Effect of standard therapies on pulmonary functions and clinical outcomes
Glucocorticoid (GC) therapy is well established to help delay and increase the maximum VC plateau though this is then followed by the same rate of loss. McDonald found that compared to untreated individuals whose VC peaked at 1.85 liters between ages of 12.0 to 12.9 yrs, those treated with GCs had a peak median FVC of 2.03 liters at age 17.0 to 17.9 years, both increasing and delaying the maximum VC. As well, the age at which VC fell below 1 liter was delayed from 20.0-20.9 until 23.0-23.9 years 16.
In addition to regular monitoring of pulmonary function and gas exchange, international guidelines recommend preventive and supportive respiratory therapies for individuals with DMD; lung volume recruitment strategies, manual and mechanical cough assistance and noninvasive ventilation (NIV) 22,24. A number of these therapies have effects on respiratory function and its evolution.
Lung Volume Recruitment (LVR). LVR, the active or passive stacking of breaths with a resuscitation bag or mouthpiece ventilator in order to achieve a maximum insufflation capacity (MIC) has been demonstrated to have a beneficial effect, not only on cough flows but on lung mechanics. There is evidence for short term improvement in respiratory system compliance and observational evidence for a longer-term effect on important measures such as rate of loss of VC as a result of LVR.
Molgat-Seon demonstrated that respiratory system compliance can be significantly improved for an hour after a session of LVR25 and Chiou showed that the peak/plateau VC can be delayed by 5 years and the post-peak rate of decline significantly decreased 15. The mechanism for improvement in loss of VC is most likely related to the establishment and maintenance of a maximum insufflation capacity (MIC). The MIC-VC difference and the resulting peak cough flow are the measures of effectiveness of LVR. In a small retrospective study, McKim demonstrated that the rate of decline of VC %pred after age 18 can be reduced to 0.5% per year26 compared to a recent cohort of 47 DMD subjects not using GCs with mean age of 17.5 ±4.7 years and a mean rate of FVC%p decline of 4.68%/yr 27. In addition, the MIC-VC difference can be maintained for over 8 years at a level sufficient to achieve effective cough flows 28.
Noninvasive ventilation (NIV). NIV has provided the most profound effect on survival in DMD, from the late teens to at least the late 20’s, even into the 40s in the presence of favorable cardiac function and 24 hour, continuous NIV/mouthpiece ventilation, in spite of little or no measurable pulmonary function 29-31. Initiation of NIV can be considered, in pharmacotherapy trials, as an important outcome to be delayed as a consequence of improved muscle function. However, if necessary and initiated, NIV can have important and significant effects on sleep quality, quality of life and, of course on survival, even with no measurable VC 32,33.
A small number of publications indicate an improvement in the rate of loss of VC in other progressive neuromuscular conditions such as ALS, as a result of NIV initiation 34. The introduction of daytime NIV (mouthpiece ventilation) in DMD patients has been demonstrated to increase the endurance of fatigued inspiratory muscles35. In a 3-month prospective controlled trial, Schonhofer et al. demonstrated a significant increase in inspiratory threshold load endurance time of 278 +/- 269% indicating improved inspiratory muscle function 36.
Nickol et al 37 studied 12 subjects with neuromuscular disease (NMD, not specified), baseline mean TLC 62%pred and another 8 with scoliosis, after three months of NIV and found a significant increase in maximum expired pressure (MEP) and hypercapneic ventilatory response (HCVR) as well as a trend toward increases in inspiratory strength indicated by more negative maximum inspiratory esophageal (SnPes), sniff nasal inspiratory pressure (SNIP). No significant increase was noted in maximum inspiratory pressure (MIP). Given the small number of subjects, lack of significance in respiratory muscle function could have been as a result of a beta error.
Mechanical In-Exsufflation (MI-E). Mechanical cough assistance, generally administered through a noninvasive mask at pressures of +/- 40 cmH2O or greater, has not only been associated with reduced hospitalizations and intubations due to more effective airway clearance38 but has also been demonstrated to improve vital capacity and lung mechanics.
In a study of 21 patients with NMD, 10 of whom had DMD (VC 11%Pred, all using NIV) Stehling et al demonstrated an average improvement of 28% in VC, from 0.48 +/- 0.15 to 0.59 +/- 0.25 liters after one year of twice daily MI-E therapy 39. As average MI-E pressures were only +25.1+5.3 and - 25.6 + 5.7 cmH2O, a greater effect on VC might be anticipated with pressures more commonly utilized clinically. Although these were older individuals (age 20.6 +/- 3.9 yrs) with severe respiratory muscle weakness, regular use of MI-E clearly has the capacity to improve measures such as VC.
Although data are limited, taken together, these observations suggest that standard therapies recommended by international guidelines may have a significant effect on some of the primary respiratory outcomes being evaluated in studies of molecular and gene therapies and as such, respiratory interventions should be well documented and accounted for in randomization and evaluation.