Respiratory Muscle Strength as a Predictive Biomarker for Survival in Amyotrophic Lateral Sclerosis

Abstract

Rationale: Biomarkers for survival in amyotrophic lateral sclerosis (ALS) would facilitate the development of novel drugs. Although respiratory muscle weakness is a known predictor of poor prognosis, a comprehensive comparison of different tests is lacking.Objectives: To compare the predictive power of invasive and noninvasive respiratory muscle strength assessments for survival or ventilator-free survival, up to 3 years.Methods: From a previously published report respiratory muscle strength measurements were available for 78 patients with ALS. Time to death and/or ventilation were ascertained. Receiver operating characteristic analysis was used to determine the cutoff point of each parameter.Measurements and Main Results: Each respiratory muscle strength assessment individually achieved statistical significance for prediction of survival or ventilator-free survival. In multivariate analysis sniff trans-diaphragmatic and esophageal pressure, twitch trans-diaphragmatic pressure (Tw Pdi), age, and maximal static expiratory mouth pressure were significant predictors of ventilationfree survival and Tw Pdi and maximal static expiratory mouth pressure for absolute survival. Although all measures had good specificity, there were differing sensitivities. All cutoff points for the VC were greater than 80% of normal, except for prediction of 3-month outcomes. Sequential data showed a linear decline for direct measures of respiratory muscle strength, whereas VC showed little to no decline until 12 months before death/ventilation. Conclusions:The most powerful biomarker for mortality stratification was Tw Pdi, but the predictive power of sniff nasal inspiratory pressure was also excellent. A VC within normal range suggested a good prognosis at 3 months but was of little other value.Keywords: amyotrophic lateral sclerosis; survival; diaphragm; maximal inspiratory pressure; sniff nasal inspiratory pressure Author Contributions: All authors contributed to the concept of the study, critically reviewed the manuscript, and approved this submission for publication. R.A.L. made the original measurements and reviewed the source data to create the material for the present analysis. K.Y. and E.J. undertook statistical analysis of the survival data to provide the analysis results for this paper. M.I.P. reviewed the source data with R.A.L. to create the material for the present analysis and prepared the first and subsequent draft of the manuscript. P.N.L. and J.M. were supervisors for the neurologic and respiratory muscle aspects, respectively, of the original data collection.

Diaphragm Dysfunction: Diagnostic Approaches and Management Strategies

“…However, in the context of degenerative myopathies or neurological diseases, respiratory muscle weakness frequently progresses relentlessly with the underlying disease and will very frequently negatively impact quality of life and vital prognosis [31,34,35,36,142]. Although acute high spinal cord injury will frequently cause acute respiratory failure requiring ventilatory support, spontaneous diaphragm motor recovery can be observed within the first month, presumably because of the resorption of local edema, or even up to 14 months after the initial injury [143].…”

What causes amyotrophic lateral sclerosis?

“…Despite this, because respiratory function is difficult to measure reliably with non-invasive methods, measurement of respiratory function is generally used as a guide to the use of respiratory support rather than prognostication 47 . There have been many attempts at prognostic modelling, using either clinical features alone or biological markers such as albumin, creatinine, or neurofilament levels 48, 49 .…”

The Pathophysiology of Respiratory Failure: Control of Breathing, Respiratory Load, and Muscle Capacity

“…In this context, SNIP and MIP seem to follow a more linear decrease over time than VC, thus allowing a better anticipation of respiratory failure [71]. …”