Hoehn-Yahr stage II-III) and advanced stages of PD (ie, Hoehn-Yahr stage IV). Each symbol
represents a single subject. Mean values are indicated by a horizontal bar. N.S. ⫽ no significant
difference.
change in flow-volume curves in patients with PD. patients with neurogenic dysphagia, including pa-
Reduced expiratory muscle strength is thought to be tients with PD, did not have a reduced cough reflex
an important factor in decreased cough peak flow.16 sensitivity. The apparent contradiction between their
Since the effective cough could require more deli- studies and ours seems to be based on differences in
cate coordination of pharyngeal, laryngeal, and re- the severity of the disease rather than on differences
spiratory muscles than forced expiratory flow,32 the in methodology. Since patients with early PD are less
cough might be more susceptible to the disease than likely to have aspiration pneumonia, it is important to
the maximal expiratory flow-volume curve. FVC classify the stages of the disease to correlate the
values tended to decrease in the advanced stages of clinical significance of mortality from PD with im-
PD (Table 1). Therefore, a failure to inspire to total paired cough efficacy. Moreover, gender differences
lung capacity levels also may have contributed to a in cough reflex sensitivity have been reported using
lowered cough peak flow. However, judging from various stimuli.18 –20 Women have a more sensitive
the relatively large decrease in cough peak flow with cough reflex than men, whether in premenopausal or
increasing severity of disease, compared with the postmenopausal states.18 In the present study, we
smaller decrease in FVC, we speculate that a signif- focused on the cough reflex sensitivity of female
icant influence of this mechanism is unlikely. patients with different stages of PD and found that
Our finding about the sensory component of cough reflex sensitivity was significantly impaired in
cough in patients with PD differs from those of female patients with advanced stages of PD.
previous reports. Fontana and colleagues16 showed It is well-known that cough reflex sensitivity is
that cough reflex sensitivity was not significantly seriously impaired in elderly patients with aspiration
different between healthy control subjects and pa- pneumonia.33 SP, which may play an important role
tients with PD. Smith and Wiles17 reported that in the cough reflex,21 was found to be decreased in
1012 Clinical Investigations
Downloaded From: http://publications.chestnet.org/ on 05/19/2015Figure 2. Comparison of cough reflex sensitivity among control subjects and patients with mild PD (ie,
Hoehn-Yahr stage II-III) and severe PD (ie, Hoehn-Yahr stage IV). Each symbol represents a single
subject. Mean values are indicated by a horizontal bar. See the legend of Figure 1 for abbreviation not
used in the text.
the sputum of elderly patients with aspiration pneu- cough intensity and reflex sensitivity may play im-
monia.34 Since the major cause of death in patients portant roles in the development of aspiration pneu-
with PD is aspiration pneumonia, we hypothesized monia in PD patients. A strong relationship between
that sputum SP concentrations in patients with PD impaired cough reflex sensitivity and the risk of
also were lower. Indeed, SP concentrations in the aspiration pneumonia has been shown in stroke
saliva of patients with PD were found to be lower patients.6 Smith Hammond and colleagues5 have
than those of age-matched control subjects.35 More- shown that an impaired cough intensity, as assessed
over, the loss of SP-containing neurons in the brain- by the flow of voluntary cough, was a risk factor for
stem36 and striatum37 from autopsy samples of PD aspiration in stroke patients. Thus, the combined
patients have been reported, suggesting the systemic impairment of both the motor and sensory compo-
depletion of SP in patients with advanced stages of nents of cough might be a common mechanism of
PD. Therefore, we measured the sputum SP con- aspiration pneumonia for patients with both stroke
centration in patients in various stages of PD and and PD.
showed a significantly decreased concentration of Because aspiration pneumonia is the most com-
sputum SP only in patients with advanced PD. The mon cause of death in PD patients,1 the related
result suggests that the sputum SP concentration conditions should be treated more extensively in
may be related to the sensory component of cough order to improve their survival. This study and
rather than to the motor component in patients with observations of the elderly with cerebral vascular
PD. In guinea pigs, SP released from the sensory diseases34 suggest that reduced SP concentration is
nerves in the airway has been shown as a possible related to aspiration pneumonia in patients with
endogenous substance causing cough.38,39 advanced PD. The effort to increase the concentra-
Since aspiration pneumonia usually occurs in the tion of SP by angiotensin-converting enzyme inhib-
advanced stages of PD, the combined impairment of itors25 could be useful to reduce the risk of pneumo-
www.chestjournal.org CHEST / 124 / 3 / SEPTEMBER, 2003 1013
Downloaded From: http://publications.chestnet.org/ on 05/19/2015Figure 3. Comparison of sputum SP concentration among control subjects and patients with mild PD
(ie, Hoehn-Yahr stage II-III) and severe PD (ie, Hoehn-Yahr stage IV). Each symbol represents a single
subject. Mean values are indicated by a horizontal bar. See the legend of Figure 1 for abbreviation not
used in the text.
nia in patients with PD, just as it is useful in older of voluntary cough. Neurology 2001; 56:502–506
patients with cerebral vascular diseases.24 Further 6 Addington RW, Stephens RE, Gilliland KA. Assessing the
laryngeal cough reflex and risk of developing pneumonia after
studies are needed to clarify whether interventions
stroke. Stroke 1999; 30:1203–1207
that are useful for treating aspiration pneumonia in 7 Kobayashi H, Hoshino M, Okayama K, et al. Swallowing and
the elderly40 are also beneficial for patients with PD. cough reflexes after onset of stroke [letter]. Chest 1994;
105:1623
ACKNOWLEDGMENT: The authors thank Mr. Grant for
reading the manuscript. 8 Hadjikoutis S, Eccles R, Wiles M. Coughing and choking in
motor neuron disease. J Neurol Neurosurg Psychiatry 2000;
68:601– 604
9 Szeinberg A, Tabachnik E, Rashed N, et al. Cough capacity in
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