Q J Med 2001; 94: 491-495
© 2001 Association of Physicians
Venous serum chloride and bicarbonate measurements in the evaluation of respiratory function in motor neuron disease
From the Department of Medicine (Neurology), University of Wales College of Medicine, Cardiff, UK
Received 8 November 2000 and in revised form 4 June 2001
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Summary |
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Respiratory failure, with or without pneumonia, is the usual cause of death in patients with motor neuron disease (MND). Forced vital capacity (FVC) is often used to monitor respiratory function in MND and is, in part, predictive of survival time. However, such volitional tests are unreliable in many patients, especially later in the disease, and access to hospital laboratories can also be a problem for some disabled patients. We assessed the use of domiciliary venous serum chloride and bicarbonate measurements in evaluating respiratory function in MND. Newly-diagnosed MND patients (n=23) were followed-up at home every 3 months for up to 15 months. Respiratory symptoms were measured using a questionnaire, and FVC was documented. Venous serum chloride and bicarbonate were also measured. One patient had symptoms of airway obstruction disease, and was excluded from the analysis. Ten patients developed abnormally low chloride (mean 95, range 88–97, reference interval 98–107 mmol/l) and an abnormally high bicarbonate (mean 33, range 31–37, reference interval 22–30 mmol/l) during follow-up, of whom eight died within the next 5 (mean 2.2, range 0.5–5) months; two were still alive at the end of the study but had developed respiratory symptoms. Twelve patients had normal chloride and bicarbonate during follow-up: all were still alive at 15 months, all had a FVC of >50% predicted, and only one had respiratory symptoms at their last assessment. Raised bicarbonate and low chloride were associated with the presence of respiratory symptoms suggesting respiratory muscle weakness. Venous serum chloride and bicarbonate potentially can provide useful information about respiratory status and prognosis in MND patients.
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Introduction |
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Motor neuron disease (MND) is a progressive degenerative disorder of the nervous system, affecting the anterior horn cells of the spinal cord, the motor nuclei of the brain stem, and the corticospinal tracts. Respiratory failure, with or without pneumonia, is the usual cause of death in MND patients.1 The most important cause of respiratory failure and alveolar hypoventilation is the loss of negative intrathoracic pressure, developed by the inspiratory action of the diaphragm, as a consequence of cervical anterior horn cell loss.2 Respiratory failure usually develops gradually in the advanced stages of the disease, but occasionally is precipitated when pneumonia or other pulmonary compromise leads to acute decompensation.3 Respiratory failure or arrest is occasionally the presenting symptom in patients without a prior diagnosis of MND.4
Inadequacy of inspiratory muscle function leads to global alveolar hypoventilation and respiratory acidosis. In chronic respiratory acidosis, renal tubular H+ secretion is increased and, even though the plasma bicarbonate is elevated, bicarbonate reabsorption is increased, further raising the plasma bicarbonate. Chloride excretion is increased, and plasma chloride falls as plasma bicarbonate is increased.5 Thus, venous serum bicarbonate and chloride are metabolic indicators of the degree of compensation for the chronic respiratory acidosis. A retrospective study has shown that serum chloride and bicarbonate are prognostic indicators of survival in MND.6 The purpose of this longitudinal study was to assess the use of venous serum chloride and bicarbonate measurement in the evaluation of respiratory function in MND. Preliminary data were presented previously at a meeting of the British Thoracic Society.7
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Methods |
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Patients
Patients with MND (diagnosed according to the El Escorial criteria8) were successively recruited at diagnosis (from the neurology ward, University Hospital of Wales, UHW) or on follow-up of out-patients (general neurology clinics at UHW and MND clinic at Rookwood Hospital). Patients were studied at home at 3-monthly intervals for up to 15 (range 9–15) months (from July 1998 to December 1999). The duration of the disease from the onset of MND symptoms until the end of the study or death was recorded. Deaths were recorded via listing with the Office of Population and Census Surveys (OPCS) and death certificates were obtained. The results of this research study were not used in the clinical management of the patients that proceeded through usual local patterns of care independently. The study was approved by Bro Taf Local Research Ethics Committee in Cardiff, and all patients gave consent.
Techniques
Basic demographic data were recorded at patients' first visit: sex, age, date and site of onset of symptoms, and date of diagnosis. Disability was measured according to the Rookwood modification of Barthel ADL index.9 Bulbar signs were measured using a semiquantitative scale.10 A quantitative assessment of swallowing capacity was obtained by a test in which the time and number of swallows required to consume a known volume of water was measured: swallowing capacity was expressed as volume/time (ml/s).11 Patients were asked to report any of the following respiratory symptoms during each assessment: breathlessness, orthopnoea, disturbed sleep, morning headaches, and excessive daytime sleepiness. Past medical history of primary respiratory disease, use of assisted ventilation, and smoking habit were also documented. Forced vital capacity was measured using an electronic portable spirometer (MicroLab 3300); a facemask was used in patients with bulbofacial weakness.
Venous serum chloride and bicarbonate were measured. Venous blood samples (5 ml) were taken from the brachial vein, using a 5 ml syringe and a needle, and stored in a vacutainer containing SST gel and clot activator. The samples were taken to the biochemistry department at UHW within 1 h of sampling for analysis. Blood samples were repeated at each 3-month home visit. The method used to measure chloride concentrations was the potentiometric determination of ions in unknown solutions using ion selective electrodes. Serum bicarbonate was measured by means of the differential pH rate of change for bicarbonate in serum, using both measuring and reference pH electrodes. The reference intervals used were 98–107 mmol/l for chloride, and 22–30 mmol/l for bicarbonate; these represent the values obtained in a 95% of a healthy population.
Patients were classified by survival at the end of the study, and the groups were compared for certain respiratory-related and prognostic variables. Comparisons of continuous variables between groups were made using the Kruskal–Wallis test. Fisher's exact test was used to test independence of variables.
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Results |
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Twenty-three newly diagnosed MND patients (12 male, mean age 68 (range 51–81) years) were assessed (Table 1
). Fifteen (65%) patients had amyotrophic lateral sclerosis (6 definite, 3 probable, 6 possible), seven (30%) progressive muscular atrophy and one (5%) progressive bulbar palsy. The limbs were first affected in 14 (61%) patients, while the disease onset was bulbar in nine (39%) patients. Eleven (48%) patients were smokers. One patient had symptomatic primary lung disease (chronic obstructive airway disease), and has been excluded from the analysis. None of the patients were taking medication that might induce a metabolic alkalosis (e.g. diuretics or corticosteroids).
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Ten patients developed abnormally low chloride (mean 95, range 88–97, reference interval 98–107 mmol/l), and an abnormally high bicarbonate (mean 33, range 31–37, reference interval 22–30 mmol/l) during follow-up (Table 2
). Of these, eight died within the next 5 (mean 2.2, range 0.5–5) months. Two were still alive at the end of the study but developed respiratory symptoms (breathlessness, orthopnoea, sleep disturbances, daytime somnolescence, and morning headaches). Two of the eight patients who died were treated with nocturnal non-invasive assisted ventilation by nasal mask until death: one for 1 month, and the other for 4 months. Two of the patients who died had a forced vital capacity of 60–65% predicted and six had FVC <50%. The remaining 12 patients had normal chloride and bicarbonate during follow-up: all were still alive, and all had a forced vital capacity of >50% predicted at the end of follow-up; one had respiratory symptoms (breathlessness on exertion). There was no statistical difference between the 10 patients who developed raised bicarbonate and low chloride and the remaining 12 patients in terms of sex, age, smoking habit, disability, bulbar status, timed test of swallowing or forced vital capacity at the first study assessment (Table 1
). Raised bicarbonate and low chloride were statistically associated with the presence of respiratory symptoms (orthopnoea, disturbed sleep, excessive daytime sleepiness, morning headaches) suggesting respiratory muscle weakness (p=0.0002, Fisher's exact test). The respiratory symptoms of the two patients who were treated with nocturnal non-invasive assisted ventilation improved significantly, but the abnormal venous serum chloride and bicarbonate and FVC were unchanged in one of the patients 3 months later; the other patient died before the second assessment.
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Discussion |
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Respiratory failure is a major factor in the death of many MND patients, and therefore monitoring of respiratory status and management of respiratory complications are potentially very important. Serial forced vital capacity measurement is often used to monitor respiratory function in MND and is, in part, predictive of survival time.12 However, there are several limitations to using FVC for this purpose. It is reduced by many pulmonary and cardiovascular diseases and may be a rather insensitive and non-specific measurement of respiratory muscle weakness.13 Accurate respiratory measurements with the spirometer are difficult to obtain in patients with bulbofacial weakness (a frequent manifestation in MND), because they cannot hold the mouthpiece firmly between their lips. The resultant escape of air around the mouthpiece yields values for the FVC that are spuriously low. Moreover, the accuracy of FVC measurement is dependent on effort by the patient, but such volitional tests depend on activation of corticobulbar and corticospinal pathways14 which are frequently affected by the disease. MND patients with severe upper motor neuron bulbar involvement find it very difficult to volitionally control their inspiration and expiration. In addition, other tests usually used to monitor respiratory muscle strength are either highly dependent on patients effort and co-operation (e.g. maximum inspiratory mouth pressures15) and/or require highly specialised equipment and are only available in a few centres (e.g. transdiaphragmatic pressure measurement13 and electrical16 or magnetic phrenic nerve stimulation17). Lastly, many patients have difficulties in getting to hospital in the later stages of the disease, because of disability. We assessed the use of venous serum bicarbonate and chloride measurements in the evaluation of respiratory function in patients with MND. It was evident from our results that raised bicarbonate and reduced chloride were associated with respiratory symptoms and poor prognosis. Two patients with raised bicarbonate and low chloride died despite using nocturnal assisted ventilation (NIPPV) (one in a month, the other in 4 months after raised bicarbonate was detected). Raised bicarbonate and low chloride were not corrected by NIPPV in one of the patients. It is likely that, despite symptomatic improvement, assisted ventilation was insufficient to correct the metabolic defect, or compliance may have been poor.
Ventilation of the alveoli has a profound influence on acid-base balance. Normally, about 10 000–15 000 mmol/day of carbonic acid are produced metabolically and excreted by the lungs.18 Deviations of the alveolar ventilation rate from normality induce respiratory acid-base disturbances. Alveolar hypoventilation induces hypercapnia leading to respiratory acidosis. The changes in PaCO2 induce compensatory alterations of renal bicarbonate transport: hypercapnia stimulates renal reabsorption of bicarbonate and thus the plasma bicarbonate rises. In chronic respiratory acidosis, plasma bicarbonate should rise by 0.35 mmol/l per mmHg increase in PaCO2.19 However, although the increase in total serum bicarbonate via these renal adjustments will protect against untoward acidosis, the potential adverse influence of the increased bicarbonate blunts the respiratory drive, causing perpetuation of the hypercapnia once established.20
Raised venous serum bicarbonate and low chloride are metabolic indicators of chronic respiratory acidosis; however, they do not prove per se that the respiratory failure is secondary to respiratory muscle weakness: upper airway obstruction/obstructive sleep apnoea, and chronic lung disease may be contributory factors in some patients, and thus further objective tests of respiratory muscle function and polysomnography may sometimes be required for full evaluation. Moreover, other causes of raised venous serum bicarbonate and reduced chloride such as diuretic therapy (e.g. thiazides), corticosteroid treatment, hyperaldosteronism, Cushing's syndrome, excess acid loss (e.g. persistent vomiting secondary to pyloric stenosis) must be considered.
In conclusion, either venous serum chloride or bicarbonate, measured on blood samples obtained at home or in clinic, cautiously interpreted, can provide useful information about the degree of metabolic compensation for the chronic respiratory acidosis in MND patients: the measurements, if abnormal, have important prognostic implications. Therefore, use of such a test presupposes a plan of management in relation to the results obtained. Such a plan may need to involve respiratory support, other palliative care measures and other support services, in addition to being clear about patients' wishes regarding interventions.
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Acknowledgments |
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Dr S. Hadjikoutis is supported by a bequest for MND research and a Grant from Schering AG. The venous serum chloride and bicarbonate measurements were done at the Biochemistry department, University Hospital of Wales.
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Notes |
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Address correspondence to Dr S. Hadjikoutis, Department of Neurology, Morriston Hospital, Morriston, Swansea SA6 6NL. e-mail: savvashadjikoutis{at}yahoo.com
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References |
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