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Abnormal ventilatory control in Parkinson's disease—Further evidence for non-motor dysfunction
Respiratory Physiology & Neurobiology 179 (2011) 300–304
Contents lists available at SciVerse ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Abnormal ventilatory control in Parkinson’s disease—Further evidence for non-motor dysfunction Leigh M. Seccombe a,b,∗ , Hugh L. Giddings a , Peter G. Rogers a , Alastair J. Corbett c , Michael W. Hayes c , Matthew J. Peters a,b , Elizabeth M. Veitch a a
Department of Thoracic Medicine, Concord Repatriation General Hospital, Sydney, Australia Australian School of Advanced Medicine, Macquarie University, Sydney, Australia c Department of Neurology, Concord Repatriation General Hospital, Sydney, Australia b
a r t i c l e
i n f o
Article history: Accepted 21 September 2011 Keywords: Ventilatory control Lung function Parkinson’s disease
a b s t r a c t There has been increasing recognition of pre-motor manifestations of Parkinson’s disease (PD) resulting from early brainstem involvement. We sought to determine whether ventilatory control is abnormal. Patients with PD without respiratory disease were recruited. Spirometry, lung volumes, diffusing capacity and respiratory muscle strength were assessed. Occlusion pressure and ventilation were measured with increasing CO2 . Arterial blood gases were taken at rest and following 20 min exposure to 15% O2 . A linear correlation assessed associations between respiratory function and indices of PD severity. 19 subjects (17 males) with mild-moderate PD were studied (mean (SD) age 66 (8) years). Respiratory flows and volumes were normal in 16/19. Maximum inspiratory and expiratory pressures were below LLN in 13/19 and 15/19 respectively. 7/15 had a reduced ventilatory response to hypercapnia and 11/15 had an abnormal occlusion pressure. There was no correlation between impairment of ventilatory response and reduction in respiratory muscle strength. Response to mild hypoxia was normal and there were no associations between disease severity and respiratory function. Our findings suggest that patients with mild-moderate PD have abnormal ventilatory control despite normal lung volumes and flows. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Parkinson’s disease (PD) has always been thought to involve a disturbance of respiration. James Parkinson observed in 1817 that his patients “fetched their breath rather hard” in his monograph, “An Essay on the Shaking Palsy” (Parkinson, 1817). Despite this early recognition of involvement of the respiratory system, the exact abnormalities and their causation remain unclear. The pathology of PD typically consists of degeneration of the neuronal cytoskeleton and the accumulation of proteinaceous inclusions called Lewy bodies. Although previously thought to occur principally in dopaminergic neurons in the mid-brain (sustantia nigra), the Braak staging hypothesis based on pathological studies (Braack and Braak, 2000) suggests that the earliest evidence of disease is in the medulla, enteric nervous system and olfactory bulb. It is proposed that the disease then slowly spreads trans-neuronally to the mid-brain, causing the classical motor
∗ Corresponding author at: Thoracic Medicine, Level 7 West, Concord Repatriation General Hospital, Hospital Rd, Concord 2139 NSW, Sydney, Australia. Tel.: +61 2 97677065; fax: +61 2 97675090. E-mail address: [email protected] (L.M. Seccombe). 1569-9048/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2011.09.012
features, and finally to the cortex with progressive cognitive and limbic symptoms. The hypothesis implies that there may be early pre-motor, autonomic and olfactory dysfunctions and there is now accumulating evidence supporting this, particularly relating to postural hypotension, cardiac denervation, bowel motility and hyposmia (Goldstein et al., 2010; Cheshire, 2010). These findings raise the possibility that brain-stem (medullary) ventilatory control mechanisms may be affected in PD, and should be evident in those who have progressed to mild-moderate disease. Respiratory involvement with PD could occur through both peripheral and central mechanisms. Motor manifestations such as rigidity, tremor and weakness affect the upper airway and the respiratory pump muscles. Non-motor brain stem involvement has effect at the level of respiratory control. Literature since the 1950s has yielded disparate findings. Peripheral involvement studies have demonstrated normal (Onodera et al., 2000) and restrictive (Nakano et al., 1972; De Pandis et al., 2002; Izquierdo-Alonso et al., 1994) flow volume characteristics, upper airway dysfunction (Izquierdo-Alonso et al., 1994) and reduced peak expiratory flow (Nakano et al., 1972; Izquierdo-Alonso et al., 1994; Polatli et al., 2001). Observations of reduced respiratory flow and volume have shown improvement while “on” levodopa therapy as compared to “off” (Nakano et al., 1972; De Pandis et al., 2002). Investigations into
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brainstem mediated function have been limited. Respiratory control studies have demonstrated a reduced sensitivity to progressive hypoxia (Onodera et al., 2000; Serebrovskaya et al., 1998) with no effect on progressive hypercapnia (Onodera et al., 2000). As respiratory drive under normal circumstances is more influenced by CO2 than O2 concentration, we sought to clarify whether ventilatory response to hypercapnia was altered in PD. The aim of this study was to comprehensively describe the effects of idiopathic PD both on non motor respiratory control, using ventilation, occlusion pressures, and peripheral respiratory function.
Table 1 Demographics and disease history and severity in 19 subjects with Parkinson’s disease.
2. Methods
BMI: body mass index; UPDRS: unified Parkinson’s disease rating scale (motor section); H&Y: Hoehn and Yahr. * N = 15. ** N = 16.
2.1. Subjects Patients with a diagnosis of idiopathic PD were recruited from a hospital-based PD clinic. Exclusion criteria included any clinically significant respiratory or cardiovascular disease, neurological disease other than PD, a significant smoking history (>10 pack years), structural abnormalities of the chest wall or recent upper respiratory tract infection. All testing was performed with the patient taking their usual medications; the timing of medication use in relation to the tests was not controlled. A PD history, including current medications was documented. Disease severity was assessed by the subject’s treating neurologist using the motor examination section of the unified PD rating scale (UPDRS) in the “on-state” (Fahn and Elton, 1987) and the Hoehn and Yahr scale (H&Y) (1967) within six months of recruitment to this study. 2.2. Experimental procedures 2.2.1. Respiratory flow, volume and muscle function Spirometry, diffusing capacity and lung volumes (plethysmography) were performed according to ATS/ERS criteria (Vmax Encore, Sensormedics, Yorba Linda, CA) (Brusasco et al., 2005a,b,c). Predicted values were derived from the recommendations of the European Community for Coal and Steel (Quanjer, 1983). Respiratory muscle strength was determined using methods and predictive reference equations described by Black and Hyatt (1969). 2.2.2. Hypercapnic ventilatory response and occlusion pressure Similar to the methods described by Ruppel (2003), the subject re-breathed on a closed circuit consisting of a 12 l non-diffusable bag (Erich Jaeger GmbH, Höechberg, Germany) connected via a large bore two-way tap (Collins, Braintree, MA, USA) until the fraction of end tidal CO2 exceeded 8% or until volitional fatigue. Small aliquots of 100% O2 were added to the circuit to maintain a fraction of inspired oxygen (FIO2 ) near 0.21. Ventilation (V˙ E) and occlusion pressure in the first 100 ms of an inspiratory effort against an occluded airway (P100 ) were sequentially collected (Vmax Encore, Sensormedics, Yorba Linda, CA) and plotted in the range above 40 mmHg pressure of end tidal CO2 (PETCO2 ). A linear response curve was generated. 2.2.3. Response to hypoxic gas inhalation Response to hypoxic gas was assessed using an altitude simulation test (AST) by a technique similar to that described by Gong et al. (1984). A radial arterial blood gas (ABG) was taken at rest (FIO2 0.21) and following 20 min, breathing hypoxic gas mix containing 15.1% (±0.2%) O2 , balance nitrogen (FIO2 0.15) (BOC Gases, Australia) through a two way, non-rebreathing valve (T-shape 1410, Hans Rudolph Inc., Kansas City, MO, USA) from a reservoir (30 l nondiffusing gas bag; Hans Rudolph Inc.).
Age (years) Height (cm) Weight (kg) BMI (kg m2 ) Duration of symptoms (years) Time since diagnosis (years) UPDRS (motor examination) (0–52)* H&Y score (0–5)**
Mean (SD)
Range
66 (8) 174 (7) 80 (11) 26.3 (3.7) 8 (5) 7 (5) 19 (8) 2.5 (0.5)
53–79 155–185 63–98 20.7–34.3 2–23 1–23 6–32 1–3
2.3. Statistical analysis Results are expressed as mean (SD) unless otherwise stated. A linear correlation was used to determine associations between PD severity, respiratory function and ventilatory response. The study was approved by the Sydney South West Area Health Service Ethics Review Board with formal written consent obtained from all subjects.
3. Results 3.1. Demographics and group description 19 subjects (17 male) with a diagnosis of idiopathic PD were recruited. Demographics and disease history and severity are shown in Table 1. By UPDRS motor examination, average scores reflect mildmoderate impairment (Fahn and Elton, 1987). H&Y staging (1967) classified subjects as having unilateral disease (Stage 1: n = 2), unilateral disease plus axial involvement (Stage 1.5: n = 1), bilateral disease, without impairment of balance (Stage 2: n = 4), mild bilateral disease (Stage 2.5: n = 4) or mild-moderate bilateral disease (Stage 3: n = 5); 3 were unclassified.
3.1.1. Medication use All 19 subjects reported taking levodopa or carbidopa and 11 subjects were taking a form of dopamine agonist (9 on pramipexole, 2 on cabergolide, 1 on an apomorphine infusion overnight). 10 subjects were taking entacapone (catechol-O-methyle transferase inhibitor). Two subjects were taking amantadine. One subject had undergone deep brain stimulation.
3.2. Respiratory flow, volume and muscle function Spirometry, diffusing capacity and lung volume parameters are shown in Table 2. 16/19 (84%) had lung function within normal limits. One subject had mild airflow limitation (Pauwels et al., 2001) and two were classified as restricted (Brusasco et al., 2005d) with total lung capacity 65% and 78% of predicted. No upper airway abnormalities, such as oscillation or “sawtoothing” were noted on the flow–volume curves. The results for maximal inspiratory (PI) and expiratory (PE) pressures are shown in Figs. 1 and 2. 13/19 (68%) fell below the lower limit of normal (LLN) for PImax and 15/19 (79%) for PEmax (Black and Hyatt, 1969).
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Table 2 Complex lung function in 19 subjects with Parkinson’s disease.
FEV1 (L) FVC (L) FEV1 /FVC (%) PEF (L/s) TLC (L) FRC (L) RV (L) RV/TLC (%) TLCO Adj (mL/mmHg/min)
Mean (SD)
% Predicted (SD)
3.28 (0.71) 4.06 (0.89) 81 (6) 9.01 (2.00) 6.07 (1.01) 3.38 (0.71) 1.97 (0.36) 33 (6) 25.0 (5.1)
107 (15) 104 (14) – 115 (23) 90 (12) 96 (18) 81 (16) – 93 (14)
FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity; PEF, peak expiratory flow; TLC, total lung capacity; FRC, functional residual volume; TLCO Adj, single breath lung carbon monoxide transfer factor corrected for haemoglobin.
Fig. 1. Maximum inspiratory (PI) pressures in 19 subjects with Parkinson’s disease. Filled data points fall below the lower limit of normal (LLN).
3.3. Hypercapnic ventilatory response and occlusion pressure Four subjects were unable to maintain an adequate seal and were excluded from analysis. V˙ E and P100 at baseline was 13.4 (2.9) L min and 2.5 (0.5) cmH2 O respectively. The slope of the ventilatory response (V˙ E L min mmHg PETCO2 mmHg) was 1.21 (1.04), R2 0.91 (0.10) and occlusion pressure response (P100 cmH2 O mmHg PETCO2 ) was 0.42 (0.41), R2 0.85 (0.21). 7/15 (47%) subjects had an abnormal ventilatory response (<1 L min mmHg PETCO2 ) (Hirshman et al., 1975) and 11/15 (73%) patients had an abnormal occlusion pressure response (<0.5 cmH2 O mmHg PETCO2 ) (Lopata et al., 1980). V˙ E and P100 at 45 and 65 mmHg PETCO2 (for ease
Fig. 3. Ventilation (V˙ E) and occlusion pressure (P100 ) at 45 and 65 mmHg pressure of end tidal carbon dioxide (PETCO2 ) [for ease of presentation] in 15 subjects with Parkinson’s disease. Broken lines indicate abnormal response.
of presentation derived from the linear response curve) for each subject are presented in Fig. 3. 3.4. Response to hypoxic gas inhalation Most subjects had ABG’s within normal limits when breathing room air, at rest [FIO2 0.21 PaO2 94.9 (8.7) mmHg, PaCO2 40.5 (4.3) mmHg]; one subject with a mildly reduced PaO2 (77 mmHg) and two subjects with mildly elevated PaCO2 (47 and 50 mmHg). One subject declined arterial blood sampling. Following the AST, ABG’s were able to be collected on 16 subjects. PaO2 levels were not different to normative values as described by Kelly et al. (2006) [FIO2 0.15 PaO2 59.5 (4.4) mmHg]. 3.5. Correlations There were no associations between PD severity, respiratory function or hypercapnic ventilatory responses. There was no association between PImax % predicted and P100 response to hypercapnia (R2 = 0.08) or P100 at 65 mmHg PETCO2 (R2 = 0.08). 4. Discussion 4.1. Main findings
Fig. 2. Maximum expiratory (PE) pressures in 19 subjects with Parkinson’s disease. Filled data points fall below the lower limit of normal (LLN).
This patient group with mild-moderate PD on optimal treatment has normal respiratory flow and volumes. Respiratory muscle weakness is common, but insufficient to cause restriction.
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Respiratory control is however abnormal. There is a marked impairment of the response to hypercapnia but not to mild hypoxia. This abnormality of respiratory drive is consistent with the Braak (Braack and Braak, 2000) hypothesis suggesting early brainstem involvement in PD. 4.2. Subject selection as compared to previous studies Our finding of normal respiratory flow and volume does not support previous studies demonstrating restrictive abnormalities. Direct comparison of the relative severity of PD in our patients with those previously studied is difficult. The PD assessment tools (Fahn and Elton, 1987; Hoehn and Yahr, 1967) employed in our study were previously not always used or available. Also, in contrast to some previous studies, we were careful to ensure that only patients who had idiopathic PD were included, and that subjects with other respiratory disease or significant past smoking were excluded. Importantly it has been suggested that restrictive lung volume changes are a marker of disease progression (Polatli et al., 2001). Therefore our data suggests that abnormality of ventilatory control may be a relatively early event in the clinical course of PD. 4.3. Impaired respiratory drive to hypercapnia We have demonstrated impaired respiratory drive in response to hypercapnia. As suggested by West (2000) the abnormal occlusion pressure response indicates central drive impairment independent of mechanical factors (such as muscle weakness). However Whitelaw and Derenne (1993) have since acknowledged that respiratory muscle myopathy can also have an inhibitory affect on this “central” measure. We have considered whether our measures of the ventilatory response to hypercapnia were abnormal only because of reduced muscle strength. Firstly, although the subjects in this study did have respiratory muscle pressure below the lower limit of normal, it was not to the level where extra-pulmonary restriction is seen. Secondly, there was no relationship between maximal respiratory muscle strength and the linear occlusion pressure response or occlusion pressure at 65 mm PETCO2 . Finally, across the group, the average value for P100 at a PETCO2 of 65 mmHg was 27% of PImax , suggesting that there was capacity for additional occlusion pressure response if brain stem drive was higher. Nonetheless, it is possible that reduced respiratory muscle strength contributed in some part to the abnormal response seen. There is limited published data in relation to hypercapnic ventilatory responses in PD. Onodera et al. (2000) found a normal hypercapnic response in PD patients while taking dopaminergic medication. By comparison, we did not compare our PD patients responses to control data as a group, but rather individually to published normative data (Hirshman et al., 1975). A reduction in chemosensitivity to progressive hypoxia in PD has been demonstrated (Onodera et al., 2000; Serebrovskaya et al., 1998). The mild hypoxic challenge that we used did not elicit a response. Further study monitoring P100 and V˙ E during progressive hypoxia is warranted. 4.4. Early brainstem involvement in PD It has recently been recognised that some of the earliest pathological changes of PD are seen in the brainstem, rather than the extra-pyramidal grey matter nuclei of the substantia nigra and pars compacta. Braack and Braak (2000) describe six pathological stages, with the typical motor manifestations of PD only starting to be seen in stages 3–4. Loss of smell and constipation are seen early, often pre-dating the typical motor findings, corresponding with early involvement of the olfactory bulb and dorsal motor nucleus
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of the vagal nerve. Along with these phenomena, abnormalities of respiratory control may also be amongst the earliest changes in PD. 4.5. Effect of therapeutic regimes All subjects in this study were on dopamine receptor activators during assessment. The effect of dopamine on ventilatory control on those with or without PD is varied. Hsiao et al. (1989) showed that ventilatory control to both hypoxia and hypercapnia is elevated in cats following domperidone, while Olson et al. (1982) demonstrated that healthy subject’s ventilatory response to hypercapnia decreased following dopamine infusions. Importantly, Blain et al. (2010) recent work on dogs has identified a strong connection between the central and peripheral chemoreceptors, suggesting that there is not a clear distinction between the two processes as previously thought. Which of these observations may be important in interpreting our data is not clear. While dopamine D1 receptor agonists have been shown to augment respiratory drive (Lalley, 2008), the dopamine agonists used for PD treatment are active at D2 receptors. Nonetheless, we cannot exclude an effect of treatment. We could not assess our subjects after medication withdrawal or in the “off” state for those who experience on–off phenomenon. We did consider this but there were practical difficulties. Mouthpiece seal and retention could not be achieved and accurate data could not be generated. In addition, the “off” state is discomforting for subjects and their carers raising ethical issues. To explore this question further we believe that it will be necessary to study a group with early-mild PD. 5. Conclusion In summary, an abnormal ventilatory response to CO2 is a feature of mild-moderate PD independent of mechanical factors, which were mostly preserved. Respiratory function and ventilatory response may worsen as the disorder progresses, but at later stages measurement becomes more difficult. Idiopathic PD and other Parkinsonian syndromes are associated with excess morbidity and mortality from respiratory causes (Brown, 1994), with pneumonia continuing to be the leading cause of death in end-stage PD (Hoehn and Yahr, 1967; Wang et al., 2002). Impaired respiratory drive may contribute to this independent of the contribution of respiratory muscle weakness. References Black, L.F., Hyatt, R.E., 1969. Maximal respiratory pressures: normal values and relationship to age and sex. Am. Rev. Respir. Dis. 99, 696–702. Blain, G.M., Smith, C.A., Henderson, K.S., Dempsey, J.A., 2010. Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 . J. Physiol. 588, 2455–2471. Braack, H., Braak, E., 2000. Pathoanatomy of Parkinson’s disease. J. Neurol. 247 (Suppl. 2), II/3-II/10. Brown, L.K., 1994. Respiratory dysfunction in Parkinson’s disease. Clin. Chest Med. 15, 715–727. Brusasco, V., Crapo, R., Viegi, G., 2005a. Series ATS/ERS task force: standardisation of lung function testing. Standardisation of spirometry. Eur. Respir. J. 26, 319–338. Brusasco, V., Crapo, R., Viegi, G., 2005b. Series ATS/ERS task force: standardisation of lung function testing Standardisation of the measurement of lung volumes. Eur. Respir. J. 26, 511–522. Brusasco, V., Crapo, R., Viegi, G., 2005c. Series ATS/ERS task force: standardisation of lung function testing. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur. Respir. J. 26, 720–735. Brusasco, V., Crapo, R., Viegi, G., 2005d. Series ATS/ERS task force: interpretative strategies for lung function tests. Eur. Respir. J. 26, 948–968. Cheshire, W.P., 2010. Autonomic assessment in Parkinson’s disease: a measured stride forward. Eur. J. Neurol. 17, 173–174. De Pandis, M.F., Starace, A., Stefanelli, F., Marruzo, P., Meoli, I., De Simone, G., Prati, R., Stocchi, F., 2002. Modification of respiratory function parameters in patients with severe Parkinson’s disease. Neurol. Sci. 23, S69–S70. Fahn, S., Elton, R.L., UPDRS program members, 1987. Unified Parkinsons Disease Rating Scale. In: Fahn, S., Marsden, C.D., Goldstein, M., Calne, D.B. (Eds.), Recent
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Developments in Parkinsons Disease, vol. 2. Macmillan Healthcare Information, Florham Park, New Jersey, pp. 153–163. Goldstein, D.S., Sewell, L.T., Holmes, C., 2010. Association of anosmia with autonomic dysfunction in Parkinson disease. Neurology 74, 245–251. Gong Jr., H., Tashkin, D.P., Lee, E.Y., Simmons, M.S., 1984. Hypoxia-altitude simulation test. Evaluation of patients with chronic airway obstruction. Am. Rev. Respir. Dis. 130, 980–986. Hirshman, C.A., McCullough, R.E., Weil, J.V., 1975. Normal values for hypoxic and hypercapnic ventilatory drives in man. J. Appl. Physiol. 38, 1095–1098. Hoehn, M.M., Yahr, M.D., 1967. Parkinsonism: onset, progression, and mortality. Neurology 17, 427–442. Hsiao, C., Lahiri, S., Mokashi, A., 1989. Peripheral and central dopamine receptors in respiratory control. Respir. Physiol. 76, 327–336. Izquierdo-Alonso, J.L., Jimenez-Jimenez, F.J., Cabrera-Valdivia, F., Mansilla-Lesmes, M., 1994. Airways dysfunction in patients with Parkinson’s disease. Lung 172, 47–55. Kelly, P.T., Swanney, M.P., Frampton, C., Seccombe, L.M., Peters, M.J., Beckert, L.E., 2006. Normobaric hypoxic inhalation test vs response to airline flight in healthy passengers. Aviat. Space Environ. Med. 101, 799–801. Lalley, P.M., 2008. Opioidergic and dopaminergic modulation of respiration. Resp. Physiol. Neurobiol. 164, 160–167. Lopata, M., Önal, E., Evanich, M.J., Lourenc¸o, R.V., 1980. Respiratory neuromuscular response to CO2 rebreathing with inspiratory flow resistance in humans. Resp. Physiol. 39, 95–110. Nakano, K.K., Bass, H., Tyler, H.R., 1972. Levodopa in Parkinson’s disease. Arch. Intern. Med. 130, 346–348. Olson, L.G., Hensley, M.J., Saunders, N.A., 1982. Ventilatory responsiveness to hypercapnic hypoxia during dopamine infusion in humans. Am. Rev. Respir. Dis. 126, 783–787.
Onodera, H., Okabe, S., Kikuchi, Y., Tsuda, T., Itoyama, Y., 2000. Impaired chemosensitivity and perception of dyspnoea in Parkinson’s disease. Lancet 356, 739–740. Parkinson, J., 1817. An Essay on the Shaking Palsy. Sherwood, Neely and Jones, London. Pauwels, R.A., Buist, A.S., Calverley, P.M., Jenkins, C.R., Hurd, S.S., GOLD Scientific Committee, 2001. Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease. Am. J. Respir. Crit. Care Med. 163, 1256–1276. ˝ Polatli, M., Akyol, A., C¸ilda˘g, O., Bayulkem, K., 2001. Pulmonary function tests in Parkinson’s disease. Eur. J. Neurol. 8, 341–345. Quanjer, P.H., 1983. European Community for Coal and Steel. Standardized lung function testing. Bull. Eur. Physiopathol. Respir. 19 (Suppl. 5), 7–21. Ruppel, G., 2003. Ventilation and ventilatory control tests. In: Ruppel, G. (Ed.), Manual of Pulmonary Function Testing. , 8th ed. Mosby, St Louis Missouri, pp. 127–146. Serebrovskaya, T., Karaban, I., Mankovskaya, I., Bernardi, L., Passino, C., Appenzeller, O., 1998. Hypoxic ventilatory responses and gas exchange in patients with Parkinson’s disease. Respiration 65, 28–33. Wang, X., Guangfa, Y., Haibo, C., Xiaojie, C., 2002. Clinical course and cause of death in elderly patients with idiopathic Parkinson’s disease. Chin. Med. J. 115, 1409–1411. West, J.B., 2000. Control of ventilation. In: West, J.B. (Ed.), Pulmonary Physiology. The Essentials. , 6th ed. Lippincott, Williams and Wilkins, Baltimore, Maryland, p. 111. Whitelaw, W.A., Derenne, J.-P., 1993. Airway occlusion pressure. J. Appl. Physiol. 74, 1475–1483.
Contents lists available at SciVerse ScienceDirect
Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Abnormal ventilatory control in Parkinson’s disease—Further evidence for non-motor dysfunction Leigh M. Seccombe a,b,∗ , Hugh L. Giddings a , Peter G. Rogers a , Alastair J. Corbett c , Michael W. Hayes c , Matthew J. Peters a,b , Elizabeth M. Veitch a a
Department of Thoracic Medicine, Concord Repatriation General Hospital, Sydney, Australia Australian School of Advanced Medicine, Macquarie University, Sydney, Australia c Department of Neurology, Concord Repatriation General Hospital, Sydney, Australia b
a r t i c l e
i n f o
Article history: Accepted 21 September 2011 Keywords: Ventilatory control Lung function Parkinson’s disease
a b s t r a c t There has been increasing recognition of pre-motor manifestations of Parkinson’s disease (PD) resulting from early brainstem involvement. We sought to determine whether ventilatory control is abnormal. Patients with PD without respiratory disease were recruited. Spirometry, lung volumes, diffusing capacity and respiratory muscle strength were assessed. Occlusion pressure and ventilation were measured with increasing CO2 . Arterial blood gases were taken at rest and following 20 min exposure to 15% O2 . A linear correlation assessed associations between respiratory function and indices of PD severity. 19 subjects (17 males) with mild-moderate PD were studied (mean (SD) age 66 (8) years). Respiratory flows and volumes were normal in 16/19. Maximum inspiratory and expiratory pressures were below LLN in 13/19 and 15/19 respectively. 7/15 had a reduced ventilatory response to hypercapnia and 11/15 had an abnormal occlusion pressure. There was no correlation between impairment of ventilatory response and reduction in respiratory muscle strength. Response to mild hypoxia was normal and there were no associations between disease severity and respiratory function. Our findings suggest that patients with mild-moderate PD have abnormal ventilatory control despite normal lung volumes and flows. © 2011 Elsevier B.V. All rights reserved.
1. Introduction Parkinson’s disease (PD) has always been thought to involve a disturbance of respiration. James Parkinson observed in 1817 that his patients “fetched their breath rather hard” in his monograph, “An Essay on the Shaking Palsy” (Parkinson, 1817). Despite this early recognition of involvement of the respiratory system, the exact abnormalities and their causation remain unclear. The pathology of PD typically consists of degeneration of the neuronal cytoskeleton and the accumulation of proteinaceous inclusions called Lewy bodies. Although previously thought to occur principally in dopaminergic neurons in the mid-brain (sustantia nigra), the Braak staging hypothesis based on pathological studies (Braack and Braak, 2000) suggests that the earliest evidence of disease is in the medulla, enteric nervous system and olfactory bulb. It is proposed that the disease then slowly spreads trans-neuronally to the mid-brain, causing the classical motor
∗ Corresponding author at: Thoracic Medicine, Level 7 West, Concord Repatriation General Hospital, Hospital Rd, Concord 2139 NSW, Sydney, Australia. Tel.: +61 2 97677065; fax: +61 2 97675090. E-mail address: [email protected] (L.M. Seccombe). 1569-9048/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.resp.2011.09.012
features, and finally to the cortex with progressive cognitive and limbic symptoms. The hypothesis implies that there may be early pre-motor, autonomic and olfactory dysfunctions and there is now accumulating evidence supporting this, particularly relating to postural hypotension, cardiac denervation, bowel motility and hyposmia (Goldstein et al., 2010; Cheshire, 2010). These findings raise the possibility that brain-stem (medullary) ventilatory control mechanisms may be affected in PD, and should be evident in those who have progressed to mild-moderate disease. Respiratory involvement with PD could occur through both peripheral and central mechanisms. Motor manifestations such as rigidity, tremor and weakness affect the upper airway and the respiratory pump muscles. Non-motor brain stem involvement has effect at the level of respiratory control. Literature since the 1950s has yielded disparate findings. Peripheral involvement studies have demonstrated normal (Onodera et al., 2000) and restrictive (Nakano et al., 1972; De Pandis et al., 2002; Izquierdo-Alonso et al., 1994) flow volume characteristics, upper airway dysfunction (Izquierdo-Alonso et al., 1994) and reduced peak expiratory flow (Nakano et al., 1972; Izquierdo-Alonso et al., 1994; Polatli et al., 2001). Observations of reduced respiratory flow and volume have shown improvement while “on” levodopa therapy as compared to “off” (Nakano et al., 1972; De Pandis et al., 2002). Investigations into
L.M. Seccombe et al. / Respiratory Physiology & Neurobiology 179 (2011) 300–304
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brainstem mediated function have been limited. Respiratory control studies have demonstrated a reduced sensitivity to progressive hypoxia (Onodera et al., 2000; Serebrovskaya et al., 1998) with no effect on progressive hypercapnia (Onodera et al., 2000). As respiratory drive under normal circumstances is more influenced by CO2 than O2 concentration, we sought to clarify whether ventilatory response to hypercapnia was altered in PD. The aim of this study was to comprehensively describe the effects of idiopathic PD both on non motor respiratory control, using ventilation, occlusion pressures, and peripheral respiratory function.
Table 1 Demographics and disease history and severity in 19 subjects with Parkinson’s disease.
2. Methods
BMI: body mass index; UPDRS: unified Parkinson’s disease rating scale (motor section); H&Y: Hoehn and Yahr. * N = 15. ** N = 16.
2.1. Subjects Patients with a diagnosis of idiopathic PD were recruited from a hospital-based PD clinic. Exclusion criteria included any clinically significant respiratory or cardiovascular disease, neurological disease other than PD, a significant smoking history (>10 pack years), structural abnormalities of the chest wall or recent upper respiratory tract infection. All testing was performed with the patient taking their usual medications; the timing of medication use in relation to the tests was not controlled. A PD history, including current medications was documented. Disease severity was assessed by the subject’s treating neurologist using the motor examination section of the unified PD rating scale (UPDRS) in the “on-state” (Fahn and Elton, 1987) and the Hoehn and Yahr scale (H&Y) (1967) within six months of recruitment to this study. 2.2. Experimental procedures 2.2.1. Respiratory flow, volume and muscle function Spirometry, diffusing capacity and lung volumes (plethysmography) were performed according to ATS/ERS criteria (Vmax Encore, Sensormedics, Yorba Linda, CA) (Brusasco et al., 2005a,b,c). Predicted values were derived from the recommendations of the European Community for Coal and Steel (Quanjer, 1983). Respiratory muscle strength was determined using methods and predictive reference equations described by Black and Hyatt (1969). 2.2.2. Hypercapnic ventilatory response and occlusion pressure Similar to the methods described by Ruppel (2003), the subject re-breathed on a closed circuit consisting of a 12 l non-diffusable bag (Erich Jaeger GmbH, Höechberg, Germany) connected via a large bore two-way tap (Collins, Braintree, MA, USA) until the fraction of end tidal CO2 exceeded 8% or until volitional fatigue. Small aliquots of 100% O2 were added to the circuit to maintain a fraction of inspired oxygen (FIO2 ) near 0.21. Ventilation (V˙ E) and occlusion pressure in the first 100 ms of an inspiratory effort against an occluded airway (P100 ) were sequentially collected (Vmax Encore, Sensormedics, Yorba Linda, CA) and plotted in the range above 40 mmHg pressure of end tidal CO2 (PETCO2 ). A linear response curve was generated. 2.2.3. Response to hypoxic gas inhalation Response to hypoxic gas was assessed using an altitude simulation test (AST) by a technique similar to that described by Gong et al. (1984). A radial arterial blood gas (ABG) was taken at rest (FIO2 0.21) and following 20 min, breathing hypoxic gas mix containing 15.1% (±0.2%) O2 , balance nitrogen (FIO2 0.15) (BOC Gases, Australia) through a two way, non-rebreathing valve (T-shape 1410, Hans Rudolph Inc., Kansas City, MO, USA) from a reservoir (30 l nondiffusing gas bag; Hans Rudolph Inc.).
Age (years) Height (cm) Weight (kg) BMI (kg m2 ) Duration of symptoms (years) Time since diagnosis (years) UPDRS (motor examination) (0–52)* H&Y score (0–5)**
Mean (SD)
Range
66 (8) 174 (7) 80 (11) 26.3 (3.7) 8 (5) 7 (5) 19 (8) 2.5 (0.5)
53–79 155–185 63–98 20.7–34.3 2–23 1–23 6–32 1–3
2.3. Statistical analysis Results are expressed as mean (SD) unless otherwise stated. A linear correlation was used to determine associations between PD severity, respiratory function and ventilatory response. The study was approved by the Sydney South West Area Health Service Ethics Review Board with formal written consent obtained from all subjects.
3. Results 3.1. Demographics and group description 19 subjects (17 male) with a diagnosis of idiopathic PD were recruited. Demographics and disease history and severity are shown in Table 1. By UPDRS motor examination, average scores reflect mildmoderate impairment (Fahn and Elton, 1987). H&Y staging (1967) classified subjects as having unilateral disease (Stage 1: n = 2), unilateral disease plus axial involvement (Stage 1.5: n = 1), bilateral disease, without impairment of balance (Stage 2: n = 4), mild bilateral disease (Stage 2.5: n = 4) or mild-moderate bilateral disease (Stage 3: n = 5); 3 were unclassified.
3.1.1. Medication use All 19 subjects reported taking levodopa or carbidopa and 11 subjects were taking a form of dopamine agonist (9 on pramipexole, 2 on cabergolide, 1 on an apomorphine infusion overnight). 10 subjects were taking entacapone (catechol-O-methyle transferase inhibitor). Two subjects were taking amantadine. One subject had undergone deep brain stimulation.
3.2. Respiratory flow, volume and muscle function Spirometry, diffusing capacity and lung volume parameters are shown in Table 2. 16/19 (84%) had lung function within normal limits. One subject had mild airflow limitation (Pauwels et al., 2001) and two were classified as restricted (Brusasco et al., 2005d) with total lung capacity 65% and 78% of predicted. No upper airway abnormalities, such as oscillation or “sawtoothing” were noted on the flow–volume curves. The results for maximal inspiratory (PI) and expiratory (PE) pressures are shown in Figs. 1 and 2. 13/19 (68%) fell below the lower limit of normal (LLN) for PImax and 15/19 (79%) for PEmax (Black and Hyatt, 1969).
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Table 2 Complex lung function in 19 subjects with Parkinson’s disease.
FEV1 (L) FVC (L) FEV1 /FVC (%) PEF (L/s) TLC (L) FRC (L) RV (L) RV/TLC (%) TLCO Adj (mL/mmHg/min)
Mean (SD)
% Predicted (SD)
3.28 (0.71) 4.06 (0.89) 81 (6) 9.01 (2.00) 6.07 (1.01) 3.38 (0.71) 1.97 (0.36) 33 (6) 25.0 (5.1)
107 (15) 104 (14) – 115 (23) 90 (12) 96 (18) 81 (16) – 93 (14)
FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity; PEF, peak expiratory flow; TLC, total lung capacity; FRC, functional residual volume; TLCO Adj, single breath lung carbon monoxide transfer factor corrected for haemoglobin.
Fig. 1. Maximum inspiratory (PI) pressures in 19 subjects with Parkinson’s disease. Filled data points fall below the lower limit of normal (LLN).
3.3. Hypercapnic ventilatory response and occlusion pressure Four subjects were unable to maintain an adequate seal and were excluded from analysis. V˙ E and P100 at baseline was 13.4 (2.9) L min and 2.5 (0.5) cmH2 O respectively. The slope of the ventilatory response (V˙ E L min mmHg PETCO2 mmHg) was 1.21 (1.04), R2 0.91 (0.10) and occlusion pressure response (P100 cmH2 O mmHg PETCO2 ) was 0.42 (0.41), R2 0.85 (0.21). 7/15 (47%) subjects had an abnormal ventilatory response (<1 L min mmHg PETCO2 ) (Hirshman et al., 1975) and 11/15 (73%) patients had an abnormal occlusion pressure response (<0.5 cmH2 O mmHg PETCO2 ) (Lopata et al., 1980). V˙ E and P100 at 45 and 65 mmHg PETCO2 (for ease
Fig. 3. Ventilation (V˙ E) and occlusion pressure (P100 ) at 45 and 65 mmHg pressure of end tidal carbon dioxide (PETCO2 ) [for ease of presentation] in 15 subjects with Parkinson’s disease. Broken lines indicate abnormal response.
of presentation derived from the linear response curve) for each subject are presented in Fig. 3. 3.4. Response to hypoxic gas inhalation Most subjects had ABG’s within normal limits when breathing room air, at rest [FIO2 0.21 PaO2 94.9 (8.7) mmHg, PaCO2 40.5 (4.3) mmHg]; one subject with a mildly reduced PaO2 (77 mmHg) and two subjects with mildly elevated PaCO2 (47 and 50 mmHg). One subject declined arterial blood sampling. Following the AST, ABG’s were able to be collected on 16 subjects. PaO2 levels were not different to normative values as described by Kelly et al. (2006) [FIO2 0.15 PaO2 59.5 (4.4) mmHg]. 3.5. Correlations There were no associations between PD severity, respiratory function or hypercapnic ventilatory responses. There was no association between PImax % predicted and P100 response to hypercapnia (R2 = 0.08) or P100 at 65 mmHg PETCO2 (R2 = 0.08). 4. Discussion 4.1. Main findings
Fig. 2. Maximum expiratory (PE) pressures in 19 subjects with Parkinson’s disease. Filled data points fall below the lower limit of normal (LLN).
This patient group with mild-moderate PD on optimal treatment has normal respiratory flow and volumes. Respiratory muscle weakness is common, but insufficient to cause restriction.
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Respiratory control is however abnormal. There is a marked impairment of the response to hypercapnia but not to mild hypoxia. This abnormality of respiratory drive is consistent with the Braak (Braack and Braak, 2000) hypothesis suggesting early brainstem involvement in PD. 4.2. Subject selection as compared to previous studies Our finding of normal respiratory flow and volume does not support previous studies demonstrating restrictive abnormalities. Direct comparison of the relative severity of PD in our patients with those previously studied is difficult. The PD assessment tools (Fahn and Elton, 1987; Hoehn and Yahr, 1967) employed in our study were previously not always used or available. Also, in contrast to some previous studies, we were careful to ensure that only patients who had idiopathic PD were included, and that subjects with other respiratory disease or significant past smoking were excluded. Importantly it has been suggested that restrictive lung volume changes are a marker of disease progression (Polatli et al., 2001). Therefore our data suggests that abnormality of ventilatory control may be a relatively early event in the clinical course of PD. 4.3. Impaired respiratory drive to hypercapnia We have demonstrated impaired respiratory drive in response to hypercapnia. As suggested by West (2000) the abnormal occlusion pressure response indicates central drive impairment independent of mechanical factors (such as muscle weakness). However Whitelaw and Derenne (1993) have since acknowledged that respiratory muscle myopathy can also have an inhibitory affect on this “central” measure. We have considered whether our measures of the ventilatory response to hypercapnia were abnormal only because of reduced muscle strength. Firstly, although the subjects in this study did have respiratory muscle pressure below the lower limit of normal, it was not to the level where extra-pulmonary restriction is seen. Secondly, there was no relationship between maximal respiratory muscle strength and the linear occlusion pressure response or occlusion pressure at 65 mm PETCO2 . Finally, across the group, the average value for P100 at a PETCO2 of 65 mmHg was 27% of PImax , suggesting that there was capacity for additional occlusion pressure response if brain stem drive was higher. Nonetheless, it is possible that reduced respiratory muscle strength contributed in some part to the abnormal response seen. There is limited published data in relation to hypercapnic ventilatory responses in PD. Onodera et al. (2000) found a normal hypercapnic response in PD patients while taking dopaminergic medication. By comparison, we did not compare our PD patients responses to control data as a group, but rather individually to published normative data (Hirshman et al., 1975). A reduction in chemosensitivity to progressive hypoxia in PD has been demonstrated (Onodera et al., 2000; Serebrovskaya et al., 1998). The mild hypoxic challenge that we used did not elicit a response. Further study monitoring P100 and V˙ E during progressive hypoxia is warranted. 4.4. Early brainstem involvement in PD It has recently been recognised that some of the earliest pathological changes of PD are seen in the brainstem, rather than the extra-pyramidal grey matter nuclei of the substantia nigra and pars compacta. Braack and Braak (2000) describe six pathological stages, with the typical motor manifestations of PD only starting to be seen in stages 3–4. Loss of smell and constipation are seen early, often pre-dating the typical motor findings, corresponding with early involvement of the olfactory bulb and dorsal motor nucleus
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of the vagal nerve. Along with these phenomena, abnormalities of respiratory control may also be amongst the earliest changes in PD. 4.5. Effect of therapeutic regimes All subjects in this study were on dopamine receptor activators during assessment. The effect of dopamine on ventilatory control on those with or without PD is varied. Hsiao et al. (1989) showed that ventilatory control to both hypoxia and hypercapnia is elevated in cats following domperidone, while Olson et al. (1982) demonstrated that healthy subject’s ventilatory response to hypercapnia decreased following dopamine infusions. Importantly, Blain et al. (2010) recent work on dogs has identified a strong connection between the central and peripheral chemoreceptors, suggesting that there is not a clear distinction between the two processes as previously thought. Which of these observations may be important in interpreting our data is not clear. While dopamine D1 receptor agonists have been shown to augment respiratory drive (Lalley, 2008), the dopamine agonists used for PD treatment are active at D2 receptors. Nonetheless, we cannot exclude an effect of treatment. We could not assess our subjects after medication withdrawal or in the “off” state for those who experience on–off phenomenon. We did consider this but there were practical difficulties. Mouthpiece seal and retention could not be achieved and accurate data could not be generated. In addition, the “off” state is discomforting for subjects and their carers raising ethical issues. To explore this question further we believe that it will be necessary to study a group with early-mild PD. 5. Conclusion In summary, an abnormal ventilatory response to CO2 is a feature of mild-moderate PD independent of mechanical factors, which were mostly preserved. Respiratory function and ventilatory response may worsen as the disorder progresses, but at later stages measurement becomes more difficult. Idiopathic PD and other Parkinsonian syndromes are associated with excess morbidity and mortality from respiratory causes (Brown, 1994), with pneumonia continuing to be the leading cause of death in end-stage PD (Hoehn and Yahr, 1967; Wang et al., 2002). Impaired respiratory drive may contribute to this independent of the contribution of respiratory muscle weakness. References Black, L.F., Hyatt, R.E., 1969. Maximal respiratory pressures: normal values and relationship to age and sex. Am. Rev. Respir. Dis. 99, 696–702. Blain, G.M., Smith, C.A., Henderson, K.S., Dempsey, J.A., 2010. Peripheral chemoreceptors determine the respiratory sensitivity of central chemoreceptors to CO2 . J. Physiol. 588, 2455–2471. Braack, H., Braak, E., 2000. Pathoanatomy of Parkinson’s disease. J. Neurol. 247 (Suppl. 2), II/3-II/10. Brown, L.K., 1994. Respiratory dysfunction in Parkinson’s disease. Clin. Chest Med. 15, 715–727. Brusasco, V., Crapo, R., Viegi, G., 2005a. Series ATS/ERS task force: standardisation of lung function testing. Standardisation of spirometry. Eur. Respir. J. 26, 319–338. Brusasco, V., Crapo, R., Viegi, G., 2005b. Series ATS/ERS task force: standardisation of lung function testing Standardisation of the measurement of lung volumes. Eur. Respir. J. 26, 511–522. Brusasco, V., Crapo, R., Viegi, G., 2005c. Series ATS/ERS task force: standardisation of lung function testing. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. Eur. Respir. J. 26, 720–735. Brusasco, V., Crapo, R., Viegi, G., 2005d. Series ATS/ERS task force: interpretative strategies for lung function tests. Eur. Respir. J. 26, 948–968. Cheshire, W.P., 2010. Autonomic assessment in Parkinson’s disease: a measured stride forward. Eur. J. Neurol. 17, 173–174. De Pandis, M.F., Starace, A., Stefanelli, F., Marruzo, P., Meoli, I., De Simone, G., Prati, R., Stocchi, F., 2002. Modification of respiratory function parameters in patients with severe Parkinson’s disease. Neurol. Sci. 23, S69–S70. Fahn, S., Elton, R.L., UPDRS program members, 1987. Unified Parkinsons Disease Rating Scale. In: Fahn, S., Marsden, C.D., Goldstein, M., Calne, D.B. (Eds.), Recent
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