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.