Abstract
Cough function is impaired after stroke; this may be important for protection against chest infection. Reflex cough (RC) intensity indices have not been described after stroke. RC, voluntary cough (VC) and respiratory muscle strength were studied in patients within 2 weeks of hemispheric infarct. The null hypotheses were that patients with cortical hemisphere stroke would show the same results as healthy controls on: 1) objective indices of RC and VC intensity; and 2) respiratory muscle strength tests.
Peak cough flow rate (PCFR) and gastric pressure (Pga) were measured during maximum VC and RC. Participants also underwent volitional and nonvolitional respiratory muscle testing. Nonvolitional expiratory muscle strength was assessed by measuring Pga increase after magnetic stimulation over the T10 nerve roots (twitch T10 Pga). Stroke severity was scored using the National Institutes of Health Stroke Scale (NIHSS; maximum = 31).
18 patients (mean±sd age 62±15 yrs and NIHSS score 14±8) and 20 controls (56±16 yrs) participated. VC intensity was impaired in patients (PCFR 287±171 versus 497±122 L·min−1) as was VC Pga (98.5±61.6 versus 208.5±61.3 cmH2O; p<0.001 for both). RC PCFR was reduced in patients (204±111 versus 379±110 L·min−1; p<0.001), but RC Pga was not significantly different from that of controls (179.0±78.0 versus 208.0±77.4 cmH2O; p = 0.266). Patients exhibited impaired volitional respiratory muscle tests, but twitch T10 Pga was normal.
VC and RC are both impaired in hemispheric stroke patients, despite preserved expiratory muscle strength. Cough coordination is probably cortically modulated and affected by hemispheric stroke.
Stroke accounts for >5 million deaths annually worldwide 1. Most stroke deaths are caused by complications, of which chest infections are the most important. One large study showed that 30% of acute stroke patients diagnosed with pneumonia had died before hospital discharge 2. Aspiration is common after stroke, and is associated with an 11-fold increase in the risk of chest infections 3.
Cough is important for clearing the lungs of aspirated material. This is demonstrated by studies showing a higher incidence of aspiration and chest infections in stroke patients with a weak voluntary cough (VC) 4, 5, and a significant association between absent cough reflex in acute stroke patients and subsequent development of pneumonia 6. A strong cough, whether VC or reflex cough (RC), requires powerful coordinated contraction of expiratory (abdominal) muscles, along with adequate inspiration prior to cough, low upper airways resistance, adequate duration of glottis closure, fast and complete glottis opening, and the ability to keep small airways patent during sudden rises in intrathoracic pressure 7. That some of these abilities are impaired after stroke is suggested by studies of stroke patients showing asymmetry of ventilation, reduced movement of the diaphragm and chest on the hemiparetic side, poor performance on volitional respiratory muscle tests, and reduced VC flow rates and sound 8–10. As might be expected, more recent studies suggest cortical involvement in cough production. Cortical activation during VC has been demonstrated in healthy volunteers in functional magnetic resonance imaging studies 11, 12. Using transcranial magnetic stimulation, increased latency and decreased amplitude of the motor-evoked potentials from the abdominal (expiratory) muscles, and reduction of the evoked rise in gastric pressure (Pga), have recently been shown in acute stroke patients compared with controls, suggesting impaired cortical control of the abdominal muscles after stroke 13. However, RC may be more important than VC in ensuring adequate airway protection and clearance after acute stroke 6, 14. RC is thought to originate primarily in the brainstem, but previous studies have noted cortical stroke patients with absence of RC in response to food swallowing 6 or an inhaled noxious substance 15. However, these studies did not describe intensity measures (flow, pressure or sound) for any RC produced. Therefore, we considered further evaluation of RC in hemispheric stroke to be worthwhile. The null hypothesis was that patients with cortical hemisphere stroke would show the same results as a group of age-matched nonstroke controls on objective indices of both RC and VC intensity. As a secondary hypothesis, it was sought to confirm the prior observation 13 that stroke patients showed no evidence of abdominal muscle weakness, as judged by peripheral nerve stimulation, but did when assessed by voluntary tests of abdominal muscle strength. It was anticipated that both of the null hypotheses would be refuted, as previous studies suggested that an intact cerebral cortex is required for effective VC and RC. The primary outcome measure of cough intensity was cough flow rate for both VC and RC.
MATERIALS AND METHODS
Study subjects
45 consecutive patients admitted to the stroke unit of King’s College Hospital (London, UK) within 2 weeks of a first-ever middle cerebral artery territory ischaemic stroke were screened. Six patients were excluded, as they did not wish to take part. Six patients with lacunar infarcts were excluded and 15 were unsuitable due to diabetes, excess alcohol consumption, respiratory or neurological disease other than stroke, or inability to follow commands. 18 adults (seven females) were studied. 20 healthy controls (five females) were recruited from a volunteer database and studied. The mean age and the proportion of female subjects were not significantly different between groups. Institutional ethical approval was obtained (LREC 02-120), and the subjects gave written informed consent.
Baseline assessments
Smoking history, alcohol and angiotensin-converting enzyme (ACE) inhibitor use, height and weight were documented for all subjects. For patients, stroke diagnosis and location were confirmed by brain computed tomography. Stroke severity on admission was assessed using the National Institutes of Health Stroke Scale (NIHSS) score. NIHSS score is a clinical stroke assessment tool for the evaluation of neurological status in acute stroke patients. The maximum score is 31, reflecting the most severe impairment 16. Patients had a bedside swallowing assessment within 24 h of admission, using radio-opaque contrast to detect aspiration 17. A hand-held spirometer (Jaeger SpiroPro; Erich Jaeger, Hoechberg, Germany) was used to measure forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), which were expressed as percentage of that predicted for age, sex and height 18. Oxygen saturations were measured with subjects at rest, and breathing room air (Ohmeda Biox 3740 Pulse Oximeter; BOC Healthcare, Manchester, UK). Radiologists’ reports of chest radiography examinations (for patients only) were acquired from the hospital records.
Respiratory muscle strength measurements
Measurements were made under controlled laboratory conditions with subjects on a bed, with the back rest at 45°, but otherwise in accordance with the American Thoracic Society/European Respiratory Society statement 19. This ensured that patients had the head end of the bed raised at an angle of >30°, recommended to prevent aspiration and enabling inclusion of subjects unable to sit upright. Pga and oesophageal pressure (Poes) were measured using balloon catheters (CooperSurgical, Trumbull, CT, USA) inserted nasally. The catheters and a pneumotachograph were attached to individual pressure transducers (MP45; Validyne, Northridge, CA, USA). The transducer signals were amplified (CD-280 amplifier; Validyne) and acquired at 2 kHz using an analogue-to-digital converter (Powerlab; ADinstruments, Chalgrove, UK) and a computer running Chart 5 software (ADinstruments). Transdiaphragmatic pressure (Pdi) was obtained by online subtraction of Poes from Pga.
Respiratory muscle strength was assessed volitionally by measuring maximum static expiratory mouth pressure (PE,max), maximum static inspiratory mouth pressure (PI,max) and sniff pressures. The subjects made strong expiratory efforts from total lung capacity (for PE,max) or inspiratory efforts from functional residual capacity (for PI,max) against a closed shutter. The maximum (for PE,max) or minimum (for PI,max) mean pressure over 1 s was recorded. The maximum nasal, oesophageal (sniff Poes) and transdiaphragmatic (sniff Pdi) pressure changes achieved during a sniff from functional residual capacity were also measured. Volitional respiratory muscle tests were performed at least three times until consistency was achieved. Nonvolitional assessment of expiratory (abdominal) muscle strength was made using magnetic stimulation over the spine at the level of the 10th thoracic nerve roots (T10) 19. A magnetic stimulator (MagStim 200; Magstim Co., Whitland, UK) set to 100% output and a 90-mm diameter circular coil were used. Subjects rested for 20 min before stimulation to minimise twitch potentiation. A minimum of three stimulations were performed and the evoked rise in Pga above baseline (twitch T10 Pga) measured. The mean of three reproducible twitch responses was calculated.
VC and RC tests
Airflow rates before, during and after cough were measured with subjects wearing a face mask (Hans-Rudolf, Shawnee, KS, USA) connected to a pneumotachograph (Fleisch; Phipps and Bird, Richmond, VA, USA). Cough inspiratory and expiratory volumes were calculated online by integration of the flow signal (fig. 1). VC was assessed before RC in order to avoid any effect of tartaric acid on VC. Subjects were told to inhale maximally and produce the biggest VC possible until five consistent readings of maximum cough Pga were achieved. RC was induced by nebulising escalating doses of 5, 10, 15 and 20% weight/volume l-tartaric acid solution. l-tartaric acid is thought to act on airway C-fibres to precipitate cough 14. The l-tartaric acid was administered using a Porta-Neb® compressor and Sidestream® nebuliser (Philips Respironics, Chichester, UK) attached to the pneumotachograph and face-mask via a T-piece connector. The data sheet for the nebuliser states that 80% of the particles delivered are ≤0.5 μm in diameter. Solutions were administered for 1 min during normal breathing. Dose escalation was undertaken until five or more coughs were produced; if a subject failed to respond to 20% tartaric acid, no further solutions were administered. Corresponding cough spikes on the flow and Pga traces were counted as coughs; all cough spikes within a cough bout were counted.
Voluntary cough trace for a stroke patient with a guide to the measurements made: a) flow and b) gastric pressure (Pga). max: maximum; PCFR: peak cough flow rate.
Peak cough flow rate (PCFR) was the maximum expiratory flow achieved during cough. PCFR was recorded, and expressed as a percentage of peak expiratory flow rate, to correct for a difference in height between the groups. Cough inspiratory volume and cough expiratory volume (fig. 1) were expressed as a percentage of the predicted FVC 18. Cough Pga was the maximum rise in Pga during cough (fig. 1).
For each subject, the five coughs (VC and RC) with the biggest PCFRs were averaged and the following derived measures determined (fig. 1). 1) Compression time: duration of zero airflow from the time cough Pga started to rise to the onset of expiratory flow; this is likely to represent the glottis closure period. 2) Cough pressure acceleration: the maximum cough Pga divided by the time taken to reach maximum, starting from the onset of expiratory flow. 3) Cough volume acceleration: PCFR divided by the time taken to reach maximum flow.
Sample size and data analysis
The primary outcome measure was cough flow rate, for both VC and RC. In a previous study with similar methods, healthy subjects had a mean±sd VC PCFR of 351±112 L·min−1, which was 200 L·min−1 greater than that of the stroke group 13. Using these data and G*Power v3.0.8 software (created by F. Faul, University of Kiel, Kiel, Germany); it was calculated that 13 subjects in each group were required for an 85% chance of detecting a 150 L·min−1 difference in PCFR between groups, at a significance level of 5%. Statistical analyses were performed using Prism 5.00 (GraphPad, La Jolla, CA, USA), Confidence Interval Analysis 2.2.0 20 and SPSS 16.0.1 (SPSS, Inc., Chicago, IL, USA). p<0.05 was considered significant. Data were tested for normality using the D’Agostino and Pearson omnibus method; unpaired t-tests or Mann–Whitney U-tests for two independent groups were used for comparisons 20.
Univariate and multiple linear regression was used to investigate possible causes of impaired VC and RC flow rates. Patients and controls were analysed together, with controls being assigned a stroke severity score (NIHSS score) of zero for the purposes of these analyses. Cough flow rate, for both VC and RC, was the dependent variable and stroke severity (NIHSS score), height and FEV1/FVC ratio were entered as independent predictors. All models included a constant.
RESULTS
Participants
The baseline characteristics of participants are given in table 1. Acute hemispheric infarction was present in the left hemisphere in nine patients and the right hemisphere in nine patients. Of the left infarcts, three were frontal, one was frontoparietal, one was temporofrontoparietal and four were capsulostriate. Of the right infarcts, three were frontal, one was frontoparietal, four were temporofrontoparietal and one was capsulostriate. Six out of 18 patients had been treated with thrombolysis.
Pulmonary function and respiratory muscle tests
Results are given in table 2. Patients showed significant impairments on spirometry and volitional respiratory muscle tests. There was no difference between the patient and control groups on the nonvolitional expiratory muscle strength test for twitch T10 Pga. The patients’ mean±sd twitch T10 Pga of 26.4±6.6 cmH2O was well above the published normal minimum value of 16 cmH2O, indicating that the expiratory muscles themselves were not weak but that the stroke patients could not fully recruit them volitionally.
Patients’ oxygen saturations were lower than those of controls and their respiratory frequencies were higher (table 2). Nurses measured patients’ oxygen saturations hourly for the first 48 h after stroke and then every 4 h subsequently. No patient had an oxygen saturation recording of <92% at any time.
Reports of chest radiographs taken during the admission for stroke were available for 14 out of 18 patients. For 10 patients, the radiologist reported the lung fields and pleura to be clear. For two patients, chest radiographs were reported as showing signs of chronic obstructive pulmonary disease (COPD), although these patients had not been diagnosed with COPD previously. One radiograph showed interstitial pulmonary oedema, but, as the relevant patient was unable to perform spirometry or cough, this did not affect group results for these tests. One radiograph showed a small left pleural effusion.
Voluntary cough
VC was significantly impaired in patients (table 3; fig 2). Two patients were unable to produce any VC manoeuvres and so were excluded from the cough intensity analysis. The patients’ mean cough Pga of 98.5 cmH2O was well below the cut-off value of 130 cmH2O used to aid diagnosis of expiratory muscle weakness 21.
Voluntary cough in normal subject (-----) compared to stroke patient (––—): a) flow; b) gastric pressure (Pga). ········: zero flow.
Reflex cough
Results for RC are given in table 4. Traces of RC for a control participant and a severely affected stroke patient are given in figure 3. The median concentration of l-tartaric acid solution required to produce five coughs was 10% for both patients and controls. One patient and two controls found l-tartaric acid inhalation intolerable and so the RC test was not performed. Three (17.6%) of the remaining 17 patients had no reflex cough response to 20% tartaric acid; all 18 normal subjects produced a cough response (0% nonresponders).
10-s trace of a, b) flow and c, d) gastric pressure (Pga) in a, c) a healthy control subject and b, d) a severely affected patient. ········: zero flow.
The subjects who did not cough were not included in the cough intensity analysis. The patients’ mean RC Pga of 179.0 cmH2O was well above the normal cut-off value of 130 cmH2O for VC Pga 21.
Predictors of VC and RC flow rate
The results of univariate linear regression with PCFR as the dependent variable and stroke severity as the predictor are shown in figure 4, for both VC and RC. VC flow rate was predicted by a model including NIHSS score, height and FEV1/FVC ratio (adjusted r2 = 0.653; p<0.001). Stroke severity (NIHSS score) had the greatest and most significant effect (regression coefficient -12.6 L·min−1 per point of NIHSS score, 95% CI -19.2– -6.1; p<0.001). Further details of the linear regression model are given in the online supplementary material (table S1). The only significant predictor of RC flow rate was NIHSS score; details are given in figure 4. ACE inhibitor use was tried as a predictor for both VC and RC, but did not exert a statistically significant effect.
Univariate linear regression. Regression line (—––) and 95% mean prediction interval (-----) drawn on a scatter diagram relating: a) voluntary cough (VC) flow rate in 36 subjects able to produce a VC; and b) reflex cough (RC) flow rate in 32 subjects able to produce a RC and stroke severity. The regression slope is: a) -15 L·min−1 per point of National Institutes of Health Stroke Scale (NIHSS) score (95% CI -20– -9 L·min−1; p<0.001; adjusted r2 = 0.465); and b) -11 L·min−1 per one point of NIHSS score (95% CI -16– -6 L·min−1; p<0.001; adjusted r2 = 0.367).
DISCUSSION
The present study shows that VC and RC are both impaired after acute hemispheric infarction. Impairments of respiratory muscle function measured by volitional tests, and reductions in VC flows and Pga in stroke patients have been described previously 4, 5, 13, 22, but RC may be considered more important for airway protection and clearance 23. The novel and important finding of the present study is that, despite patients achieving normal RC Pga, flow rates and expiratory volumes for RC are both decreased.
Critique of the method
The differences in RC flow rate, RC expired air volume and RC volume acceleration between patients and controls could not be attributed to differences in air volume inspired prior to cough, concentration of l-tartaric acid solution required to produce five or more coughs, duration of glottis closure, peripheral nerve conduction or expiratory muscle strength. Higher stroke severity score predicted impairment of both VC and RC flow rates, suggesting a physiological basis for impaired cough in acute stroke.
Spirometry, respiratory muscle strength and VC are measured by volitional tests, in the sense that they require a patient to make a maximal effort and their interpretation depends on the vigour of that effort being maximal. Stroke patients may theoretically perform badly, because the tests depend upon subject understanding and effort 19, although the more obvious manifestations of stroke concern motor skills. Even so, these factors would not affect RC, where any impairment observed is likely to be due to nonvolitional factors. Pga and glottis closure times in patients were no different to controls. RC inspired air volume tended to be smaller for patients, but this did not reach statistical significance.
It is possible that reduced functional residual capacity (FRC) in patients may have contributed to reduced cough flow rates, as a lower starting lung volume results in higher airway resistance and reduced flow rates. Little is known about FRC in stroke patients at rest (and none at all during cough), but one small study showed normal FRC in moderately severe patients at 2–4 weeks after onset 9. Patients had more airway obstruction than controls (significantly reduced FEV1 and FEV1/FVC ratio). Airway obstruction would be expected to lead to a reduced VC flow rate, although, from the regression models, the influence of FEV1/FVC ratio on VC flow rates was smaller and less significant than the effect of stroke severity. Neither FEV1 nor FEV1/FVC ratio were significant predictors of RC flow rate.
Previous studies have separately described intra-abdominal pressure changes during RC and VC in normal subjects 23, but this is the first study to describe PCFRs, volumes and pressures during RC and VC in an homogeneous sample of stroke patients and controls. One merit of the present study is that subjects with diabetes or previous heavy alcohol use were excluded, because these may affect cough 24, 25. Similarly, application of lidocaine to the pharynx (to allow passage of pressure catheters) can alter cough 26; therefore, cough tests were performed ≥90 min after administration. Finally, although ACE inhibitor use was recorded because of the previously described effect on cough 27, it was not found to be a significant independent predictor of cough flow rate in the present study.
Significance of the findings
The rapid rise in Pga but not expiratory flow during RC suggests that the sensory pathways are intact, since abdominal muscles must be recruited to generate a positive Pga. However, the slower rise in expiratory flow suggests an additional flow limitation as a manifestation of ischaemic cortical injury. We suspect that this injury may affect the coordinated activation of the upper airway muscles with the abdominal and thoracic muscles used for cough production 7. Cortical involvement in RC and VC is supported by studies showing voluntary suppression of capsaicin-induced RC in healthy volunteers 28, absent or delayed conduction in corticorespiratory tracts on stimulating the affected hemisphere of stroke patients 13 and cortical modulation of pharyngeal coordination in stroke 29.
This study is of modest size, but the sample appears representative and shows baseline characteristics similar to those in other studies. The patients’ mean VC PCFR was similar to that found 6 days after stroke onset in a recent study of 96 patients (261±188 L·min−1) 23. As the definition of effective cough remains elusive 14, it is impossible to know whether the reduction in patients’ cough flows are clinically meaningful. One method would be to correlate cough impairments with incidence of chest infections, but the number of events in the present study (n = 2) precludes such analysis. RC produced in the laboratory does not accurately replicate the response to aspirated fluid or food, which cannot easily be studied for safety reasons. Although desirable, measurements and imaging of the upper airways during cough could not be performed because of logistical and patient discomfort considerations.
The present study shows that acute stroke patients have impaired VC and RC; this may result in impaired lung clearance. The data suggest that impairment may be, in part, due to ineffective coordination of different muscle groups following cerebral injury. Further studies are required into the mechanisms that may underlie RC and VC impairment, and to test interventions that may improve cough function, in order to try and reduce the incidence and consequences of aspiration after stroke.
Acknowledgments
G. Rafferty and A. Lunt (both Division of Asthma, Allergy and Lung Biology, Dept of Respiratory Medicine, King’s College London School of Medicine, London, UK) gave methodological and technical support. K. Mills (Academic Neurosciences, King’s College London School of Medicine) gave support with neurophysiology techniques.
Footnotes
This article has supplementary material available from www.erj.ersjournals.com
Support Statement
K. Ward is funded by the Medical Research Council and the Royal College of Physicians (G070138), and was previously funded by the Stroke Association (Grant TSA 2004/05). M.I. Polkey's salary is part-funded by the National Institute for Health Research Respiratory Biomedical Research Unit at the Royal Brompton Hospital and Imperial College (all London, UK).
Statement of Interest
None declared.
- Received January 20, 2010.
- Accepted March 26, 2010.
- ©ERS 2010
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