Selected articles from ATS - 2003,2002,2001 - American Thoracic Society
1) Effect Of Deflazacort On
Pulmonary Function In Duchenne Muscular Dystrophy
Daigneault, P., Lapierre, G., Laberge, S., Vanasse, M. Service de
pneumologie pdiatrique,
Hopital Sainte Justine, Universit
de Montral,
Montral,
Qubec,
Canada.
RATIONALE: Duchenne muscular dystrophy (DMD) is an X-linked disorder presenting
as a progressive deterioration of muscular function in young boys. Treatment is
mostly supportive. Corticosteroids may help slow the progression of the disease.
In previous studies, deflazacort has shown limited side effects compared to
prednisone and has been used in our clinic for almost a decade. METHODS:
Deflazacort was offered to patients when functional losses became apparent,
usually between 6 and 9 years of age. We reviewed all patient files from our DMD
clinic. 38 patients had been treated for at least one year and before loss of
ambulation. All other patients (33) with enough clinical information were used
as a control group. Studied variables included ability to walk, muscle strength,
pulmonary function tests, presence of scoliosis, weight and height. RESULTS:
Treated patients walk at a later age (p<.05). Measured strength, percent
predicted forced vital capacity, inspiratory and expiratory strengths are all
significantly greater in treated patients (p<.05). Incidence of scoliosis is
reduced in treated patients (0%) vs untreated patients (73%). Treated boys are
shorter on average, but weight for height remains unchanged. CONCLUSIONS:
Deflazacort is able to delay the deterioration of lung function, prevent
scoliosis, and delay loss of ambulation in patients with DMD.
2) Sleep Related Breathing
Disorder in Duchenne Muscular Dystrophy
D.M. Cooper, S. Suresh, P. Wales, M. Harris. Mater Children's
Hospital, Brisbane, Queensland, Australia
Duchenne muscular dystrophy is a progressive neuromuscular disease with death
occurring secondary to respiratory failure. Sleep hypoventilation occurs as one
of the early signs of respiratory failure.
Aim: To study the presentation of sleep related disorders in patients with
Duchenne muscular dystrophy.
Method: Retrospective review of patients with Duchenne muscular dystrophy
attending a tertiary paediatric sleep clinic over a 5-year period. Symptoms
reported, lung function and polysomnographic indices were reviewed.
Results: Total of 34 patients with Duchenne muscular dystrophy attended our
sleep clinic. Age of referral varied from 1-15years(Median 10). 20 (60%) of them
reported sleep symptoms. FVC was 15-103% predicted (Median 58%). 32 progressed
to have polysomnography of which 16 were normal studies. 9 had obstructive sleep
apnoea(Median age 8 years). These patients subsequently had adenotonsillectomy.
7 showed varying degrees of hypoventilation/respiratory failure and non-invasive
ventilation(NIV) was offered. The median FVC and age for this group were 27% and
13 years. Post NIV there was significant improvement in Respiratory disturbance
index [RDI] (p=0.03).
Conclusions: The prevalence of sleep related disorders in DMD is significant.
There is a bimodal presentation with obstructive sleep apnoea occurring at an
earlier age and central hypoventilation occurring at the beginning of the second
decade. Our group had OSAS in 23 % of patients. In patients with early stages of
respiratory failure assessment with polysomnography helped in identifying sleep
hypoventilation and initiating NIV. NIV is well tolerated and results in
improvement of polysomnographic indices and symptoms.
DMD | Control | p | |
FVC (%pred) | 58 ± 16 | 100 ± 17 | 0.0007 |
TLC (%pred) | 78 ± 19 | 97 ± 13 | 0.07 |
ETCO2 (torr, sleep baseline) | 38.5 ± 3.4 | 40.2 ± 2.7 | NS |
ETCO2 highest (torr, sleep) | 46.1 ± 3.6 | 46.2 ± 2.1 | NS |
SpO2 (%, sleep baseline) | 96 ± 1 | 98 ± 1 | NS |
SpO2 nadir (%, sleep) | 91 ± 2.5 | 95 ± 1.3 | 0.007 |
RDI (events/h) | 1.0 ± 0.8 | 0.2 ± 0.2 | 0.02 |
Sleep period time (SPT, min) | 422 ± 64 | 429 ± 24 | NS |
Stage 1-2 (% SPT) | 46 ± 8 | 41 ± 14 | NS |
Stage 3-4 (% SPT) | 28 ± 10 | 36 ± 13 | NS |
Wakefulness (% SPT) | 10 ± 9 | 6 ± 4 | NS |
REM (% SPT) | 16 ± 5 | 17 ± 5 | NS |
4) Contribution Of Neuronal NO Synthase
(NOS1) To FeNO Evidence: From Duchenne Muscular Dystrophy
H. Grasemann, F. Ratjen, H. Amthor, T. Voit, V. Straub. Children's
Hospital, University of Essen, Essen, Germany
Exhaled nitric oxide (FENO) is increased in asthma and may reflect
disease activity. However, little is known about the exact molecular and
cellular source of FENO. There is recent evidence from genetic
studies in asthma that NOS1 may contribute substantially to FENO (Wechsler
et al, AJRCCM 2000). NOS1 protein is targeted to the surface membrane by binding
to dystrophin. The absence of dystrophin in Duchenne muscular dystrophy (DMD) is
accompanied by a loss of NOS1 from the sarcolemma. The aim of our study was to
test whether the loss of NOS1 expression in DMD would be reflected in FENO.
Thirteen male DMD patients (6 - 23 years of age) were compared to eleven healthy,
non-smoking non-asthmatic male controls (7 - 24 years). Mean (+ SEM) FENO
was significantly (p < 0.02) lower in DMD than in controls (7.5 + 1.4
ppb vs. 16.6 + 3.2 ppb). Low FENO did not result from
decreased (54.4 + 5.1 % predicted) forced vital capacity (FVC) in DMD
patients since restriction of FVC to 62.5 + 1.1 % of predicted normal
values in five healthy subjects did not effect FENO. This is the
first study to show that FENO is decreased in DMD. These findings
provide further evidence that NOS1 contributes significantly to airway NO
concentrations.
5) Monitoring of Diaphragm Electrical
Activity and Pressure in Advanced Duchenne Muscular Dystrophy
J.C. Beck, J. Weinberg, C.H. Hamnegrd,
J. Olofson, G. Grimby, C. Sinderby. Department of Pediatrics, University of
Montreal, Montreal, QC, Canada; Department of Neurology, Huddinge Hospital,
Huddinge, Sweden; Department of Medicine, Gteborg
University, Gteborg,
Sweden; Department of Rehabilitation Medicine, Gteborg
University, Gteborg,
Sweden; Department of Medicine, University of Montreal, Montreal, QC, Canada
Due to the impaired transformations of neural respiratory activity into pressure,
neural activity goes up with inspiratory muscle weakness. It is likely that in
neuromuscular disorders, diaphragm pressure generation is diminished before its
electrical activity (the latter representing neural activation). In order to
test this hypothesis, eight patients with advanced respiratory muscle paralysis
due to Duchenne Muscular Dystrophy (DMD), age 25.3 +2.2 years and vital
capacity 0.4 +0.2 L, were studied during tidal breathing, maximal
inspirations, maximal sniff inhalations, and cervical electromagnetically evoked
diaphragm contractions. All patients but two were prescribed home mechanical
ventilation (5 non-invasive and 1 tracheostomy). Transdiaphragmatic pressure (Pdi)
and diaphragm electrical activity (EAdi) were measured using an esophageal
catheter. Flow was also measured. During tidal breathing (tidal volume 0.20 +0.08
L, breathing frequency 25 +7, inspiratory EAdi was clearly detectable and
was 12 +7 times the noise fluctuations, and represented 45 +19 %
of the maximum EAdi. Mean inspiratory and sniff Pdi"s were 1.5 +1.2
and 7.6 +3.6 cmH2O, respectively (Pdi/Pdimax=18 +13%). Twitch Pdi
deflections could not be detected. Twitch latency time was normal (8.2 +1.3
ms). The results of this study show that despite near complete diaphragm
paralysis in advanced DMD, it is still feasible to monitor diaphragm electrical
activity with an esophageal electrode array. This may open future possiblitity
for long-term evaluation and neural control of mechanical ventilation in these
patients.
6) Prognosis of Duchenne Muscular Dystrophy: A Decade of Mechanical
Ventilation
F. Yasuma, M. Sakai, M. Konagaya, T. Kawamura. Suzuka National
Hospital, Suzuka, Mie Pref., Japan; Kyoto University, Kyoto, Kyoto, Japan
[Objectives] We retrospectively analyzed the survival rate of 141 inpatients
with Duchenne Muscular Dystrophy (DMD) to estimate the factors affecting their
prognosis.
[Methods] The subjects were 141 Japanese inpatients with DMD (all males), who
had been chronically hospitalized during the recent 23 years from 1980 to 2002.
The survival rate was calculated with the Kaplan-Meier method, and the Log-Rank
method was used to compare the survival rate between the subgroups younger and
older than 10.6 years of age on entry (midpoint; ranging from 4.5 to 24.0), the
entries before and after 1981/4/6 (midpoint; ranging from 1965/11/5 to
2000/3/29), and the subgroups treated with and without mechanical ventilation
(MV). The Cox proportional-hazard regression model was used to identify
independent predictors influencing the survival rate.
[Results] Ninety five patients had been dead and forty-six were alive at the end
point. Although 54 patients were treated with MV and nine of them were
tracheostomized, none of the rest of 87 patients was treated with MV or
tracheostomy. In comparison between the subgroups, the significant differences
were found in the date of entry (p=0.025) and the use of IPPV (p<0.001), but
not in the age on entry (p=0.20). In the multiple regression analysis, the
significant negative correlation between the survival rate and age of entry
(p=0.034) and the significant positive correlation between the survival rate and
use of MV (p<0.001) were found, however, the negative correlation between the
survival rate and date of entry was not significant (p=0.375). Hence, the entry
at younger age and MV significantly affected the prognosis.
[Conclusion] We conclude, as in the primary evidence, that the recent improved
prognosis in DMD has been attributable to MV.
7) Longitudinal Modeling Of Lung Function
In Duchenne's Muscular Dystrophy (DMD)
R G Norman 1,2, M A Scott 2, I N Cabrera 3,
K Axen 3, F Haas 1, K I Berger 1. Depts of 1Pulm/Crit
Care Med & 3Rehab Med, NYU Med School, 2NYU Steinhardt
School of Ed.
Longitudinal modeling of lung function in DMD is complicated by a mixture of
both growth and decline in lung function within each subject and an unknown
point of separation between these phases (change point). Linear mixed effects (LME)
models can be used assuming a fixed change point for all cases, however, this
assumption may be incorrect. This abstract describes an extension of linear
mixed effects modeling in which random change points are integrated into the
model as parameters and estimated using an EM algorithm.
METHODS: Data from pulmonary function tests performed during routine medical
care in 56 patients with DMD were collected from medical records. From 1 to 24 (median
= 6) tests were performed on each subject over ages ranging from 5 to 39. A
standard LME model incorporating age and height terms was extended to include
model parameters for possible change point values (ages 12, 14 and 16). LME
models were fit using the NLME library in S plus. The new random change point
model was implemented with a generalized EM algorithm using custom code. The
goodness of fit of the new model was compared to fixed change point LME models
using the -2 log likelihood criterion.
RESULTS: The random change point model provided a better fit (-2LL =110.6) than
fixed change points of 12 (-2LL=143.4), 14 (-2LL=114.7) or 16 (-2LL=152.9). The
model indicates an average increase of 0.09 liters/year during the growth phase
and a decline of .13 liters/year following the change point. Height was not
significant in any model, once all of the other controls and random effects were
in place. The distribution of change points is 27.8% for age 12, 61.2% for age
14 and 11.0% for age 16.
CONCLUSIONS: The technique described allows for estimation of lung function
during both growth and decline with simultaneous estimation of the change point
between these phases. Model fit is better than other standard techniques and
does not require the assumption of a fixed change point. This model can be used
as a prognostic indicator in DMD.
8) Forced Oscillatory (IOS) Assessment of
Pulmonary Function and Bronchodilator Response in Children with Neuromuscular
Disorders
G.D. Sharma, M. Cooper, H. Arora, L.A. Lester, M.D. Goldman.
Rush-Presbyterian-St.Luke Medical Center, Chicago, IL; Univ.of California Los
Angeles, Los Angeles, CA
Children with neuromuscular disorders (NMD) associated weakness can develop
reactive airway disease secondary to aspiration and gastro-esophageal reflux.
These patients are often unable to perform spirometry maneuver due to inadequate
effort and inability to perform forced and prolonged exhalation. We used the
Impulse Oscillation System (IOS, Jaeger) to measure pulmonary function and
response to beta2-agonist bronchodilator (BD) in 5 children (age 6-14 yrs) with
NMD. Clinical diagnoses included spinal muscular atrophy, Duchenne muscular
dystrophy, and myotonic dystrophy. All children had clinical history suggestive
of dysphagia and/reflux and had signs and symptoms suggestive of reactive airway
disease. We also assessed 9 asthmatic children (age 3-10 yrs) who were unable to
perform spirometry. All children underwent IOS testing (triplicate tests of
20-30 sec duration) before and after a dose of nebulized BD. Measurements
included resistance at 5-35 Hz, integrated low frequency reactance (AX) between
5 hz and resonant frequency (Fres). In NMD patients, mean values for
pre-bronchodilator AX, resistance at 5Hz, resistance at 20Hz, were 16.41, 7.07,
5.32 cm H20/l/s and corresponding figures for post-bronchodilator were 8.73,
6.06, and 4.54 (p 0.068, n=5). Similar results for asthmatic children showed a
significant change after bronchodilator (p< 0.05). This technique allows
determination of bronchodilator responsiveness in children unable to perform
spirometry and has potential usefulness in assessment of NMD in whom an
unexpected airway obstruction and reversibility was observed.
9) Effect of a Specific Respiratory Muscle Training in mdx Mouse on
Function and Proteins Structure of the Diaphragm
S. Matecki, F. Rivier, G. Hugon, G. Gayraud, A. Michel, C. Prefaut,
D. Mornet, M. Ramonatxo. Laboratoire de Physiologie des Interactions, Service
Central de Physiologie Clinique, Hpital
Arnaud de Villeneuveve, Montpellier, France; Unite de Recherche UI28, IFR 24,
Groupe Muscles et Pathologies, Institut-Bouisson-Bertrand, Montpellier, France;
Unite U454, Laboratoire de Pharmacologie, Facult
de Pharmacie, Montpellier, France
The cellular mechanisms induced by a beneficial respiratory muscle training in
children with Duchenne Muscular Dystrophy (DMD) are unknown. The aim of this
study was thus to investigate the functional effect induced by a specific
respiratory muscle training in mdx mouse diaphragm. In 10 mdx mouse, we
reproduced by hypercapnic stimulation of ventilation (8% CO2), during 6 weeks/
30 min per day, a specific respiratory muscle training. 10 mdx mice served as
controls. Diaphragmatic force frequency relationships showed that this specific
respiratory training improves the tetanic force production of the diaphragm (8.0
+ 0.5 N/cm2 in the control group and 9.5 + 0.7 N/cm2 in the
training group at 120 Hz) but not endurance. We found no difference between the
groups in diaphragm muscular fiber type and in citrate synthase activity.
Western blot analysis of diaphragm showed: 1) an over-expression of
alpha-dystrobrevin in training group compared to control group (8100+710
versus 6100+520 arbitrary units, p<0.01) and a decrease in utrophin
expression in training group compared to control group (2100+320 versus
3100+125 arbitrary units, p<0.05). In conclusion, The overexpression
of alpha-dystrobrevin which seems have more a signalling than a mechanical role
in muscle could be interpreted as an important pathway to improve muscular
function and could be seen as a possible way for therapeutic intervention in
patient with DMD.
10) A Randomised Controlled Comparison Of Cough Inexsufflation (MI-E),
Non-Invasive Ventilation (NIV), And Physiotherapy Assistance (PAC) On Peak Cough
Flow (PCF) In Children And Adolescents With Neuromuscular Disease
M CHATWIN, E ROSS, A H NICKOL, M I POLKEY & A K SIMONDS. Sleep
and Ventilation Dept, Royal Brompton and Harefield NHS Trust, London, UK
Recurrent chest infections are a major cause of morbidity and mortality in
patients with neuromuscular disease (NMD). Both inspiratory and expiratory
muscle weakness can produce a decrease in PCF. Subjects 10 patients age
range 10-17 (median 14) years; diagnoses included: spinal muscular atrophy,
Duchenne and congenital muscular dystrophy. The following indices of respiratory
muscle strength were assessed: sniff nasal inspiratory pressure (SNIP) (meanSD,
cmH2O) 2613,
PImax 2214,
whistle mouth pressure (Pmow) 1910,
PEmax 1911
and PCF of 13253L/min
in patients and 10 age matched controls; SNIP 9717,
PImax 10330,
Pmow 11538,
PEmax 9738
and a PCF of and 534128L/min.
Methods The MI-E (JH Emerson Co) was compared to traditional methods of
cough enhancement: PAC and NIV assisted cough. PCF was measured using a
pneumotachograph attached to a full-facemask. Subjects performed an unassisted
cough (UAC) and the following in a random order: PAC; NIV; MI-E and exsufflation
alone (E) assisted coughs. Results See graph for patient group. All
interventions improved PCF and were well tolerated. There was a significant
increase in PCF in both the patient and control Groups, with E and MI-E
(*P<0.01). Conclusion The greatest PCF was achieved with a combination
of insufflation-exsufflation.
11) A Randomised Controlled Comparison Of Cough Inexsufflation (MI-E),
Non-Invasive Ventilation (NIV), And Physiotherapy Assistance (PAC) On Peak Cough
Flow (PCF) In Adults With Neuromuscular Disease (NMD)
M CHATWIN, A H NICKOL, E ROSS, N
MUSTFA, M I POLKEY & A K SIMONDS Sleep and Ventilation Department, Royal
Brompton Hospital, and Respiratory
Muscle Laboratory, Kings College Hospital, London, UK
Recurrent chest infections are a major cause of morbidity and mortality in
patients with NMD. Both inspiratory and expiratory muscle weakness can produce a
decrease in PCF. Subjects 14 patients age range 18-56 (median 27) years;
diagnoses included: spinal muscular atrophy, Duchenne and congenital muscular
dystrophy. The following indices of respiratory muscle strength were assessed:
sniff nasal inspiratory pressure (SNIP) (meanSD
cmH2O) 2419,
PImax 2518,
whistle mouth pressure (Pmow) 1915,
PEmax 2016
and PCF of 15472L/min
in patients and 11 aged matched controls: SNIP 9229,
PImax 10333,
Pmow 14551,
PEmax 121
39 and a PCF of and 631139L/min.
Methods The MI-E (JH Emerson Co) was compared to traditional methods of
cough enhancement; PAC and NIV assisted cough. PCF was measured using a
pneumotachograph attached to a full-facemask. Subjects performed an unassisted
cough (UAC) and the following in a random order: PAC; NIV; MI-E and Results
See graph for patient results. There was a significant increase E and MI-E
(*P<0.01), but no change in PCF in the control group. Conclusion The
greatest increase in PCF was achieved with a combination of insufflation and
exsufflation.
12) Use Of The Mechanical In/Exsufflator (MIE) In Pediatric Patients With
Neuromuscular Disease And Impaired Cough
L.J. Miske, E. Hickey, S. Kolb, H.B. Panitch, Philadelphia, PA
Impaired cough secondary to neuromuscular disease (NMD) can cause serious
respiratory complications including atelectasis, pneumonia, small airway
obstruction and acidosis. These problems can be avoided by the use of the MIE, a
device that delivers a positive pressure insufflation followed by an expulsive
exsufflation, thereby simulating a normal cough. Use of the MIE in adults with
impaired cough results in improved cough flows and enhanced airway clearance.
There are, however, no reports of use of the MIE in children. We retrospectively
reviewed the medical records of 42 patients (25 males) with NMD and impaired
cough in whom MIE was initiated to determine its safety, tolerance and
effectiveness. The median age at initiation of MIE use was 16.2 yrs (range: 3
mos to 28.7 yrs). Diagnoses included: Duchenne Muscular Dystrophy (DMD) (n=15),
Spinal Muscular Atrophy (n=14), Myopathy (n=8), Other NMD (n=5). Mechanical
ventilation via tracheostomy was used by 22 patients, 18 received non-invasive
ventilatory support and 2 required no ventilatory support. Appropriate
inspiratory and expiratory pressures were determined clinically in the Pulmonary
Function Laboratory or hospital. Duration of use was 11.6 ± 9.5 (range 0-39)
mos. One infant died from her disease before using it at home. Four patients
chose not to continue with MIE: 2 felt it was ineffective and 2 preferred other
devices. Two others reported complications: 1 with DMD developed PVC's during
MIE use, and one parent felt her infant with SMA did worse. Chronic atelectasis
resolved in 4 patients after beginning MIE and 4 patients have experienced a
reduction in frequency of pneumonias. We conclude that in 85% of our population
the use of a MIE was safe, tolerated and effective in preventing long term
pulmonary complications
13) Ventilatory Responses To Hypercapnia In mdx Adult Mice
S. Matecki, A. Michel, S. Jaber, C. Prefaut, M. Ramonatxo,
Montpellier, France
Nightly hypoventilation with hypercapnia and hypoxemia are characteristics
periodically observed in Duchenne muscular dystrophy (DMD). This ventilatory
control alteration may be due to the lack of dystrophin.
To investigate the role of dystrophin in the ventilatory response, we analyzed
the magnitude and pattern of breathing responses to hypercapnia (8% CO2,
21% O2, 71% N2) in adult mdx mice and their wild-type
littermates (C57). Ventilation, breath duration, and tidal volume were measured
using whole-body plethysmography. We did not find significant difference between
mdx and C57 mice in breathing frequency (325 ± 63 versus 320 ± 49 cycles per
minute), tidal volume (25,9 ± 6 versus 25 ± 5 l/g)
and minute ventilation (8.5 ± 3 versus 8.0 ± 1.8 ml/g/min). However, in mdx
mice, mean inspiratory to total time of the respiratory cycle (Ti/Ttot) was
significantly weaker (0.43 ± 0.03 versus 0.54 ± 0.02).
In conclusion, as minute ventilation was the same in the two groups, differences
observed in response to hypercapnic stimulus, seem more an adaptation of
ventilatory control secondary to respiratory muscle weakness than an alteration
of ventilatory control. Moreover, this hypercapnic stimulus could therefore be
useful for evaluating the effects of specific respiratory training of
respiratory muscle of mdx mice by hyperventilation as recommended in DMD
children.
14) Increased Stiffness In Diaphragm And Bicepsfemoris Muscles Of Young -Sarcoglycan
Deficient Mice
Nisha Patel 1, Suneal R. Jannapureddy 1, Imran
Chaudhry 1, Michael Lopez, Eva Engvall 2, and Aladin M.
Boriek 1. Department of Medicine 1, Baylor College of
Medicine, Houston, TX 77030. Burnham Institute 2, La Jolla, CA 92037.
Alpha-sarcoglycan (SG)
is a transmembrane protein of the dystrophin- associated complex. Absence of SG
causes a form of limb-girdle muscular dystrophy. We hypothesized that SG
contributes to force transmission in muscles. We used bicepsfemoris and
diaphragm muscles of 8 normal mice (weight: 23.6
7.2 g; age: 43.5
15.9 days old) and 7 SG
deficient mice (weight: 17.8
2.6 g; age: 32.3
2.4 days old). After anesthetizing the mouse, either the diaphragm or
bicepsfemoris muscle was excised and submerged in Krebs-Ringer solution bubbled
with 95% O2 - 5% CO2. Length-tension relationships along
and transverse to muscle fibers were determined by passively lengthening and
shortening the muscle in the direction of the muscle fibers (AF) as well as
transverse to the fibers (TF) in an in-vitro biaxial apparatus. At a
tension of 5 g/cm, the extensibility ratios ()
in the bicepsfemoris of the control mice were greater than SG
deficient mice (+/+ AF =
1.17
0.13, -/- AF =
1.12
0.09; +/+ TF =
1.16
0.12, -/- TF =
1.12
0.05; p < .05). Similarly, in the diaphragm,
was greater in control mice compared to knockouts (+/+ AF =
1.45
0.14, -/- AF =
1.21
0.07; +/+ TF =
1.15
0.17, -/- TF =
1.10
0.09; p < .05). During biaxial loading of the diaphragm, controls were more
extensible than SG
null mice (+/+ BA =
1.40
0.17, -/- BA =
1.15
0.12; p < .05). These data suggest increased muscle stiffness in these SG
deficient mice.
15) Presentation Of Respiratory Failure In Neuromuscular Disease Children
S. Sritippayawan, S. Kun, T.G. Keens, S.L. Davidson Ward, Los
Angeles, CA
Ideally, home mechanical ventilation (HMV) should be initiated non-emergently in
children with progressive neuromuscular disease (NMD) and respiratory failure (RF)
after discussion of the options with patients/families. However, HMV was
emergently initiated in 43/52 (82%) NMD patients with RF without prior
discussion of the options with patients/families. Only 9/52 (17%) had HMV
initiated non-emergently following such discussion. Were there missed
opportunities to discuss the options prior to initiating HMV in the emergent
patients? To answer this, we documented the presentation of RF in 52 progressive
NMD patients (age between 0-24 yr old; 26% female). The time from onset of
weakness to HMV varied from 0 in some of the congenital patients to >10 yrs
in Duchenne muscular dystrophy. 24/52 (46%) patients required HMV following RF
with pneumonia. Prior to HMV, 11/43 (26%) of the emergent and 5/9 (56%) of the
non-emergent group, had PFT done; all were abnormal. Prior to HMV, 9/43 (21%) of
the emergent and 7/9 (77%) of the non-emergent group, had PSG done; all but one
were abnormal. 27/39 (69%) patients, whose hospitalization data were available,
had 1
episode (range: 1-10) of pneumonia prior to HMV. In the emergent group, there
were opportunities for discussion of the options prior to HMV in all 43 patients,
which could have occurred during 72 hospitalizations for pneumonia, 9
pre-operative evaluations, 32 abnormal PFT, and 15 abnormal PSG. We conclude
that most NMD children had HMV emergently initiated after pneumonia with RF
without prior discussion with the patients/families. We speculate that
opportunities for discussion of the options prior to HMV were missed or
ineffective in the emergent HMV group.
Diagnosis | In High School | Completed High School | Enrolled/completed college | Employed | Living Independently |
MD | 0 | 10 (55%) | 7 (39%) | 1 (5.5%) | 1 (5.5%) |
SMA | 5 (45%) | 3 (27%) | 3 (25%) | 1 (9%) | 2 (18%) |
18) Isometric Contractile Properties Of Alpha-Sarcoglycan Deficient
Diaphragm During Uniaxial And Biaxial Loading
I. Chaudhry, M. Lopez, A. Jain, E. Engvall, A. Boriek, Houston, TX,
La Jolla, CA
-sarcoglycan
is a transmembrane protein and lack of it causes limb-girdle muscular dystrophy.
-sarcoglycan
may involve in force transmission from the cytoskeleton to the extracellular
matrix. We investigated in vitro contractile properties of the -sarcoglycan-deficient
mouse diaphragm. The diaphragm is pressurized in vivo, and we thus
quantitatively characterized contractile properties under biaxial loads.
METHODS. Muscles from 7 normal 129SV mice (weight: 17.36 ± 4.66 g; age: 30 ±
13 d) and 8 -sarcoglycan-deficient
129SV mice (weight: 17.56 ± 1.66 g; age: 30 ± 11 d) were used. The left costal
diaphragm was excised and stimulated at 100 Hz preceded by twitches under the
presence of uniaxial, 1 g biaxial and 2 g biaxial loading (BAL) conditions.
RESULTS. Muscle stress was depressed in -sarcoglycan-deficient
as compared to normal diaphragm at (a) uniaxial load, 41.63±2.02 N/cm2
vs. 30.49±1.06 N/cm2 (b) 1 g BAL, 46.89±1.62 N/cm2 vs.
32.96±1.56 N/cm2 (c) 2 g BAL, 44.94±1.71 N/cm2 vs. 32.22±1.46
N/cm2. Furthermore, transverse stress altered muscle stress in normal
mice (uniaxial 41.85±1.71 N/cm2 vs. 1 g BAL 47.77±1.45 N/cm2)
but the effect was negligible in -sarcoglycan-deficient
mice (uniaxial 30.49±1.06 N/cm2 vs. 1 g BAL 32.96±1.56 N/cm2).
CONCLUSION: Disruption of the sarcoglycan complex causes depression in diaphragm
maximal tetanic stress. Furthermore, compared to controls, passive transverse
stress did not appear to alter contractile force depression in the -sarcoglycan
deficient diaphragm.
19) Non-Invasive Assessment Of Respiratory Muscle Fatigue In Children
L.T. Mulreany, D.J. Weiner, J. McDonough, H.B. Panitch, J.L. Allen,
Philadelphia, PA
BACKGROUND. The tension-time index (TTI) is the dimensionless product of (i) the
ratio of mean transdiaphragmatic pressure (Pdi) to maximal transdiaphragmatic
pressure (Pdimax) and (ii) the ratio of inspiratory time (TI) to
total respiratory cycle time (TTOT). The TTI is one measure of diaphragmatic
fatigue. The invasive nature of the test (requiring esophageal and gastric
pressure transducers) has limited its usefulness in children. A non-invasive
measurement (TTmus), based on mouth occlusion pressure 100 milliseconds after
the onset of inspiration (P100), extrapolated to mean inspiratory
pressure (PI), and maximal inspired pressure measured at the mouth (MIP), has
been found to correlate well with the TTI [Ramonatxo, J Appl Physiol. 1995;
78:p646]. This measurement likely reflects fatigue of all inspiratory muscles
rather than just the diaphragm. There are, as yet, only limited data using this
technique in children. METHODS. We measured lung function and TTmus in 22
children. Subjects were grouped as controls (n=12), having obstructive lung
disease (n=8, including CF, bronchiectasis, and asthma), or having restrictive
lung diseases (n=2, muscular dystrophy and an unspecified myopathy). Inspiratory
flow was occluded for 250 milliseconds with a balloon in the inspiratory limb
that was inflated during exhalation. Data were collected for 3 minutes during
quiet breathing using a computerized system. TTmus was calculated from P100,
MIP at functional residual capacity, TI, and TTOT as previously described.
RESULTS. TTmus was significantly higher in subjects with restrictive lung
disease (TTmus=0.199 ± 0.12, p<0.05 by ANOVA), and was higher in obstructive
patients (TTmus=0.122 ± 0.07) than in controls (TTmus=0.067 ± 0.03). Most of
the variation of TTmus was due to variation in PI /MIP and not due to variation
in TI/TTOT. CONCLUSION. Children with lung diseases, especially restrictive
diseases, may be at higher risk for respiratory muscle fatigue which may
predispose to respiratory insufficiency. Non-invasive measurement of TTmus may
detect early respiratory muscle fatigue. As such, further study is warranted to
evaluate the clinical utility of this measurement in children.
20) Regenerative Potential Of Dystrophin-Deficient Muscles
With Advanced Disease: Implications For Gene Therapy In The Dystrophic Diaphragm
G.H. Guibinga, S. Ebihara, J. Nalbantoglu, G. Karpati, B.J. Petrof,
Montreal, PQ, Canada
Duchenne muscular dystrophy (DMD) and its murine homolog (mdx) are caused by
defects in the dystrophin gene. Adenoviral vectors (AdV) represent a potential
method for restoring a functional dystrophin gene in this setting. Immature
regenerating myofibers are the principal target for AdV in muscle, and this is
likely related at least in part to greater expression of the
Coxsackie/adenovirus attachment receptor (CAR). However, spontaneous
regeneration is reduced in dystrophin-deficient muscles with advanced pathology.
Therefore, in the current study we have sought to evaluate the regenerative
potential of dystrophin-deficient diaphragm and limb muscles with advanced
pathology. First, the soleus muscle of 14-17 mo old mdx mice was injected with
notexin, a substance which induces transient necrosis followed by vigorous
regeneration in normal muscle. Five days after notexin delivery to mdx mice,
marked overexpression of CAR was found, and AdV containing a dystrophin minigene
(AdV-Dys) was injected into the regenerating muscle. At 50 days after AdV-Dys
delivery, improved force-generating capacity and protection against high-stress
lengthening contractions was observed as compared to an untreated muscle. Given
the phenotypic resemblance between the diaphragm of adult mdx mice and DMD, we
then determined the functional impact of notexin administration on the mdx
diaphragm. An effective regenerative response was also observed, as evidenced by
widespread embryonic myosin heavy chain staining at day 5 and no functional
deficit compared to untreated muscle at 60 days. These results suggest that
regeneration can be effectively induced in the dystrophic diaphragm, and this
strategy may facilitate molecular therapeutic intervention with adenoyiral
vectors in DMD.
21) Response Of Dystrophin-Deficient Skeletal Muscle To
Ischemia/Reperfusion-Induced Oxidative Stress
R. W. R. Dudley, W. -K. Cho, S. N. Hussain, S. Mohammed, L. Lands,
and B. J. Petrof. Respiratory Division, Royal Victoria Hospital,
Meakins-Christie Laboratories, McGill University Health Center, Montreal,
Canada.
Mutations in the gene encoding the cytoskeletal protein dystrophin cause
Duchenne Muscular Dystrophy (DMD), but the precise mechanism by which lack of
dystrophin leads to muscle destruction with attendant respiratory failure
remains unresolved. It has been postulated that free radicals may play a role in
this process, and displacement of neuronal nitric oxide synthase (nNOS) from the
sarcolemma to the cytosol has been implicated. Here we used hindlimb tourniquet
application to subject the tibialis anterior (TA) of adult dystrophic (mdx;
n=7) and normal control mice (C57B16; n=7) to ischemia-reperfusion (I/R) injury,
a model of in vivo oxidative stress. Evans blue dye (EBD), a low
molecular weight tracer, was injected i.v. to determine the level of sarcolemmal
damage after I/R. Glutathione analysis and immunoblotting for protein carbonyls
were used as markers of overall oxidative stress, while 3-nitrotyrosine
formation was used as an indicator of nitrosative stress. Within each mouse
strain, I/R caused significant increases in EBD uptake and protein carbonyls as
well as a significant decrease in total glutathione, but no differences were
seen between the mdx and control mice. However, mdx muscles
demonstrated increased protein tyrosine nitration after I/R. In particular, a
protein band of ~58 kDa showed a 37393%
(p<0.05) increase in 3-nitrotyrosine immunoreactivity in mdx, while
increasing by only 10313%
in controls. Our results suggest that dystrophic muscles of adult mdx
mice are not abnormally vulnerable to sarcolemmal injury and certain oxidative
modifications following I/R, but do display increased susceptibility to protein
tyrosine nitration relative to controls. We speculate that nNOS displacement to
the cytosol in mdx muscle may play a role in this enhanced
3-nitrotyrosine formation.
22) Long-Term Effects of Nocturnal Noninvasive Ventilation
in Children with Neuromuscular Disorders (NMD)
U. Mellies, R. Ragette, C. Schwake, T. Voit, H. Teschler. University
of Essen, Children's Hospital, Essen, Germany; Ruhrlandklinik, Department of
Pneumology and Sleep Medicine, Essen, Germany
Objective: Aim of the study was to investigate the long-term impact of
nocturnal non-invasive ventilation (NIV) on sleep, sleep disordered breathing
(SDB) and respiratory function in children with NMD. Methods: Thirty
patients (12.3
4.1 years) with various inherited NMD were treated with NIV for respiratory
failure (RF, n=14) or symptomatic SDB (n=16). Patients were prospectively
followed over 25.3
12.7 month. In addition 10 succesfully treated patients were studied before and
after 3 nights withdrawal from NIV. Results: NIV normalized nocturnal gas
exchange in all patients and diurnal gas exchange in patients with RF. The
effects persisted long-term: nocturnal transcutaneous PCO2 improved from
(baseline vs. latest control) 53.7
9.9 to 41.6
4.8 mmHg, diurnal PaCO2 from 56.4
9.5 to 42.8
2.6mmHg (p <0.001 for all). NIV improved respiratory disturbance index,
arousals from sleep, nocturnal heart rate (p <0.01 for all) and sleep
architecture (p <0.05). Vital capacity decreased in five adolescents with
Duchenne muscular dystrophy -183
111 ml/year but remained stable ( +8
78 ml/year) in 25 children with other conditions. Peak inspiratory pressure
increased slightly in all NMD (from 2.5
1.3 to 2.8
1.2 kPa, p <0.05). Three nights withdrawal from NIV resulted in prompt
deterioration of SDB and gas exchange back to base-line but could be instantly
normalized by resumption of NIV. Conclusion: There is sufficient evidence
that NIV has favourable long-term impact on sleep disordered breathing and
respiratory function in children with NMD. NIV is indicated in children with
symptomatic SDB or respiratory failure.