Impaired Efficacy of Cough in Patients With Parkinson Disease

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
             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:

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tivity) 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
             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

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ugation 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.
                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

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Figure 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

             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

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Figure 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-

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Figure 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;
             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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