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Original Research Pulmonary Physiology
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Forced Oscillation Technique in Spinal Muscular Atrophy Leanne M. Gauld, MD; Lucy A. Keeling, BExSc; Claire E. Shackleton, BSc(Hons); and Peter D. Sly, PhD
BACKGROUND: Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. METHODS: Children with SMA aged , 10 years were recruited. FOT was performed every 3 months for 12 months (five visits). Spirometry and assisted and unassisted peak cough flow (PCF) were performed where possible. Polysomnography was performed on children with type 2 SMA. Clinical information included SMA type, chest infections, Cobb angle, medications, and mobility. Regression analysis assessed relationships between FOT and FVC, PCF, and apnea/hypopnea index (AHI). Analysis of variance sought relationships to clinical characteristics.
Twelve children (seven male) were recruited; mean age was 6.26 ( ⫾ 2.59) years. Respiratory reactance at 8 Hz (Xrs8) (mean z score, 11.41; SD, 1.90; P , .03) and respiratory resistance at 8 Hz (Rrs8) (mean z score, 10.66; SD, 1.34; P 5 .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8 z score worsened (rate of change of 11.08, P , .001) and Rrs8 z score worsened (rate of change 10.51, P , .001). No relationship (P . .05) was found between clinical characteristics and FOT values. RESULTS:
FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted. CHEST 2014; 146(3):795-803 CONCLUSIONS:
Manuscript received January 20, 2014; revision accepted March 13, 2014; originally published Online First May 8, 2014. ABBREVIATIONS: AHI 5 apnea/hypopnea index; FOT 5 forced oscillation technique; NIV 5 noninvasive ventilation; PCF 5 peak cough flow; Rrs 5 respiratory resistance; SMA 5 spinal muscular atrophy; Tcco2 5 transcutaneous partial pressure of CO2; Xrs 5 respiratory reactance AFFILIATIONS: From the Queensland Children’s Medical Research Institute (Drs Gauld and Sly and Mss Keeling and Shackleton); and Royal Children’s Hospital Brisbane (Drs Gauld and Sly), The State of Queensland (Queensland Health), Herston, QLD, Australia.
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Part of this article has been presented in abstract form (Gauld L, Keeling L, Sly P, Shackleton C. Eur Respir J. 2013;42(suppl 57):227S). FUNDING/SUPPORT: The research was supported by the ANZ Queensland Community Foundation–the Catherine Hannay Estate. CORRESPONDENCE TO: Leanne M. Gauld, MD, Department of Respiratory Medicine, Royal Children’s Hospital, Herston Rd, Herston, QLD, 4006, Australia; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0166
795
Spinal muscular atrophy (SMA) is an autosomalrecessive neuromuscular disease affecting 12 to 60 per million live births.1,2 It is classified by age of diagnosis, clinical characteristics, and expected course.3 Typically, type 1 is diagnosed at , 6 months, and death occurs at , 18 months of age. Type 2 is diagnosed at 6 to 18 months and sit, but do not walk; death occurs at . 2 years of age. Type 3 is diagnosed at . 18 months and walk; death occurs in adulthood.3,4 In SMA, progressive weakness affects intercostals with relative diaphragm sparing.3,5,6 Progressive inspiratory and expiratory muscle weakness with reduced lung and chest wall compliance causes alveolar hypoventilation and reduced cough efficacy. Children typically have a barrel chest and use abdominal muscles to assist breathing.6 Bulbar dysfunction develops. Progressive scoliosis is common, worsening respiratory restriction.7,8 Children develop recurrent chest infections or aspiration, and respiratory failure ensues, initially during sleep, leading to death.9-11 Objective respiratory measures such as vital capacity, maximal inspiratory and expiratory pressures, sniff nasal inspiratory pressures, and inspiratory vital
Materials and Methods Subjects All children with SMA known to the Neuromuscular Service of the Royal Children’s Hospital Brisbane aged , 10 years were invited to participate. Children were identified by searching the comprehensive Queensland Pediatric Neuromuscular Service database (Queensland population, 4.5 million; 900,000 children , 15 years).17 Additionally, one child from New South Wales learned of the research through social media and requested inclusion. No child included in the study had a tracheostomy. Research Design Recruited children underwent assessment for diagnosis and clinical characteristics by a pediatrician. Polysomnography was organized for subjects no longer walking. Those using nocturnal noninvasive ventilation (NIV) had a titration rather than a diagnostic study. Children had visits every 3 months for 12 months (baseline and four quarterly visits), during which anthropometric measurements, FOT, spirometry, and PCF measurements were performed where able. Children were well at the times of testing. Where children were not able to perform FOT, they were given the opportunity to try again every 3 months for a 12-month period.
capacity are useful in monitoring progress, timing polysomnography, and assessing risk for chest infection admission in neuromuscular disease.2,5,6,12 However, most require concentration, cooperation, and performance of complex respiratory maneuvers. Acceptable and repeatable tests are rarely feasible in children , 6 years old.13-15 In SMA, respiratory function is often impaired by this age. In Duchenne muscular dystrophy, peak cough flow (PCF) . 160 L/min is required for effective airway clearance; below this, admissions with chest infections occur.12 There are no published reference values for young children. Polysomnography assesses sleep breathing but is labor intensive.10,11 Alternative objective respiratory assessments are essential. The forced oscillation technique (FOT) is a commercially available respiratory test requiring only tidal breathing.14 Reference values exist for children ⱖ 2 years.16 Its usefulness in neuromuscular disease has not been assessed. There is a need for objective, noninvasive, nonvolitional respiratory measurements useful in young children with neuromuscular disorders, such as SMA. This study aimed to assess feasibility and clinical relevance of FOT in young children with SMA. seated with the head in a neutral position, connected to the oscillation device via a mouthpiece with bacterial filter (SureGard; Bird Healthcare) and noseclip in place. Cheeks and lower jaw were supported. Measurements were obtained using a commercially available device (12M; Chess Medical, marketed by Cosmed) according to the American Thoracic Society/European Respiratory Society guidelines.14 Pseudorandom noise forcing, signal containing, integer-multiple frequencies between 4 Hz and 48 Hz were applied. Equipment was calibrated daily using known resistance. Children were instructed to breathe normally. A minimum of three and a maximum of 12 acceptable measurements were obtained. Individual measurements were excluded if there was mouth leak, mouth movement, swallowing, glottis closure, or audible noise. Measurements were examined post hoc for evidence of inadequate measurement quality at specific frequencies. Measurement quality was acceptable if the coherence function at an individual frequency was ⱖ 0.95; measurements where at least three individual frequencies had a coherence , 0.95 were excluded.21 Variables recorded were respiratory resistance (Rrs) and reactance (Xrs) at 6, 8, and 10 Hz (Rrs6, Rrs8, Rrs10 and Xrs6, Xrs8, Xrs10) and average resistance (Rrs4-24).20 Predicted values and z scores were calculated from height, using reference data.16,20
Clinical Characteristics and Anthropometric Measurements Baseline data included age, sex, genotype, SMA type,3 mobility, chest infection and medication history. A spinal series was performed, and maximum Cobb angle recorded.18 Ulna length measurements (millimeters) determined standing height, as only three children could stand.19
Spirometry: All children able to reasonably understand instructions attempted spirometry. FVC and FEV1 were measured with the Sensormedics Vmax 20C Encore System (CareFusion Corp) in the seated position with a noseclip and bacterial filter (SureGard; Bird Healthcare). A minimum of three satisfactory recordings were required according the accepted criteria of the American Thoracic Society/European Respiratory Society.22 Predicted values and z scores were calculated.23
Pulmonary Function Tests Forced Oscillation Technique: The method of respiratory impedance measurement has previously been described.16,20 Briefly, children were
Peak Cough Flow: PCFs were recorded seated with a noseclip and a bacterial filter (SureGard; Bird Healthcare) by a mass flow sensor (Sensormedics Vmax 20C Encore System; CareFusion Corp). For the
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assisted PCF, a trained person assisted the cough with a timed bilateral chest wall compression in conjunction with the child’s cough. A minimum of three and a maximum of five coughs were performed and the highest value recorded. Polysomnography: Polysomnography was performed (Embla 2.0; Flaga Medical Devices), including transcutaneous partial pressure of CO2 (Tcco2). Sleep stages and respiratory events were scored manually using standard American Academy of Sleep Medicine criteria.24 In brief, apneas and hypopneas lasted at least two respiratory cycles and were accompanied by a fall in oxygen saturation of . 3% or an arousal . 3 s. An apnea/hypopnea index (AHI) was calculated as the overall number of events per hour. Hypoventilation was defined as Tcco2 . 55 mm Hg.
Results Nineteen children aged , 10 years with SMA were identified, and 13 were recruited (Fig 1). One child with SMA type 2 (subject 8) died following initial assessment. One child failed to attend the final visit. Follow-up was complete on all others. Baseline characteristics are summarized in Table 1. In young children with SMA, FOT is feasible. Acceptable FOT was obtained in 12 children (seven boys)
Data Analysis The paired t test compared measured and predicted FOT values. Regression analysis assessed relationships between FVC, PCF, and AHI to FOT. Pearson correlation assessed relationships between spirometry and FOT z scores. Relationships between clinical and polysomnography data and FOT measurements were sought using analysis of variance and regression analysis. For longitudinal data, a rate of change was calculated. Stata version 11 (StataCorp LP) was used. Significance was accepted at .05. Ethical Considerations The study was conducted in accordance with the amended Declaration of Helsinki. The project and written informed consent were approved by the Human Research Ethics Committee of the Royal Children’s Hospital (HREC/11/QRCH/22) and University of Queensland (2012000102).
(mean age, 6.26 [⫾ 2.59] years). One child aged 2 years was unable to perform the test. Respiratory tests are summarized in Table 2. Reactance z scores were significantly abnormal (Xrs8 mean z score, 11.41; SD, 1.90; P , .03). Resistance z scores tended to be positive compared with normal, but this only reached statistical significance for Rrs10 (mean z score, 11.13; SD, 0.88; P , .001). Five children (42%) had an Xrs8 z score . 11.64 (95th percentile), and four children (33%) had a Rrs8 z score . 11.64. Although Xrs8 tended to be more
Figure 1 – Flow diagram of recruited children. FOT 5 forced oscillation technique; NSW 5 New South Wales; SMA 5 spinal muscular atrophy.
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8.9
5.1
4
6
4.5
3
6.7
3.7
2
5
3.3
F
M
F
F
M
M
Age at Visit 1, y Sex
2
2
2
2
2
2
Type of SMA
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Genotype
Valproate from 3 to 8y
Valproate and carnitine from 2 y
Wheelchair
Wheelchair
Nil
Wheelchair
Valproate from 3 y
Valproate from 20 mo
Wheelchair
Wheelchair
Valproate and carnitine from 18 mo
Medications for Disease Modification
Wheelchair
Ambulation
] Clinical Characteristics of Recruited Subjects
1
Subject No.
TABLE 1
14° T5-L4
42° T6-L3 spinal rods
Yes
85° T1-L5
No
No
85° T5-L5
23° T9-L4 22° C6-T9
No
No
13° T2-10
Cobb Angle
No
Surgical Spinal Fixation
42.4
49.8
4.6
2.0
5 managed at home, 2 ward admissions No
No
No
NIV
60
57.6
6.8
4.3
2 managed at home, 1 ward admission
2 ward admissions, 1 admission to intensive care for NIV
Other
PEG feeding; constipation management
NGT feeding
Nil
Constipation management
Aged 2 y, PEG inserted
Aged 2 y
Constipation Aged 2 y, management fracture management
Previous Anesthetic
Nocturnal Aged 9 y, spinal NIV ¿xation began following PSG
(Continued)
PEG feeding
Nil Nocturnal Aged 3 y, NIV hypospadias began repair following PSG
1.3 47.4 Nocturnal 4 managed (on NIV) (on NIV) NIV at home, 2 began admissions 6 mo to intensive prior care for NIV, 1 to the admission study to high dependency for NIV
5 managed at home, 2 ward admissions, 2 intensive care admissions for NIV
50.1
4.8
AHI
Maximum TcCO2, mm Hg
1 managed at home
Chest Infections in Preceding Year
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799
8.9
9.8
2.7
4.4
8.3
8
9
10
11
12
M
M
M
F
F
M
3
3
3
2
2
2
Type of SMA
Homozygous SMN1 deletion, exon 7-8
3 duplications SMN2
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Muscle biopsy and clinical diagnosis
Genotype
Nil
Valproate from 2 to 4y
Wheelchair
Wheelchair
Wheelchair
Valproate from 18 mo Nil
Walking
Walking
Nil
Nil
Ambulation
Walking
Medications for Disease Modification
14° T5-L2
0
No
No
0
66° T9-L4
No
No
22° T2-12 75° L1-5
30° T4-L4
Cobb Angle
Yes
No
Surgical Spinal Fixation
Nil signi¿cant
Nil signi¿cant
1 managed at home
...
...
...
...
...
...
Nil
No
No
Nil
Nil
Nil
Nil
Nil
Nil
PEG feeding; constipation management Aged 4 y, PEG insertion
5 managed at home
5 ward admissions, 2 admissions to intensive care for NIV
2.0 47.3 Nocturnal 5 managed at NIV home, 1 ward (on NIV) (on NIV) began admission age 4 y
Other
PEG feeding; this child died soon after the ¿rst visit
No
Previous Anesthetic
Aged 5 y, PEG insertion; aged 7 y, spinal ¿xation
2.4
NIV
0 45.6 Nocturnal (on NIV) (on NIV) NIV began age 6 y
54.8
AHI
Very poor nutrition
Maximum TcCO2, mm Hg Nil
Chest Infections in Preceding Year
AHI 5 apnea/hypopnea index; F 5 female; M 5 male; NGT 5 nasogastric tube; NIV 5 noninvasive ventilation; PEG 5 percutaneous endoscopic gastrostomy; PSG 5 polysomnography; SMA 5 spinal muscular atrophy; SMN 5 survival motor neuron; TcCO2 5 transcutaneous partial pressure of CO2.
8.9
Age at Visit 1, y Sex
] (continued)
7
Subject No.
TABLE 1
TABLE 2
] Pulmonary Function Test Results, Visit 1
Test Results
Mean Value (SD)
% Predicted Value (SD)
Mean z Score (SD)
Comparison With Predicted Value, P
FOT values (n 5 12) Rrs4-24
8.36 (3.03)
...
11.31 (1.50)
, .02
Rrs6
9.21 (3.42)
...
10.55 (1.32)
5 .18
Rrs8
9.27 (3.40)
...
10.66 (1.34)
5 .12
Rrs10
9.44 (2.70)
...
11.13 (0.88)
, .01
Xrs6
24.62 (2.13)
...
11.56 (1.67)
, .01
Xrs8
23.83 (2.24)
...
11.41 (1.90)
, .03
Xrs10
23.91 (2.17)
...
1 1.49 (1.76)
, .02
Spirometry (n 5 5) FVC, L
0.97 (0.55)
56.61 (31.07)
25.45 (4.23)
, .001
FEV1, L
0.86 (0.53)
52.73 (31.92)
26.03 (4.50)
, .001
Peak cough Àow, n 5 10 Unassisted, L/min
119.34 (42.37)
...
...
...
Assisted, L/min
125.90 (43.84)
...
...
...
FOT 5 forced oscillation technique; Rrs 5 respiratory resistance; Xrs 5 respiratory reactance.
abnormal in children with type 2 than type 3 SMA, this did not reach statistical significance.
Mean (SD) and predicted values are summarized in Table 2.
Longitudinal measurements are summarized in Figure 2. Over 12 months, Xrs8 z score worsened (rate of change of 11.08 z score per annum, P , .001) and Rrs8 z score worsened (10.51 z scores per annum, P , .04) (Table 3). Rate of change of spirometry was not undertaken due to small numbers with repeat measurements (n 5 3).
A linear relationship occurs between Xrs8 and FVC (R2, 0.54), % FVC (R2, 0.50), FVC z score (R2, 0.64), FEV1 (R2, 0.35), % FEV1 (R2, 0.50), FEV1 z score (R2, 0.51), unassisted PCF (R2, 0.33), and assisted PCF (R2, 0.43) (Fig 3). There is a significant correlation between FVC z score and Xrs z score at 6 Hz and 8 Hz (20.72, P , .02; 20.69, P , .02, respectively). Similarly, there is a significant correlation between FEV1 z score and Xrs z score at 6 Hz and 8 Hz (20.63, P , .04; 20.60, P , .05, respectively). There is no significant correlation between spirometry z scores and Rrs values at 6 Hz, 8 Hz, or 10 Hz. There is a weak linear relationship between AHI and Xrs8 (R2, 0.32) and Rrs8 (R2, 0.27) for the eight children in
Six children were aged . 6 years, and five performed spirometry at least once: four with SMA type 2 and one with SMA type 3, who had normal spirometry for age.
TABLE 3
] Overall Rate of Change in FOT Values Over
z Scores
Figure 2 – Longitudinal measurements for Rrs8 and Xrs8 over 12 mo. The child who died soon after her first visit is shown with open symbols. Rrs 5 respiratory resistance; Xrs 5 respiratory reactance.
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12 Mo
Rate of Change per Annum
P Value
95% CI
Rrs6
10.40
.02
20.08 to 0.88
Rrs8
10.51
.04
20.03 to 0.98
Rrs10
10.77
, .001
0.33 to 1.21
Xrs6
11.27
, .001
0.71 to 1.82
Xrs8
11.08
, .001
0.52 to 1.64
Xrs10
11.04
, .001
0.50 to 1.58
See Table 2 legend for expansion of abbreviations.
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Figure 3 – A-C, Xrs8 has a linear relationship to (A) FVC ( R2, 0.54), (B) unassisted peak cough flow ( R2, 0.33), and (C) assisted peak cough flow ( R2, 0.43). See Figure 2 legend for expansion of abbreviation.
whom a polysomnography was undertaken, although three were using NIV and numbers are small. No significant relationship (P . .05) was found between clinical characteristics (sex, SMA type, mobility, medication use, previous spinal surgery, nocturnal NIV) and FOT. There was no relationship between Cobb angle and resistance (R2, 0.03-0.17) or reactance (R2, 0.008-0.06) or chest infection history and resistance (R2, 0.005-0.13) or reactance (R2, 0.001-0.04).
Discussion In young children with neuromuscular weakness, FOT is feasible, as shown in this group with SMA; only one child (age 2 years) was unable to perform the test. Nonvolitional and noninvasive tests are readily performed in young children. Sniff nasal inspiratory pressure is feasible in children . 6 years of age with SMA and reference values exist . 6 years.2,25 Spirometry generally becomes reliable and repeatable . 6 years.22 Many children with SMA have abnormal respiratory function by this age, and objective monitoring in younger children would enhance assessment. Mean FOT values were abnormal with values being . 95th percentile for reactance in 42% and resistance in 33%. Reactance measures elasticity (relationship between pressure and volume) and inertive properties (relationship between pressure and volume acceleration) of the lung.14 With a stiff chest wall and reduced lung volumes, it is expected to be reduced and worsen over time. In this study, it was significantly increased compared with journal.publications.chestnet.org
normal (more elastic), and increased further over 12 months (11.08 z scores). Resistance mainly measures viscous resistance in large airways and, to a lesser extent, tissue resistance.14 In SMA, tissue compliance is reduced due to underinflation and microatelectasis.26,27 As compliance reduces, it is expected that tissue resistance and Rrs values increase over time, as has been found (10.51 z scores per annum). There is a wider spread of FOT values at the initial visit than subsequently. This likely represents a learning effect. As with many respiratory tests, there is a learning period required. Longitudinal assessments and other clinical markers are important in overall assessment of individuals. Inclusion of a control group may have better characterized the learning effect. Several groups have assessed the rate of change of FVC or % FVC, and results have varied.2,28,29 Two studies have grouped type 2 and 3 patients with SMA and included children and adults.28,29 The younger group28 had no change in FVC over 12 months. Younger children are expected to have an increase in FVC with growth, and no change in observed values would likely result in a reduction in predicted values. The older group29 had a fall in % FVC of 1.1% per annum. Khirani et al2 found a decline in % FVC of 9.8% per annum in type 2 and 4.2% in type 3. Patients in all three studies were older than the current group, and changes in respiratory function may differ in different age groups, due to the progressive nature of SMA. The current study has shown that resistance and reactance become more abnormal 801
over 12 months. Numbers were too small to gain appreciation of differences in FOT between SMA types. Although FOT provides an objective measure, it does not measure the same aspects of respiratory function as other tests. However, it is expected that a relationship exists between FOT and spirometry, as was found. There was a reasonable correlation between reactance and spirometry, although the relationship to resistance was not statistically significant. PCF measures cough capacity. It is a volitional test that requires coughing into a mouthpiece. It is easily mastered by young children. Assisting the cough increases the PCF and is commonly used in conjunction with physiotherapy to aid airway clearance.30 It is expected the PCF will be more severely impaired in those with more severe weakness and that the reactance is lower in weaker children. A linear relationship was found between assisted and unassisted PCF and Xrs8, supporting the expected association. No associations were seen between clinical characteristics and FOT. Respiratory tests are influenced by many factors including chest wall movement, lung parenchyma, and airway pathology. Likewise, the influence of clinical factors on the respiratory system is complex, and abnormalities in respiratory measurements may be multifactorial. Clinical factors are also multifaceted. History of chest infections, for instance, may be influenced by frequency of viral encounters, and scoliosis will have a different influence in the thoracic than lumber spine. Understandably, an association between clinical characteristics and FOT was not found. Large patient numbers may be required to better define these relationships. In older children with Duchenne muscular dystrophy, daytime markers for sleep-disordered breathing include respiratory function.31 Polysomnography can be prioritized to those with the highest likelihood of sleep-disordered breathing. There is no currently known association between respiratory function and need for NIV in SMA, although this has not been extensively researched, and FOT has only recently become available.32 Further investigation into the usefulness of FOT in predicting sleep-
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disordered breathing is required. It is encouraging that with a small sample, there is a relationship between FOT and AHI. Predicted values of FOT are derived from standing height. Many children with SMA are unable to stand for accurate height measurement. Arm span has been used to predict height, but accurate measurement is difficult with spinal deformity or joint contractures. Ulna length measurement is straightforward, and accurate prediction equations exist for children ⱖ 6 years of age.19 The prediction equations have been extrapolated to younger children in this study. This research group is currently undertaking further work to extend the ulna prediction equations to 1 year, and the tight linear relationship is maintained in younger children.33 It, hence, seems reasonable to use extrapolated equations. Reference data for FOT was developed for white children from a reference population within Australia and Italy. It is the most appropriate reference data available for FOT testing in Queensland. The major study limitation is small patient numbers. SMA is uncommon. All patients known to have SMA in Queensland were identified. It is unlikely patients were missed, as the diagnosis is generally confirmed within the tertiary service, with follow-up by the neuromuscular service. Genuine efforts were made to include all identified children. Most not enrolling have disengaged from tertiary medical services, and the status of the three who could not be contacted is unknown. Further advancement of this work may be achieved by including additional centers in the future.
Conclusions In conclusion, in young children with SMA, FOT is feasible, with abnormal values of resistance and reactance on grouped data. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, and AHI). Further research on the value of FOT in managing individuals is warranted. Objective respiratory measurements in young children with SMA may be important in designing future clinical trials of diseasemodifying treatments34-38 and in clinical assessment in young children.
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Acknowledgments Author contributions: L. M. G. takes full responsibility for the integrity of the data and accuracy of data analysis and integrity of the submission as a whole. L. M. G. contributed to study design, approvals, grant application, recruitment, data analysis, and the writing and revision of the manuscript; L. A. K. and C. E. S. contributed substantially to data acquisition; P. D. S. contributed substantially to interpretation of data; and L. A. K., C. E. S., and P. D. S. contributed to the revision of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
References 1. Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord. 1991;1(1):19-29. 2. Khirani S, Colella M, Caldarelli V, et al. Longitudinal course of lung function and respiratory muscle strength in spinal muscular atrophy type 2 and 3. Eur J Paediatr Neurol. 2013;17(6):552-560. 3. Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992;2(5-6):423-428. 4. Elsheikh B, Prior T, Zhang X, et al. An analysis of disease severity based on SMN2 copy number in adults with spinal muscular atrophy. Muscle Nerve. 2009;40(4):652-656. 5. Nicot F, Hart N, Forin V, et al. Respiratory muscle testing: a valuable tool for children with neuromuscular disorders. Am J Respir Crit Care Med. 2006;174(1):67-74. 6. Wang CH, Finkel RS, Bertini ES, et al; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007; 22(8):1027-1049. 7. Robinson D, Galasko CS, Delaney C, Williamson JB, Barrie JL. Scoliosis and lung function in spinal muscular atrophy. Eur Spine J. 1995;4(5):268-273. 8. Tangsrud SE, Carlsen KC, Lund-Petersen I, Carlsen KH. Lung function measurements in young children with spinal muscle atrophy; a cross sectional survey on the effect of position and bracing. Arch Dis Child. 2001;84(6):521-524. 9. Manni R, Cerveri I, Ottolini A, et al. Sleep related breathing patterns in patients with spinal muscular atrophy. Ital J Neurol Sci. 1993;14(7):565-569. 10. Mellies U, Dohna-Schwake C, Stehling F, Voit T. Sleep disordered breathing in spinal muscular atrophy. Neuromuscul Disord. 2004;14(12):797-803. journal.publications.chestnet.org
11. Testa MB, Pavone M, Bertini E, Petrone A, Pagani M, Cutrera R. Sleep-disordered breathing in spinal muscular atrophy types 1 and 2. Am J Phys Med Rehabil. 2005;84(9):666-670. 12. Dohna-Schwake C, Ragette R, Teschler H, Voit T, Mellies U. Predictors of severe chest infections in pediatric neuromuscular disorders. Neuromuscul Disord. 2006;16(5):325-328. 13. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(3): 1107-1136. 14. Beydon N, Davis SD, Lombardi E, et al; American Thoracic Society/European Respiratory Society Working Group on Infant and Young Children Pulmonary Function Testing. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med. 2007;175(12):1304-1345. 15. American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166(4):518-624. 16. Calogero C, Simpson SJ, Lombardi E, et al. Respiratory impedance and bronchodilator responsiveness in healthy children aged 2-13 years. Pediatr Pulmonol. 2013;48(7):707-715. 17. National regional profile: Queensland. Australian Bureau of Statistics website. http://www.abs.gov.au/AUSSTATS/ [email protected]/Latestproducts/3Population/ People12007-2011?opendocument& tabname=Summary&prodno=3&issue= 2007-2011. Published 2012. Accessed August 27, 2013. 18. Cobb JR. Outline for the study of scoliosis. In: Instructional Courses Lectures, American Academy of Orthopaedic Surgeons. Vol 5. Ann Arbor, MI: JW Edwards; 1948:261-275. 19. Gauld LM, Kappers J, Carlin JB, Robertson CF. Height prediction from ulna length. Dev Med Child Neurol. 2004; 46(7):475-480. 20. Hall GL, Sly PD, Fukushima T, et al. Respiratory function in healthy young children using forced oscillations. Thorax. 2007;62(6):521-526. 21. Frey U. Forced oscillation technique in infants and young children. Paediatr Respir Rev. 2005;6(4):246-254. 22. Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. 23. Gauld LM, Kappers J, Carlin JB, Robertson CF. Prediction of childhood pulmonary function using ulna length. Am J Respir Crit Care Med. 2003;168(7): 804-809. 24. Berry RB, Budhiraja R, Gottlieb DJ, et al; American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8(5):597-619.
25. Stefanutti D, Fitting JW. Sniff nasal inspiratory pressure. Reference values in Caucasian children. Am J Respir Crit Care Med. 1999;159(1):107-111. 26. Schramm CM. Current concepts of respiratory complications of neuromuscular disease in children. Curr Opin Pediatr. 2000;12(3):203-207. 27. Gibson GJ, Pride NB, Davis JN, Loh LC. Pulmonary mechanics in patients with respiratory muscle weakness. Am Rev Respir Dis. 1977;115(3):389-395. 28. Kaufmann P, McDermott MP, Darras BT, et al; Muscle Study Group; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy. Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. Arch Neurol. 2011;68(6):779-786. 29. Steffensen BF, Lyager S, Werge B, Rahbek J, Mattsson E. Physical capacity in non-ambulatory people with Duchenne muscular dystrophy or spinal muscular atrophy: a longitudinal study. Dev Med Child Neurol. 2002;44(9):623-632. 30. Chatwin M, Ross E, Hart N, Nickol AH, Polkey MI, Simonds AK. Cough augmentation with mechanical insufflation/exsufflation in patients with neuromuscular weakness. Eur Respir J. 2003;21(3):502-508. 31. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Am J Respir Crit Care Med. 2000;161(1):166-170. 32. Lyager S, Steffensen B, Juhl B. Indicators of need for mechanical ventilation in Duchenne muscular dystrophy and spinal muscular atrophy. Chest. 1995;108(3): 779-785. 33. Keeling LA, Sly PD, Shackleton CE, Gauld LM. Height prediction from ulna length in young children. Respirology. 2012;17. 34. Chen TH, Chang JG, Yang YH, et al. Randomized, double-blind, placebocontrolled trial of hydroxyurea in spinal muscular atrophy. Neurology. 2010;75(24):2190-2197. 35. Swoboda KJ, Scott CB, Crawford TO, et al; Project Cure Spinal Muscular Atrophy Investigators Network. SMA CARNI-VAL trial part I: doubleblind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS ONE. 2010;5(8):e12140. 36. Swoboda KJ, Scott CB, Reyna SP, et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS ONE. 2009;4(5):e5268. 37. Kissel JT, Scott CB, Reyna SP, et al; Project Cure Spinal Muscular Atrophy Investigators’ Network. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS ONE. 2011;6(7):e21296. 38. Liang W-C, Yuo C-Y, Chang J-G, et al. The effect of hydroxyurea in spinal muscular atrophy cells and patients. J Neurol Sci. 2008;268(1-2):87-94.
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Original Research Pulmonary Physiology
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Forced Oscillation Technique in Spinal Muscular Atrophy Leanne M. Gauld, MD; Lucy A. Keeling, BExSc; Claire E. Shackleton, BSc(Hons); and Peter D. Sly, PhD
BACKGROUND: Spinal muscular atrophy (SMA) causes respiratory compromise that is difficult to assess in young children. The forced oscillation technique (FOT) is commercially available for children as young as 2 years of age and is nonvolitional. The aim of this study was to assess the usefulness of FOT in young children with SMA. METHODS: Children with SMA aged , 10 years were recruited. FOT was performed every 3 months for 12 months (five visits). Spirometry and assisted and unassisted peak cough flow (PCF) were performed where possible. Polysomnography was performed on children with type 2 SMA. Clinical information included SMA type, chest infections, Cobb angle, medications, and mobility. Regression analysis assessed relationships between FOT and FVC, PCF, and apnea/hypopnea index (AHI). Analysis of variance sought relationships to clinical characteristics.
Twelve children (seven male) were recruited; mean age was 6.26 ( ⫾ 2.59) years. Respiratory reactance at 8 Hz (Xrs8) (mean z score, 11.41; SD, 1.90; P , .03) and respiratory resistance at 8 Hz (Rrs8) (mean z score, 10.66; SD, 1.34; P 5 .12) were abnormal. Four children performed spirometry. Linear relationships to Xrs8 exist: FVC (R2, 0.54), unassisted PCF (R2, 0.33), assisted PCF (R2, 0.43), and AHI (R2, 0.32). Over 12 months, Xrs8 z score worsened (rate of change of 11.08, P , .001) and Rrs8 z score worsened (rate of change 10.51, P , .001). No relationship (P . .05) was found between clinical characteristics and FOT values. RESULTS:
FOT is feasible in young children with SMA, with abnormal values of reactance and resistance on grouped data, worsening over 12 months. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, AHI). Further research on the value of FOT in managing individuals is warranted. CHEST 2014; 146(3):795-803 CONCLUSIONS:
Manuscript received January 20, 2014; revision accepted March 13, 2014; originally published Online First May 8, 2014. ABBREVIATIONS: AHI 5 apnea/hypopnea index; FOT 5 forced oscillation technique; NIV 5 noninvasive ventilation; PCF 5 peak cough flow; Rrs 5 respiratory resistance; SMA 5 spinal muscular atrophy; Tcco2 5 transcutaneous partial pressure of CO2; Xrs 5 respiratory reactance AFFILIATIONS: From the Queensland Children’s Medical Research Institute (Drs Gauld and Sly and Mss Keeling and Shackleton); and Royal Children’s Hospital Brisbane (Drs Gauld and Sly), The State of Queensland (Queensland Health), Herston, QLD, Australia.
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Part of this article has been presented in abstract form (Gauld L, Keeling L, Sly P, Shackleton C. Eur Respir J. 2013;42(suppl 57):227S). FUNDING/SUPPORT: The research was supported by the ANZ Queensland Community Foundation–the Catherine Hannay Estate. CORRESPONDENCE TO: Leanne M. Gauld, MD, Department of Respiratory Medicine, Royal Children’s Hospital, Herston Rd, Herston, QLD, 4006, Australia; e-mail: [email protected] © 2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-0166
795
Spinal muscular atrophy (SMA) is an autosomalrecessive neuromuscular disease affecting 12 to 60 per million live births.1,2 It is classified by age of diagnosis, clinical characteristics, and expected course.3 Typically, type 1 is diagnosed at , 6 months, and death occurs at , 18 months of age. Type 2 is diagnosed at 6 to 18 months and sit, but do not walk; death occurs at . 2 years of age. Type 3 is diagnosed at . 18 months and walk; death occurs in adulthood.3,4 In SMA, progressive weakness affects intercostals with relative diaphragm sparing.3,5,6 Progressive inspiratory and expiratory muscle weakness with reduced lung and chest wall compliance causes alveolar hypoventilation and reduced cough efficacy. Children typically have a barrel chest and use abdominal muscles to assist breathing.6 Bulbar dysfunction develops. Progressive scoliosis is common, worsening respiratory restriction.7,8 Children develop recurrent chest infections or aspiration, and respiratory failure ensues, initially during sleep, leading to death.9-11 Objective respiratory measures such as vital capacity, maximal inspiratory and expiratory pressures, sniff nasal inspiratory pressures, and inspiratory vital
Materials and Methods Subjects All children with SMA known to the Neuromuscular Service of the Royal Children’s Hospital Brisbane aged , 10 years were invited to participate. Children were identified by searching the comprehensive Queensland Pediatric Neuromuscular Service database (Queensland population, 4.5 million; 900,000 children , 15 years).17 Additionally, one child from New South Wales learned of the research through social media and requested inclusion. No child included in the study had a tracheostomy. Research Design Recruited children underwent assessment for diagnosis and clinical characteristics by a pediatrician. Polysomnography was organized for subjects no longer walking. Those using nocturnal noninvasive ventilation (NIV) had a titration rather than a diagnostic study. Children had visits every 3 months for 12 months (baseline and four quarterly visits), during which anthropometric measurements, FOT, spirometry, and PCF measurements were performed where able. Children were well at the times of testing. Where children were not able to perform FOT, they were given the opportunity to try again every 3 months for a 12-month period.
capacity are useful in monitoring progress, timing polysomnography, and assessing risk for chest infection admission in neuromuscular disease.2,5,6,12 However, most require concentration, cooperation, and performance of complex respiratory maneuvers. Acceptable and repeatable tests are rarely feasible in children , 6 years old.13-15 In SMA, respiratory function is often impaired by this age. In Duchenne muscular dystrophy, peak cough flow (PCF) . 160 L/min is required for effective airway clearance; below this, admissions with chest infections occur.12 There are no published reference values for young children. Polysomnography assesses sleep breathing but is labor intensive.10,11 Alternative objective respiratory assessments are essential. The forced oscillation technique (FOT) is a commercially available respiratory test requiring only tidal breathing.14 Reference values exist for children ⱖ 2 years.16 Its usefulness in neuromuscular disease has not been assessed. There is a need for objective, noninvasive, nonvolitional respiratory measurements useful in young children with neuromuscular disorders, such as SMA. This study aimed to assess feasibility and clinical relevance of FOT in young children with SMA. seated with the head in a neutral position, connected to the oscillation device via a mouthpiece with bacterial filter (SureGard; Bird Healthcare) and noseclip in place. Cheeks and lower jaw were supported. Measurements were obtained using a commercially available device (12M; Chess Medical, marketed by Cosmed) according to the American Thoracic Society/European Respiratory Society guidelines.14 Pseudorandom noise forcing, signal containing, integer-multiple frequencies between 4 Hz and 48 Hz were applied. Equipment was calibrated daily using known resistance. Children were instructed to breathe normally. A minimum of three and a maximum of 12 acceptable measurements were obtained. Individual measurements were excluded if there was mouth leak, mouth movement, swallowing, glottis closure, or audible noise. Measurements were examined post hoc for evidence of inadequate measurement quality at specific frequencies. Measurement quality was acceptable if the coherence function at an individual frequency was ⱖ 0.95; measurements where at least three individual frequencies had a coherence , 0.95 were excluded.21 Variables recorded were respiratory resistance (Rrs) and reactance (Xrs) at 6, 8, and 10 Hz (Rrs6, Rrs8, Rrs10 and Xrs6, Xrs8, Xrs10) and average resistance (Rrs4-24).20 Predicted values and z scores were calculated from height, using reference data.16,20
Clinical Characteristics and Anthropometric Measurements Baseline data included age, sex, genotype, SMA type,3 mobility, chest infection and medication history. A spinal series was performed, and maximum Cobb angle recorded.18 Ulna length measurements (millimeters) determined standing height, as only three children could stand.19
Spirometry: All children able to reasonably understand instructions attempted spirometry. FVC and FEV1 were measured with the Sensormedics Vmax 20C Encore System (CareFusion Corp) in the seated position with a noseclip and bacterial filter (SureGard; Bird Healthcare). A minimum of three satisfactory recordings were required according the accepted criteria of the American Thoracic Society/European Respiratory Society.22 Predicted values and z scores were calculated.23
Pulmonary Function Tests Forced Oscillation Technique: The method of respiratory impedance measurement has previously been described.16,20 Briefly, children were
Peak Cough Flow: PCFs were recorded seated with a noseclip and a bacterial filter (SureGard; Bird Healthcare) by a mass flow sensor (Sensormedics Vmax 20C Encore System; CareFusion Corp). For the
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assisted PCF, a trained person assisted the cough with a timed bilateral chest wall compression in conjunction with the child’s cough. A minimum of three and a maximum of five coughs were performed and the highest value recorded. Polysomnography: Polysomnography was performed (Embla 2.0; Flaga Medical Devices), including transcutaneous partial pressure of CO2 (Tcco2). Sleep stages and respiratory events were scored manually using standard American Academy of Sleep Medicine criteria.24 In brief, apneas and hypopneas lasted at least two respiratory cycles and were accompanied by a fall in oxygen saturation of . 3% or an arousal . 3 s. An apnea/hypopnea index (AHI) was calculated as the overall number of events per hour. Hypoventilation was defined as Tcco2 . 55 mm Hg.
Results Nineteen children aged , 10 years with SMA were identified, and 13 were recruited (Fig 1). One child with SMA type 2 (subject 8) died following initial assessment. One child failed to attend the final visit. Follow-up was complete on all others. Baseline characteristics are summarized in Table 1. In young children with SMA, FOT is feasible. Acceptable FOT was obtained in 12 children (seven boys)
Data Analysis The paired t test compared measured and predicted FOT values. Regression analysis assessed relationships between FVC, PCF, and AHI to FOT. Pearson correlation assessed relationships between spirometry and FOT z scores. Relationships between clinical and polysomnography data and FOT measurements were sought using analysis of variance and regression analysis. For longitudinal data, a rate of change was calculated. Stata version 11 (StataCorp LP) was used. Significance was accepted at .05. Ethical Considerations The study was conducted in accordance with the amended Declaration of Helsinki. The project and written informed consent were approved by the Human Research Ethics Committee of the Royal Children’s Hospital (HREC/11/QRCH/22) and University of Queensland (2012000102).
(mean age, 6.26 [⫾ 2.59] years). One child aged 2 years was unable to perform the test. Respiratory tests are summarized in Table 2. Reactance z scores were significantly abnormal (Xrs8 mean z score, 11.41; SD, 1.90; P , .03). Resistance z scores tended to be positive compared with normal, but this only reached statistical significance for Rrs10 (mean z score, 11.13; SD, 0.88; P , .001). Five children (42%) had an Xrs8 z score . 11.64 (95th percentile), and four children (33%) had a Rrs8 z score . 11.64. Although Xrs8 tended to be more
Figure 1 – Flow diagram of recruited children. FOT 5 forced oscillation technique; NSW 5 New South Wales; SMA 5 spinal muscular atrophy.
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8.9
5.1
4
6
4.5
3
6.7
3.7
2
5
3.3
F
M
F
F
M
M
Age at Visit 1, y Sex
2
2
2
2
2
2
Type of SMA
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Genotype
Valproate from 3 to 8y
Valproate and carnitine from 2 y
Wheelchair
Wheelchair
Nil
Wheelchair
Valproate from 3 y
Valproate from 20 mo
Wheelchair
Wheelchair
Valproate and carnitine from 18 mo
Medications for Disease Modification
Wheelchair
Ambulation
] Clinical Characteristics of Recruited Subjects
1
Subject No.
TABLE 1
14° T5-L4
42° T6-L3 spinal rods
Yes
85° T1-L5
No
No
85° T5-L5
23° T9-L4 22° C6-T9
No
No
13° T2-10
Cobb Angle
No
Surgical Spinal Fixation
42.4
49.8
4.6
2.0
5 managed at home, 2 ward admissions No
No
No
NIV
60
57.6
6.8
4.3
2 managed at home, 1 ward admission
2 ward admissions, 1 admission to intensive care for NIV
Other
PEG feeding; constipation management
NGT feeding
Nil
Constipation management
Aged 2 y, PEG inserted
Aged 2 y
Constipation Aged 2 y, management fracture management
Previous Anesthetic
Nocturnal Aged 9 y, spinal NIV ¿xation began following PSG
(Continued)
PEG feeding
Nil Nocturnal Aged 3 y, NIV hypospadias began repair following PSG
1.3 47.4 Nocturnal 4 managed (on NIV) (on NIV) NIV at home, 2 began admissions 6 mo to intensive prior care for NIV, 1 to the admission study to high dependency for NIV
5 managed at home, 2 ward admissions, 2 intensive care admissions for NIV
50.1
4.8
AHI
Maximum TcCO2, mm Hg
1 managed at home
Chest Infections in Preceding Year
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799
8.9
9.8
2.7
4.4
8.3
8
9
10
11
12
M
M
M
F
F
M
3
3
3
2
2
2
Type of SMA
Homozygous SMN1 deletion, exon 7-8
3 duplications SMN2
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Homozygous SMN1 deletion, exon 7-8
Muscle biopsy and clinical diagnosis
Genotype
Nil
Valproate from 2 to 4y
Wheelchair
Wheelchair
Wheelchair
Valproate from 18 mo Nil
Walking
Walking
Nil
Nil
Ambulation
Walking
Medications for Disease Modification
14° T5-L2
0
No
No
0
66° T9-L4
No
No
22° T2-12 75° L1-5
30° T4-L4
Cobb Angle
Yes
No
Surgical Spinal Fixation
Nil signi¿cant
Nil signi¿cant
1 managed at home
...
...
...
...
...
...
Nil
No
No
Nil
Nil
Nil
Nil
Nil
Nil
PEG feeding; constipation management Aged 4 y, PEG insertion
5 managed at home
5 ward admissions, 2 admissions to intensive care for NIV
2.0 47.3 Nocturnal 5 managed at NIV home, 1 ward (on NIV) (on NIV) began admission age 4 y
Other
PEG feeding; this child died soon after the ¿rst visit
No
Previous Anesthetic
Aged 5 y, PEG insertion; aged 7 y, spinal ¿xation
2.4
NIV
0 45.6 Nocturnal (on NIV) (on NIV) NIV began age 6 y
54.8
AHI
Very poor nutrition
Maximum TcCO2, mm Hg Nil
Chest Infections in Preceding Year
AHI 5 apnea/hypopnea index; F 5 female; M 5 male; NGT 5 nasogastric tube; NIV 5 noninvasive ventilation; PEG 5 percutaneous endoscopic gastrostomy; PSG 5 polysomnography; SMA 5 spinal muscular atrophy; SMN 5 survival motor neuron; TcCO2 5 transcutaneous partial pressure of CO2.
8.9
Age at Visit 1, y Sex
] (continued)
7
Subject No.
TABLE 1
TABLE 2
] Pulmonary Function Test Results, Visit 1
Test Results
Mean Value (SD)
% Predicted Value (SD)
Mean z Score (SD)
Comparison With Predicted Value, P
FOT values (n 5 12) Rrs4-24
8.36 (3.03)
...
11.31 (1.50)
, .02
Rrs6
9.21 (3.42)
...
10.55 (1.32)
5 .18
Rrs8
9.27 (3.40)
...
10.66 (1.34)
5 .12
Rrs10
9.44 (2.70)
...
11.13 (0.88)
, .01
Xrs6
24.62 (2.13)
...
11.56 (1.67)
, .01
Xrs8
23.83 (2.24)
...
11.41 (1.90)
, .03
Xrs10
23.91 (2.17)
...
1 1.49 (1.76)
, .02
Spirometry (n 5 5) FVC, L
0.97 (0.55)
56.61 (31.07)
25.45 (4.23)
, .001
FEV1, L
0.86 (0.53)
52.73 (31.92)
26.03 (4.50)
, .001
Peak cough Àow, n 5 10 Unassisted, L/min
119.34 (42.37)
...
...
...
Assisted, L/min
125.90 (43.84)
...
...
...
FOT 5 forced oscillation technique; Rrs 5 respiratory resistance; Xrs 5 respiratory reactance.
abnormal in children with type 2 than type 3 SMA, this did not reach statistical significance.
Mean (SD) and predicted values are summarized in Table 2.
Longitudinal measurements are summarized in Figure 2. Over 12 months, Xrs8 z score worsened (rate of change of 11.08 z score per annum, P , .001) and Rrs8 z score worsened (10.51 z scores per annum, P , .04) (Table 3). Rate of change of spirometry was not undertaken due to small numbers with repeat measurements (n 5 3).
A linear relationship occurs between Xrs8 and FVC (R2, 0.54), % FVC (R2, 0.50), FVC z score (R2, 0.64), FEV1 (R2, 0.35), % FEV1 (R2, 0.50), FEV1 z score (R2, 0.51), unassisted PCF (R2, 0.33), and assisted PCF (R2, 0.43) (Fig 3). There is a significant correlation between FVC z score and Xrs z score at 6 Hz and 8 Hz (20.72, P , .02; 20.69, P , .02, respectively). Similarly, there is a significant correlation between FEV1 z score and Xrs z score at 6 Hz and 8 Hz (20.63, P , .04; 20.60, P , .05, respectively). There is no significant correlation between spirometry z scores and Rrs values at 6 Hz, 8 Hz, or 10 Hz. There is a weak linear relationship between AHI and Xrs8 (R2, 0.32) and Rrs8 (R2, 0.27) for the eight children in
Six children were aged . 6 years, and five performed spirometry at least once: four with SMA type 2 and one with SMA type 3, who had normal spirometry for age.
TABLE 3
] Overall Rate of Change in FOT Values Over
z Scores
Figure 2 – Longitudinal measurements for Rrs8 and Xrs8 over 12 mo. The child who died soon after her first visit is shown with open symbols. Rrs 5 respiratory resistance; Xrs 5 respiratory reactance.
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12 Mo
Rate of Change per Annum
P Value
95% CI
Rrs6
10.40
.02
20.08 to 0.88
Rrs8
10.51
.04
20.03 to 0.98
Rrs10
10.77
, .001
0.33 to 1.21
Xrs6
11.27
, .001
0.71 to 1.82
Xrs8
11.08
, .001
0.52 to 1.64
Xrs10
11.04
, .001
0.50 to 1.58
See Table 2 legend for expansion of abbreviations.
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Figure 3 – A-C, Xrs8 has a linear relationship to (A) FVC ( R2, 0.54), (B) unassisted peak cough flow ( R2, 0.33), and (C) assisted peak cough flow ( R2, 0.43). See Figure 2 legend for expansion of abbreviation.
whom a polysomnography was undertaken, although three were using NIV and numbers are small. No significant relationship (P . .05) was found between clinical characteristics (sex, SMA type, mobility, medication use, previous spinal surgery, nocturnal NIV) and FOT. There was no relationship between Cobb angle and resistance (R2, 0.03-0.17) or reactance (R2, 0.008-0.06) or chest infection history and resistance (R2, 0.005-0.13) or reactance (R2, 0.001-0.04).
Discussion In young children with neuromuscular weakness, FOT is feasible, as shown in this group with SMA; only one child (age 2 years) was unable to perform the test. Nonvolitional and noninvasive tests are readily performed in young children. Sniff nasal inspiratory pressure is feasible in children . 6 years of age with SMA and reference values exist . 6 years.2,25 Spirometry generally becomes reliable and repeatable . 6 years.22 Many children with SMA have abnormal respiratory function by this age, and objective monitoring in younger children would enhance assessment. Mean FOT values were abnormal with values being . 95th percentile for reactance in 42% and resistance in 33%. Reactance measures elasticity (relationship between pressure and volume) and inertive properties (relationship between pressure and volume acceleration) of the lung.14 With a stiff chest wall and reduced lung volumes, it is expected to be reduced and worsen over time. In this study, it was significantly increased compared with journal.publications.chestnet.org
normal (more elastic), and increased further over 12 months (11.08 z scores). Resistance mainly measures viscous resistance in large airways and, to a lesser extent, tissue resistance.14 In SMA, tissue compliance is reduced due to underinflation and microatelectasis.26,27 As compliance reduces, it is expected that tissue resistance and Rrs values increase over time, as has been found (10.51 z scores per annum). There is a wider spread of FOT values at the initial visit than subsequently. This likely represents a learning effect. As with many respiratory tests, there is a learning period required. Longitudinal assessments and other clinical markers are important in overall assessment of individuals. Inclusion of a control group may have better characterized the learning effect. Several groups have assessed the rate of change of FVC or % FVC, and results have varied.2,28,29 Two studies have grouped type 2 and 3 patients with SMA and included children and adults.28,29 The younger group28 had no change in FVC over 12 months. Younger children are expected to have an increase in FVC with growth, and no change in observed values would likely result in a reduction in predicted values. The older group29 had a fall in % FVC of 1.1% per annum. Khirani et al2 found a decline in % FVC of 9.8% per annum in type 2 and 4.2% in type 3. Patients in all three studies were older than the current group, and changes in respiratory function may differ in different age groups, due to the progressive nature of SMA. The current study has shown that resistance and reactance become more abnormal 801
over 12 months. Numbers were too small to gain appreciation of differences in FOT between SMA types. Although FOT provides an objective measure, it does not measure the same aspects of respiratory function as other tests. However, it is expected that a relationship exists between FOT and spirometry, as was found. There was a reasonable correlation between reactance and spirometry, although the relationship to resistance was not statistically significant. PCF measures cough capacity. It is a volitional test that requires coughing into a mouthpiece. It is easily mastered by young children. Assisting the cough increases the PCF and is commonly used in conjunction with physiotherapy to aid airway clearance.30 It is expected the PCF will be more severely impaired in those with more severe weakness and that the reactance is lower in weaker children. A linear relationship was found between assisted and unassisted PCF and Xrs8, supporting the expected association. No associations were seen between clinical characteristics and FOT. Respiratory tests are influenced by many factors including chest wall movement, lung parenchyma, and airway pathology. Likewise, the influence of clinical factors on the respiratory system is complex, and abnormalities in respiratory measurements may be multifactorial. Clinical factors are also multifaceted. History of chest infections, for instance, may be influenced by frequency of viral encounters, and scoliosis will have a different influence in the thoracic than lumber spine. Understandably, an association between clinical characteristics and FOT was not found. Large patient numbers may be required to better define these relationships. In older children with Duchenne muscular dystrophy, daytime markers for sleep-disordered breathing include respiratory function.31 Polysomnography can be prioritized to those with the highest likelihood of sleep-disordered breathing. There is no currently known association between respiratory function and need for NIV in SMA, although this has not been extensively researched, and FOT has only recently become available.32 Further investigation into the usefulness of FOT in predicting sleep-
802 Original Research
disordered breathing is required. It is encouraging that with a small sample, there is a relationship between FOT and AHI. Predicted values of FOT are derived from standing height. Many children with SMA are unable to stand for accurate height measurement. Arm span has been used to predict height, but accurate measurement is difficult with spinal deformity or joint contractures. Ulna length measurement is straightforward, and accurate prediction equations exist for children ⱖ 6 years of age.19 The prediction equations have been extrapolated to younger children in this study. This research group is currently undertaking further work to extend the ulna prediction equations to 1 year, and the tight linear relationship is maintained in younger children.33 It, hence, seems reasonable to use extrapolated equations. Reference data for FOT was developed for white children from a reference population within Australia and Italy. It is the most appropriate reference data available for FOT testing in Queensland. The major study limitation is small patient numbers. SMA is uncommon. All patients known to have SMA in Queensland were identified. It is unlikely patients were missed, as the diagnosis is generally confirmed within the tertiary service, with follow-up by the neuromuscular service. Genuine efforts were made to include all identified children. Most not enrolling have disengaged from tertiary medical services, and the status of the three who could not be contacted is unknown. Further advancement of this work may be achieved by including additional centers in the future.
Conclusions In conclusion, in young children with SMA, FOT is feasible, with abnormal values of resistance and reactance on grouped data. Xrs8 is related to respiratory tests used to monitor progress in SMA (FVC, PCF, and AHI). Further research on the value of FOT in managing individuals is warranted. Objective respiratory measurements in young children with SMA may be important in designing future clinical trials of diseasemodifying treatments34-38 and in clinical assessment in young children.
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Acknowledgments Author contributions: L. M. G. takes full responsibility for the integrity of the data and accuracy of data analysis and integrity of the submission as a whole. L. M. G. contributed to study design, approvals, grant application, recruitment, data analysis, and the writing and revision of the manuscript; L. A. K. and C. E. S. contributed substantially to data acquisition; P. D. S. contributed substantially to interpretation of data; and L. A. K., C. E. S., and P. D. S. contributed to the revision of the manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
References 1. Emery AE. Population frequencies of inherited neuromuscular diseases—a world survey. Neuromuscul Disord. 1991;1(1):19-29. 2. Khirani S, Colella M, Caldarelli V, et al. Longitudinal course of lung function and respiratory muscle strength in spinal muscular atrophy type 2 and 3. Eur J Paediatr Neurol. 2013;17(6):552-560. 3. Munsat TL, Davies KE. International SMA consortium meeting. (26-28 June 1992, Bonn, Germany). Neuromuscul Disord. 1992;2(5-6):423-428. 4. Elsheikh B, Prior T, Zhang X, et al. An analysis of disease severity based on SMN2 copy number in adults with spinal muscular atrophy. Muscle Nerve. 2009;40(4):652-656. 5. Nicot F, Hart N, Forin V, et al. Respiratory muscle testing: a valuable tool for children with neuromuscular disorders. Am J Respir Crit Care Med. 2006;174(1):67-74. 6. Wang CH, Finkel RS, Bertini ES, et al; Participants of the International Conference on SMA Standard of Care. Consensus statement for standard of care in spinal muscular atrophy. J Child Neurol. 2007; 22(8):1027-1049. 7. Robinson D, Galasko CS, Delaney C, Williamson JB, Barrie JL. Scoliosis and lung function in spinal muscular atrophy. Eur Spine J. 1995;4(5):268-273. 8. Tangsrud SE, Carlsen KC, Lund-Petersen I, Carlsen KH. Lung function measurements in young children with spinal muscle atrophy; a cross sectional survey on the effect of position and bracing. Arch Dis Child. 2001;84(6):521-524. 9. Manni R, Cerveri I, Ottolini A, et al. Sleep related breathing patterns in patients with spinal muscular atrophy. Ital J Neurol Sci. 1993;14(7):565-569. 10. Mellies U, Dohna-Schwake C, Stehling F, Voit T. Sleep disordered breathing in spinal muscular atrophy. Neuromuscul Disord. 2004;14(12):797-803. journal.publications.chestnet.org
11. Testa MB, Pavone M, Bertini E, Petrone A, Pagani M, Cutrera R. Sleep-disordered breathing in spinal muscular atrophy types 1 and 2. Am J Phys Med Rehabil. 2005;84(9):666-670. 12. Dohna-Schwake C, Ragette R, Teschler H, Voit T, Mellies U. Predictors of severe chest infections in pediatric neuromuscular disorders. Neuromuscul Disord. 2006;16(5):325-328. 13. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(3): 1107-1136. 14. Beydon N, Davis SD, Lombardi E, et al; American Thoracic Society/European Respiratory Society Working Group on Infant and Young Children Pulmonary Function Testing. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children. Am J Respir Crit Care Med. 2007;175(12):1304-1345. 15. American Thoracic Society/European Respiratory Society. ATS/ERS Statement on respiratory muscle testing. Am J Respir Crit Care Med. 2002;166(4):518-624. 16. Calogero C, Simpson SJ, Lombardi E, et al. Respiratory impedance and bronchodilator responsiveness in healthy children aged 2-13 years. Pediatr Pulmonol. 2013;48(7):707-715. 17. National regional profile: Queensland. Australian Bureau of Statistics website. http://www.abs.gov.au/AUSSTATS/ [email protected]/Latestproducts/3Population/ People12007-2011?opendocument& tabname=Summary&prodno=3&issue= 2007-2011. Published 2012. Accessed August 27, 2013. 18. Cobb JR. Outline for the study of scoliosis. In: Instructional Courses Lectures, American Academy of Orthopaedic Surgeons. Vol 5. Ann Arbor, MI: JW Edwards; 1948:261-275. 19. Gauld LM, Kappers J, Carlin JB, Robertson CF. Height prediction from ulna length. Dev Med Child Neurol. 2004; 46(7):475-480. 20. Hall GL, Sly PD, Fukushima T, et al. Respiratory function in healthy young children using forced oscillations. Thorax. 2007;62(6):521-526. 21. Frey U. Forced oscillation technique in infants and young children. Paediatr Respir Rev. 2005;6(4):246-254. 22. Miller MR, Hankinson J, Brusasco V, et al; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005;26(2):319-338. 23. Gauld LM, Kappers J, Carlin JB, Robertson CF. Prediction of childhood pulmonary function using ulna length. Am J Respir Crit Care Med. 2003;168(7): 804-809. 24. Berry RB, Budhiraja R, Gottlieb DJ, et al; American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8(5):597-619.
25. Stefanutti D, Fitting JW. Sniff nasal inspiratory pressure. Reference values in Caucasian children. Am J Respir Crit Care Med. 1999;159(1):107-111. 26. Schramm CM. Current concepts of respiratory complications of neuromuscular disease in children. Curr Opin Pediatr. 2000;12(3):203-207. 27. Gibson GJ, Pride NB, Davis JN, Loh LC. Pulmonary mechanics in patients with respiratory muscle weakness. Am Rev Respir Dis. 1977;115(3):389-395. 28. Kaufmann P, McDermott MP, Darras BT, et al; Muscle Study Group; Pediatric Neuromuscular Clinical Research Network for Spinal Muscular Atrophy. Observational study of spinal muscular atrophy type 2 and 3: functional outcomes over 1 year. Arch Neurol. 2011;68(6):779-786. 29. Steffensen BF, Lyager S, Werge B, Rahbek J, Mattsson E. Physical capacity in non-ambulatory people with Duchenne muscular dystrophy or spinal muscular atrophy: a longitudinal study. Dev Med Child Neurol. 2002;44(9):623-632. 30. Chatwin M, Ross E, Hart N, Nickol AH, Polkey MI, Simonds AK. Cough augmentation with mechanical insufflation/exsufflation in patients with neuromuscular weakness. Eur Respir J. 2003;21(3):502-508. 31. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Am J Respir Crit Care Med. 2000;161(1):166-170. 32. Lyager S, Steffensen B, Juhl B. Indicators of need for mechanical ventilation in Duchenne muscular dystrophy and spinal muscular atrophy. Chest. 1995;108(3): 779-785. 33. Keeling LA, Sly PD, Shackleton CE, Gauld LM. Height prediction from ulna length in young children. Respirology. 2012;17. 34. Chen TH, Chang JG, Yang YH, et al. Randomized, double-blind, placebocontrolled trial of hydroxyurea in spinal muscular atrophy. Neurology. 2010;75(24):2190-2197. 35. Swoboda KJ, Scott CB, Crawford TO, et al; Project Cure Spinal Muscular Atrophy Investigators Network. SMA CARNI-VAL trial part I: doubleblind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy. PLoS ONE. 2010;5(8):e12140. 36. Swoboda KJ, Scott CB, Reyna SP, et al. Phase II open label study of valproic acid in spinal muscular atrophy. PLoS ONE. 2009;4(5):e5268. 37. Kissel JT, Scott CB, Reyna SP, et al; Project Cure Spinal Muscular Atrophy Investigators’ Network. SMA CARNIVAL TRIAL PART II: a prospective, single-armed trial of L-carnitine and valproic acid in ambulatory children with spinal muscular atrophy. PLoS ONE. 2011;6(7):e21296. 38. Liang W-C, Yuo C-Y, Chang J-G, et al. The effect of hydroxyurea in spinal muscular atrophy cells and patients. J Neurol Sci. 2008;268(1-2):87-94.
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