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 ventilation-free 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; diaphragm; maximal inspiratory pressure; sniff nasal inspiratory pressure; survival.

Figure 1.

Cutoff values of the respiratory muscle strength parameters with greatest sensitivity for prediction of time to death or noninvasive ventilation. Graphical analysis showing the cutoff point identified from the receiver operating characteristic analysis for the prediction of death or noninvasive ventilation for the key respiratory muscle strength parameters as a function of time before that event. MEP = maximal static expiratory mouth pressure; MIP = maximal static inspiratory mouth pressure; SNIP = sniff nasal inspiratory pressure; Sn Pdi = sniff trans-diaphragmatic pressure; Tw Pdi = twitch trans-diaphragmatic pressure.

Figure 2.

Kaplan-Meier analysis (for the composite endpoint of death or noninvasive ventilation use) for the (A) VC, (B) sniff nasal inspiratory pressure, and (C) maximal static inspiratory mouth pressure. The participants were categorized into three subgroups: greater than or equal to 80% predicted (i.e., within the normal range), 45 to less than 80% predicted, and less than 45% predicted. The P values of log-rank tests of equality over subgroups are all less than or equal to 0.0001.

Figure 3.

Longitudinal respiratory muscle strength data in a subset of patients for whom sequential measures were available (n = 25) for the (A) VC, (B) sniff nasal inspiratory pressure (SNIP), (C) twitch trans-diaphragmatic pressure (Twi Pdi), (D) sniff trans-diaphragmatic pressure (Sniff Pdi), (E) maximal static inspiratory mouth pressure (MIP), (F) maximal static expiratory mouth pressure (MEP), and (G) gastric pressure during maximal cough (Cough Pga). Each series of dots represents the trajectory of this parameter for an individual patient. NIV = noninvasive ventilation.

Figure 4.

The correlation of twitch trans-diaphragmatic pressure (Twi Pdi) with (A) sniff trans-diaphragmatic pressure (Sn Pdi), (B) sniff nasal inspiratory pressure (SNIP), (C) maximal static inspiratory mouth pressure (MIP), and (D) VC.