Pulmonary predictors of survival in amyotrophic lateral sclerosis: Use in clinical trial design

Abstract

The rapidity of progression of amyotrophic lateral sclerosis (ALS) to death or respiratory failure impacts patients, clinicians, and clinical investigators. This study compared the abilities of various pulmonary function tests to predict tracheostomy-free survival. We evaluated 95 ALS patients by determining upright and supine forced vital capacity (FVC), maximal inspiratory (MIP) and expiratory (MEP) pressures, arterial partial pressure of carbon dioxide (PaCO 2 ), and transdiaphragmatic sniff pressures (Pdi-sniff). Tracheostomy-free survival time was measured from the date of spirometry. Supine FVC, upright FVC, MIP, MEP, and Pdi-sniff were significantly associated with tracheostomy-free survival after controlling for nonpulmonary factors, whereas PaCO 2 was not. A normal supine FVC, MIP, or MEP was highly predictive for one-year survival. These tests are well suited to predict survival for trial enrollment and patient counseling. Supine FVC's simplicity of use and availability to ALS investigators makes it a particularly attractive predictor of one-year survival in ALS. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that ultimately leads to respiratory failure and death. A large degree of interpatient variability exists in the rate of progression, with some patients dying or requiring respiratory support within months and others having relatively prolonged survival. 10,17 The consequent uncertainty in survival is not only difficult for patients and their families, but also frustrates research on ALS, as it may be difficult to assemble a cohort of patients that can be expected to complete a clinical trial.Certain nonpulmonary factors, including female gender, advanced age, short time from symptom onset to diagnosis, and bulbar onset of disease are associated with shorter survival. 4,5,12,18 However, as ALS overwhelmingly brings death via respiratory compromise, pulmonary function tests should be particularly appropriate predictors of individual survival. 11,14 Upright forced vital capacity (FVC), the best studied of pulmonary tests, correlates with survival in ALS, 12,18 but may not be the best available pulmonary function test for the prediction of death or respiratory failure. Supine FVC and maximal inspiratory pressures (MIP) are more sensitive than upright FVC for the detection of respiratory muscle weakness. 8,9 Unlike upright FVC, maximal expiratory pressure (MEP) and other tests of expiratory function can predict a patient's ability to cough and clear airway secretions, 15 but these tests have not previously been shown to predict survival in ALS. The purpose of this study was to evaluate and compare the ability of the available pulmonary function tests to predict tracheostomy-free survival.We studied a cohort of ALS patients to evaluate the association between these pulmonary function tests and survival. The findings have relevance to the Abbreviations: ALS, amyotrophic lateral sclerosis; BiPAP, bilevel positive airway pressure; ⌬FVC, change (decline) from upri...

Clinical Measures of Disease Progression in Amyotrophic Lateral Sclerosis

“…FVC essentially measures the full extent of a breath capable by a patient, excluding the dead space of the lung and upper airways. Other measures of pulmonary function in ALS have also been studied, including maximal voluntary inspiratory or expiratory pressures, but it is not clear that these offer any advantage over the FVC [39].…”

Motor unit number estimates and quantitative motor unit analysis in healthy subjects and patients with amyotrophic lateral sclerosis

“…Such studies have utilized a variety of methods, including measures of maximal isometric strength, activities of daily living scales, and a number of functional measures, most commonly pulmonary function. [1][2][3]17,21,33 Although they have shown considerable success in documenting and predicting the course of disease, 15,18,25,27,30,36 their ability to represent the underlying pathophysiology of ALS is limited as these measures of impairment or disability do not directly measure the changes occurring within the motor unit (MU) pool as a result of the disease.…”

Respiratory Support in Patients With Amyotrophic Lateral Sclerosis

“…If NIV can reduce diaphragmatic muscle overload and reduce macro-motor unit drop-out, then it may have a favorable effect on the course of the disease. In several studies NIV has been proposed to decrease the rate of decline of lung function, 4,6,12 but another study showed that, while the rate of lung function decline slows over time, this slowing was independent of initiation of NIV. 5 There may still be advantages to earlier NIV initiation that are unrelated to a modification of the progress of the disease.…”