Cough Threshold in People With Spinal Cord Injuries.

Key Words: Citric acids, Cough, Smoking, Spinal cord injury.

Coughing is an important mechanism to clear mucus or sputum from the conducting airways.[1] People with spinal cord injury (SCI) have impaired coughing ability due to factors such as the paralysis or weakness of expiratory muscles.[2,3] Several methods have been proposed to improve the coughing ability of people with SCI.[4,5] There is a lack of studies, however, concerning the sensory and autonomic components (vagal afferent and efferent) of the cough reflex in people with SCI.

The cough reflex arises from the rapidly adapting receptors located in the airways and is mediated by vagal afferents to the cough center in the brain stem.[1,6] The central output then sends information via vagal efferents to airway smooth muscles and via spinal nerves to the expiratory muscles to produce coughs.[1,3] With power spectral analysis of parasympathetic vagal tone, transient bradycardia was observed in patients with acute[7] and chronic[8] tetraplegia. Dicpinigaitis et al[9] further demonstrated bronchial hyperresponsiveness to methacholine (acetylcholine agonist) in patients with cervical spinal cord injury. Transection of the cervical or thoracic spine interrupts the sympathetic innervation, but the vagal nuclei of the brain stem remain intact.[7-9] Such unopposed vagal tone might be expected to cause enhanced vagal activity to the heart and airways.[7-9] Therefore, we hypothesized that the interruption of sympathetic out-flow in people with SCI results in an increase in cough sensitivity (ie, a decrease in the cough threshold). The change in cough sensitivity may affect the chest care given by physical therapists and the administration of cough medicine.

Coughing can be induced voluntarily or reflexively.[1] Bickerman and Barach[10] were the first researchers to use citric acid aerosol ([C.sub.6][H.sub.8][O.sub.7] [multiplied by] [H.sub.2]O) to provoke the cough reflex in humans. The lowest concentration of a chemical irritant that elicits one to several coughs is known as the cough threshold.[11] Previous studies[12,13] have shown a wide interindividual and intraindividual response to citric acid. Cough threshold to citric acid, however, was reproducible with careful control of the time of the day the stimulus is introduced, the inspiratory flow rate, and the mode of inhalation.[12-14] In general, the citric acid stimulus to cough has been shown to be reliable, reproducible, and consistent for quantifying the "sensitivity" of the cough reflex in people with and without SCI.[12-14]

Some of our patients with SCI are smokers. Taylor et al[15] reported that smoking is associated with an increase in cough sensitivity. Therefore, the purpose of our study was to compare the cough threshold in smokers and nonsmokers with and without SCI.

Method

Subjects

The participants were 26 people with cervical and thoracic spinal cord (C4-T12) lesions and 18 people without spinal injury. Only male subjects were recruited because males have a high incidence of spinal injury compared with females.[16] All subjects had neither systemic medical problems nor respiratory tract inflammation recently. The subjects with ASIA class A SCIs[17] had complete lesions for least 1 year (range= 1-20 years). The smokers were identified as having smoked at least 2 cigarettes a day for more than 1 year. Therefore, the subjects were divided into 4 groups: (1) smokers with SCI (7 with tetraplegia and 8 with paraplegia), (2) nonsmokers with SCI (6 with tetraplegia and 5 with paraplegia), (3) smokers without SCI (n=9), and (4) nonsmokers without SCI (n=9). Ail subjects gave informed consent for this study.

The characteristics of the subjects are presented in Table 1. There were no differences in age, height, or weight among the 4 groups. There also was no difference in duration of injury between the smokers and nonsmokers with SCI and no difference in the amount (pack-years) of cigarette smoking between subjects with and without SCI.

Table 1. Basic Data of Smoking and Nonsmoking Subjects With and Without Spinal Cord Injury (SCI)

                                    Subjects With SCI

                                                 Nonsmoking
                               Smoking (n=15)      (n=11)

Item                          [bar] X    SD    [bar] X    SD

Age (y)                         36.3     5.1     35.9     6.2
Height (cm)                    167.7     5.8    167.3     4.2
Weight (kg)                     62.2    11.0     59.8    13.3
Years since onset of injury      9.4     6.0     10.0     6.2
Cigarette (pack-years)(a)        5.0     4.2

                                  Subjects Without SCI

                                                Nonsmoking
                              Smoking (n=9)      (n=9)

Item                          [bar] X   SD    [bar] X   SD

Age (y)                         31.8    9.0     30.7    6.0
Height (cm)                    169.6    2.9    172.6    5.4
Weight (kg)                     67.9    9.0     68.6    6.2
Years since onset of injury
Cigarette (pack-years)(a)        7.0    6.1

(a) Pack-years indicate the multiplication of packs/day/year and years

Citric Acid Cough Threshold

The citric acid aerosol was generated by a disposable jet nebulizer,(*) which was driven by a DeVilbiss Pulmi-Aide compressor/nebulizer (model 5650D)([dagger]) at the maximum output of 0.35 mL/min. The particle size of the aerosol was 0.5 to 5 [micro]m, as stated by the manufacturer. Aerosols of citric acid were delivered with an incremental doubling concentration from 62.5 mmol to 2 mol (ie, 62.5 mmol, 125 mmol, 250 mmol, 500 mmol, 1 mol, and 2 mol).[14] Citric acid aerosols were delivered until cough responses were observed. Five minutes was allowed to elapse between any 2 applications of the aerosol. At any one concentration, sterilized citric acid aerosol was administered by 6 successive deep inhalations. The first concentration of citric acid that induced at least 2 coughs within 3 minutes was defined as the citric acid cough threshold. The cough threshold was also expressed as the logarithmic concentration of citric acid for statistical analysis.[14] The force of the cough was not monitored, but the cough was identified by the chestwall movement and the acoustic response due to the sudden opening of the vocal cords.

Measurement of Cough Response

The cough response was recorded by a phonemeter (model TR-21A([double dagger])) attached to the side of the subject's Adam's apple to detect the sudden change in waveform of the sound. The chest excursion during a cough was detected by a pneumobelt (Pneumotrace Respiration Transducer, model 1130([sections])) around the lower ribs. Both the sound wave and the chest excursion signals were recorded by a polygraph,([parallel]) as shown in Figure 1. The acoustic characteristics of cough were consistently observed in association with pneumobelt traces, which was considered valid for chest motion.[18]

[Figure 1 ILLUSTRATION OMITTED]

Measurement of Lung Function

Lung function was measured by a spirometer (Microspiro HI-601(#)), which was valid and accurate.[19] Because citric acid may cause bronchoconstriction, both the forced vital capacity (FVC) and forced expiratory volume in 1 second ([FEV.sub.1]) were measured immediately before and 3 minutes after the inhalation of citric acid aerosol to ensure that there was no change in expiratory flow volume. The decrease in [FEV.sub.1]/FVC (%) indicated bronchoconstriction.[9,14]

Data Analysis

All data were stored in a computer. The statistical analysis was performed using SPSS for Windows.(**) A 2-way ANOVA was used to analyze the effects of spinal injury and smoking on cough sensitivity. A Newman-Keuls test was used to differentiate differences between any 2 groups. If there was no interaction between spinal injury and smoking, the main effect was compared by an independent t test. The lung function before and after use of the citric acid aerosol was compared by a paired t test. All data were expressed as means and standard deviations. The level of significance was set at P [is less than] .05.

Results

Citric Acid Cough Threshold

The 2-way ANOVA indicated that there were main effects of spinal injury and smoking, although the interaction between SCI and smoking was not statistically significant (Tab. 2). As shown in Fig. 2, the mean cough thresholds of the subjects with SCI (both smokers and nonsmokers) were lower than those of the subjects without SCI (both smokers and nonsmokers). Furthermore, the mean effective citric acid cough threshold in the subjects with SCI patients who smoked was 209 mmol (range=102-427), which was lower than that of the subjects with SCI who did not smoke ([bar] X=417 mmol, range=224-776). The mean citric acid cough threshold for the subjects without SCI who smoked ([bar] X=467 mmol, range=224-977) was lower than that of the subjects without SCI who did not smoke ([bar] X=1,072 mmol, range=562-2,041).

[Figure 2 ILLUSTRATION OMITTED]

Table 2. Results of Two-Way Analysis of Variance for Effects of Injury and Smoking on Cough Threshold (N=44)

Item                      df    SS     MS    F value     P

Main effect A (injury)     1   1.54   1.54    17.53    .000
Main effect B (smoking)    1   1.17   1.17    13.27    .001
A x B interaction          1   0.01   0.01     0.14    .714
Total                     43   6.44   0.15

Pulmonary Lung Function Parameters

The FVC and [FEV.sub.1] were less in the smokers and nonsmokers with SCI than in the smokers and nonsmokers without SCI (Tab. 3). There was no difference, however, in the ratio of [FEV.sub.1]/FVC (%) among the 4 groups. Alter citric aerosol inhalation, there was no change in lung function in any group.

Table 3. Lung Function Measures Before and After Citric Acid Aerosol Inhalation(a)

                            Subjects With SCI

                               Smoking
                               (n=15)

Item                        [bar] X   SD

Before aerosol inhalation
  FVC (L)                     2.9     0.9(b,c)
  [FEV.sub.1] (L)             2.6     0.8(b,c)
  [FEV.sub.1]/FVC (%)        92.4     5.1
After aerosol inhalation
  FVC (L)                     2.9     0.9(b,c)
  [FEV.sub.1] (L)             2.7     0.8(b,c)
  [FEV.sub.1]/FVC (%)        93.4     4.5

                            Subjects With SCI

                              Nonsmoking
                                (n=11)

Item                        [bar] X   SD

Before aerosol inhalation
  FVC (L)                     2.5     0.5(b,c)
  [FEV.sub.1] (L)             2.2     0.6(b,c)
  [FEV.sub.1]/FVC (%)        89.4     6.8
After aerosol inhalation
  FVC (L)                     2.4     0.5(b,c)
  [FEV.sub.1] (L)             2.2     0.5(b,c)
  [FEV.sub.1]/FVC (%)        92.4     8.2

                                 Subjects Without SCI

                               Smoking        Nonsmoking
                                (n=9)           (n=9)

Item                        [bar] X   SD    [bar] X   SD

Before aerosol inhalation
  FVC (L)                     4.0     0.5     3.9     0.2
  [FEV.sub.1] (L)             3.5     0.4     3.4     0.1
  [FEV.sub.1]/FVC (%)        88.2     4.2    87.9     3.0
After aerosol inhalation
  FVC (L)                     3.9     0.5     3.7     0.4
  [FEV.sub.1] (L)             3.4     0.4     3.3     0.3
  [FEV.sub.1]/FVC (%)        87.9     3.2    88.6     4.5

(a) SCI=spinal cord injury, FVC=forced vital capacity, [FEV.sub.1]=forced expiratory volume in 1 second, [FEV.sub.1]/FVC (%)=percentage of forced expiratory volume in 1 second to forced vital capacity.

(b) Significant differences (P [is less than] .05) compared with nonsmoking subjects without SCI.

(c) Significant differences (P [is less than] .05) compared with smoking subjects without SCI.

Discussion and Conclusion

This study demonstrated that the cough threshold was reduced in subjects with SCI compared with subjects without SCI. We also showed that subjects with SCI who smoked had lower cough thresholds than did subjects with SCI who did not smoke. The results indicate, therefore, that both spinal injury and smoking can reduce cough threshold in people with SCI.

The results support our hypothesis that spinal injury is a contributing factor for reducing the cough threshold. The unopposed vagal efferents in the subjects with SCI increased their discharge to augment cough sensitivity.[20,21] The influence for lower thoracic injuries would be less. People with chronic SCI (ie, of more than 1 year's duration) may have morphological or osmolarity changes in the airway epithelium to increase the exposure of the receptor to chemical irritant,[22] thus increasing the vagal afferent or efferent activities. Because there was no change in pulmonary function following application of citric acid aerosol in either the subjects with SCI or the subjects without SCI (Tab. 3), the observed changes of citric acid cough threshold in the subjects with SCI would not be due to the effect of bronchoconstriction. This view agrees with the finding of Dicpinigaitis et al.[9]

Our findings suggest that the ability to sense irritants in the airways is increased in people with SCI. The advantage of increased cough sensitivity is to detect chemical irritants or sputum easily and possibly help the clearance of the airways by coughing. The disadvantages of increased sensitivity are associated with frequent coughing and throat discomfort. Because huffing (known as "forced expiration") produces less discomfort in the throat than does coughing,[23] people with SCI may try huffing. Huffing creates forced expiratory flows at different lung volumes through an open glottis (with their mouth open) and produces intrapulmonary pressures much lower than those produced by coughing.[23] Less compression and narrowing of the airway during a huff may increase airflow and the efficiency of bronchial clearance.

We showed that the mean value of citric acid cough threshold in the subjects without SCI who did not smoke was 1,072 mmol (ie, 225 mg/mL). Previous researchers[14,24,25] reported mean values for citric acid cough threshold ranging from 59 to 724 mg/mL in subjects without pulmonary problems who did not smoke. Schmidt et al[25] reported the mean value of cough threshold for current smokers to be 40 mg/mL (ie, 190 mmol), with a range of 20 to 80 mg/mL. The mean values of cough threshold in our subjects without SCI (both smokers and nonsmokers) were within the ranges of previous studies. We believed the high intersubject variability with application of citric acid aerosol to be partly due to an inborn trait.[24] The reproducibility of citric acid cough thresholds, however, was high.[14,24] Although the sample size in our study was small, the power (1 - [Beta]) for statistical analysis in this study was from 0.7 to 0.8 in the 4 groups, which was, in our opinion, within the acceptable range.[26]

The results of our study indicate that cigarette smoking decreased the mean cough thresholds in both subjects with SCI and subjects without SCI, as compared with the subjects with similar characteristics who did not smoke. Although the underlying mechanism of smoking effects on citric acid cough threshold is not clear, a study of guinea pigs indicated that smoking increases epithelial permeability and thus enhances cough sensitivity following exposure to cigarette smoke.[27] The increase in cough sensitivity in our subjects with SCI who smoked would enhance their frequency of coughing. Furthermore, cigarette smoking may cause airflow obstruction.[23] Therefore, smoking should be discouraged, and a chest care program with huffing could be tried in people with SCI. The mechanism of huffing is to produce dynamic squeezing and vibratory action to mobilize the secretions from the airways.[28] As secretions reach the upper airways, a huff at a high lung volume can be used to clear them.

(*) Salter Labs, W Sycamore Rd, Arvin, CA 93203.

([dagger]) Sunrise Medical, Somerset, PA 15501.

([double dagger]) Grass Instrument Co, 101 Old Colony Ave, PO Box 516, Quincy, MA 02169.

([sections]) UFI, 545 Main St, Morro Bay, CA 93442.

([parallel]) Gould Inc, 3631 Perkins Ave, Cleveland, OH 44114.

(#) Chest MI Inc, 3-6-10, Hongo, Bunkyo-ku, Tokyo, 113 Japan.

(**) SPSS Inc, 444 N Michigan Ave, Chicago, IL 60611.

References

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[2] Wang AY, Jaeger RJ, Yarkony GM, Turba RM. Cough in spinal cord injured patients: the relationship between motor level and peak expiratory flow. Spinal Cord. 1997;35:299-302.

[3] Estenne M, De Troyer A. Respiratory muscle involvement in tetraplegia. In: Tobin M, ed. Problems in Respiratory Care: The Respiratory Muscles. Vol 3. Philadelphia, Pa: JB Lippincott Co; 1990:360-374.

[4] Jaeger RJ, Turba RM, Yarkony GM, Roth EJ. Cough in spinal cord injured patients: comparison of three methods to produce cough. Arch Phys Med Rehabil. 1993;74:1358-1361.

[5] Lin KH, Lai YL, Wu HD, et al. Effects of an abdominal binder and electrical stimulation on cough in patients with spinal cord injury. J Formos Med Assoc. 1998;97:292-295.

[6] Stockwell M, Lang S, Yip R, et al. Lack of importance of the superior laryngeal nerves in citric acid cough in humans. J Appl Physiol. 1993;75:613-617.

[7] Kawamoto M, Sakimura S, Takasaki M. Transient increase of parasympathetic tone in patients with cervical spinal cord trauma. Anaesth Intensive Care. 1993;21:218-221.

[8] Inoue K, Miyaki S, Kumashiro M, et al. Power spectral analysis of heart rate variability in traumatic quadriplegic humans. Am J Physiol. 1990;258:H1722-H1726.

[9] Dicpinigaitis PV, Spungen AM, Bauman WA, et al. Bronchial hyper-responsiveness after cervical spinal cord injury. Chest. 1994;105: 1073-1076.

[10] Bickerman HA, Barach AL. The experimental production of cough in human subjects induced by citric acid aerosols: preliminary studies on the evaluation of antitussive agents. Am J Med Sci. 1954;228: 156-163.

[11] Pounsford JC, Birch MJ, Saunders KB. Effect of bronchodilators on the cough response to inhaled citric acid in normal and asthmatic subjects. Thorax. 1985;40:662-667.

[12] Rees PJ, Clark TJH. Assessment of antitussive effects by citric acid threshold. Br J Dis Chest. 1983;77:94-97.

[13] Barros MJ, Zammattio SJ, Rees PJ. Importance of inspiratory flow rate in the cough response to citric acid inhalation in normal subjects. Clin Sci (Colch). 1990;78:521-525.

[14] Auffarth B, de Monchy JG, van der Mark TW, et al. Citric acid cough threshold and airway responsiveness in asthmatic patients and smokers with chronic airflow obstruction. Thorax. 1991;46:638-642.

[15] Taylor DR, Reid WD, Pare PD, Fleetham JA. Cigarette smoke inhalation patterns and bronchial reactivity. Thorax. 1988;43:65-70.

[16] Lin KH, Chuang CC, Kao MJ, et al. Quality of life of spinal cord injured patients in Taiwan: a subgroup study. Spinal Cord. 1997;35: 841-849.

[17] Standards for Neurological and Functional Classification of Spinal Cord Injury. Rev ed. Chicago, Ill: American Spinal Injury Association; 1992.

[18] Similowski T, Fleury B, Launois S, et al. Cervical magnetic stimulation: a new painless method for bilateral phrenic nerve stimulation in conscious humans. J Appl Physiol. 1989;67:1311-1318.

[19] Microspiro HI-601 Operation Manual. Tokyo, Japan: Chest MI Inc; 1993.

[20] Barnes PJ. Neural control of human airways in health and disease. Am Rev Respir Dis. 1986;134:1289-1314.

[21] Richardson JB, Ferguson CC. Neuromuscular structure and function in the airways. Fed Proc. 1979;38:202-208.

[22] Godden DJ, Borland C, Lowry R, Higenbottam TW. Chemical specificity of coughing in man. Clin Sci (Colch). 1986;70:301-306.

[23] Bach JR. Pulmonary Rehabilitation: The Obstructive and Paralytic Conditions. Philadelphia, Pa: Hanley & Belfus Inc; 1996.

[24] Banner AS, Drummer A. Relationship between citric acid cough threshold and ventilatory response to [CO.sub.2] in normal subjects [abstract]. Am Rev Respir Dis. 1987; 135 (suppl) :A489.

[25] Schmidt D, Jorres RA, Magnussen H. Citric acid-induced cough thresholds in normal subjects, patients with bronchial asthma, and smokers. Eur J Med Res. 1997;2:384-388.

[26] Dawson-Saunders B, Trapp BG. Basic and Clinical Biostatistics. East Norwalk, Conn: Appleton & Lange; 1990:118-119.

[27] Boucher RC, Johnson J, Inoue S, et al. The effect of cigarette smoke on the permeability of guinea pig airways. Lab Invest. 1980;43:94-100.

[28] Pryor JA. Respiratory Care. London, England: Churchill Livingstone; 1991:79-85.

KH Lin, PhD, RPT, is Associate Professor, School of Therapy, College of Medicine, National Taiwan University, No.7, Chung-Shan S Rd, Taipei, Taiwan, Republic of China ([e-mail]). Address all correspondence to Dr Lin.

YL Lai is with the Department of Physiology, College of Medicine, National Taiwan University.

HD Wu is with the Department of Integrated Diagno-therapeutics, National Taiwan University Hospital.

TQ Wang is with the Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital.

YH Wang is with the Department of Physical Medicine and Rehabilitation, National Taiwan University Hospital.

Concept and research design were provided by KH Lin and HD Wu; writing, by KH Lin, YL Lai, and Professor Yu Ru Kou (Department of Physiology, National Yang-Ming University); data collection, by KH Lin; and data analysis, by KH Lin, HiD Wu, Professor Huei-Chen Huang (Department of Pharmacology, College of Medicine, National Taiwan University), Dr Jau-Yih Tsauo (School of Physical Therapy, National Taiwan University), and Shiao-Chi Wu (Institute of Public Health, National Yang-Ming University). Project management was provided by KH Lin and Professor Shang-Ming Yu (Institute of Anatomy, National Yang-Ming University); fund procurement, by KH Lin and YL Lai; subjects, by KH Lin, YH Wang, and TQ Wang; facilities and equipment, by KH Lin and HD Wu; institutional liaisons, by KH Lin and YL Lai; and clerical support, by Hui-Wen Yang. Consultation (including review of manuscript before submission) was provided by YL Lai, HD Wu, and Yu Ru Kou. Shang-Ming Yu provided technical assistance. Huei-Chen Huang made invaluable suggestions.

This study was approved by the National Science Council, Taipei, Taiwan, Republic of China and was supported by a grant (NSC 85-2331-B-002-151) from the National Science Council.

This article was submitted March 25, 1998, and was accepted July 23, 1999.3