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Neuromuscular transmission in hypoxemic patients with chronic obstructive pulmonary disease
Respiratory Physiology & Neurobiology 189 (2013) 112–116
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Respiratory Physiology & Neurobiology journal homepage: www.elsevier.com/locate/resphysiol
Neuromuscular transmission in hypoxemic patients with chronic obstructive pulmonary disease Gazi Gulbas a,∗ , Yuksel Kaplan b , Ozden Kamisli b , Hilal Ermis a , Suat Kamisli b , Cemal Ozcan b a b
Inonu University, Department of Pulmonary Diseases, Turkey Inonu University, Department of Neurology, Turkey
a r t i c l e
i n f o
Article history: Accepted 16 July 2013 Keywords: COPD Single-fiber EMG Neuromuscular transmission Hypoxemia
a b s t r a c t Many studies have focused on the systemic effects of chronic obstructive pulmonary disease (COPD), but none has examined neuromuscular junction transmission (NMT). We evaluated NMT dysfunction using single-fiber electromyography (SFEMG) in patients with COPD. Twenty patients with COPD and 20 age-matched healthy controls were included in the study. All patients and controls underwent SFEMG. Abnormal NMT was found in seven of 20 patients (35%), but in none of the control subjects. The COPD patients were subgrouped according to the presence of hypoxemia. The patients with normoxemia were classified as Group 1, and the patients with hypoxemia were classified as Group 2. Abnormal NMT was found in six patients in Group 2 and in one in Group 1. While there was significant difference in terms of abnormal NMT between Group 2 and the controls, there was none between Group 1 and the controls. Our results show that NMT abnormalities can be present in hypoxemic patients with COPD. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Chronic obstructive pulmonary disease (COPD) is characterized by progressive, irreversible airway obstruction and recurrent exacerbations (Senior and Shapiro, 1998). In addition to pulmonary abnormalities, COPD has multisystem involvement with significant extrapulmonary manifestations, so-called systemic effects, and comorbidity factors that complicate the progression of COPD (Couillard et al., 2010). There is growing awareness about the cardiovascular, neurological, psychiatric, and endocrinological comorbidities associated with COPD. Although many studies have examined COPD and its systemic involvement over the last decade, much remains unknown. As pulmonary function deteriorates and the disease progresses, the risk of alveolar hypoxia and consequent hypoxemia increases in COPD patients (Rabe et al., 2007). It now seems clear that tissue hypoxia has a key role in many of the maladaptive processes and extrapulmonary comorbidities in COPD (Kent et al., 2011).
∗ Corresponding author at: Department of Pulmonary Diseases, Inonu University, 44069 Malatya, Turkey. Tel.: +90 5422204449; fax: +90 4223411000. E-mail addresses: [email protected] (G. Gulbas), [email protected] (Y. Kaplan), [email protected] (O. Kamisli), [email protected] (H. Ermis), [email protected] (S. Kamisli), [email protected] (C. Ozcan). 1569-9048/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2013.07.017
Various electrophysiological studies of patients with COPD have demonstrated that it affects both the central and peripheral nervous systems, either sequentially or simultaneously. COPD and chronic hypoxia were shown to cause polyneuropathy (PNP) by Appenzeller et al. (1968). Following this first report on neurological manifestations of COPD, numerous studies have confirmed that PNP is common among patients with COPD, with an incidence of 28–95%, and that neuropathy increases with hypoxia (Kayacan et al., 2001; Agrawal et al., 2007; Oncel et al., 2010). Moreover, Ozge et al. (2001) demonstrated that the rate of axonal neuropathy was significantly higher in the hypoxemic group than in the normoxemic group and the severity of neuropathy was correlated with the degree of hypoxemia in patients with COPD. To our knowledge, neuromuscular junction transmission (NMT) has not been studied in patients with COPD. Single-fiber electromyography (SFEMG), established by Stalberg and Eskedt in the 1960s (Sanders and Stalberg, 1996) is a valuable electrophysiological technique for assessing NMT. It has been used for the diagnosis of neuromuscular disorders and is the most sensitive test of impaired NMT (Farrugia et al., 2009). With impaired NMT, nerve impulses fail to generate an action potential, and an abnormal blocking jitter is seen (Ad Hoc Committee of the AAEM Special Interest Group on Single Fiber EMG, 1992). The first aim of this study was to determine NMT dysfunction using SFEMG in patients with COPD. The second aim of the study was to evaluate the relationship of chronic hypoxemia with NMT dysfunction in COPD patients.
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2. Materials and methods
2.3. Respiratory function tests and arterial blood gas analysis
2.1. Study design
Respiratory function tests and arterial blood gas analysis were performed in all patients. Spirometry was carried out on a computerized device (V max22; SensorMedics, Yorba Linda, CA, USA), with the patients sitting upright. Spirometric indices were calculated using the best of three consecutive tests according to the recommendations of American Thoracic Society. FEV1 , FVC, FEV1 /FVC, peak expiratory flow rate and forced expiratory flow (25–75%) were recorded. pH, PaO2 , arterial carbon dioxide tension (PaCO2 ) and SaO2 were analyzed in arterial blood samples collected from the radial artery. A pulmonary medicine physician completed a form including demographic data, such as age, sex, body mass index (BMI), duration of COPD symptoms (years), smoking load (packyears), and respiratory function test results and arterial blood gas analysis results.
This cross-sectional clinical study was carried out in the Departments of Pulmonary Diseases and Neurology of our hospital between March 2011 and March 2012. The study protocol was approved by the ethics committee. Patients provided signed informed consent, and all patients were given a detailed explanation of the study. This study was performed in accordance with the Declaration of Helsinki.
2.2. Study population The study population was selected of the patients with symptoms and histories compatible with COPD (onset of the disease over 40 years-old, presence of smoking history for at least 10 pack-year or occupational exposure to irritant or toxic gases or biomass exposure and postbronchodilator ratio of forced expiratory volume in one second (FEV1 ) to forced vital capacity (FVC) (FEV1 /FVC) < 0.7. The patients were diagnosed as COPD according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) criteria (Global Initiative for Chronic Obstructive Lung Disease, 2011) at the Department of Pulmonary Diseases before being enrolled. All patients were consecutive and were admitted to the outpatient clinic of the Department of Pulmonary Diseases. Patients were included only if they had regular follow-up over the preceding 1 year. All patients were studied when they were clinically stable. While one-half of the patients with COPD were selected from normoxemic patients, the other half of the patients with COPD who were enrolled in the study had been on long-term oxygen treatment (LTOT) for at least one year due to chronic hypoxemia. LTOT was prescribed based on the international criteria; i.e., arterial oxygen tension (PaO2 ) ≤ 55 mmHg or arterial oxygen saturation (SaO2 ) ≤ 88%, or PaO2 56–59 mmHg or SaO2 = 89% while at rest and breathing room air, along with hematocrit > 55%, congestive heart failure or pulmonary hypertension (Gulbas et al., 2012). Control subjects were selected randomly from healthy volunteers and matched to cases by age (±1 year). All healthy volunteers were nonsmokers and had no symptoms suggestive of any systemic or neurological diseases. All patients were evaluated by a neurologist, and all underwent a detailed neurological examination. We excluded patients with a history of neurological disease, patients with any neurological complaints or findings suggestive of any neuromuscular disorder or other nervous system involvement and those with diabetes mellitus, chronic renal failure, thyroid disease, malnutrition, chronic alcoholism, pulmonary and extra pulmonary malignancies or history of intake of any drugs or agents that could have a potential effect on the NMT or were known neurotoxins. We also excluded any patient with subclinical nervous system involvement detected by electrophysiological studies. To restrict the subjects to COPD patients, other causes of hypoxemia including restrictive lung disease, pulmonary arterial hypertension, congenital heart disease and or interstitial lung disease were excluded based on the laboratory and clinical findings. Posteroanterior and left lateral chest X-rays, electrocardiogram, hemogram, urine analysis and protein electrophoresis were performed. The erythrocyte sedimentation rate and levels of serum electrolytes, fasting serum glucose, urea, creatinine, transaminases, vitamin B12 , and folic acid were determined to detect conditions that could predispose an individual to neurological or systemic diseases.
2.4. Procedure used for SFEMG Nerve conduction studies, concentric needle electromyography (EMG) and SFEMG of the extensor digitorum communis muscle were performed. Nerve conduction studies assessed the motor nerve conductions of the median, ulnar, peroneal and tibial nerves, as well as sensory nerve conductions of the median, ulnar, and sural nerves. Single-fiber EMG studies were performed during voluntary contraction of the extensor digitorum communis muscle using an EMG machine (Dantec, Skovlunde, Denmark) with a filter setting of 500 Hz–10 kHz. Electrophysiological studies were conducted in a warm room, such that the skin temperature of the extremities was maintained at ≥32 ◦ C. Recordings from a single fiber electrode were used. We accepted only potentials with a stable shape, a rise time of <0.3 ms and amplitude of >200 V for jitter analysis, and 50–100 consecutive traces were obtained for each jitter analysis. Ten to 20 different potential pairs were recorded from each subject, and the jitter values of these potential pairs were calculated. The mean consecutive difference (MCD) was used as the jitter value. If the MCD/mean sorted-data difference (MSD) ratio was >1.25 as the jitter value, MSD was calculated. The mean of the obtained jitter values and the number of individual abnormal jitter values exceeding the upper limit of normal were also calculated for each subject. The range of normal values, which was derived from a multicenter study, was used for individual and mean jitter results. We considered “abnormal NMT” to have occurred when a subject had more than two individual abnormal jitter values or had an abnormal mean jitter value. We compared the parameters between the patients with COPD and controls. We also subdivided the COPD patients based on presence of chronic hypoxemia and compared NMT abnormalities, demographic data, and respiratory and laboratory findings between these subgroups.
2.5. Statistical analysis The Statistical Package for the Social Sciences version 15 (SPSS, Chicago, IL, USA) was used for all statistical analyses. Data are presented as mean ± standard deviation. We used Student’s t-test and the Mann–Whitney U test to compare continuous parametric variables between the groups. Fisher’s exact chi-squared test was used to compare categorical variables. Values of p < 0.05 were considered to indicate significance.
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Table 1 Comparison of demographic and clinical characteristics between the patient groups. Parameter
All patients (n = 20)
Group 1 (n = 10)
Group 2 (n = 10)
p-Value
Gender (male/female) Age (years) Smoking load (pack-years) Duration of COPD (years) BMI (kg/m2 ) PAP (mmHg) FEV1 (%) FVC (%) pH PaO2 (mmHg) PaCO2 (mmHg) SO2 (%)
20/0 65.85 ± 6.76 54.3 ± 21.21 5 ± 2.95 25.64 ± 5.39 33.86 ± 18.45 53.05 ± 19.31 83.65 ± 23.03 7.42 ± 0.02 58.10 ± 15.68 44.43 ± 10.76 87.00 ± 11.24
10/0 65.90 ± 7.62 54.4 ± 17.5 4 ± 2.49 24.74 ± 5.84 22.00 ± 8.24 61.40 ± 20.86 92.50 ± 22.32 7.44 ± 0.05 71.53 ± 7.70 37.29 ± 5.74 95.03 ± 1.96
10/0 65.80 ± 6.19 54.2 ± 25.3 6 ± 3.16 26.54 ± 5.04 41.77 ± 19.43 44.70 ± 14.03 74.80 ± 20.05 7.41 ± 0.06 44.67 ± 7.69 51.58 ± 9.90 78.97 ± 10.93
ns ns ns ns ns ≤0.05 ≤0.05 ns ns ≤0.05 ≤0.05
ns, not significant; COPD, chronic obstructive pulmonary disease; BMI, body mass index; PAP, pulmonary artery pressure; FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity; PCO2 , arterial carbon dioxide tension; PO2 , arterial oxygen tension; SO2 , arterial oxygen saturation.
Fig. 1. The disturbance of the spirometric stage according to the GOLD criteria for each groups.
jitter values of the patients were abnormally high, only 2 of 237 (0.8%) were abnormal for the controls. There were significantly more abnormal individual jitter values within the patients than in the control group (p < 0.05). Abnormal NMT was found in 7 of 20 patients (35%), but in none of the control subjects. Six patients in Group 2 and one in Group 1 had abnormal NMT. As we made a comparison between the patient groups regarding abnormal NMT, a significant difference between Group 2 and 1 was found (p = 0.02). While there was also a significant difference between Group 2 and the control group, there was no significant difference between Group 1 and the control group (p = 0.0004, p = 0.33, respectively). The SFEMG findings are summarized in Table 2. When we also compared between Group 2 and 1 regarding the nerve conduction velocities of upper and lower limbs, there was no significant difference (p > 0.05). These findings are summarized in Table 3. 4. Discussion
3. Results During the study 172 patients with COPD presented to the Pulmonary Diseases Department. Of these, 152 did not meet the inclusion criteria and were excluded; thus, 20 patients were evaluated. The patients were divided into two subgroups according to the presence of hypoxemia. Patients with normoxemia were classified as Group 1 and patients with hypoxemia were classified as Group 2. Each group consisted of 10 patients, and 20 subjects formed the control group. All patients and controls were male. According to COPD severity based on the GOLD criteria; one (10%), five (50%), and four (40%) patients in Group 1 were evaluated as stages I to III, respectively. Three (30%) and seven (70%) patients in Group 2 were evaluated as stages II and III, respectively. Fig. 1 presents the distribution of the spirometric stage according to the GOLD criteria for each group. 3.1. Demographic and clinical characteristics The mean ages of the patient subgroups and controls were 65.9 ± 7.62, 65.8 ± 6.19 and 65.9 ± 8.86 years, respectively. No significant difference in age, smoking load (pack-years), COPD duration (years) or BMI was observed between the two COPD groups. FEV1 , PaO2 , PaCO2 , SO2 , and pulmonary artery pressure differed significantly between the two COPD groups (p ≤ 0.05). The basic demographic data and clinical characteristics of the patient groups are described in Table 1. 3.2. SFEMG findings In total, 249 individual jitter values were recorded from the patients and 237 from the control subjects. While 18 of 249 (7.2%)
We evaluated NMT using SFEMG in patients with COPD and in subjects with no clinical feature suggestive of a neuromuscular junction disorder or another neurological/systemic disease. Our study demonstrated that NMT abnormalities were present in patients with COPD globally. To evaluate the effect of hypoxemia on NMT among the patients with COPD, we selected one-half of the patients from those having hypoxemia. At the same time, when the patients were divided into subgroups according to the presence of chronic hypoxemia, we only found significant abnormal NMT in COPD patients with chronic hypoxemia. Although COPD is evidently of respiratory origin, many extrapulmonary manifestations exist, and a number of common comorbidities complicate the natural history of COPD, thereby alter the disease prognosis and quality of life. These comorbidities include muscular dysfunctions, nutritional and metabolic abnormalities, hormonal deficits, anemia, an increased prevalence of osteoporosis, lung cancer, cardiovascular diseases, diabetes, anxiety, and depression (Decramer et al., 2008; Couillard et al., 2010). The associated neurological manifestations such as peripheral neuropathy and peripheral muscle dysfunction have been well described in the literature. Additionally; motor neuron involvement, encephalopathy, cognitive dysfunction, optic nerve involvement, and impairment of the eighth cranial nerve and brainstem functions have been observed in patients with COPD (Atis et al., 2001; Kayacan et al., 2001; Ozge et al., 2005; Gupta et al., 2008, 2010). Among these manifestations, peripheral muscle dysfunction is clearly demonstrated by significant losses in both strength and locomotory endurance in COPD patients compared with healthy subjects (Couillard et al., 2010). Moreover; effort intolerance, exertional desaturation, loss of autonomy, reduced level of regular physical activity, quadriceps strength loss, breathlessness,
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Table 2 Single-fiber electromyography (SFEMG) findings in the patient groups and the controls. Subjects
Individual jitter values (n)
Abnormally high jitter values n (%)
Abnormal neuromuscular transmission (n)
p-Value
All patients (n = 20) Group 1 (n = 10) Group 2 (n = 10) Controls (n = 20)
249 114 135 237
18/249 (7.2%) 2/114 (1.7%) 16/135 (11.8%) 2/237 (0.8%)
7 1 6 0
0.0004# 0.02* 0.33**
# * **
p: between Group 2 and Controls. p: between Group1 and 2. p: between Group 1 and Controls.
and quality of life status are now recognized as independent predictors of survival in these patients (Decramer et al., 2008; Couillard et al., 2010). Although the exact pathophysiological mechanisms remain unclear, muscle dysfunction may result from a multitude of factors including deconditioning, systemic inflammation, oxidative stress, nutritional imbalance, reduced anabolic status, systemic corticosteroids, hypoxemia, hypercapnia, electrolyte disturbances or cardiac failure (Wagner, 2006; Decramer et al., 2008; Reid et al., 2009; Man et al., 2009; Couillard et al., 2010). The basic causes of hypoxemia in COPD patients are poor distribution of ventilation to perfusion resulting from progressive airflow limitation and emphysematous destruction of pulmonary vascular bed (Struss et al., 1997; Kent et al., 2011). The previous study demonstrated a relationship between the severity of neuropathy and the degree of hypoxemia in patients with COPD (Ozge et al., 2001). Although several factors likely play a role in the genesis of systemic inflammation, chronic hypoxemia seems to be an independent factor (Agusti, 2005; Kent et al., 2011). The transcription factor nuclear B (NFB) is the master regulator of cellular inflammatory responses controlling the expression of key inflammatory cytokines (Garvey et al., 2009). In chronic hypoxemia, NFB also appears to interact with hypoxia-inducible factor (HIF)1␣ to promote the expression of inflammatory genes, such as cyclo-oxygenase II (Fitzpatrick et al., 2011). Evidence of a role for hypoxia in the induction of an NFB response comes from several experimental and clinical studies (Kent et al., 2011). Oxidative stress appears to be particularly prominent in chronically hypoxemic patients, in whom markers of oxidative stress are significantly increased in peripheral muscle specimens (Koechlin et al., 2005). Among several factors, systemic inflammation and oxidative stress caused by chronic hypoxemia may be the most important pathophysiological mechanisms leading the development of comorbidities in COPD. As well as indirect effects of hypoxemia such as systemic inflammation and oxidative stress, hypoxemia results in peripheral nerve damage directly in COPD, with the injury
to the vasa nervorum. We also aimed to investigate the potential effect of COPD and hypoxemia related with COPD on NMT in our study. Although numerous studies have examined peripheral muscle dysfunction, neuropathy and associated conditions in COPD patients, we could not find any studies that had evaluated neuromuscular junction function in patients with COPD or other disorders causing hypoxemia which could allow a comparison with our results. SFEMG is a valuable technique and is the most sensitive way to assess neuromuscular junction function and associated disorders. In the present study, 35% of the COPD patients exhibited NMT abnormalities, but there were no NMT abnormalities in the control group. To evaluate the effect of chronic hypoxemia, we selected one-half of the patients from those who have used LTOT at least for 1 year and had chronic hypoxemia. When we compared the normoxemic patients with the control group, no significant difference was found (p = 0.33). Whereas, the comparison of the hypoxemic patients with both the normoxemic patients and the control subjects revealed significant differences both between the hypoxemic patients and the normoxemic patients and also between the hypoxemic patients and the control subjects (p = 0.02, p = 0.003, respectively). These findings support the hypothesis that NMT abnormality may be a consequence of the direct and the indirect effects of hypoxemia in patients with COPD. Also, these findings should not be specific to COPD, but should also exist in other hypoxemic diseases, such as pulmonary arterial hypertension, congenital heart disease, or lung fibrosis. Tobacco smoke contains extremely high concentrations of free radicals. In addition, it can increase the generation and activation of endogenous free radicals (Arnson et al., 2010). Despite contrary opinions, several studies have shown that nicotine has neurotoxic effects. Several studies described the possibility that nicotine could act as a toxin inducing oxidative stress by depleting glutathione (Ferrea and Winterer, 2009). To prevent the confusing role of the tobacco smoke regarding the potential acute neurotoxic effects on NMT, we did not include current smokers in our study.
Table 3 Nerve conduction velocity parameters of lower and upper limb in the Group 1 and 2. Parameters
Group 1 (n = 10)
Median sensory DL Median sensory CV Ulnar sensory DL Ulnar sensory CV Median motor DL Median motor CV Ulnar motor DL Ulnar motor CV Peroneal DL Peroneal motor CV Posterior tibial DL Posterior tibial motor CV Sural sensory DL Sural sensory CV Sural A
2.33 39.37 1.95 43.90 3.34 59.57 2.28 58.81 3.55 50.76 3.57 49.78 2.96 39.63 13.29
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.649 11.58 0.26 3.59 0.91 4.08 0.28 6.11 1.0 10.61 0.55 6.00 0.45 3.28 5.54
CV: conduction velocity, DL: distal latency, A: amplitude, ms: millisecond.
Group 2 (n = 10) 2.25 43.48 1.84 45.47 3.08 58.65 2.29 60.50 33.69 50.62 3.60 47.75 2.86 39.69 13.57
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.38 7.32 0.24 4.15 0.43 7.88 0.18 4.75 0.56 5.27 0.56 11.72 0.41 4.57 6.35
t
p
0.47 −1.44 1.56 −1.44 1.23 0.55 −0.11 −1.06 −0.58 0.06 −0.17 0.81 0.79 −0.05 −0.16
0.64 0.158 0.13 0.157 0.23 0.588 0.92 0.294 0.57 0.957 0.87 0.422 0.43 0.962 0.872
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As this is the first study evaluating the neuromuscular junction transmission in COPD patients, it is difficult to determine whether the NMT abnormality was the result of hypoxemia, or the consequence of the other factors. Moreover, we did not investigate the presence of NMT abnormalities in patients who were hypoxic because of other reasons, such as pulmonary arterial hypertension, congenital heart disease or lung fibrosis, and herewith do not know whether we could have found similar abnormalities in these conditions. Our study had several limitations. Firstly, as our groups of COPD patients consisted of only men, the results of our study are limited to male patients with COPD. Secondly, the high incidence of NMT abnormalities in Group 2 might have been attributable to chronic hypoxemia, but it is difficult to establish a causal mechanism between COPD and NMT abnormalities. In addition, we did not include patients who had hypoxemia for other reasons and have no data regarding similar abnormalities in these patients. Despite the small number of the patients included in the present study, the results show that NMT abnormalities are present in patients with COPD globally, but significant only in patients with hypoxemia. Further comprehensive studies are needed to clarify whether patients with NMT abnormalities have different clinical characteristics or prognoses and whether these abnormalities contribute to a poor disease course in COPD patients. Furthermore, our findings need to be compared with the findings of the patients having chronic hypoxemia caused by diseases other than COPD. 5. Conclusions It is well known that muscular dysfunction has a negative effect on the quality of life, disease progression and survival. Unfortunately, there is no effective drug treatment for this condition. The discovery of new pathophysiological mechanisms such as the NMT abnormalities found in this study may lead to the earlier use of O2 (LTOT) or non-invasive ventilation if the benefits are supported by subsequent trials. Conflict of interest None declared. References Ad Hoc Committee of the AAEM Special Interest Group on Single Fiber EMG, 1992. Single fiber EMG reference values: a collaborative effort. Muscle and Nerve 15, 151–161. Agrawal, D., Vohra, R., Gupta, P.P., Sood, S., 2007. Subclinical peripheral neuropathy in stable middle-aged patients with chronic obstructive pulmonary disease. Singapore Medical Journal 48 (10), 887–894. Agusti, A.G., 2005. Systemic effects of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society 2, 367–370. Arnson, Y., Shoenfeld, Y., Amital, H., 2010. Effects of tobacco smoke on immunity, inflammation and autoimmunity. Journal of Autoimmunity 34, 258–265. Appenzeller, O., Parks, R.D., MacGee, J., 1968. Peripheral neuropathy in chronic disease of the respiratory tract. American Journal of Medicine 44 (6), 873–880. Atis, S., Ozge, A., Sevim, S., 2001. The brainstem auditory evoked potential abnormalities in severe chronic obstructive pulmonary disease. Respirology 6 (September (3)), 225–229.
Couillard, A., Muir, J.F., Veale, D., 2010. COPD recent findings: impact on clinical practice. COPD 7 (3), 204–213. Decramer, M., Rennard, S., Troosters, T., Mapel, D.W., Giardino, N., Mannino, D., Wouters, E., Sethi, S., Cooper, C.B., 2008. COPD as a lung disease with systemic consequences – clinical impact, mechanisms, and potential for early intervention. COPD 5 (4), 235–256. Farrugia, M.E., Weir, A., Cleary, M., Cooper, S., Metcalfand, R., Mallik, A., 2009. Concentric and single fiber EMG needle electrodes yield comparable jitter results in myasthenia gravis. Muscle and Nerve 39, 579–585. Ferrea, S., Winterer, G., 2009. Neuroprotective and neurotoxic effects of nicotine. Pharmacopsychiatry 42, 255–265. Fitzpatrick, S.F., Tambuwala, M.M., Bruning, U., Schaible, B., Scholz, C.C., Byrne, A., O’Connor, A., Gallagher, W.M., Lenihan, C.R., Garvey, J.F., Howell, K., Fallon, P.G., Cummins, E.P., Taylor, C.T., 2011. An intact canonical NF-(kappa)B pathway is required for inflammatory gene expression in response to hypoxia. Journal of Immunology 186, 1091–1096. Garvey, J.F., Taylor, C.T., McNicholas, W.T., 2009. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. European Respiratory Journal 33, 1195–1205. Global Initiative for Chronic Obstructive Lung Disease, 2011. Global Strategy for Diagnosis, Management, and Prevention of COPD Revised 2011, www.goldcopd.com (Date last revised: 2011. Date last accessed: September 12, 2012). Gulbas, G., Gunen, H., In, E., Kilic, T., 2012. Long-term follow-up of chronic obstructive pulmonary disease patients on long-term oxygen treatment. International Journal of Clinical Practice 66 (2), 152–157. Gupta, P.P., Sood, S., Atreja, A., Agarwal, D., 2008. Evaluation of brain stem auditory evoked potentials in stable patients with chronic obstructive pulmonary disease. Annals of Thoracic Medicine 3 (4), 128–134. Gupta, P.P., Sood, S., Atreja, A., Agarwal, D., 2010. Assessment of visual evoked potentials in stable COPD patients with no visual impairment. Annals of Thoracic Medicine 5 (4), 222–227. Kayacan, O., Beder, S., Deda, G., Karnak, D., 2001. Neurophysiological changes in COPD patients with chronic respiratory insufficiency. Acta Neurologica Belgica 101 (3), 160–165. Kent, B.D., Mitchell, P.D., McNicholas, W.T., 2011. Hypoxemia in patients with COPD: cause effects, and disease progression. International Journal of COPD 6, 199–208. Koechlin, C., Maltais, F., Saey, D., Michaud, A., LeBlanc, P., Hayot, M., Préfaut, C., 2005. Hypoxaemia enhances peripheral muscle oxidative stress in chronic obstructive pulmonary disease. Thorax 60, 834–841. Man, W.D., Kemp, P., Moxham, J., Polkey, M.I., 2009. Skeletal muscle dysfunction in COPD: clinical and laboratory observations. Clinical Science (London) 117 (7), 251–264. Oncel, C., Baser, S., Cam, M., Akdag, B., Taspinar, B., Evyapan, F., 2010. Peripheral neuropathy in chronic obstructive pulmonary disease. COPD 7 (1), 11–16. Ozge, A., Atis, S., Sevim, S., 2001. Subclinical peripheral neuropathy associated with chronic obstructive pulmonary disease. Electromyography and Clinical Neurophysiology 41, 185–191. Ozge, C., Ozge, A., Yilmaz, A., Yalcinkaya, D.E., Calikoglu, M., 2005. Cranial optic nerve involvements in patients with severe COPD. Respirology 10 (5), 666–672. Rabe, K.F., Hurd, S., Anzueto, A., Barnes, P.J., Buist, S.A., Calverley, P., Fukuchi, Y., Jenkins, C., Rodriguez-Roisin, R., van Weel, C., Zielinski, J., 2007. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. American Journal of Respiratory and Critical Care Medicine 176, 532–555. Reid, W.D., Rurak, J., Harris, R.L., 2009. Skeletal muscle response to inflammationlessons for chronic obstructive pulmonary disease. Critical Care Medicine 37 (10 Suppl.), S372–S383. Sanders, D.B., Stalberg, E.V., 1996. AAEM minimonograph: single fiber EMG. Muscle and Nerve 19, 1069–1083. Senior, R.M., Shapiro, S.D., 1998. Chronic obstructive pulmonary disease: epidemiology, pathopyhsiology and pathogenesis. In: Fishman, A.P. (Ed.), Fishman’s Pulmonary Disease and Disorders. McGraw Hill Book Company, New York, pp. 659–682. Struss, D.T., Peterkin, I., Guzman, D.A., Guzman, C., Troyer, A.K., 1997. Chronic obstructive pulmonary disease: effects of hypoxia on neurological and neuropsychological measures. Journal of Clinical and Experimental Neuropsychology 19, 515–524. Wagner, P.D., 2006. Skeletal muscles in chronic obstructive pulmonary disease: deconditioning or myopathy? Respirology 11 (6), 681–686.
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Neuromuscular transmission in hypoxemic patients with chronic obstructive pulmonary disease Gazi Gulbas a,∗ , Yuksel Kaplan b , Ozden Kamisli b , Hilal Ermis a , Suat Kamisli b , Cemal Ozcan b a b
Inonu University, Department of Pulmonary Diseases, Turkey Inonu University, Department of Neurology, Turkey
a r t i c l e
i n f o
Article history: Accepted 16 July 2013 Keywords: COPD Single-fiber EMG Neuromuscular transmission Hypoxemia
a b s t r a c t Many studies have focused on the systemic effects of chronic obstructive pulmonary disease (COPD), but none has examined neuromuscular junction transmission (NMT). We evaluated NMT dysfunction using single-fiber electromyography (SFEMG) in patients with COPD. Twenty patients with COPD and 20 age-matched healthy controls were included in the study. All patients and controls underwent SFEMG. Abnormal NMT was found in seven of 20 patients (35%), but in none of the control subjects. The COPD patients were subgrouped according to the presence of hypoxemia. The patients with normoxemia were classified as Group 1, and the patients with hypoxemia were classified as Group 2. Abnormal NMT was found in six patients in Group 2 and in one in Group 1. While there was significant difference in terms of abnormal NMT between Group 2 and the controls, there was none between Group 1 and the controls. Our results show that NMT abnormalities can be present in hypoxemic patients with COPD. © 2013 Elsevier B.V. All rights reserved.
1. Introduction Chronic obstructive pulmonary disease (COPD) is characterized by progressive, irreversible airway obstruction and recurrent exacerbations (Senior and Shapiro, 1998). In addition to pulmonary abnormalities, COPD has multisystem involvement with significant extrapulmonary manifestations, so-called systemic effects, and comorbidity factors that complicate the progression of COPD (Couillard et al., 2010). There is growing awareness about the cardiovascular, neurological, psychiatric, and endocrinological comorbidities associated with COPD. Although many studies have examined COPD and its systemic involvement over the last decade, much remains unknown. As pulmonary function deteriorates and the disease progresses, the risk of alveolar hypoxia and consequent hypoxemia increases in COPD patients (Rabe et al., 2007). It now seems clear that tissue hypoxia has a key role in many of the maladaptive processes and extrapulmonary comorbidities in COPD (Kent et al., 2011).
∗ Corresponding author at: Department of Pulmonary Diseases, Inonu University, 44069 Malatya, Turkey. Tel.: +90 5422204449; fax: +90 4223411000. E-mail addresses: [email protected] (G. Gulbas), [email protected] (Y. Kaplan), [email protected] (O. Kamisli), [email protected] (H. Ermis), [email protected] (S. Kamisli), [email protected] (C. Ozcan). 1569-9048/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.resp.2013.07.017
Various electrophysiological studies of patients with COPD have demonstrated that it affects both the central and peripheral nervous systems, either sequentially or simultaneously. COPD and chronic hypoxia were shown to cause polyneuropathy (PNP) by Appenzeller et al. (1968). Following this first report on neurological manifestations of COPD, numerous studies have confirmed that PNP is common among patients with COPD, with an incidence of 28–95%, and that neuropathy increases with hypoxia (Kayacan et al., 2001; Agrawal et al., 2007; Oncel et al., 2010). Moreover, Ozge et al. (2001) demonstrated that the rate of axonal neuropathy was significantly higher in the hypoxemic group than in the normoxemic group and the severity of neuropathy was correlated with the degree of hypoxemia in patients with COPD. To our knowledge, neuromuscular junction transmission (NMT) has not been studied in patients with COPD. Single-fiber electromyography (SFEMG), established by Stalberg and Eskedt in the 1960s (Sanders and Stalberg, 1996) is a valuable electrophysiological technique for assessing NMT. It has been used for the diagnosis of neuromuscular disorders and is the most sensitive test of impaired NMT (Farrugia et al., 2009). With impaired NMT, nerve impulses fail to generate an action potential, and an abnormal blocking jitter is seen (Ad Hoc Committee of the AAEM Special Interest Group on Single Fiber EMG, 1992). The first aim of this study was to determine NMT dysfunction using SFEMG in patients with COPD. The second aim of the study was to evaluate the relationship of chronic hypoxemia with NMT dysfunction in COPD patients.
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2. Materials and methods
2.3. Respiratory function tests and arterial blood gas analysis
2.1. Study design
Respiratory function tests and arterial blood gas analysis were performed in all patients. Spirometry was carried out on a computerized device (V max22; SensorMedics, Yorba Linda, CA, USA), with the patients sitting upright. Spirometric indices were calculated using the best of three consecutive tests according to the recommendations of American Thoracic Society. FEV1 , FVC, FEV1 /FVC, peak expiratory flow rate and forced expiratory flow (25–75%) were recorded. pH, PaO2 , arterial carbon dioxide tension (PaCO2 ) and SaO2 were analyzed in arterial blood samples collected from the radial artery. A pulmonary medicine physician completed a form including demographic data, such as age, sex, body mass index (BMI), duration of COPD symptoms (years), smoking load (packyears), and respiratory function test results and arterial blood gas analysis results.
This cross-sectional clinical study was carried out in the Departments of Pulmonary Diseases and Neurology of our hospital between March 2011 and March 2012. The study protocol was approved by the ethics committee. Patients provided signed informed consent, and all patients were given a detailed explanation of the study. This study was performed in accordance with the Declaration of Helsinki.
2.2. Study population The study population was selected of the patients with symptoms and histories compatible with COPD (onset of the disease over 40 years-old, presence of smoking history for at least 10 pack-year or occupational exposure to irritant or toxic gases or biomass exposure and postbronchodilator ratio of forced expiratory volume in one second (FEV1 ) to forced vital capacity (FVC) (FEV1 /FVC) < 0.7. The patients were diagnosed as COPD according to the Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) criteria (Global Initiative for Chronic Obstructive Lung Disease, 2011) at the Department of Pulmonary Diseases before being enrolled. All patients were consecutive and were admitted to the outpatient clinic of the Department of Pulmonary Diseases. Patients were included only if they had regular follow-up over the preceding 1 year. All patients were studied when they were clinically stable. While one-half of the patients with COPD were selected from normoxemic patients, the other half of the patients with COPD who were enrolled in the study had been on long-term oxygen treatment (LTOT) for at least one year due to chronic hypoxemia. LTOT was prescribed based on the international criteria; i.e., arterial oxygen tension (PaO2 ) ≤ 55 mmHg or arterial oxygen saturation (SaO2 ) ≤ 88%, or PaO2 56–59 mmHg or SaO2 = 89% while at rest and breathing room air, along with hematocrit > 55%, congestive heart failure or pulmonary hypertension (Gulbas et al., 2012). Control subjects were selected randomly from healthy volunteers and matched to cases by age (±1 year). All healthy volunteers were nonsmokers and had no symptoms suggestive of any systemic or neurological diseases. All patients were evaluated by a neurologist, and all underwent a detailed neurological examination. We excluded patients with a history of neurological disease, patients with any neurological complaints or findings suggestive of any neuromuscular disorder or other nervous system involvement and those with diabetes mellitus, chronic renal failure, thyroid disease, malnutrition, chronic alcoholism, pulmonary and extra pulmonary malignancies or history of intake of any drugs or agents that could have a potential effect on the NMT or were known neurotoxins. We also excluded any patient with subclinical nervous system involvement detected by electrophysiological studies. To restrict the subjects to COPD patients, other causes of hypoxemia including restrictive lung disease, pulmonary arterial hypertension, congenital heart disease and or interstitial lung disease were excluded based on the laboratory and clinical findings. Posteroanterior and left lateral chest X-rays, electrocardiogram, hemogram, urine analysis and protein electrophoresis were performed. The erythrocyte sedimentation rate and levels of serum electrolytes, fasting serum glucose, urea, creatinine, transaminases, vitamin B12 , and folic acid were determined to detect conditions that could predispose an individual to neurological or systemic diseases.
2.4. Procedure used for SFEMG Nerve conduction studies, concentric needle electromyography (EMG) and SFEMG of the extensor digitorum communis muscle were performed. Nerve conduction studies assessed the motor nerve conductions of the median, ulnar, peroneal and tibial nerves, as well as sensory nerve conductions of the median, ulnar, and sural nerves. Single-fiber EMG studies were performed during voluntary contraction of the extensor digitorum communis muscle using an EMG machine (Dantec, Skovlunde, Denmark) with a filter setting of 500 Hz–10 kHz. Electrophysiological studies were conducted in a warm room, such that the skin temperature of the extremities was maintained at ≥32 ◦ C. Recordings from a single fiber electrode were used. We accepted only potentials with a stable shape, a rise time of <0.3 ms and amplitude of >200 V for jitter analysis, and 50–100 consecutive traces were obtained for each jitter analysis. Ten to 20 different potential pairs were recorded from each subject, and the jitter values of these potential pairs were calculated. The mean consecutive difference (MCD) was used as the jitter value. If the MCD/mean sorted-data difference (MSD) ratio was >1.25 as the jitter value, MSD was calculated. The mean of the obtained jitter values and the number of individual abnormal jitter values exceeding the upper limit of normal were also calculated for each subject. The range of normal values, which was derived from a multicenter study, was used for individual and mean jitter results. We considered “abnormal NMT” to have occurred when a subject had more than two individual abnormal jitter values or had an abnormal mean jitter value. We compared the parameters between the patients with COPD and controls. We also subdivided the COPD patients based on presence of chronic hypoxemia and compared NMT abnormalities, demographic data, and respiratory and laboratory findings between these subgroups.
2.5. Statistical analysis The Statistical Package for the Social Sciences version 15 (SPSS, Chicago, IL, USA) was used for all statistical analyses. Data are presented as mean ± standard deviation. We used Student’s t-test and the Mann–Whitney U test to compare continuous parametric variables between the groups. Fisher’s exact chi-squared test was used to compare categorical variables. Values of p < 0.05 were considered to indicate significance.
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Table 1 Comparison of demographic and clinical characteristics between the patient groups. Parameter
All patients (n = 20)
Group 1 (n = 10)
Group 2 (n = 10)
p-Value
Gender (male/female) Age (years) Smoking load (pack-years) Duration of COPD (years) BMI (kg/m2 ) PAP (mmHg) FEV1 (%) FVC (%) pH PaO2 (mmHg) PaCO2 (mmHg) SO2 (%)
20/0 65.85 ± 6.76 54.3 ± 21.21 5 ± 2.95 25.64 ± 5.39 33.86 ± 18.45 53.05 ± 19.31 83.65 ± 23.03 7.42 ± 0.02 58.10 ± 15.68 44.43 ± 10.76 87.00 ± 11.24
10/0 65.90 ± 7.62 54.4 ± 17.5 4 ± 2.49 24.74 ± 5.84 22.00 ± 8.24 61.40 ± 20.86 92.50 ± 22.32 7.44 ± 0.05 71.53 ± 7.70 37.29 ± 5.74 95.03 ± 1.96
10/0 65.80 ± 6.19 54.2 ± 25.3 6 ± 3.16 26.54 ± 5.04 41.77 ± 19.43 44.70 ± 14.03 74.80 ± 20.05 7.41 ± 0.06 44.67 ± 7.69 51.58 ± 9.90 78.97 ± 10.93
ns ns ns ns ns ≤0.05 ≤0.05 ns ns ≤0.05 ≤0.05
ns, not significant; COPD, chronic obstructive pulmonary disease; BMI, body mass index; PAP, pulmonary artery pressure; FEV1 , forced expiratory volume in 1 s; FVC, forced vital capacity; PCO2 , arterial carbon dioxide tension; PO2 , arterial oxygen tension; SO2 , arterial oxygen saturation.
Fig. 1. The disturbance of the spirometric stage according to the GOLD criteria for each groups.
jitter values of the patients were abnormally high, only 2 of 237 (0.8%) were abnormal for the controls. There were significantly more abnormal individual jitter values within the patients than in the control group (p < 0.05). Abnormal NMT was found in 7 of 20 patients (35%), but in none of the control subjects. Six patients in Group 2 and one in Group 1 had abnormal NMT. As we made a comparison between the patient groups regarding abnormal NMT, a significant difference between Group 2 and 1 was found (p = 0.02). While there was also a significant difference between Group 2 and the control group, there was no significant difference between Group 1 and the control group (p = 0.0004, p = 0.33, respectively). The SFEMG findings are summarized in Table 2. When we also compared between Group 2 and 1 regarding the nerve conduction velocities of upper and lower limbs, there was no significant difference (p > 0.05). These findings are summarized in Table 3. 4. Discussion
3. Results During the study 172 patients with COPD presented to the Pulmonary Diseases Department. Of these, 152 did not meet the inclusion criteria and were excluded; thus, 20 patients were evaluated. The patients were divided into two subgroups according to the presence of hypoxemia. Patients with normoxemia were classified as Group 1 and patients with hypoxemia were classified as Group 2. Each group consisted of 10 patients, and 20 subjects formed the control group. All patients and controls were male. According to COPD severity based on the GOLD criteria; one (10%), five (50%), and four (40%) patients in Group 1 were evaluated as stages I to III, respectively. Three (30%) and seven (70%) patients in Group 2 were evaluated as stages II and III, respectively. Fig. 1 presents the distribution of the spirometric stage according to the GOLD criteria for each group. 3.1. Demographic and clinical characteristics The mean ages of the patient subgroups and controls were 65.9 ± 7.62, 65.8 ± 6.19 and 65.9 ± 8.86 years, respectively. No significant difference in age, smoking load (pack-years), COPD duration (years) or BMI was observed between the two COPD groups. FEV1 , PaO2 , PaCO2 , SO2 , and pulmonary artery pressure differed significantly between the two COPD groups (p ≤ 0.05). The basic demographic data and clinical characteristics of the patient groups are described in Table 1. 3.2. SFEMG findings In total, 249 individual jitter values were recorded from the patients and 237 from the control subjects. While 18 of 249 (7.2%)
We evaluated NMT using SFEMG in patients with COPD and in subjects with no clinical feature suggestive of a neuromuscular junction disorder or another neurological/systemic disease. Our study demonstrated that NMT abnormalities were present in patients with COPD globally. To evaluate the effect of hypoxemia on NMT among the patients with COPD, we selected one-half of the patients from those having hypoxemia. At the same time, when the patients were divided into subgroups according to the presence of chronic hypoxemia, we only found significant abnormal NMT in COPD patients with chronic hypoxemia. Although COPD is evidently of respiratory origin, many extrapulmonary manifestations exist, and a number of common comorbidities complicate the natural history of COPD, thereby alter the disease prognosis and quality of life. These comorbidities include muscular dysfunctions, nutritional and metabolic abnormalities, hormonal deficits, anemia, an increased prevalence of osteoporosis, lung cancer, cardiovascular diseases, diabetes, anxiety, and depression (Decramer et al., 2008; Couillard et al., 2010). The associated neurological manifestations such as peripheral neuropathy and peripheral muscle dysfunction have been well described in the literature. Additionally; motor neuron involvement, encephalopathy, cognitive dysfunction, optic nerve involvement, and impairment of the eighth cranial nerve and brainstem functions have been observed in patients with COPD (Atis et al., 2001; Kayacan et al., 2001; Ozge et al., 2005; Gupta et al., 2008, 2010). Among these manifestations, peripheral muscle dysfunction is clearly demonstrated by significant losses in both strength and locomotory endurance in COPD patients compared with healthy subjects (Couillard et al., 2010). Moreover; effort intolerance, exertional desaturation, loss of autonomy, reduced level of regular physical activity, quadriceps strength loss, breathlessness,
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Table 2 Single-fiber electromyography (SFEMG) findings in the patient groups and the controls. Subjects
Individual jitter values (n)
Abnormally high jitter values n (%)
Abnormal neuromuscular transmission (n)
p-Value
All patients (n = 20) Group 1 (n = 10) Group 2 (n = 10) Controls (n = 20)
249 114 135 237
18/249 (7.2%) 2/114 (1.7%) 16/135 (11.8%) 2/237 (0.8%)
7 1 6 0
0.0004# 0.02* 0.33**
# * **
p: between Group 2 and Controls. p: between Group1 and 2. p: between Group 1 and Controls.
and quality of life status are now recognized as independent predictors of survival in these patients (Decramer et al., 2008; Couillard et al., 2010). Although the exact pathophysiological mechanisms remain unclear, muscle dysfunction may result from a multitude of factors including deconditioning, systemic inflammation, oxidative stress, nutritional imbalance, reduced anabolic status, systemic corticosteroids, hypoxemia, hypercapnia, electrolyte disturbances or cardiac failure (Wagner, 2006; Decramer et al., 2008; Reid et al., 2009; Man et al., 2009; Couillard et al., 2010). The basic causes of hypoxemia in COPD patients are poor distribution of ventilation to perfusion resulting from progressive airflow limitation and emphysematous destruction of pulmonary vascular bed (Struss et al., 1997; Kent et al., 2011). The previous study demonstrated a relationship between the severity of neuropathy and the degree of hypoxemia in patients with COPD (Ozge et al., 2001). Although several factors likely play a role in the genesis of systemic inflammation, chronic hypoxemia seems to be an independent factor (Agusti, 2005; Kent et al., 2011). The transcription factor nuclear B (NFB) is the master regulator of cellular inflammatory responses controlling the expression of key inflammatory cytokines (Garvey et al., 2009). In chronic hypoxemia, NFB also appears to interact with hypoxia-inducible factor (HIF)1␣ to promote the expression of inflammatory genes, such as cyclo-oxygenase II (Fitzpatrick et al., 2011). Evidence of a role for hypoxia in the induction of an NFB response comes from several experimental and clinical studies (Kent et al., 2011). Oxidative stress appears to be particularly prominent in chronically hypoxemic patients, in whom markers of oxidative stress are significantly increased in peripheral muscle specimens (Koechlin et al., 2005). Among several factors, systemic inflammation and oxidative stress caused by chronic hypoxemia may be the most important pathophysiological mechanisms leading the development of comorbidities in COPD. As well as indirect effects of hypoxemia such as systemic inflammation and oxidative stress, hypoxemia results in peripheral nerve damage directly in COPD, with the injury
to the vasa nervorum. We also aimed to investigate the potential effect of COPD and hypoxemia related with COPD on NMT in our study. Although numerous studies have examined peripheral muscle dysfunction, neuropathy and associated conditions in COPD patients, we could not find any studies that had evaluated neuromuscular junction function in patients with COPD or other disorders causing hypoxemia which could allow a comparison with our results. SFEMG is a valuable technique and is the most sensitive way to assess neuromuscular junction function and associated disorders. In the present study, 35% of the COPD patients exhibited NMT abnormalities, but there were no NMT abnormalities in the control group. To evaluate the effect of chronic hypoxemia, we selected one-half of the patients from those who have used LTOT at least for 1 year and had chronic hypoxemia. When we compared the normoxemic patients with the control group, no significant difference was found (p = 0.33). Whereas, the comparison of the hypoxemic patients with both the normoxemic patients and the control subjects revealed significant differences both between the hypoxemic patients and the normoxemic patients and also between the hypoxemic patients and the control subjects (p = 0.02, p = 0.003, respectively). These findings support the hypothesis that NMT abnormality may be a consequence of the direct and the indirect effects of hypoxemia in patients with COPD. Also, these findings should not be specific to COPD, but should also exist in other hypoxemic diseases, such as pulmonary arterial hypertension, congenital heart disease, or lung fibrosis. Tobacco smoke contains extremely high concentrations of free radicals. In addition, it can increase the generation and activation of endogenous free radicals (Arnson et al., 2010). Despite contrary opinions, several studies have shown that nicotine has neurotoxic effects. Several studies described the possibility that nicotine could act as a toxin inducing oxidative stress by depleting glutathione (Ferrea and Winterer, 2009). To prevent the confusing role of the tobacco smoke regarding the potential acute neurotoxic effects on NMT, we did not include current smokers in our study.
Table 3 Nerve conduction velocity parameters of lower and upper limb in the Group 1 and 2. Parameters
Group 1 (n = 10)
Median sensory DL Median sensory CV Ulnar sensory DL Ulnar sensory CV Median motor DL Median motor CV Ulnar motor DL Ulnar motor CV Peroneal DL Peroneal motor CV Posterior tibial DL Posterior tibial motor CV Sural sensory DL Sural sensory CV Sural A
2.33 39.37 1.95 43.90 3.34 59.57 2.28 58.81 3.55 50.76 3.57 49.78 2.96 39.63 13.29
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.649 11.58 0.26 3.59 0.91 4.08 0.28 6.11 1.0 10.61 0.55 6.00 0.45 3.28 5.54
CV: conduction velocity, DL: distal latency, A: amplitude, ms: millisecond.
Group 2 (n = 10) 2.25 43.48 1.84 45.47 3.08 58.65 2.29 60.50 33.69 50.62 3.60 47.75 2.86 39.69 13.57
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
0.38 7.32 0.24 4.15 0.43 7.88 0.18 4.75 0.56 5.27 0.56 11.72 0.41 4.57 6.35
t
p
0.47 −1.44 1.56 −1.44 1.23 0.55 −0.11 −1.06 −0.58 0.06 −0.17 0.81 0.79 −0.05 −0.16
0.64 0.158 0.13 0.157 0.23 0.588 0.92 0.294 0.57 0.957 0.87 0.422 0.43 0.962 0.872
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As this is the first study evaluating the neuromuscular junction transmission in COPD patients, it is difficult to determine whether the NMT abnormality was the result of hypoxemia, or the consequence of the other factors. Moreover, we did not investigate the presence of NMT abnormalities in patients who were hypoxic because of other reasons, such as pulmonary arterial hypertension, congenital heart disease or lung fibrosis, and herewith do not know whether we could have found similar abnormalities in these conditions. Our study had several limitations. Firstly, as our groups of COPD patients consisted of only men, the results of our study are limited to male patients with COPD. Secondly, the high incidence of NMT abnormalities in Group 2 might have been attributable to chronic hypoxemia, but it is difficult to establish a causal mechanism between COPD and NMT abnormalities. In addition, we did not include patients who had hypoxemia for other reasons and have no data regarding similar abnormalities in these patients. Despite the small number of the patients included in the present study, the results show that NMT abnormalities are present in patients with COPD globally, but significant only in patients with hypoxemia. Further comprehensive studies are needed to clarify whether patients with NMT abnormalities have different clinical characteristics or prognoses and whether these abnormalities contribute to a poor disease course in COPD patients. Furthermore, our findings need to be compared with the findings of the patients having chronic hypoxemia caused by diseases other than COPD. 5. Conclusions It is well known that muscular dysfunction has a negative effect on the quality of life, disease progression and survival. Unfortunately, there is no effective drug treatment for this condition. The discovery of new pathophysiological mechanisms such as the NMT abnormalities found in this study may lead to the earlier use of O2 (LTOT) or non-invasive ventilation if the benefits are supported by subsequent trials. Conflict of interest None declared. References Ad Hoc Committee of the AAEM Special Interest Group on Single Fiber EMG, 1992. Single fiber EMG reference values: a collaborative effort. Muscle and Nerve 15, 151–161. Agrawal, D., Vohra, R., Gupta, P.P., Sood, S., 2007. Subclinical peripheral neuropathy in stable middle-aged patients with chronic obstructive pulmonary disease. Singapore Medical Journal 48 (10), 887–894. Agusti, A.G., 2005. Systemic effects of chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society 2, 367–370. Arnson, Y., Shoenfeld, Y., Amital, H., 2010. Effects of tobacco smoke on immunity, inflammation and autoimmunity. Journal of Autoimmunity 34, 258–265. Appenzeller, O., Parks, R.D., MacGee, J., 1968. Peripheral neuropathy in chronic disease of the respiratory tract. American Journal of Medicine 44 (6), 873–880. Atis, S., Ozge, A., Sevim, S., 2001. The brainstem auditory evoked potential abnormalities in severe chronic obstructive pulmonary disease. Respirology 6 (September (3)), 225–229.
Couillard, A., Muir, J.F., Veale, D., 2010. COPD recent findings: impact on clinical practice. COPD 7 (3), 204–213. Decramer, M., Rennard, S., Troosters, T., Mapel, D.W., Giardino, N., Mannino, D., Wouters, E., Sethi, S., Cooper, C.B., 2008. COPD as a lung disease with systemic consequences – clinical impact, mechanisms, and potential for early intervention. COPD 5 (4), 235–256. Farrugia, M.E., Weir, A., Cleary, M., Cooper, S., Metcalfand, R., Mallik, A., 2009. Concentric and single fiber EMG needle electrodes yield comparable jitter results in myasthenia gravis. Muscle and Nerve 39, 579–585. Ferrea, S., Winterer, G., 2009. Neuroprotective and neurotoxic effects of nicotine. Pharmacopsychiatry 42, 255–265. Fitzpatrick, S.F., Tambuwala, M.M., Bruning, U., Schaible, B., Scholz, C.C., Byrne, A., O’Connor, A., Gallagher, W.M., Lenihan, C.R., Garvey, J.F., Howell, K., Fallon, P.G., Cummins, E.P., Taylor, C.T., 2011. An intact canonical NF-(kappa)B pathway is required for inflammatory gene expression in response to hypoxia. Journal of Immunology 186, 1091–1096. Garvey, J.F., Taylor, C.T., McNicholas, W.T., 2009. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. European Respiratory Journal 33, 1195–1205. Global Initiative for Chronic Obstructive Lung Disease, 2011. Global Strategy for Diagnosis, Management, and Prevention of COPD Revised 2011, www.goldcopd.com (Date last revised: 2011. Date last accessed: September 12, 2012). Gulbas, G., Gunen, H., In, E., Kilic, T., 2012. Long-term follow-up of chronic obstructive pulmonary disease patients on long-term oxygen treatment. International Journal of Clinical Practice 66 (2), 152–157. Gupta, P.P., Sood, S., Atreja, A., Agarwal, D., 2008. Evaluation of brain stem auditory evoked potentials in stable patients with chronic obstructive pulmonary disease. Annals of Thoracic Medicine 3 (4), 128–134. Gupta, P.P., Sood, S., Atreja, A., Agarwal, D., 2010. Assessment of visual evoked potentials in stable COPD patients with no visual impairment. Annals of Thoracic Medicine 5 (4), 222–227. Kayacan, O., Beder, S., Deda, G., Karnak, D., 2001. Neurophysiological changes in COPD patients with chronic respiratory insufficiency. Acta Neurologica Belgica 101 (3), 160–165. Kent, B.D., Mitchell, P.D., McNicholas, W.T., 2011. Hypoxemia in patients with COPD: cause effects, and disease progression. International Journal of COPD 6, 199–208. Koechlin, C., Maltais, F., Saey, D., Michaud, A., LeBlanc, P., Hayot, M., Préfaut, C., 2005. Hypoxaemia enhances peripheral muscle oxidative stress in chronic obstructive pulmonary disease. Thorax 60, 834–841. Man, W.D., Kemp, P., Moxham, J., Polkey, M.I., 2009. Skeletal muscle dysfunction in COPD: clinical and laboratory observations. Clinical Science (London) 117 (7), 251–264. Oncel, C., Baser, S., Cam, M., Akdag, B., Taspinar, B., Evyapan, F., 2010. Peripheral neuropathy in chronic obstructive pulmonary disease. COPD 7 (1), 11–16. Ozge, A., Atis, S., Sevim, S., 2001. Subclinical peripheral neuropathy associated with chronic obstructive pulmonary disease. Electromyography and Clinical Neurophysiology 41, 185–191. Ozge, C., Ozge, A., Yilmaz, A., Yalcinkaya, D.E., Calikoglu, M., 2005. Cranial optic nerve involvements in patients with severe COPD. Respirology 10 (5), 666–672. Rabe, K.F., Hurd, S., Anzueto, A., Barnes, P.J., Buist, S.A., Calverley, P., Fukuchi, Y., Jenkins, C., Rodriguez-Roisin, R., van Weel, C., Zielinski, J., 2007. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. American Journal of Respiratory and Critical Care Medicine 176, 532–555. Reid, W.D., Rurak, J., Harris, R.L., 2009. Skeletal muscle response to inflammationlessons for chronic obstructive pulmonary disease. Critical Care Medicine 37 (10 Suppl.), S372–S383. Sanders, D.B., Stalberg, E.V., 1996. AAEM minimonograph: single fiber EMG. Muscle and Nerve 19, 1069–1083. Senior, R.M., Shapiro, S.D., 1998. Chronic obstructive pulmonary disease: epidemiology, pathopyhsiology and pathogenesis. In: Fishman, A.P. (Ed.), Fishman’s Pulmonary Disease and Disorders. McGraw Hill Book Company, New York, pp. 659–682. Struss, D.T., Peterkin, I., Guzman, D.A., Guzman, C., Troyer, A.K., 1997. Chronic obstructive pulmonary disease: effects of hypoxia on neurological and neuropsychological measures. Journal of Clinical and Experimental Neuropsychology 19, 515–524. Wagner, P.D., 2006. Skeletal muscles in chronic obstructive pulmonary disease: deconditioning or myopathy? Respirology 11 (6), 681–686.