Pilot Study of Nuclear Scintigraphy To Assess Cough Clearance in
DMD
To the Editor:
Respiratory muscle weakness as a consequence of neuromuscular disease
results in ineffective cough, atelectasis, and pneumonia. Augmented
airway clearance treatments such as mechanical in-exsufflation and high
frequency chest compression have been shown to decrease morbidity and
mortality in children with neuromuscular disease, although the evidence
supporting these therapies in clearance of airway secretions is
indirect.
We sought to pilot the use of nuclear imaging of the clearance of
pulmonary secretions before and after voluntary coughing and airway
clearance treatment to explore the role of measures of pulmonary
function to predict airway clearance. This technique has been used for
some time in patients with cystic fibrosis but has not been applied to
patients with neuromuscular disease or to assess the utility of airway
clearance devices. To this end, we recruited 7 outpatient subjects
(7.8-21 years of age) with Duchenne Muscular Dystrophy when clinically
well and categorized as “Early Ambulatory” (requiring minimal
assistive devices, n=4); “Early Non-ambulatory” (using wheelchair some
of time, n=2); and “Late Non-Ambulatory” (always using wheelchair,
n=1). This study was approved by local Institutional Review Board.
Spirometry was performed according to ATS specifications and normalized
using Global Lung Initiative equations. Peak cough flow was measured
from total lung capacity (TLC) and data was normalized with previously
published equations[1]. Maximal inspiratory pressure (MIP) and
maximal expiratory pressure (MEP) were measured at the mouth using a
hand-held pressure manometer and maximal pressure from FRC was also be
measured at the nares (SNIP) during a sniff maneuver[2] using a
small nasal occluder and handheld transducer Maximal static pressures
and SNIP pressures were normalized using previously published data.
For imaging of mucus clearance, 4 mCi of Technetium [Tc-99m]
sulfur-colloid particles in 2 ml of normal saline were delivered by
nebulizer using a defined breathing pattern for 2 minutes [3].
During continuous imaging, subjects were asked to voluntarily cough
every 10 seconds for 1 minute using guidance from a metronome, and this
sequence was repeated 3 times. The subject then received an airway
clearance treatment for 30 minutes using a high frequency chest
compression device with pressure adjusted between 80-100% of maximum,
and compression frequencies cycled between 5Hz-15Hz. The device was
paused every 10 minutes at which time the patient was asked to cough
every 10 seconds over 1 minute.
Image analysis was performed according to previously published methods.
Measurements of radioactivity in the right lung were corrected for
background and radioactive decay and normalized by starting radioactive
counts. A single retention curve was generated from the initial cough
clearance period and the period during which the high frequency chest
compression device was operated. Cough clearance (CC) represents the
percent of total deposited radioactivity cleared during the associated
period. We designated the percentage cleared by 18 voluntary coughs over
3 minutes as CCvol, and the percentage cleared during
three 10 min periods of HFCC and 18 voluntary coughs over 3 minutes as
CCHFCC. CCvol and CCHFCCwere correlated with physiologic measures including peak cough flow
(PCF), MIP/MEP, and SNIP using Spearman’s correlation.
Pulmonary function was overall well preserved (FVC 92% ± 35%).
Respiratory muscle strength (in cmH2O) decreased with
disease severity (e.g. MIP EA 73.5 ± 26, ENA 62.5 ± 14.8, LNA 47). Peak
cough flow (% predicted) decreased with severity (EA 94±11, ENA 79±9,
LNA 46). Complete details are provided in the online supplement.
Representative imaging of two subjects is shown (Figure 1). Significant
intra-subject differences were seen in clearance with voluntary cough
and with cough augmented with HFCC vest (Figure 2). Voluntary cough was
responsible for 46-96% of the total clearance and HFCC-augmented
clearance for 3-53% of total clearance. For most patients, the kinetics
of clearance with HFCC-augmented cough did not appear very different
than for voluntary cough.
Statistical comparisons between disease stages were hampered by the
small sample size in each group. Nonetheless, while there appeared to be
a trend for decreasing CCvol with stage of disease
(Figure 2), age, and PCF, we found no statistically significant
correlations between voluntary cough clearance and measures of pulmonary
function (FVC, r=0.39), respiratory muscle strength (PCF, r=-0.63; SNIP
r=-0.12, MIP r=0.43, MEP r=0.29), age (r=-0.57), height (r=-0.49),
weight (r=-0.37). Additionally, we did not find statistically
significant correlations between augmented cough clearance and measures
of pulmonary function (FVC, r=0.40), respiratory muscle strength (PCF,
r=-0.08; SNIP r=-.02, MIP r=-0.07, MEP r=0.05), age (r=-0.39), height
(r=-0.75), weight (r=-0.03).
This study is the first we are aware of to directly examine cough
clearance of secretions using nuclear scintigraphy in patients with DMD.
Importantly, the measurements were well tolerated by subjects. We did
not find a relationship between CPF, respiratory muscle strength, or
spirometry and voluntary cough clearance. However, these results must be
qualified based on the small number of enrolled subjects. We do note
that many of the patients had good cough clearance. Additionally, HFCC
did not consistently alter the rate of secretion clearance above noted
with voluntary cough.
While Bach et al[4] showed that PCF >160 L/min was a
predictor of successful tracheal decannulation in adults with
neuromuscular disease, Airen et al[5] found that the majority of
healthy children <13 years old generated PCFs < 270
l/min despite having the ability to generate MEP > 60
cmH2O. This suggests that PCF may change with age and
that an absolute threshold cannot be used across the age span. There are
no studies specifically examining use of HFCC in patients with DMD. As
patients with DMD are expected to have impairment in cough, mechanical
in-exsufflation would be expected to assist with airway clearance by
replacing the function of weak respiratory muscles in a way that HFCC
does not. Lechtzin et al[6] showed that in adults with neuromuscular
diseases, HFCC decreased inpatient costs and costs for treating
pneumonia compared to the year prior to initiating HFCC. Measures of
pulmonary function, including PCF, were not assessed. It would be of
interest to examine secretion removal with in-exsufflation using this
nuclear imaging method.
While we were not able to demonstrate a relationship between cough
clearance and measures of respiratory muscle strength, peak cough flow,
or FVC, it is possible that this relationship exists and would be
demonstrated in a larger population. However, the longstanding
assumption that PCF is a reliable indicator of need for airway
clearance, especially in children, is not supported by these data. The
biggest limitation of our pilot study is the small sample size. We
suspect enrollment was limited due to preference for interventional
studies. Another limitation is that for our population, the impairment
of respiratory muscle strength was mild for most subjects. Additional
subjects with more advanced weakness may have helped clarify the
relationship between respiratory muscle strength and airway clearance.
Finally, there can be day-to-day variations of clearance.
There are now a number of airway clearance technologies being proposed
for patients with neuromuscular and airway diseases (e.g. cystic
fibrosis, ciliary dyskinesia). These include high frequency chest
compression vests, battery-powered vests, in-exsufflation devices (with
or without oscillation), intrapulmonary percussive ventilation devices,
and handheld oscillating positive expiratory pressure devices. We
propose that the imaging methodology used in this study could be
utilized to compare these different techniques, some of which are costly
and with limited or no comparison data. In addition, there are patients
that will be unable to cooperate with pulmonary function measurements
and an imaging assessment of airway clearance may be useful to determine
optimal strategies.
In conclusion, we demonstrated that use of nuclear scintigraphy is a
feasible technique to examine airway clearance for patients with
respiratory muscle weakness, as it has been used for patients with
cystic fibrosis. Additional studies will be needed to further examine
the relationship between pulmonary function measures and secretion
removal.
Daniel J. Weiner MD1,
Hoda Abdel Hamid MD2,
Timothy E. Corcoran PhD3
Divisions of Pediatric Pulmonology1 and
Neurology2, Department of Pediatrics
UPMC Children’s Hospital of Pittsburgh
Division of Pulmonary, Allergy and Critical Care
Medicine3, Department of Medicine
University of Pittsburgh School of Medicine