Maximum inspiratory pressure as a clinically meaningful trial endpoint for neuromuscular diseases: a comprehensive review of the literature

We identified 8 publications in which MIP was used as a primary or secondary endpoint in a randomized controlled trial (RCT) of a pharmacologic therapy in a broad spectrum of conditions (Table 1) [26, 30‐36]. One of these studies was in patients with Duchenne muscular dystrophy [36]. Across the studies, the MIP endpoint was reported to be a sensitive and specific clinical measure for evaluation of the pharmacologic interventions, all of which directly targeted the respiratory musculature.

A search of the clinical trials database revealed 31 open trials where MIP was cited as either a primary or secondary endpoint (Table 2). The trials reflected a range of clinical conditions; approximately 1 in 3 were in individuals with a NMD (including ALS, Duchenne muscular dystrophy, myasthenia gravis, Pompe disease, and X-linked myotubular myopathy). This suggests that MIP is gaining momentum as clinical endpoint for monitoring respiratory muscle function in these patients.

As noted, respiratory failure is a common cause of premature death in patients with NMD [19]. Consequently, patients with progressive disease require frequent monitoring of their pulmonary function. Sensitive, noninvasive predictive measures are needed to quantify the risk of mortality due to respiratory failure in these patients; predictive measures could also quantify the potential mortality risk benefit of a therapeutic intervention.

Studies have investigated the correlation between MIP and survival in various conditions (Table 3) [37‐51]. In regard to NMD, the majority of data comes from patients with ALS. All ALS published studies we identified consistently found a correlation between MIP and survival [37‐41]. A cohort study in 95 patients with ALS found a significant association between MIP and 1-year survival (P < 0.05) [37]. The study found that, whereas a normal (>80% predicted) supine FVC predicted a > 80% chance of 1-year tracheostomy-free survival, a normal MIP or MEP predicted a > 90% chance of survival. In a second ALS study, reduced MIP predicted poor 2-years survival. Extensively controlled for nonpulmonary factors known to predict survival in ALS, Kaplan-Meier and receiver operating characteristic curve analysis showed that 2-years survival was more probable in patients with initially normal MIP values (P = 0.0001) compared with patients who had initially reduced MIP (<70 cm H₂O; P < 0.05) [38]. In a third study of ALS patients (N = 21), MIP (−60 cm H₂O or less) was 100% sensitive as a “threshold” for predicting 18-months survival, whereas FVC (<80% of predicted) was not as sensitive for predicting survival (<80% sensitive) [39]. In a fourth study of 53 patients with ALS, comparison of baseline data in patients who were dead or alive at 18 months showed that survivors had a higher mean MIP (38 ± 24% predicted) than nonsurvivors (20 ± 18% predicted; P < 0.01). The absence of cough spikes (defined as peak flow rate transients during voluntary cough) had no significant influence on survival [40]. Finally, clinical results from a 5-years prospective, comparative trial of patients with ALS using noninvasive ventilation found that determinants of respiratory function (including MIP [P = 0.0001]) were an independent predictor of 5-years survival, emphasizing the potential utility of MIP as a prognostic indicator in patients with ALS [41].

In a further study recently published by one of the current authors [52], multiple outcome measures were obtained in 78 patients with ALS who were then followed until death. Low values for MIP were highly specific predictors of time to death or initiation of NIV; conversely, while VC was also a specific predictor, the cut points suggested by ROC analysis were >80% of normal at all time points except for 3 months mortality prediction (when it was 78%), suggesting that a normal VC was of limited practical value. However, a small (N = 18) study of MIP and survival in patients with Duchenne muscular dystrophy [53] did not find a predictive association. It should be noted that participants had extremely low values of MIP and VC at the start of study and that the analysis did not include the use of noninvasive ventilation.

Some studies in non-neuromuscular diseases—chronic obstructive pulmonary disease (COPD) [42‐45], cystic fibrosis [49], liver cirrhosis [50], hypercapnic respiratory failure [46], and congestive heart failure [47, 48, 51]—suggest that MIP may correlate with survival, while others report no correlation [54‐59] (Table 3), indicating that further investigation is needed. We also caution that in non-neuromuscular disease states, a reduced MIP may simply reflect generalized cachexia, which is a recognized marker of a poor prognosis and hyperinflation [60] in pulmonary disease.

As NMD pathology progresses and patients develop respiratory dysfunction, QoL (with respect to a patient’s physical, emotional, social functioning, mental health, bodily pain, endurance, and general health perceptions) and sleep can be severely impacted [18, 61, 62]. The relationship between changes in MIP and QoL in NMD was addressed in 2 studies from our literature search: one in ALS [18] and one in patients with post-poliomyelitis syndrome [63].

Bourke et al. evaluated the impact of noninvasive intervention on QoL in 22 patients with ALS using the 36-Item Short Form (SF-36) and the National Center for Health Statistics General Well-Being Schedule and concluded that respiratory muscle weakness had an impact on QoL [18]. Overall, the researchers found that patients with ALS with significantly lower QoL displayed lower MIP values. Lower MIP values corresponded with lower SF-36 scores in all domains except the pain and physical components [18]. Instruments specifically assessing respiratory and sleep-related problems (eg, the Epworth Sleepiness Scale [ESS]) were most sensitive to changes in MIP [18]. In this regard, ESS scores were highest (indicating sleep disruption) in patients with MIP values below 50% and were lowest in patients with MIP values above 50% (10.3 and 4.8%, respectively; P = 0.01) [18].

Similar to the findings of Bourke et al., a cross-sectional study of 52 patients with post-poliomyelitis syndrome observed a significant correlation between MIP and both the fatigue severity scale and the Multidimensional Fatigue Inventory (MFI) (r = −0.31 and r = −0.41, respectively; P < 0.05). The researchers also found that a 10-unit decline for MIP (% predicted) corresponded to patients scoring a 0.3-unit increase on the General Fatigue dimension of the MFI scale [63]. This dimension of the MFI scale ranges from 4 to 20, with higher scores indicating more severe fatigue.

In patients with NMD whose lungs are restricted from fully expanding, spirometry is widely used to assess respiratory muscle function. Patients performing spirometry are asked to take a maximal inspiration and perform a FVC maneuver. A drop of more than 20% of FVC going from the upright to the supine position is a useful diagnostic of diaphragmatic weakness [64]. FVC, however, has a curvilinear relationship with respiratory muscle strength, and substantial weakness may be present while FVC is still within the normal range [65].

Lung volume measurements are sometimes performed in patients with NMD, including TLC and functional residual capacity (FRC; defined as the amount of air in the lungs following normal expiration). In these patients, when inspiratory muscles are weak, then a maximum effort may be insufficient to fully expand the lungs, and the TLC and FRC will be reduced [22, 24]. Similarly, if abdominal muscle strength is impaired, residual volume may also be elevated [22].

When carbon monoxide gas transfer is measured, the classic picture of respiratory muscle weakness is a low diffusion capacity (DL_CO) and an elevated transfer coefficient (K_CO). However, a study in patients with NMDs showed that the rise in K_CO was often less than expected; in patients with combined inspiratory and expiratory muscle weakness, a reduced value was observed [66]. The results demonstrated the limitations of using K_CO in the diagnosis of respiratory muscle weakness. Gas exchange anomalies can also be multifactorial in their origin, for example, mechanical problems and airway obstructions can affect results [67].

While the above discussed spirometry tests have utility, they can be considered insensitive measures of respiratory muscle function since a significant reduction in lung volume may not be observed until severe impairment of respiratory muscles has occurred [67]. Also, other factors such as airway obstruction due to asthma or lower airway obstruction may affect the reliability of some spirometry results [5, 68‐70]. Consistent with these limitations, when measured within 30 days of the need for tracheostomy in a clinical trial of therapeutics for ALS [71], VC was ≥ 60% predicted in 14% of ALS patients (n = 50).

MIP has physiological relationships with spirometry endpoints [65]. Specifically, in patients with a NMD, several studies have shown a correlation between MIP and FVC. In a study of patients with Duchenne muscular dystrophy, a significant 1-year decrease in MIP was associated with decreases in FVC, FEV₁ (defined as forced expiratory volume in 1 sec), and peak expiratory flow rate (P < 0.05 for all measures) [72]. Similarly, Schmidt et al. found a significant association between MIP and upright FVC in a 1-year cohort study of 95 patients with ALS [37].

Also, the LOTS study investigated the effect of alglucosidase alfa treatment in patients with late-onset Pompe disease [73]. Patients who entered an open-label extension phase of this trial showed additional improvement in MIP but a slight decline in FVC from week 78 through week 104; a statistical correlation however was not reported [74]. Finally, a RCT conducted by Cheah et al. to assess the effects of a 12-weeks inspiratory muscle training program in patients with ALS found that improvements in MIP reflected improvements in FVC and TLC [75]. In 3 RCTs where MIP improvements were observed following pharmacologic treatment in patients with non-neuromuscular diseases, these values also correlated with improvements in other pulmonary measures, including FVC (as well as airway resistance and MEP) [26, 30, 31].

Additional non-RCT studies supporting a correlation between MIP and spirometry in patients with NMDs have also been performed in patients with Pompe disease, Guillain-Barré syndrome, and myasthenia gravis [70, 74, 76, 77]. In a prospective cohort study in patients with Pompe disease, MIP and MEP were both strongly correlated with VC (r = 0.75 and r = 0.79, respectively) [76]. Follow-up data (median 1.6 years) showed that VC (upright or supine) deteriorated by 0.9–1.2% points per year, respectively, with deteriorations in MIP and MEP of 3.2% (P = 0.018) and 3.8% (P < 0.01) per year, respectively [76]. In a study of patients with respiratory muscle weakness and one study of multiple NMDs, MIP was found to significantly correlate with FRC (r = 0.62; P < 0.001) and VC (r = 0.88; P < 0.001) [77]. A direct investigation of the sensitivity of MIP versus VC in patients with either Guillain-Barré syndrome (n = 40) or myasthenia gravis (n = 44) found a linear relationship between the 2 measurements [70].

Taken together, these studies demonstrate that in patients with NMD there is a correlation between MIP and FVC, FEV₁, body plethysmography, and diffusion techniques. In addition, MIP could have utility as a clinical endpoint in therapeutic trials for the treatment of neuromuscular diseases. A recent study in ALS patients with progressive respiratory dysfunction provided indirect evidence that reductions in MIP occur prior to reductions in FVC [28]. In patients with ALS, clinicians detected the progression of respiratory dysfunction 6.5 months earlier when monitoring MIP compared with FVC alone. This indicates that MIP may be a more sensitive measure of respiratory disease progression, supporting its potential utility as a clinical trial endpoint.

Walking tests are an integrated assessment of cardiac, pulmonary, circulatory, and muscular capacity, providing a measure of the functional exercise level required to undertake daily physical activities. Neuromuscular and pulmonary studies investigating the impact of MIP on ambulatory measures showed that, in some cases, improvements in MIP coincided with improvements in walking tests [25, 34, 54, 74, 75, 78‐85]. Two studies were identified comparing MIP with walking tests: one in Pompe disease and one in ALS. The study of patients with Pompe disease [74] receiving enzyme replacement therapy found that changes in the 6-min walk test (6MWT) were directionally consistent with changes in MIP. However, no such association was found in the study of patients with ALS [75].