Khan A. 2023. Respiratory Management of Patients With Neuromuscular Weakness

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Respiratory Management of Patients with Neuromuscular Weakness: An American

College of Chest Physicians Clinical Practice Guideline and Expert Panel Report
Akram Khan, MD, Lindsy Frazer-Green, PhD, Reshma Amin, MD, Lisa Wolfe, MD,
Garner Faulkner, RRT, Kenneth Casey, MD, Girish Sharma, MD, Bernardo Selim,
MD, David Zielinski, MD, Loutfi S. Aboussouan, MD, Douglas McKim, MD, Peter Gay,
MD
PII: S0012-3692(23)00353-7
DOI: https://doi.org/10.1016/j.chest.2023.03.011
Reference: CHEST 5572
To appear in: CHEST
Received Date: 30 November 2022

Revised Date: 27 February 2023
Accepted Date: 5 March 2023
Please cite this article as: Khan A, Frazer-Green L, Amin R, Wolfe L, Faulkner G, Casey K, Sharma
G, Selim B, Zielinski D, Aboussouan LS, McKim D, Gay P, Respiratory Management of Patients with
Neuromuscular Weakness: An American College of Chest Physicians Clinical Practice Guideline and
Expert Panel Report, CHEST (2023), doi: https://doi.org/10.1016/j.chest.2023.03.011.
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Copyright © 2023 Published by Elsevier Inc under license from the American College of Chest
Physicians.
Title Page
Respiratory Management of Patients with Neuromuscular Weakness: An American College of

Chest Physicians Clinical Practice Guideline and Expert Panel Report
1. Akram Khan, MD
2. Lindsy Frazer-Green, PhD
3. Reshma Amin, MD
4. Lisa Wolfe, MD
5. Garner Faulkner, RRT
6. Kenneth Casey, MD
7. Girish Sharma, MD
8. Bernardo Selim, MD
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9. David Zielinski, MD
10. Loutfi S. Aboussouan, MD
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11. Douglas McKim, MD
12. Peter Gay, MD
Affiliations
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Div. of Pulmonary Allergy and Critical Care Medicine, Oregon Health & Science University,
Portland, OR
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American College of Chest Physicians, Glenview, IL
3
Div. of Respiratory Medicine, The Hospital for Sick Kids, Toronto, Ontario
4
Dept. of Medicine, Northwestern University, Chicago, IL
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UPMC Presbyterian Shadyside, Pittsburgh, PA
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Dept. of Sleep Medicine, William S. Middleton Memorial Veterans Hospital, Shorewood Hills,
WI (Retired)
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Dept. of Pediatrics, Rush University Medical Center, Chicago, IL
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Dept. of Pulmonary Medicine, Mayo Clinic, Rochester, MN
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Dept. of Pediatrics, McGill University, Montreal, Quebec
10
Dept. of Pulmonary Medicine, Cleveland Clinic, Cleveland, OH
11
Dept. of Medicine, The Ottawa Hospital Research Institute, Ottawa, Ontario
12
Dept. of Pulmonary Medicine, Mayo Clinic, Rochester, MN
Conflicts of Interest: see e-Appendix 1
Funding/Support:
American College of Chest Physicians funded this guideline.
Disclaimer:
CHEST Guidelines are intended for general information, are not medical advice, and do not
replace professional medical care and physician advice, which should always be sought for any
medical condition. The complete disclaimer for this guideline can be accessed at
http://www.chestnet.org/Guidelines-and-Resources.
Correspondence to:
Akram Khan, MD, Division of Pulmonary and Critical Care Medicine, School of Medicine,
Oregon Health & Science University, 3181 S.W. Sam Jackson Park Rd. Portland, OR 97239; e-
mail: khana@ohsu.edu
Acknowledgement
AK and LFG had full access to all of the data in the study and take full responsibility for the
integrity of the data and the accuracy of the data analysis. RA, LW, GF, GS, BS, DZ, LSA, DM,
and PG contributed substantially to the study design, data interpretation, and writing of the
manuscript. KC contributed substantially to the study design and data interpretation.
Acknowledgments
We thank Andrea Pauls Backman (Les Turner ALS Foundation) for providing the patient
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perspective during all phases of guideline development and for comments on the manuscript and
Haeun Jung and Randall Clark for assistance with making the figures and tables.
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Endorsements: This guideline is endorsed by the American Academy of Sleep Medicine, the
American Association for Respiratory Care, the American Thoracic Society, and the
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Canadian Thoracic Society re
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1 Word Count: 6469
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3 Respiratory Management of Patients with Neuromuscular Weakness: An American College of
4 Chest Physicians Clinical Practice Guideline and Expert Panel Report
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6 Abstract (Word count 247)
7
8 Background:
9 Respiratory failure is a significant concern in neuromuscular diseases (NMD). This CHEST
10 guideline examines the literature on the respiratory management of patients with NMD to
11 provide evidence-based recommendations.
12
13 Methods:
14 An expert panel conducted a systematic review addressing the respiratory management of NMD
15 and applied the GRADE approach for assessing the certainty of the evidence and formulating
16 and grading recommendations. A modified Delphi technique was used to reach a consensus on
17 the recommendations.
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19 Results:
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20 Based on 128 studies, the panel generated 15 graded recommendations, a good practice
21 statement, and one consensus-based statement.
22
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23 Conclusions:
24 Evidence of best practices for respiratory management in NMD is limited and is based primarily
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25 on observational data in amyotrophic lateral sclerosis. The panel found that pulmonary function
26 tests every six months may be beneficial and used to initiate NIV when clinically indicated. An
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27 individualized approach to NIV settings may benefit patients with chronic respiratory failure and
28 sleep-disordered breathing related to NMD. When resources allow, polysomnography or
29 overnight oximetry can help guide the initiation of NIV. The panel provided guidelines for
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30 mouthpiece ventilation, transition to home mechanical ventilation, salivary secretion

31 management, and airway clearance therapies.
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33 The guideline panel emphasizes that NMD pathologies represent a diverse group of disorders
34 with differing rates of decline in lung function. The clinician’s role is to add evaluation at the
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35 bedside to shared decision-making with patients and families, including respect for patient
36 preferences and treatment goals, considerations of quality of life, and appropriate use of
37 available resources in decision-making.
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38 Abbreviations
39
40 ADA = Americans with Disabilities Act of 1990
41 ALS= Amyotrophic lateral sclerosis
42 ALSFRS-RS: Amyotrophic Lateral Sclerosis Functional Rating Scale- respiratory subscale
43 BT = Botulinum toxin
44 CHEST = American College of Chest Physicians
45 DMD= Duchenne Muscular Dystrophy
46 EtCO2 = End-tidal carbon dioxide
47 HFCWO= High-frequency chest wall oscillation
48 LVR= Lung volume recruitment
49 MAC = Manually Assisted Cough
50 MEP = Maximum Expiratory Pressure
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51 MIP = Maximum Inspiratory Pressure
52 MI-E= Mechanical insufflation-exsufflation
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53 MPV= Mouthpiece ventilation
54 MV = Mechanical ventilation
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55 NIV= Non-invasive ventilation
56 NMD= Neuromuscular disease
57 oximetry
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58 OSA = Obstructive Sleep Apnea
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59 PCF= Peak cough flow
60 PEEP = Positive End Expiratory Pressure
61 PFT= Pulmonary function testing
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62 PSG= Polysomnography
63 RT= Radiation therapy
64 SDB= Sleep-disordered breathing
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65 SNIP = Sniff Nasal Inspiratory Pressure

66 TV = Tidal Volume
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67 TcCO2 = transcutaneous carbon dioxide

68 VC= Vital capacity
69
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70 SUMMARY OF RECOMMENDATIONS AND SUGGESTIONS
71
72 Use and Timing of Pulmonary Function Testing
73
74 1. For patients with neuromuscular disease (NMD) at risk for respiratory complications,
75 we recommend pulmonary function testing (PFT) to assist with management decisions
76 (Good Practice Statement).
77
78 Remarks: PFT is a low-cost intervention. The panel recommends that spirometry with forced
79 or slow vital capacity (FVC or SVC) and maximum inspiratory and expiratory pressure
80 (MIP/MEP) or SNIP and PCF be considered in patients with NMD when available according
81 to regional practice patterns.
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83 2. For patients with NMD at risk for respiratory failure, we suggest pulmonary function
84 testing at a minimum of every six months as appropriate to the course of the specific NMD.
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85 (Conditional Recommendation, Ungraded Consensus-based Statement).
86
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87 Remarks When performing spirometry, the panel suggests one or more of the following: vital
88 capacity FVC or SVC, MIP/MEP, SNIP, and PCF at least every six months, according to
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89 regional practice patterns and availability. Clinicians should adjust the testing frequency
90 based on the progression rate of individual NMD.
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92 Screening for Respiratory Failure and Sleep-Related Breathing Disorders
93
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94 3. For symptomatic patients with NMD who have normal PFT and overnight oximetry
95 (ONO), we suggest that clinicians consider polysomnography (PSG) to assess whether non-
96 invasive ventilation (NIV) is clinically indicated (conditional recommendation, very low
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97 certainty of evidence).
98
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99 Remarks:
100 A PSG can be used to assess whether NIV is indicated in symptomatic patients with normal
101 PFT and ONO. This may require an appropriate testing facility in the community, preferably
102 with ADA access, NMD protocols, equipment for NMD, and space for bedside caregivers.
103 Clinical indications may vary based on the patient's age and disease progression. PSG may be
104 the preferred option for pediatric patients.
105
106 Use of Non-invasive Ventilation
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108 4. For patients with NMD and chronic respiratory failure, we recommend using NIV for
109 treatment (strong recommendation, very low certainty of evidence).
110
111 Remarks: The clinical indications for NIV can vary depending on NMD, patient age, and rate
112 of disease progression. Any fall in FVC to <80% of predicted with symptoms or FVC to <50%
113 of predicted without symptoms or SNIP /MIP to < -40 cm H2O or hypercapnia would support
114 the initiation of NIV or further testing as clinically indicated for individual NMD. See the text
115 and the supplement for more details.
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117 5. For patients with NMD and sleep-related breathing disorders, we suggest using NIV for
118 treatment (conditional recommendation, very low certainty of evidence).
119
120 Remarks: The panel suggests using the AASM criteria for sleep-disordered breathing and
121 hypoventilation for adult patients and the ERS criteria for pediatric patients.
122
123 Respiratory Parameters for Initiation of NIV
124
125 6. For patients with NMD, we suggest the use of diagnostic tests such as forced vital
126 capacity (FVC), MIP/MEP, ONO, or evidence of sleep-disordered breathing or
127 hypoventilation on PSG to predict the timing of NIV initiation (conditional
128 recommendation, very low certainty of evidence).
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130 Remarks: PSG is not necessary for adult patients to initiate NIV, and PFT criteria alone may
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131 be adequate. See the comments for recommendations 4 & 5 above.
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133 7. For patients with NMD requiring NIV, we suggest individualizing NIV treatment to
134 achieve ventilation goals (conditional recommendation, very low certainty of evidence).
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135
136 Remarks: NIV can be optimized by adjusting parameters such as mode of ventilation,
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137 inspiratory time, and inspiratory and expiratory pressures. There is no strong evidence to
138 support one mode of ventilation over another, although a backup respiratory rate may lead to
139 better patient-ventilator synchrony and improved gas exchange. Patients with bulbar
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140 impairment may not be able to tolerate NIV or achieve adequate ventilation. The panel
141 suggests an ongoing assessment of sleep quality, digital downloads, leaks, oximetry
142 (capnography where available), and determining optimal settings along with optimizing
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143 secretion management.

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145 8. For patients with NMD and preserved bulbar function using NIV, we suggest
146 mouthpiece ventilation (MPV) for daytime ventilatory support as an adjunct to nocturnal
147 mask NIV (conditional recommendation, very low certainty of evidence).
148
149 Remarks: Although MPV has been used in various NMDs to help delay the transition to
150 mechanical ventilation (MV), disease-specific considerations such as the development of
151 bulbar symptoms in certain NMDs (e.g., ALS) may limit the use of this option.
152
153 Use of Mechanical Ventilation
154
155 9. For NMD patients failing NIV or intolerant of NIV (including extended daytime NIV
156 use), worsening bulbar function, frequent aspiration, insufficient cough, episodes of chest
157 infection despite adequate secretion management, or declining lung function, we suggest
158 invasive home MV via tracheostomy as an alternative to NIV (conditional
160
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161 Remark: Discussions regarding the use of MV should be started early in the course of the
162 illness and include goals of care discussion, the potential need for institutionalization, and the
163 burden on caregivers. The panel suggests optimizing secretion management and airway
164 clearance, using patient preference, treatment goals, quality of life considerations, and
165 available resources (cost and care providers) to help make decisions.
166
167 Sialorrhea Management

168
169 10. For patients with NMD and sialorrhea, we suggest a therapeutic trial of an
170 anticholinergic medication as first-line therapy with continued use only if there are
171 perceived benefits compared to side effects (conditional recommendation, very low
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174 Remarks: The panel suggests an initial trial of an inexpensive oral anticholinergic
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175 medication. Clinicians can also consider more expensive but potentially longer-acting
176 anticholinergic patch medication as the first or second-line therapy for sialorrhea.
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178 11. For patients with NMD and sialorrhea who have an inadequate response or are
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intolerant of the side effects of anticholinergic therapy, we suggest botulinum toxin (BT)
180 therapy to salivary glands (conditional recommendation, very low certainty of evidence).
181
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182 Remarks: See individual studies for doses of BT. It is unclear whether clinicians should
183 consider BT or radiation therapy (RT) first and can base their decision on local expertise.
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185 12. For patients with NMD and sialorrhea who have an inadequate response or are
186 intolerant of the side effects of anticholinergic therapy, we suggest salivary gland radiation
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187 therapy (RT) (conditional recommendation, very low certainty of evidence).

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189 Remarks: Data on RT are limited. See individual studies for doses. It is unclear whether
190 clinicians should consider BT or RT first and can base their decision on local expertise.
191
192 Airway Clearance Therapies
193
194 13. We suggest clinicians consider glossopharyngeal breathing for lung volume recruitment
195 (LVR) and airway clearance for patients with NMD and hypoventilation (conditional
197
198 Remarks: LVR is low-cost and can be performed by the patient independently with minimal
199 assistance and training.
200
201 14. For patients with NMD and reduced cough effectiveness, we suggest manually assisted
202 cough techniques independently or added to other modalities such as LVR (conditional
204
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205 Remarks: Manually assisted cough techniques are low-cost but require caregiver assistance
206 and training.
207
208 15. For patients with NMD and reduced lung function or cough effectiveness, we suggest
209 regular use of LVR (breath stacking) using a handheld resuscitation bag or mouthpiece
210 (conditional recommendation, very low certainty of evidence).
211
212 Remarks: LVR with a handheld device or mouthpiece is low-cost but requires caregiver
213 assistance and training. Manually assisted cough is more effective when added to volume
214 recruitment or the expiratory phase of mechanical cough assist.
215
216 16. For patients with NMD and reduced cough effectiveness, which cannot be adequately
217 improved with alternative techniques, we suggest the addition of regular Mechanical
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218 Insufflation-Exsufflation (cough assist device) (conditional recommendation, very low
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220
221 Remarks: Implementing the recommendation requires caregiver assistance and training and a
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222 Mechanical In-Exsufflation device (cough assist device), which can increase costs and should
223 be considered based on local resources.
224
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225 17. For patients with NMD and difficulties with secretion clearance, we suggest using high-
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226 frequency chest wall oscillation (HFCWO) for secretion mobilization. In addition, we
227 suggest that HFCWO be combined with airway clearance therapies such as cough
228 assistance or LVR (conditional recommendation, very low certainty of evidence).
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230 Remarks: Implementing the recommendation requires caregiver assistance and training and
231 an HFCWO device, which can increase costs and should be considered based on local
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232 resources and shared decision-making.

233
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234 BACKGROUND
235
236 Respiratory failure is a common complication in neuromuscular (NMD) patients.1 Respiratory
237 muscle weakness in patients with NMD can lead to inadequate ventilation, hypoventilation at
238 night, and the inability to mobilize secretions that are frequently the cause of death in this
239 population.2,3 Sleep-related breathing disorders are common initial symptoms of NMD.4 Data on
240 the treatment of respiratory failure in NMD are limited. NMDs present at different ages and
241 progress at variable rates, making it difficult to provide a single set of guidelines. A Cochrane
242 review found no studies that compared invasive and non-invasive mechanical ventilation or
243 intermittent positive pressure versus negative pressure ventilation.5 There is limited guidance on
244 this topic from professional societies.2,6-17 The Swiss and French societies have proposed recent
245 guidelines; however, they have limited application in the United States due to the lack of
246 respiratory therapist support in the US and the national coverage determination for using in-
247 home mechanical ventilation with a different standard of care.16-18
248
249 Patients with NMD are often cared for by interprofessional teams consisting of pulmonologists,
250 neurologists, respiratory therapists, physical and occupational therapists, pediatricians, internists,
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251 and family physicians. This document aims to guide providers involved in the respiratory care of
252 patients with NMD with the understanding that there are variations in the patterns of respiratory
253 muscle involvement and timing of clinical presentation and progression of NMDs, which would
254 require an understanding of the patient’s underlying disease process before using the
255 recommendations.
256 METHODS
257
258 Expert Panel Composition
259
260 The Chair of the panel (AK) was reviewed for potential conflicts of interest (COI) and approved
261 by the American College of Chest Physicians (CHEST) Professional Standards Committee
262 (PSC). The Chair nominated additional panelists based on their expertise in potential guideline
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263 questions, which the PSC approved after reviewing their COI disclosures. The panel includes
264 adult and pediatric pulmonologists, critical care specialists, sleep medicine specialists, a
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265 respiratory therapist, a methodologist, and a patient representative. COI are listed in e-Appendix
266 1.
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268 Panelists were required to disclose any potential financial or intellectual COIs throughout
269
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guideline development. Panelists found to have no substantial COIs were approved, whereas
270 nominees with potential intellectual or financial COIs that were manageable were "approved
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271 with management." Panelists approved with management were prohibited from voting on
272 recommendations in which they had substantial COI. A grid was created to track COI for each
273 clinical question and was used during discussion and voting to ensure transparency and
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274 observation of the management terms (e-Appendix 1). A panelist submitted a late COI
275 disclosure related to a relationship with a company with a premarket product in the area
276 addressed by this guideline. The relationship occurred during the development but was not
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277 disclosed a priori for review by the PSC as required by CHEST policy. When reporting the
278 relationship, a post hoc review determined that prior work with unrelated products and the
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279 existence of the relationship did not influence or alter the final recommendations.
280
281 Question Development and Systematic Literature Searches
282
283 The panel drafted nine clinical questions using the population, intervention, comparator, and
284 outcome (PICO) format (Table 1). These questions were selected based on the approved scope
285 of the guideline. Based on PICO questions, database-specific search strategies were developed
286 using a combination of medical subject headings and keywords from the National Library of
287 Medicine. MEDLINE via PubMed and the Cochrane Library was initially searched in November
288 2018. The study selection process is detailed in e-Appendix 2. Based on searches for the nine
289 PICO questions, 6,761 records were screened from which 108 unique studies were included in
290 the analysis. A comprehensive search update was conducted in September 2020. Seven hundred
291 thirty-five records were screened from which 18 additional studies were included in the
292 synthesis. In July 2021, a further search update for PICO 9 was conducted to incorporate
293 evidence on the use of anticholinergics. One hundred sixty-three records were screened, and two
294 studies were included. The searches were restricted to English-language publications but were
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295 not limited by study design or publication date. Reference lists of relevant identified studies were
296 also reviewed, and panelists conducted ongoing surveillance of the literature.
297
298 Study Selection and Data Abstraction
299
300 Literature search results were reviewed for relevance over two rounds of study selection that
301 followed a standard process of independent, duplicate work with disagreement resolution via
302 discussion. The panelists screened identified studies using predefined inclusion and exclusion
303 criteria based on the PICO components of the clinical questions and the study design (Table 1, e-
304 Appendix 2 & 3). Screening forms were created using the web-based systematic review
305 software DistillerSR (Evidence Partners; 2018, accessed November 2018- March 2019), and the
306 software was used to facilitate the selection process. This process was initially applied to the title
307 and abstract screening, then to full-text screening (e-Appendix 2 & 3). The aim of this process
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308 was to identify all studies meeting the inclusion criteria.
309
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310 Structured data tables were used to abstract data on study characteristics and outcomes. The
311 methodologist independently performed data abstraction, and a second panelist independently
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312 reviewed the abstracted data. Discrepancies were resolved by discussion.
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314 Risk of Bias Assessment
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316 The methodologist assessed the risk of bias in all included studies using DistillerSR (Evidence
317 Partners; 2020; accessed November 2019-June 2020). DistillerSR Assessment forms were
318 selected, as appropriate, based on the study design. The forms were adapted from Version 2 of
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319 the Cochrane risk-of-bias tool for randomized trials (RoB2), the CLARITY Group at McMaster
320 University's Tool to Assess Risk of Bias in Cohort Studies, the CLARITY Group at McMaster
321 University's Tool to Assess Risk of Bias in Case-Control Studies, and the Documentation and
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322 Appraisal Review Tool for systematic reviews.19-22

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324 Data Analysis

325
326 The limited available homogeneous evidence precluded the pooling of data from individual
327 studies and meta-analyses. The textual description of the effects reported in the studies was
328 provided by the outcome of interest for each PICO question. Study findings were presented in
329 evidence tables to compare results from each included study reporting on the outcome of interest.
330
331 Assessing the Certainty of the Evidence
332
333 The certainty of the evidence was assessed for each outcome of interest using the Grading of
334 Recommendations, Assessment, Development, and Evaluation (GRADE) approach.23,24 This
335 approach categorizes certainty as high, moderate, low, or very low, reflecting the extent to which
336 panelists are confident in the findings to support a recommendation (Table 2). 23,24 Evidence
337 profiles, including a summary of the results and the certainty of evidence assessment, were
338 created using the GRADEPro Guideline Development Tool.25
339
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340 Recommendation Drafting
341
342 The panel used the evidence profiles to create evidence-to-decision (EtD) frameworks for each
343 PICO question.26 Using the EtD, panelists drafted recommendations that were graded using the
344 CHEST grading system based on the GRADE approach (Table 3).27 In instances of insufficient
345 evidence where guidance was still warranted, a conditional suggestion was developed, and
346 "Ungraded Consensus-Based Statement" replaced the grade.28
347
348 Consensus Development
349
350 All drafted recommendations were presented to the panel in an anonymous online voting survey.
351 Panelists without a relevant COI voted on each recommendation to achieve consensus using a
352 modified Delphi technique.28 Panelists also had the option to provide open-ended feedback on
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353 each statement. Each guidance statement required a 75% voting participation rate and at least
354 80% consensus for approval and inclusion in the guideline. Based on the feedback provided, the
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355 panel revised any recommendation that did not meet these criteria and distributed and completed
356 a new voting survey that included suggested changes for up to three rounds. After 3 rounds, all
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357 recommendations reached consensus.
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359 Use and Timing of Pulmonary Function Testing
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361 Evidence and Evidence-to-Decision
362
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363 To evaluate the utility of PFT in NMD, the panel reviewed 1,561 abstracts and selected 22
364 studies for review (e-Tables 1a-1c).29-50 All evidence was determined to be indirect, as it
365 assessed the predictive value of PFTs to assess survival, respiratory events, and sleep-disordered
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366 breathing, which differed from the research question focused on the utility of PFTs to predict
367 disease progression. The identified evidence was used to develop a good practice statement. The
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368 desirable effects were determined to be large, as evidence and standard clinical practice suggest
369 that PFT is a common diagnostic test to assess the progression of respiratory failure and
370 predictors of survival in patients with NMD (e-Appendix 4). No clear harms were identified, and
371 undesirable effects were determined to be trivial. The balance of effects strongly favors the
372 intervention and supports its use as standard clinical practice.
373
374 Among the PFT testing parameters identified as predictors of clinical outcomes, the panel
375 recommends the measurement of Vital Capacity (FVC or SVC), MIP/MEP, SNIP, or PCF in
376 patients with NMD. A review of 142 abstracts did not identify any studies that addressed the
377 impact of the frequency of PFTs on disease progression, quality of life, or clinical utilization in
378 NMD. Based on expert opinion, the panel felt that testing and follow-up at least every six months
379 has benefits over yearly or as-needed testing. In addition, the panel did not identify any harm
380 from the timing of testing, so the balance of desirable and undesirable effects favors earlier
381 testing. Using a consensus-based approach, the panel chose a time interval of 6 months,
382 acknowledging that while the rate of progression of each NMD is different, in some NMDs, such
383 as ALS, patients may have a significant change in respiratory parameters in 3-6 months, while in
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384 stable or slowly progressing diseases such as DMD, PFT could be done at less frequent intervals
385 such as every 12 months.
386
387 Additional Comments/ Implementation Recommendations
388 PFT is a low-cost intervention that can be performed in the office or with home-based
389 monitoring.51 Spirometry should be performed with a mouthpiece and a nasal clip or a mask (if
390 the patient cannot close their mouth). FVC is considered abnormal if <80% of the predicted
391 value, MIP less than –60 cm H2O, MIP <40 cm H2O and PCF < 270L/min in individuals >= 12
392 years of age (see Figure 1).10,52-54 SNIP can be substituted for MIP in case of significant
393 NMD.10,52-54 The panel found limited data on supine vs. erect PFTs as studies were based on
394 retrospective data with small sample sizes.30,46,49,55-57 Access to supine testing is also limited by
395 the use of body boxes for testing in the US. Although the panel did not make a recommendation
396 in this area, we do not limit or advise against the use of supine testing when available. Similarly,
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397 while the panel recommended testing every 6 months, more frequent testing may be performed
398 based on patient symptoms.
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400 Certain populations, such as patients with bulbar dysfunction, may not be able to perform PFTs.
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401 Daytime PFTs can also be a good measure of sleep-related hypoventilation and correlate with
402 time spent with oxygen saturation =<90% and PCO2 >= 45 mm Hg on ABG.31,34 More frequent
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403 testing may be possible with the help of trained caregivers and home-based monitoring.51 The
404 frequency of respiratory testing and the role of supine vs. erect spirometry are important areas of
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405 future research. Home testing may allow for more frequent tests at shorter intervals and help
406 determine the optimal interval for testing for various NMD disorders, especially those with faster
407 progression.
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409 Screening for Respiratory Failure and Sleep-Related Breathing Disorders

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413 The panel reviewed 2,192 abstracts and selected five studies for review (e-Table 2).58-62
414 Observational studies of the three types of sleep testing- overnight oximetry (ONO), traditional
415 type I in-lab polysomnography (PSG), and home sleep testing (HST)- suggest moderate desirable
416 effects as a result of identifying sleep-disordered breathing (SDB) and minimal undesirable
417 effects with no indication of harm (e-Appendix 4). There were no data available on the
418 frequency or timing of PSG, ONO, or HST with respect to NMD diagnoses, with a consensus
419 recommendation to consider sleep history and symptoms to determine the need for testing (see
420 Figure 1). The balance of risk and benefits was considered to favor the intervention, with very
421 low certainty of evidence. Based on very limited evidence, transcutaneous and end-tidal CO2
422 may be helpful in detecting hypoventilation and initiating and managing NIV.40,63-65 Home-based
423 overnight capnography is feasible and has been used as one of the criteria to initiate respiratory
424 support.40,65
425
426 PSG is not necessary for adult patients to manage NMD if PFT or overnight oximetry (ONO)
427 criteria support using NIV (see Figure 1).66 Sleep testing can be helpful when there is concern
428 that PFT and clinical evaluation are not capturing complications such as hypoventilation.13,40,58-
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429 Full PSG is suggested at least once in pediatric patients and adults with symptoms such as
430 daytime tiredness, fatigue, excessive daytime sleepiness, history of snoring, apneic episodes, or
431 pauses in breathing.13,66 Nocturnal ONO and capnography can detect early signs of nocturnal
432 hypoventilation in some adult NMD populations.67 ONO also has the advantages of low cost and
433 easy repeatability. ONO can be used to assess nocturnal desaturation to <88% for 5 minutes,
434 which may qualify patients with NMD for NIV in the absence of OSA, and for monitoring the
435 adequacy of NIV support to ensure that oxygen saturations are > 90% for more than 90% of the
436 recording on NIV.
437
438 Additional Comments / Implementation Recommendations
439
440 The use of PSG in patients with NMD depends on the availability of sleep laboratories,
441 preferably with access compliant with the Americans with Disabilities Act (ADA), trained staff,
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442 and protocols to address hypoventilation and OSA. The limited availability of such laboratories
443 will likely significantly impact provider decisions to use PSG. ONO or PFT could be used as an
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444 alternative to PSG and can be considered more frequently, for example, every six months or as
445 indicated to help with NIV decisions.67 Hypoventilation is difficult to detect during PSG.13-15,69,70
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446 Patients with NMD are at risk for respiratory complications related to hypoventilation, which
447 often manifest during sleep, especially REM sleep.61,68,71
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448
449 The panel recommends using the AASM guidelines for scoring hypoventilation in adults15 and
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450 the ERS guidelines for pediatric patients as these define pediatric hypoventilation, specifically in
451 those with neuromuscular disease.13 In children and adults, the surrogates of arterial PCO2 are
452 end-tidal PCO2 (EtCO2), which can be affected by mask leak during titration or transcutaneous
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453 PCO2 (TcCO2). Capillary blood gas (CBG) may be used in children instead of arterial blood gas
454 (ABG). Hypoventilation is scored in adults on PSG when the arterial PCO2 (or surrogate) is ≥ 55
455 mm Hg for ≥ 10 minutes or there is an increase in the arterial PCO2 (or surrogate) ≥ 10 mm Hg
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456 (in comparison to an awake supine value) to a value exceeding 50 mm Hg for ≥ 10 minutes.15
457 For pediatric patients, hypoventilation is scored when the arterial PCO2 (or surrogate) is ≥ 50
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458 mm Hg for >= 2% of total sleep time or SpO2 is =< 90% for 2% of the recording time.13,14 The
459 value of testing to identify SDB and hypoventilation may vary across specific NMDs and impact
460 patient decisions. For example, pediatric patients and NMD associated with cardiomyopathies
461 are more likely to benefit from this diagnostic intervention.40,65
462 Use of Non-invasive Ventilation

463
465 The panel reviewed 763 abstracts and selected 25 studies for review (e-Tables 3a-3e).72-96 The
466 intervention was the use of NIV, and the comparator was no NIV. Outcomes included survival,
467 respiratory function, sleep, cognitive function, and quality of life (e-Appendix 4). The desirable
468 effects of NIV were moderate, and the undesirable effects were small, with a no clear harm, with
469 a net benefit that favors NIV. Given the life-threatening nature of chronic respiratory failure,
470 despite the low certainty of the evidence, the panel made a strong recommendation for the use of
471 NIV based on the GRADE guidelines.24 In the opinion of the panel, there was probably no
472 important uncertainty or variability in how patients value these results, such as improved
473 survival. Studies on sleep quality and respiratory parameters during sleep were observational,
12
474 with no direct comparisons between NIV and continuous positive airway pressure (CPAP). The
475 panel provided a conditional recommendation for using NIV for sleep-related breathing
476 disorders. Although no cost-effectiveness study was conducted for chronic respiratory failure or
477 sleep-related breathing disorders, the panel felt that the net benefit would justify the resources to
478 initiate NIV.
479
481 The evidence was predominantly from older children (>= 12 years) and adults with NMD, with
482 most studies in adults with ALS, although patients with DMD are also included. 72-97 There is
483 uncertainty as to what extent it applies to younger children with NMD. The panel anticipates that
484 NIV would be feasible to implement in many patients. However, some patients will decline, and
485 the panel recommends shared decision-making with patients and caregivers.
486
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487 Respiratory Parameters for Initiation of NIV
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488
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490 The panel reviewed 422 abstracts and selected five studies for review.98-102 The respiratory
491 parameters considered included the apnea-hypopnea index (AHI), hypoventilation indices such
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492 as time spent with oxygen saturation less than 90% during the night, EtCO2 or TcCO2, FVC,
493 MIP, MEP, PCF, and SNIP (e-Appendix 4). Outcomes included timing of NIV, care utilization,
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494 patient preference, symptom improvement, and mortality (e-Table 4). The desirable effects of
495 NIV were moderate, and the undesirable effects were small, with no clear harm, with net benefit
496 favoring NIV. The certainty of the evidence was very low. This recommendation places a higher
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497 value on the potential for improvement of outcomes that are important to patients, including
498 survival and symptom (see Figure 1) mitigation, and a lower value on the potential risks and
499 inconveniences of NIV. Given the significant impact of respiratory failure on morbidity and
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500 mortality, the testing and timing of NIV were considered a priority.
501
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503 Evidence was generated predominantly from adults with ALS, as it is the most common
504 NMD103. It must be applied judiciously to younger children, adolescents, and adults with non-
505 ALS diagnoses. The panel recommends considering PAP or NIV, as appropriate, in
506 symptomatic patients with FVC <80% of normal, those with FVC <50% of predicted value, or
507 impairment of other parameters such as MIP less than –60 cm H2O, MEP <40 cm H2O or PCF <
508 270L/min or based on the PSG results of PSG if indicated or the presence of hypercapnia (awake
509 PaCO2 > 45 mmHg).10,52,53 The panel recommends continuing to follow patients with serial PFT
510 on a 6-monthly basis and offering NIV when indicated. The panel did not distinguish between
511 the presence or absence of bulbar symptoms when offering NIV and recommends respecting
512 patient and family preferences and quality of life considerations.
513
514 Non-invasive Ventilation Strategies

515
13
517 The panel reviewed 1,383 abstracts and selected five studies for review (e-Table 5a-5e).104-108
518 There was no strong evidence to support one mode of NIV ventilation over another. However, a
519 backup respiratory rate achieves better patient-ventilator synchrony and improved gas exchange
520 (e-Appendix 4). No clear harms were identified for specific ventilator strategies, except those
521 related to inappropriate settings based on patient characteristics or inherent to NIV (mask) use.
522 The overall certainty of the evidence was very low.
523
525 The recommendation emphasizes the need to individualize NIV treatment. The optimal mode of
526 NIV for each patient can only be determined by a careful ongoing assessment of patient comfort,
527 sleep quality, digital downloads, unintentional leaks, oximetry (capnography when available),
528 and secretion management.13,66 Certain ALS patients with bulbar impairment may not tolerate
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529 NIV or achieve adequate ventilation.66
530
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531 Mouthpiece Ventilation
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532
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534 The panel reviewed 44 abstracts and selected four studies for review (e-Table 6).109-112 The
535 desirable effects of MPV are unknown but potentially include delaying or avoiding tracheostomy
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536 and improving speech, cough effectiveness, and the coordination of breathing and swallowing (e-
537 Appendix 4). Undesirable effects were considered trivial, without identified harmful
538 consequences with the balance of risk and benefits, probably favoring the intervention with very
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539 low certainty of the evidence.

540
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542 MPV or sip ventilation allows ventilatory support as needed through an angled mouthpiece and
543 has been used successfully to avoid tracheostomy.112 Progressive bulbar symptoms (e.g., in ALS)
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544 may limit the use of this option. Access to MPV is not universal, which may promote health
545 inequities. This is counterbalanced by the possible delay or avoidance of tracheostomy, reducing
546 the burden of care.112 Immediate availability of a handheld resuscitation bag for manual
547 ventilation may be required for technical or ventilator failure, along with patient and caregiver
548 training.
549
550 Use of Mechanical Ventilation
551
553 The panel reviewed 390 abstracts and selected ten studies for review (e-Table 7).83,113-121
554 Desirable effects of invasive mechanical ventilation (MV) at home by tracheostomy, including
555 survival and improvement in sleep quality, were large compared to no ventilatory support and
556 were equal to or provided a small benefit over NIV (e-Appendix 4). Undesirable effects
557 included an increased risk of hospitalization, lower quality of life, and caregiver burden. There is
558 uncertainty and variability in how patients value outcomes, such as improved survival compared
559 to undesirable effects. The preponderance of evidence favors invasive home MV via
560 tracheostomy as a treatment option for patients with progressive respiratory failure, particularly
14
561 those unable to clear secretions or changes in mental status such as frontotemporal dementia (see
562 Figure 2). However, continuous NIV may also be a possibility.112 Both invasive ventilation and
563 full-time NIV should be considered acceptable options based on patient preferences, tolerability,
564 ability to maintain mouthpiece ventilation, and availability of resources.
565
567 MV is associated with high costs and caregiver burden compared to NIV.122,123 Most evidence
568 comes from ALS patients and may not be extrapolated to NMD with different progression and
569 variable degrees of bulbar involvement. Some data suggest that in slowly progressive NMD,
570 two-thirds of the patient on MV reported an improved quality-of-life.124 Other data limitations
571 include inequalities in study groups selected for invasive home MV versus NIV, differential
572 follow-up, and treatment decisions and allocations based on patient preference. Currently, there
573 is no consensus on when, if desired, a patient should start invasive home MV, with
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574 recommendations ranging from 12-24 hours on NIV based on patient comfort and preference.
575 Many patients can manage 24-hour NIV effectively, and the decision to transition to MV must
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576 not be based solely time-based.112 Also, local expertise can drive care choice between MV and
577 NIV, such as ease of administration during sleep, oral feeding, talking, and facial expression with
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578 invasive ventilation (see Figure 2).
579
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580 Sialorrhea Management
581
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583 Management of sialorrhea was considered a high priority in NMD. The panel reviewed 2,714
584 abstracts and selected 17 studies for review (e-Tables 8a-c). Salivary secretion management
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585 included anticholinergic agents, botulinum toxin (BT) therapy, and radiation therapy (RT) (see
586 Table 4). For most salivary secretion management options, the balance of risks, including
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587 treatment-specific adverse events, and benefits, such as improvement in symptoms, was
588 considered to favor or probably favor the intervention. Exceptions were anticholinergics, where
589 the balance was neutral as some patients feel symptomatic relief while others do not tolerate
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590 them well, and RT, where it is not clear (e-Appendix 4). Specifically, the harm may outweigh
591 the benefits for RT in some cases. However, patients with significant debility from sialorrhea can
592 obtain substantial long-term permanent relief from this intervention. The certainty of the
593 evidence was low to very low for all interventions.
594
595 There is a concern for inequities in access, given the cost of some medications and variable
596 insurance coverage for RT. Most of the interventions were considered acceptable or probably
597 acceptable to the stakeholders except for RT, which was considered to be of uncertain
598 acceptability. The interventions were considered feasible to implement.
599
601 Sialorrhea is common in NMD, particularly ALS, and can be very distressing, reducing the
602 quality of life and increasing the risk of aspiration and pneumonia due to problems with
603 swallowing, airway protection, and cough effectiveness. Therefore, the panel recommends
604 starting with a trial of anticholinergic agents, which are relatively inexpensive and readily
605 available. Escalation to more expensive and more convenient anticholinergic patches or
15
606 subcutaneous glycopyrrolate formulations could be considered after those initial trials. See the
607 online supplement for individual doses used in clinical trials.
608
609 Botulinum toxin is inexpensive, injections are simple, and they are not overly uncomfortable,
610 and the beneficial effect on salivary function can last weeks to months. However, studies are
611 limited by observational data from a small number of subjects, the risk of bias, subjective
612 measurements, incomplete intervention description, and loss of follow-up. In addition, there are
613 differences in the treatments (Botulinum A vs. B, different doses and locations; parotid vs.
614 submandibular glands). See the online supplement for individual doses used in the trials. The
615 patients considered the adverse effects mild to moderate. Due to the variability in the literature,
616 the panel did not provide a recommended dose.
617
618 Limited data have been published on RT for sialorrhea in patients with NMD. The certainty of
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619 the evidence is limited by the unblinded observational design of these studies and the subjective
620 improvement assessment bias. The high variability in the protocols (for example, type of energy,
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621 strength, and duration of RT), medical center experience, and degree of sialorrhea limited the
622 comparison between studies to provide firm recommendations. The panelists recommended
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623 reserving the therapy to experienced centers. See the online supplement for individual doses used
624 in the trials. Only one trial compared BT with RT and did not show significant differences in
625 drooling between treatment modalities.125
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626
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627 Airway Clearance Techniques
628
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630
631 Impairment of cough and airway clearance due to muscle weakness, glottic dysfunction, and low
632 lung volumes increases respiratory morbidity and mortality risk. Thus, airway clearance
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633 techniques were considered a high priority in NMD, and the panel reviewed 2,714 abstracts,
634 selecting 36 studies for review (e-Table 8d-h).126-161 Airway clearance techniques included
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635 glossopharyngeal breathing (GPB), mechanical insufflation-exsufflation (MI-E), manually

636 assisted cough, LVR by air stacking, and high-frequency chest wall (HFCWO) (see Table 5).
637 These techniques involve cough augmentation to mobilize secretions and remove secretion from
638 both proximal and peripheral airways leading to desirable effects, including improved lung
639 function and reduced pulmonary morbidity. This is achieved by supporting the inspiratory or
640 expiratory muscles or both. These techniques are not mutually exclusive; a combination of
641 therapies can help achieve better secretion clearance.
642
643 For these airway clearance options, the balance of risks, including technique-specific adverse
644 events and benefits, was considered to favor or probably favor the interventions. Still, the
645 certainty of the evidence was low to very low for all interventions (e-Appendix 4). Given the
646 certainty of the evidence, the panel recommended the use of airway clearance techniques based
647 on local resources, expertise, and shared decision-making with patients. In the opinion of the
648 panel, there is no data to show superiority of one specific airway clearance technique over
649 another, and the panel recommends making decisions on the use of individual techniques based
650 on local resources, and patient-related conditions such as intellectual disability, bulbar
16
651 dysfunction, and hand dexterity in making clinical decisions. Two recent reviews have discussed
652 these issues in detail.9,12
653
654 There is a concern of inequities in access, given variable insurance coverage for MI-E and
655 HFCWO. Most of the interventions were considered acceptable or probably acceptable by
656 stakeholders except for HFCWO, which was deemed of uncertain acceptability. The
657 interventions were feasible or probably feasible except for HFCWO, where feasibility was
658 considered uncertain depending on availability at individual centers.
659
661 Low-quality evidence suggests that regularly increasing lung volumes and expiratory cough
662 flows with lung volume recruitment (LVR) has immediate and long-term effects on VC,
663 maximum inspiratory capacity, and assisted cough flows. Regular LVR may have a positive
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664 impact on clinical outcomes. There is no evidence to suggest that one method of LVR is superior
665 to another, e.g., resuscitation bag vs. mouthpiece ventilation (MPV),158 or volumetric cough
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666 mode,133 although MPV availability improves autonomous LVR. An LVR resuscitation bag is
667 inexpensive, and the technique is easy to learn for caregivers. Effectiveness can be limited by
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668 bulbar function and compliance with the respiratory system. More RCTs are needed to evaluate
669 the effectiveness of LVR with objective adherence measures.
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670
671 The advantages of LVR through glossopharyngeal breathing (GPB) include that the technique
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672 does not require resources and has no documented adverse consequences.162 However, not all
673 patients can perform GPB effectively, and training is required. Manually assisted coughing, on
674 the other hand, is readily available, can be taught in a single visit, and is feasible on its own or
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675 with an LVR maneuver.137

676
677 Mechanical insufflation-exsufflation (MI-E) is beneficial but may require caregiver assistance
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678 and may be less effective in patients with bulbar impairment.163 High-frequency chest wall
679 oscillation (HFCWO) may be used in some cases; however, there are limited data on the use of
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680 HFCWO in patients on NIV.164 The panel recommends individualized therapy as some may find
681 the treatment uncomfortable, like the frail and elderly or those with significant musculoskeletal
682 deformities. MI-E and HFCWO are also associated with high costs.
683
684 SUMMARY
685
686 Respiratory failure is common and is often the final cause of death in patients with
687 neuromuscular disease (NMD). In this manuscript, we have examined the literature on the
688 management of respiratory failure in patients with NMD to provide evidence-based and expert
689 guidance to clinicians. In addition, we offered recommendations where evidence allowed and
690 consensus-based and best practice statements in areas we thought warranted comment, despite a
691 lack of high-quality evidence.
692
693 These guidelines have several limitations. NMDs are a heterogeneous group of disorders, and it
694 is difficult to provide a unique set of recommendations for each specific NMD. In addition, there
695 are limited randomized controlled trials on specific NMDs. Furthermore, a significant portion of
17
696 the evidence is based on ALS, as data on other slowly progressive diseases are limited and
697 elements of the guideline may need to be individualized according to the rate of progression of
698 an individual patient’s illness (e-Appendix 3). Finally, the guideline focused on diagnosis and
699 initiation of therapies and did not go into the details of NIV or MV, which would require
700 separate guidelines. Despite these limitations, this guideline provides practicing clinicians with
701 the best possible evidence to help manage patients in clinical practice.
702
703 The guideline panel recommends shared decision-making with patients and their families,
704 including respect for patient preferences, treatment goals, and quality of life considerations.
705 Access to these recommendations by patients and clinicians may depend on local resources and
706 private versus public healthcare and, in some cases, may require a referral to a specialist center.
707 These guidelines should be an opportunity for advocacy to ensure equal access for those who
708 meet the suggested inclusion criteria, as some recommendations can increase health inequities.
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709 Randomized controlled trials in NMD patients in the future would help establish a higher level of
710 evidence.
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711
712 Future directions of research in this area include understanding the time interval of PFT testing
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713 based on the rate of disease progression for individual NMD; the use of end-tidal or
714 transcutaneous CO2 monitoring in the detection of hypoventilation in outpatient settings, the role
715
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of PSG in the diagnosis of NMD, understanding the impact of telemedicine in the management
716 of NIV prescription and monitoring; use of device downloads to modify the NIV prescription,
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717 use of artificial intelligence for automatic adjustment of device settings, modernizing and easing
718 access to ventilation support for NMD patients, comparison of outcomes of airway clearance and
719 secretion management techniques such as MI-E and LVR, comparison of tracheostomy with
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720 MPV. Additionally, data are needed to help modernize and improve access to ventilatory support
721 for NMD patients and better understand the role of shared decision-making with NMD patients
722 in enhancing the quality of life and long-term outcomes.
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723
724 Acknowledgments
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725 We thank Andrea Pauls Backman (Les Turner ALS Foundation) for providing the patient
726 perspective during all phases of guideline development and for comments on the manuscript and
727 Haeun Jung and Randall Clark for their assistance in making the figures and tables.
728 Endorsements: This guideline is endorsed by the American Academy of Sleep Medicine, the
729 American Association for Respiratory Care, the American Thoracic Society, and the
730 Canadian Thoracic Society
18
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1192 159. Vianello A, Corrado A, Arcaro G, Gallan F, Ori C, Minuzzo M. Mechanical insufflation-
1193 exsufflation improves outcomes for neuromuscular disease patients with respiratory
1194 tract infections. American journal of physical medicine & rehabilitation. 2005;84(2):83‐
1195 88; discussion 89‐91.
1196 160. Winck JC, Goncalves MR, Lourenco C, Viana P, Almeida J, Bach JR. Effects of mechanical
1197 insufflation-exsufflation on respiratory parameters for patients with chronic airway
1198 secretion encumbrance. Chest. 2004;126(3):774-780.
1199 161. Kang SW, Kang YS, Sohn HS, Park JH, Moon JH. Respiratory muscle strength and cough
1200 capacity in patients with Duchenne muscular dystrophy. Yonsei Med J. 2006;47(2):184-
1201 190.
1202 162. Maltais F. Glossopharyngeal breathing. American journal of respiratory and critical care
1203 medicine. 2011;184(3):381.
1204 163. Homnick DN. Mechanical insufflation-exsufflation for airway mucus clearance. Respir
1205 Care. 2007;52(10):1296-1305; discussion 1306-1297.
29
1206 164. Yuan N, Kane P, Shelton K, Matel J, Becker BC, Moss RB. Safety, tolerability, and efficacy
1207 of high-frequency chest wall oscillation in pediatric patients with cerebral palsy and
1208 neuromuscular diseases: an exploratory randomized controlled trial. Journal of child
1209 neurology. 2010;25(7):815-821.
1210
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30
1211 Table 1. Structured Clinical Questions
Topic Population Intervention(s) Comparator(s) Outcomes Study
Designs
Use of PFTs Patients PFTs and No PFTs or Disease Cohort,
with NMD measurement measurement progression, Case-
(aged >6yo) of lung of lung SDB, patient control
at risk for function function preference, RCTs,
respiratory parameters parameters clinical systematic
failure utilization review,
meta-
analyses
Excluded:
of
Case
reports and
ro
case series
(n<11)
-p
Timing of Patients Respiratory Respiratory Disease Cohort,
PFTs with NMD insufficiency insufficiency progression, Case-
re
(aged >6yo) testing at least testing once a patient control
every 6 months year preference, RCTs,
lP
clinical systematic
utilization review,
meta-
na
analyses
Excluded:
ur
Case
reports and
Jo
case series
(n<11)
Testing for Patients Testing for No testing for QoL, Cohort,
SDB with NMD SDB SDB symptom Case-
(aged >6yo) improvement, control
survival, RCTs,
patient systematic
preference, review,
clinical meta-
utilization, analyses
sleep
architecture Excluded:
Case
reports and
case series
(n<11)
31
Use of NIV Patients NIV No NIV Survival, Cohort,
with NMD disease Case-
(aged >6yo) progression, control
and QoL, RCTs,
respiratory symptom systematic
failure improvement, review,
patient and meta-
caregiver analyses
preference,
clinical Excluded:
utilization, Case
adverse reports and
events case series
of
(n<11)
Respiratory Patients Use of No Survival, Cohort,
ro
parameters with NMD respiratory consideration symptom Case-
for initiation (aged >6yo) parameters to of specific improvement, control
-p
of NIV initiate NIV respiratory patient RCTs,
parameters to preference, systematic
re initiate NIV clinical review,
utilization meta-
lP
analyses
Excluded:
na
Case
reports and
case series
ur
(n<11)
NIV Patients (comparative effectiveness) of the Survival, Cohort,
Jo
ventilation with NMD following non-invasive ventilator symptom Case-

strategies (aged >6yo) strategies; bilevel pressure- improvement, control
using NIV targeted (S mode), Back up rate QoL, patient RCTs,
(S/T,PC,PAC mode), volume preference, systematic
targeted, VAPS, negative sleep review,
pressure ventilation architecture, meta-
adverse analyses
events
Excluded:
Case
reports and
case series
(n<11)
MPV Patients MPV Other NIV Survival, Cohort,
with NMD modalities symptom Case-
(aged >6yo) (facemask, improvement, control
using NIV helmet, etc.) QoL, patient RCTs,
32
preference, systematic
adverse review,
events meta-
analyses
Excluded:
Case
reports and
case series
(n<11)
Invasive Patients Invasive home no invasive Survival, Cohort,
ventilation with NMD ventilator home ventilator symptom Case-
(aged >6yo) therapies therapies, improvement, control
of
and through palliation, QoL, patient RCTs,
respiratory tracheostomy continuous preference, systematic
ro
failure NIV adverse review,
events meta-
-p
re analyses
Excluded:
Case
lP
reports and
case series
(n<11)
na
Airway Patients Selected airway No airway Secretion Cohort,

clearance with NMD clearance clearance management, Case-
techniques (aged >6yo) therapies therapy survival, control
ur
symptom RCTs,
improvement, systematic
Jo
QoL, patient review,

preference, meta-
clinical analyses
utilization,
adverse Excluded:
events Case
reports and
case series
(n<11)
1212 Table 2. Certainty of Evidence

Certainty of
the
Evidence Level of Confidence in the Estimate of the Effect23
High We are very confident that the true effect lies close to that of the estimate of
the effect.
33
Moderate We are moderately confident in the effect estimate: The true effect is likely to
be close to the estimate of the effect, but there is a possibility that it is
substantially different.
Low Our confidence in the effect estimate is limited: The true effect may be
substantially different from the estimate of the effect.
Very Low We have very little confidence in the effect estimate: The true effect is likely
to be substantially different from the estimate of effect.
1213 Table 3. CHEST Grading System

Grade of Benefit vs Methodologic Strength of Implications
Recommendation Risk and Supporting Evidence
Burdens
Strong Benefits We are very confident that Recommendation can apply
of
recommendation, clearly the true effect lies close to to most patients in most
High-quality outweigh risk that of the estimate of the circumstances. Further
ro
evidence and burdens, effect. research is very unlikely to
or vice versa change our confidence in
-p
re the estimate of effect.
Strong Benefits We are moderately Recommendation can apply

lP
recommendation, clearly confident in the effect to most patients in most

Moderate-quality outweigh risk estimate: The true effect is circumstances. Higher
evidence and burdens, likely to be close to the quality research may well
na
or vice versa estimate of the effect, but have an important impact

there is a possibility that it on our confidence in the
ur
is substantially different. estimate of effect and may

change the estimate.
Jo
Strong Benefits Our confidence in the effect Recommendation can apply

recommendation, clearly estimate is limited: The true to most patients in many
Low-quality outweigh risk effect may be substantially circumstances. Higher
evidence and burdens, different from the estimate quality research is likely to
or vice versa of the effect. have an important impact
on our confidence in the
estimate of effect and may
well change the estimate.
Strong Benefits We have very little Recommendation can apply
recommendation, clearly confidence in the effect to most patients in many
very low-quality outweigh risk estimate: The true effect is circumstances. Higher
evidence and burdens, likely to be substantially quality research is likely to
or vice versa different from the estimate have an important impact
of effect. on our confidence in the
well change the estimate.
34
Weak Benefits We are very confident that The best action may differ
(conditional) closely the true effect lies close to depending on
recommendation, balanced with that of the estimate of the circumstances or patients'
High-quality risks and effect. or societal values. Further
evidence burden research is very unlikely to
change our confidence in
the estimate of effect.
Weak Benefits We are moderately Best action may differ

(conditional) closely confident in the effect depending on
recommendation, balanced with estimate: The true effect is circumstances or patients'
of
Moderate-quality risks and likely to be close to the or societal values. Higher
evidence burden estimate of the effect, but quality research may well
ro
there is a possibility that ithave an important impact
is substantially different. on our confidence in the
-p
change the estimate.
Weak Uncertainty in Our confidence in the effect Other alternatives may be
re
(conditional) the estimates estimate is limited: The true equally reasonable. Higher
recommendation, of benefits, effect may be substantially quality research is likely to
lP
Low-quality risks, and different from the estimate have an important impact
evidence burden; of the effect. on our confidence in the
benefits, risk estimate of effect and may
na
and burden well change the estimate.

may be closely
ur
balanced
Weak Uncertainty in We have very little Other alternatives may be
Jo
(conditional) the estimates confidence in the effect equally reasonable. Higher

recommendation, of benefits, estimate: The true effect is quality research is likely to
very low-quality risks, and likely to be substantially have an important impact
evidence burden; different from the estimate on our confidence in the
benefits, risk of effect. estimate of effect and may
and burden well change the estimate.
may be closely
balanced
Good Practice Benefits Based on indirect evidence Action is viewed as
Statement clearly or inference from already obviously beneficial or
outweigh risk commonly accepted as standard of care; It is
and burdens, beneficial practice. unlikely that direct research
or vice versa will be conducted.
Ungraded Consensus-based Suggestions
Ungraded Uncertainty Insufficient evidence for a Future research may well
Consensus- due to lack of graded recommendation. have an important impact
Based Statement evidence but on our confidence in the
35
expert opinion estimate of effect and may
that benefits change the estimate.
outweigh risk
and burdens or
vice versa.
1214
1215
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lP
na
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Jo
36
1216 Table 4 Recommended Therapies for Sialorrhea
1217
Therapy Suggestions Remarks
Anticholinergic An initial trial of an inexpensive oral Relatively inexpensive and

medications anticholinergic is suggested. readily available.
Continue to use if the benefits are Individual patient benefits
greater than the side effects. and adverse events can be
More expensive and potentially longer- easily assessed.
acting anticholinergic patch medication
can also be considered.
of
ro
-p
Botulinum toxin Limited data, doses are not defined. Inexpensive, lasting
(Botox) therapy to See individual studies for doses in the beneficial effects on
re
salivary glands supplement. salivary function.
May need to be repeated.
lP
Associated with viscous
saliva & mild to moderate
pain.
na
Salivary gland Limited data, doses not defined. Long-lasting relief,

ur
radiation therapy (RT) See individual studies for doses in the however, is associated with
supplement. irreversible dryness.
Jo
Suggest reserving RT to
experienced centers.
1218
1219
37
1220
1221 Table 5 Recommended Airway Clearance Therapies
1222
Technique Indications Description Remarks
Glossopharyngeal Hypoventilation Positive pressure Low cost

breathing (GBP/"frog breathing method using Performed by the
breathing") muscles of the mouth, patient
tongue pharynx, & independently.
larynx
Manually assisted Reduced cough Abdominal thrust or Low cost
cough (MAC) effectiveness lateral costal Requires caregiver
of
compression to assistance.
generate expiratory
ro
flow
Lung volume Reduced lung Handheld resuscitation Low cost
-p
recruitment function or cough bag or mouthpiece to Requires caregiver
(LVR/"breath effectiveness inflate lungs to assistance.
stacking") maximum inspiratory
re
capacity without
intervening expiration
lP
Mechanical Reduced cough Alternating positive Expensive MI-E

insufflation- effectiveness not and negative pressure device
exsufflation (cough improved with using a facemask or Requires caregiver
na
assist device) alternative artificial airway. assistance.

techniques Effective for both Reduces morbidity
ur
upper and lower airway & hospitalization.

secretions. Can have
procedure
Jo
intolerance.
High-frequency chest Difficulties with Fit-tested vest that Expensive
wall oscillation secretion clearance produces vibrations to HFCWO device.
(HFCWO) combined mobilize peripheral Requires caregiver
with cough assistance airway secretions assistance.
or LVR which are then cleared Can have
with cough / LVR to procedure
improve expiratory intolerance.
airflow.
1223
1224
38
1225 Figure 1 Flowchart for NIV initiation for patients with NMD showing respiratory failure
1226 symptoms.
1227
of
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lP
na
1228
1229
ur
Jo
39
1230 Figure 2 Flowchart for NIV intolerance for patients with NMD showing respiratory failure
1231 symptoms.
of
ro
1232
-p
1233 re
lP
na
ur
Jo
40
f
oo
-pr
re
lP
na
ur
Jo
Figure 1 Flowchart for NIV initiation for patients with NMD showing respiratory failure symptoms
f
oo
-pr
re
lP
na
ur
Jo
Figure 2 Flowchart for NIV tolerance

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐ The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:
of
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lP
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Management of Respiratory Failure in Patients with Neuromuscular Weakness:
CHEST Guideline and Expert Panel Report
1. Akram Khan, MD
2. Lindsy Frazer, PhD
3. Reshma Amin, MD
4. Lisa Wolfe, MD
5. Garner Faulkner, RRT
6. Kenneth Casey, MD
7. Girish Sharma, MD
of
8. Bernardo Selim, MD
9. David Zielinski, MD
ro
10. Loutfi Aboussouan, MD
11. Douglas McKim, MD
12. Peter Gay, MD
-p
re
lP
na
ur
Jo
Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data.
e-Appendix 1. Conflict of Interest Grid
Description of COI
Loutfi Aboussouan, MD, Reshma Amin, MD, FCCP Andrea Pauls Backman, MBA, Garner Faulkner II, BSRC, Lindsy Frazer-Green,
PICO Question FCCP CPA RRT, AE-C PhD
Should PFTs and/or measurement of lung function parameters None None None None None
be undertaken in patients with NMD at risk of respiratory
failure?
Should respiratory insufficiency testing be completed at least None None None None None
every 6 months vs once a year in patients with NMD?
Should testing for SDB be undertaken in patients with NMD? None None None None None
Should NIV be offered to patients with NMD and respiratory None None None None None
failure?
Should respiratory parameters be used to initiate NIV in None None None None None
patients with NMD?
f
oo
What is the comparative effectiveness of different ventilator None None None None None
strategies for patients with NMD using NIV?
Should mouthpiece ventilation be offered to patients with None None None None None
pr
NMD using NIV?
Should invasive ventilation be offered to patients with NMD None None None None None
and respiratory failure?
e-
Should airway clearance techniques be used for patients with None None None None None
NMD?
Pr
All disclosures Royalties from UpToDate; Speaker for Biogen; None None None
speaker for Cleveland Clinic Research grants to
institution from Muscular
al
Dystrophy Canada, The
Hospital for Sick Kids,
u rn Baxter Endowment Fund;
speaker for International
Pediatric Sleep Association
and American Thoracic
Jo
Society
Description of COI
Peter Gay, MD, FCCP Akram Khan, MD, FCCP Douglas McKim, MD, FCCP Bernardo Selim, MD, FCCP Girish Sharma, MD,
PICO Question FCCP
Should PFTs and/or measurement of lung function parameters None None None None None
failure?
Should respiratory insufficiency testing be completed at least None None None None None
Should testing for SDB be undertaken in patients with NMD? None None None None None
Should NIV be offered to patients with NMD and respiratory Research grant to institution None None None None
failure? from Fisher-Paykel
Should respiratory parameters be used to initiate NIV in None None None None None
patients with NMD?
What is the comparative effectiveness of different ventilator Research grant to institution None None None None
strategies for patients with NMD using NIV? from Fisher-Paykel
Should mouthpiece ventilation be offered to patients with None None None None None
NMD using NIV?
Should invasive ventilation be offered to patients with NMD None None None None None
Should airway clearance techniques be used for patients with None None None None None
NMD?
All disclosures Research grant to institution Research Research grants to institution None None
from Fisher-Paykel; Royalties from Muscular Dystrophy
from UpToDate Canada, Jessie’s Journey,
International Ventilator Users
Network
Description of COI
PICO Question Lisa Wolfe, MD, FCCP David Zielinski, MD, FCCP
Should PFTs and/or measurement of lung function parameters None None
failure?
Should respiratory insufficiency testing be completed at least None None
f
oo
Should testing for SDB be undertaken in patients with NMD? None None
Should NIV be offered to patients with NMD and respiratory None None
pr
failure?
Should respiratory parameters be used to initiate NIV in None None
patients with NMD?
e-
What is the comparative effectiveness of different ventilator None None
strategies for patients with NMD using NIV?
Pr
Should mouthpiece ventilation be offered to patients with None None
NMD using NIV?
Should invasive ventilation be offered to patients with NMD None None
al
Should airway clearance techniques be used for patients with Research grants to institution None
NMD?
All disclosures
from ResMed
rn
Consultancy for Hill-Rom;
advisory board for
u Grants
Cytokinetics; research grants

Jo
to institution from ResMed,

Hill-Rom
Online supplements are not copyedited prior to posting and the author(s) take full responsibility for the accuracy of all data. 3
e-Appendix 2. Study Selection Process
Initial Search November 2018 Search Update September 2020 Anticholinergics Search August 2021
Records Records Records

identified^ identified^ identified^
8,472 995 169
Duplicates Duplicates Duplicates
removed removed removed
1,709 263 3
f
oo
Records Records Records
screened* screened screened
732 166
pr
6,763
Titles & abstracts Titles & abstracts Titles & abstracts
e-
excluded 6,079 excluded 665 excluded 149
Pr
Full-text articles Full-text articles Full-text articles
assessed 684 assessed 67 assessed 17
al
excluded 49 excluded 15
excluded 576
u rn
included 18 included 2
Jo
included 108
Studies included in the analysis

128
^Records identified through database searching including MEDLINE and Cochrane Library, as well as bibliographic handsearching and consultation with the expert panel.
*See Table 1 for PICO elements and study design criteria. Studies not aligned with the criteria in Table 1, not including participants aged ≥6, with samples <10 individuals, studies
of spinal cord injury populations, and/or not providing data specific to the identified critical and important outcomes were excluded. These criteria were applied across all
literature searches.
e-Appendix 3. Study population characteristics per recommendation
Recommendation 1 2 3 4&5 6 7 8 9 10-14
# of studies 0 (Good
practice 22 5 25 5 5 4 10 53
statement)
Total NMD sample N/A 3,331 290 4,480 511 48172 1,575 2,469
Study N/A ALS, 3064 [92%] ALS, 76 [26.2%] ALS, 3,977 [88.8%] ALS, 428 ALS, 456
ALS, 39 ALS, 1,291 [82%] Varied NMDs,
population(s), n [% MD1, 108 [3.2%] Pompe disease, DMD, 292 [6.5%] [83.8%] [94.8%]
[54.2%] DMD, 232 1,080 [43.7%]
of total] DMD, 77 [2.3%] 65 [22.4%] MNDs, 93 [2.1%] DMD, 83 DMD, 22
DMD, 30 [14.7%] ALS, 812 [32.9%]
Varied NMDs^ Myasthenia gravis, MD1, 36 [0.8%] [16.2%] [4.6%]
[41.7%] Unspecified DMD, 482 [19.5%]
f
oo
(excluding ALS), 58 [20%] Post-polio dysfunction, Congenital MD,
Becker NMDs, 46 [2.9%] SMA, 51 [2.1%]
48 [1.4%] FSHD, 51 [17.6%] 33 [0.7%] 2 [0.4%]
muscular Myasthenia Post-polio
LGMD,34 [1%] MD1, 40 [13.8%] Unspecified NMDs, 27 Mitochondrial
dystrophy, gravis, 3 [0.2%] dysfunction, 38
pr
[0.6%] myopathy, 1
2 [2.8%] Spinal muscular [1.5%]
Pompe disease, 22 [0.2%]
Post-polio atrophy, 3 [0.2%] Myotonic
e-
[0.5%] syndrome, dystrophy, 6
1 [1.4%] [0.2%]
Pr
ALS: Amyotrophic lateral sclerosis; DMD: Duchenne muscular dystrophy; FSHD: Facioscapulohumeral muscular dystrophy; LGMD: Limb girdle muscular dystrophy; MD1:
Myotonic dystrophy type 1; MND: Motor neuron disorder; NMD: Neuromuscular disease; SMA: Spinal muscular atrophy
al
^ Varied NMDs indicate studies enrolled patients with NMD of various etiologies and primarily analyzed data for NMDs as a general condition.
u rn
Jo
e-Table 1a. Evidence Profile- Pulmonary Function Testing to Predict Survival in NMD
Certainty assessment
Impact Certainty Importance
№ of Study Risk of Other
Inconsistency Indirectness Imprecision
studies design bias considerations
SVC Decline to Predict Survival (follow up: Varied; assessed with: Cox proportional hazards regression model)
21,2 observational not not serious serious b

not serious none For 893 ALS patients, when the rate of decline of SVC ⨁◯◯◯ CRITICAL
studies serious from baseline was slower by 1.5 percentage points VERY
a
per month in the first 6 months, risk reduction was LOW
23% (95%CI 18-27) for death at any time after 6
months (p< 0.001).1
f
oo
For 469 ALS patients followed for up to 15 years,
holding constant other significant independent
variables (onset region, age, disease duration etc.),
pr
for every 1% decrease in the percentage of the
predicted value of SVC, there was a 1.02 increased
e-
probability of dying.2
Pulmonary Function Decline to Predict Survival (follow up: median 12.4 months; assessed with: univariate analysis of association between decline in pulmonary function parameters
Pr
and survival; death was defined as natural death or assisted ventilation for 23 h/day for 14 consecutive days)
13 observational not not serious serious b

serious c
none For 238 ALS patients, significant correlations were ⨁◯◯◯ CRITICAL
al
studies serious observed among all lung function parameters and VERY
death: when VC, MIP/SNIP or MEP (in % of predicted) LOW
decreased by 10%, the risk of death multiplied by
u rn 1.31 (95% CI 1.21–1.41), 1.48 (1.32–1.66) and 1.54
(1.32–1.79), respectively. When the PFC decreases by
50 L/min, the risk of death is multiplied by 1.32
(95%CI 1.19–1.75). Results did not differ significantly
Jo
after excluding patients on NIV (no data provided).
Respiratory Impairment and Survival (follow up: median 6 years; assessed with: nonparametric Spearman’s correlation coefficient; Survival measurement undefined)
14 observational not not serious serious b

serious c
none In a sample of 31 LGMD patients, comparing median ⨁◯◯◯ CRITICAL
studies serious lung parameter values between live participants VERY
(n=24) and deceased participants (n=7), no LOW
association was found between respiratory
impairment and survival: measured by baseline VC %
predicted (31 vs 35, p=0.98), MIP cmH2O (33.5 vs
29.5, p=0.36), MEP cmH2O (30.5 vs 30, p=0.84) and
nocturnal SatO2 <90% (1 vs 1.25, p=0.15).
FVC Decline to Predict Survival (follow up: Varied; assessed with: Kaplan-Meier analysis or regression analysis)
8 2,5-11
observational not not serious e
serious b
serious f
none For 80 ALS patients followed for 2 years, after ⨁◯◯◯ CRITICAL
studies serious controlling for age, site of onset, NIV and riluzole VERY
d
usage, rate of decline in seated FVC (p=0.000001) LOW
and supine FVC (p=0.0004) were significantly
associated with survival. ΔFVC had no significant
association with survival using either 15% (p=0.395)
or 20% (data not shown) of predicted value as a cut-
off point.5
f
oo
For 34 ALS/PMA patients followed for a median of 1.5
years, rapid FVC decline (>14%/year) was not
significantly associated with reduced overall survival:
pr
HR 0.472 (95%CI 0.107-1.957), p=0.299.7
For 58 DMD patients followed for a median of 7.2
e-
years, comparing individuals dying before and after
the median time of survival (20.5yr), change in % of
Pr
predicted FVC per year (p<0.0003) and maximal FVC
were predictive of survival (p<0.0005).8
For 469 ALS patients followed up to 15 years,
al
adjusting for onset region, age, and disease duration,
for every 1% decrease in the FVC% predicted there
u rn was a 1.02 increased probability of death.2
For 73 ALS patients followed for up to 6 months,

monthly decline in FVC% (HR 0.89 95%CI 0.79-1.00,
Jo
p=0.05) and sFVC% (HR 0.89 95%CI 0.81-0.99,

p=0.03) were significantly associated with survival.11
For 97 ALS patients followed for 1 year, after

adjusting for baseline FVC% and baseline ALSFRS
score, a 1% increase in the yearly rate of decline of
FVC% increased the risk of mortality by 17.3% (HR
0.827 95%CI 0.750-0.911, p=0.0001).9
For 139 ALS patients followed for 50 months, the rate

of decline in FVC <97 ml/mo (n=81) identified
patients whose survival time was greater than
patients with FVC rate of decline >97 ml/mo (n=72)
from either dyspnea onset (mean survival years
2.0±1.4 vs 1.0±0.8, respectively, p<0.05) or BiPAP
initiation (mean survival years 1.9±1.5 vs 1.0±0.9,
respectively, p<0.05).10
For 36 ALS patients followed for 5 years, ROC analysis

showed that FVC < 50% was associated with death in
ALS patients (p=0.003, AUC = 0.649).6
Cough Peak Flow to Predict Survival (follow up: median 1.5 years; assessed with: Kaplan-Meier analysis; survival from disease onset)
1 7
observational not not serious serious b
serious c
none For 34 ALS/PMA patients, no correlation was found ⨁◯◯◯ CRITICAL
studies serious between CPF (L/Min) and overall survival. A VERY
significant difference in overall survival was found LOW
between patients with CPF ≥ 220 L/min and patients
with CPF< 220 L/min: estimated median survival 6.1
years vs 2.9 years, respectively (p=0.024). Patients
f
with a CPF decline rate of ≥25% had shorter overall
oo
survival times from disease onset than those with a
decline rate of <25%: median survival 6.5 years vs
2.1 years, respectively (p<0.0001).
pr
Respiratory Function Tests to Predict Mortality at 2 Years (follow up: 2 years; assessed with: sensitivity, specificity, and AUC determined via ROC (receiver operator characteristics)
curves analysis; The specificity and sensitivity values of each RFT for multiple cut-off points are obtained from the coordinates calculated for the ROC curves)
e-
1 5
observational not not serious serious b
serious c
none For 80 ALS patients, normal supine FVC was highly ⨁◯◯◯ CRITICAL
Pr
studies serious predictive for two-year survival: VERY
LOW
Parameter Cut- Se(%) Sp AUC
off (%)
al
Seated FVC <80 58 86 82
(% <65 51 100
u rn predicted)
Supine FVC
(%
<50
<80
<65
16
72
56
100
77
88
81
predicted) <50 37 97
Jo
Difference >15 23 85 62
in FVC (% >20 5 88
predicted)
NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; PMA: Progressive muscular atrophy; NIV: Noninvasive ventilation; CI: Confidence interval; HR: Hazard ratio;
SVC: Slow vital capacity; FVC: Forced vital capacity; DMD: Duchenne muscular dystrophy; MND: Motor neuron disease; VC: Vital capacity; MIP: Maximum inspiratory pressure
(cm H2O); MEP: Maximum expiratory pressure (cm H2O; Se: Sensitivity; Sp: Specificity; LGMD: Limb girdle muscular dystrophy; SaO2: Oxygen saturation; CPF: Cough peak
flow; AUC: Area under the curve; ROC: Receiver operating characteristic
Explanations
a. One study reported loss to follow up as patients adapted to NIV suggesting a bias in the sample towards slow progressors.
b. Studies explore the predictive value of the respiratory function for survival which differs importantly from the research question focused on the utility of testing to impact
disease progression.
c. The study includes a sample that does not meet optimal information size criteria (>400 participants) so is concerning for imprecision.
d. Three of the 8 included studies are of moderate risk of bias due to considerable loss to follow-up or non-standardized co-interventions that may have impacted the outcome of
survival. This suggests a borderline risk of bias for the totality of the evidence.
e. The majority of studies suggest FVC decline is predictive of survival; 1 of the 8 studies did not find an association between FVC decline and survival.
f. The majority of studies include small samples that are concerning for imprecision; As the totality of the evidence consistently suggests FVC decline is predictive of survival this
imprecision is borderline. As the evidence was not downgraded for borderline risk of bias it has been downgraded for borderline imprecision.
e-Table 1b. Evidence Profile- Pulmonary Function Testing to Predict Respiratory Function and Events
Respiratory Parameters to Predict Hypoventilation (follow up: Cross-sectional; assessed with: Sensitivity, specificity, ROC analysis)
4 12-15
observational not not serious serious a
serious b
none Based on data from 199 ALS patients, 24 with ⨁◯◯◯ IMPORTANT
studies serious hypoventilation*, FVC was discriminative for VERY
hypoventilation14: LOW
Parameter Cut- Se Sp PPV NPV%
off % % %
f
FVC 80% 66.7 66.3 21.3 93.6
oo
MIP 60% 100 26.9 15.8 100
MEP 60% 75 52 17.7 93.8
pr
For 38 ALS patients followed up to 26mos, FVC at first
e-
evaluation (no RR provided) and FVC slope (RR 0.99
(95%CI 0.93-1.09, p=0.0595) during the first 3mos
were not significantly predictive of chronic
Pr
hypoventilation development**.12
Based on data from 65 ALS patients without bulbar
al
involvement, sniff Pdi had the greatest predictive power
for hypercapnia***:13
Parameter Cut-off OR Se Sp
u rn Sniff Pdi
(95%CI)
30cmH2O 57 (10-
(%) (%)
90 87
309)
%predicted 32% 25 (5-113) 81 85
Jo
SNP
%predicted 50% 9 (2-33) 53 89
VC
%predicted 45% 7 (2-26) 83 56
MEP
%predicted 25% 6 (2-20) 55 83
MIP
No test had significant predictive power for the presence
of hypercapnia when used to measure RMS in a
subgroup of patients with significant bulbar weakness
(n=16, no data provided).
Based on data from 50 MD1 patients, significant

negative correlation of FVC (Pearson coefficient -0.298,
p=0.04), % predicted FVC (-0.362, p=0.01), FEV1(-
0.301, p=0.03), % predicted FEV1(-0.345, p=0.01),
MVV (-0.291, p=0.04), and % predicted MVV (-0.353,
p=0.01) with hypercapnia (based on pCo2) was shown
via bivariate correlation.15
FVC to Predict Respiratory Weakness (follow up: Varied; assessed with: Kaplan-Meier analysis and cox proportional hazards model)
2 16,17
observational serious not serious serious a
serious b
none For 38 ALS patients, a significant correlation was found ⨁◯◯◯ IMPORTANT
studies c
between erect FVC%, supine FVC% and dyspnea, VERY
orthopnea, and fatigue, the largest values for e-s%FVC LOW
occurred in patients with dyspnea, orthopnea, and
fatigue, in which an average value of 19.6%, 21.4%,
and 26.3% was noted (p= 0.074, 0.018, and 0.001,
respectively).17
f
oo
For 232 ALS patients, FVC decay from one month after
the first clinical visit for ALS to 6 months after the first
clinical visit (mean (SD) 94.5 (19) vs 83.7 (24.3),
pr
respectively) was a significant predictor of functional
decay as measured by the ALSFRS (33.76 (4.3) vs 28.71
e-
(7.2), p<0.001.16
Supine Decrease in FEV1 to Predict Respiratory Weakness (follow up: Cross-sectional; assessed with: Sensitivity, specificity and ROC curve analysis)
Pr
118 observational not not serious serious a
serious b
none Based on data from 58 MD1 patients (n=15 with ⨁◯◯◯ IMPORTANT
studies serious hypercapnia; n=21 with ventilatory restriction; n=22 VERY
al
with hypoxemia), supine decrease in FEV1 greater than LOW
20% had the following predictive power for:
u rn Ventilatory Restriction- defined as VC and TLC<80% of
predicted: Se 71.4%, and Sp 78.4%.
Hypoxemia -defined as PaO2<80mmHg- Se 54.4% and

Jo
Sp 80.6%.
Hypercapnia- defined as PaCO2>45mmHg- Se 51.7%

and Sp 84.1%.
Association of SVC with Respiratory Symptom Progression (follow up: Varied; assessed with: ALS Functional Rating Scale; cox proportional hazards regression model)
3 1,19
not serious none For 893 ALS patients, when the rate of decline of SVC ⨁◯◯◯ IMPORTANT
studies serious from study baseline was slower by 1.5 percentage points VERY
per month in the first 6 months, risk reductions for LOW
events after 6 months were 19% (95%CI 12-15) for
decline in the ALSFRS-R respiratory subdomain and 22%
(95%CI 18-27) for first onset of respiratory insufficiency
or death after 6 months, 23% (95%CI 19-27).1
f
In a sample of 453 ALS patients, of those with a study
oo
baseline % predicted SVC below median (<88% at
baseline; n=154) at week 48, 39.0% developed
orthopnea and 36.4% developed respiratory insufficiency
pr
(vs 25.9% (p=0.0081) and 17.1% (p<0.0001) of
subjects with baseline % predicted SVC values at or
above median (n= 205)); 35.7% developed dyspnea (vs
e-
27.3%, not significant). At week 48, subjects with
baseline % predicted SVC values below median (<88%
predicted) were also significantly more likely to have a
Pr
change in ALSFRS-R respiratory subdomain score from
12 to below 12 (40.9% vs. 30.2%; p=0.0358) and a
change in ALSFRS-R respiratory subdomain score from
al
10 or greater to below 10 (41.6% vs. 24.4%; p=0.0005)
compared with subjects with baseline percent predicted
SVC values at or above the median.19
u rn For 232 ALS patients, SVC % predicted decay from one
month after the first clinical visit for ALS to 6 months
after the first clinical visit (94.13 (18.7) vs 83.47 (19),)
Jo
was a significant predictor of functional decay as

measured by the ALSFRS (33.76 (4.3) vs 28.71 (7.2))
(p<0.001).16
Respiratory Parameters to Predict Ventilation (follow up: Varied; assessed with: Multivariate analysis)
2 4,20
serious b
none In 124 adult NMD^ patients followed for 6.5 years, 51 ⨁◯◯◯ IMPORTANT
studies serious were initiated on HMV^^, in a multivariate model VERY
adjusting for lung function parameters, nocturnal peak LOW
TcCO2 ≥49 mmHg identified patients at risk of
subsequent HMV initiation: HR 2.6 (95% CI 1.4–4.6).20
For 34 adult LGMD patients, respiratory parameters (VC,

MIP, MEP, SatO2) at baseline were significantly
associated with the need for HMV: OR 6.80 (95%CI 1.4-
32.4), p=0.025.4
NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; ROC: Receiver operating characteristic; RR: Risk ratio; CI: Confidence interval; Se: Sensitivity; Sp:
Specificity; PPV: Positive predictive value; NPV: Negative predictive value; FVC: Forced vital capacity; MIP: Maximal inspiratory pressure; MEP: Maximal expiratory pressure;
OR: Odds ratio; SNP: maximal sniff nasal pressure; sniff Pdi: maximal sniff transdiaphragmatic pressure; VC: Vital capacity; MD1: Myotonic dystrophy 1; FEV1: forced
expiratory volume in 1 second; MVV: maximal voluntary ventilation; SD: Standard deviation; ALSRF: Amyotrophic lateral sclerosis functional rating scale; SVC: Slow vital
capacity; HMV: Home mechanical ventilation; HR: Hazard ratio; LGMD: Limb girdle muscular dystrophies; SatO2: Percentage of oxygen saturation
*Hypoventilation defined as hypercapnia pCO2 > 45 mmHg

**Chronic hypoventilation diagnosed when patient presented respiratory symptoms (such as dyspnea, morning headache, daytime hypersomnolence, etc.) and/or one of the
following: (i) FVCo50% of predicted value; (ii) PaCO2X45 mmHg; (iii) nocturnal desaturation (defined as SaO2o88% for 5 consecutive minutes).
*** Hypercapnia defined as CO tension ≥6 kPA.
^Diagnosed with 48 different types of NMD, excluding ALS (most frequent being Myotonic dystrophy 1 n=48; Spinal muscular atrophy n=13 and Duchenne or Becker muscular
dystrophy n=9)
^^HMV initiated in the presence of symptoms of hypoventilation associated with daytime arterial PaCO2 ≥45 mmHg or nocturnal desaturation ≤88% for 5 consecutive minutes,
or emergent following acute ventilatory failure.
f
Explanations
oo
a. Studies explore the predictive value of the respiratory function for respiratory dysfunction which differs importantly from the research question focused on the utility of testing
to impact disease progression.
b. Studies rely on small sample sizes that do not meet optimal information size criteria (>400 participants/events), which is concerning for imprecision.
pr
c. One study is of unclear risk of bias due to minimal methods and baseline characteristics reporting.
e-
e-Table 1c. Evidence Profile-Pulmonary Function Testing to Predict Sleep Disordered Breathing
Pr
Certaint
Impact Importance
№ Study Risk of Other y
Studies design bias considerations
al
Predictive Value of Respiratory Parameters for Sleep Hypoventilation (follow up: Cross-sectional; assessed with: Sensitivity, specificity, ROC analysis)
1 21
observatio
nal studies
not
serious
not serious serious
u
a
rnserious b
none Based on data from 19 male DMD patients (≥12yo),
FEV1 < 40% was a sensitive (91%) but not specific
⨁◯◯◯
VERY
IMPORTANT
(50%) indicator of sleep hypoventilation (TST< 90% of LOW

Jo
≥2%); a PaCO2 of > 45 mm Hg was an equally

sensitive (91%) but more specific (75%) indicator,
while a base excess of > 4 mmol/L was highly specific
(100%) but less sensitive (55%).
Predictive Value of SNIP for Sleep Disordered Breathing (assessed with: Linear regression analysis)
Certaint
Impact Importance
№ Study Risk of Other y
Studies design bias considerations
1 22
observatio serious not serious serious a
serious b
none Based on data from 31 ALS patients, 21 with SNIP ⨁◯◯◯ IMPORTANT
nal studies c
<60cmH2, an inverse significant relationship was VERY
observed between SNIP <60 cmH2O and nocturnal LOW
sleep disordered breathing markers. A linear
correlation between lower SNIP value and reduced
nocturnal SaO2 in patients with a SNIP value <60
cmH2O (r =0.449; p =0.04) was found. A negative
correlation between SNIP and time spent in SaO2
f
below 90% (TST90) (r =– 0.584; p = 0.0054), and
oo
between SNIP and oxyhemoglobin desaturation index
(events/hour) (r= –0.458; p =0.0368) was also seen
in all the patients with lower SNIP. There were no
pr
other significant correlations between SNIP and any
other clinical parameter in the whole study population.
e-
DMD: Duchenne muscular dystrophy; FEV1: forced expiratory volume in 1 second; TST: total sleep time; PaCO2: Partial pressure of carbon dioxide; ALS: Amyotrophic lateral
sclerosis; SNIP: Sniff nasal inspiratory pressure; SaO2: Oxygen saturation
Pr
Explanations
a. Study explores the predictive value of the respiratory function for survival which differs importantly from the research question focused on the utility of testing to impact
al
disease progression.
b. The small sample does not meet the optimal information size (>400 participants), suggesting imprecision.
rn
c. Baseline imbalances between study groups and lack of correction for multiple tests suggest a moderate risk of bias.
u
Bibliography
Jo
1. Andrews JA, Meng L, Kulke SF, et al. Association Between Decline in Slow Vital Capacity and Respiratory Insufficiency, Use of Assisted
Ventilation, Tracheostomy, or Death in Patients With Amyotrophic Lateral Sclerosis. JAMA neurology. 2018;75(1):58-64.
2. Pinto S, de Carvalho M. Comparison of slow and forced vital capacities on ability to predict survival in ALS. Amyotrophic lateral sclerosis &
frontotemporal degeneration. 2017;18(7-8):528-533.
3. Enache I, Pistea C, Fleury M, et al. Ability of pulmonary function decline to predict death in amyotrophic lateral sclerosis patients.
Amyotrophic lateral sclerosis & frontotemporal degeneration. 2017;18(7-8):511-518.
4. Fayssoil A, Ogna A, Chaffaut C, et al. Natural History of Cardiac and Respiratory Involvement, Prognosis and Predictive Factors for Long-Term
Survival in Adult Patients with Limb Girdle Muscular Dystrophies Type 2C and 2D. PloS one. 2016;11(4):e0153095.
5. Baumann F, Henderson RD, Morrison SC, et al. Use of respiratory function tests to predict survival in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.
2010;11(1-2):194-202.
6. Javad Mousavi SA, Zamani B, Shahabi Shahmiri S, et al. Pulmonary function tests in patients with amyotrophic lateral sclerosis and the
association between these tests and survival. Iranian journal of neurology. 2014;13(3):131-137.
7. Matsuda C, Shimizu T, Nakayama Y, Haraguchi M. Cough peak flow decline rate predicts survival in patients with amyotrophic lateral
sclerosis. Muscle & nerve. 2018.
8. Phillips MF, Quinlivan RC, Edwards RH, Calverley PM. Changes in spirometry over time as a prognostic marker in patients with Duchenne
muscular dystrophy. American journal of respiratory and critical care medicine. 2001;164(12):2191-2194.
9. Traynor BJ, Zhang H, Shefner JM, Schoenfeld D, Cudkowicz ME. Functional outcome measures as clinical trial endpoints in ALS. Neurology.
2004;63(10):1933‐1935.
10. Vender RL, Mauger D, Walsh S, Alam S, Simmons Z. Respiratory systems abnormalities and clinical milestones for patients with amyotrophic
lateral sclerosis with emphasis upon survival. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology
Research Group on Motor Neuron Diseases. 2007;8(1):36-41.
f
oo
11. Pirola A, De Mattia E, Lizio A, et al. The prognostic value of spirometric tests in Amyotrophic Lateral Sclerosis patients. Clin Neurol
Neurosurg. 2019;184:105456.
pr
12. Lo Coco D, Marchese S, Corrao S, et al. Development of chronic hypoventilation in amyotrophic lateral sclerosis patients. Respiratory
medicine. 2006;100(6):1028-1036.
e-
13. Lyall RA, Donaldson N, Polkey MI, Leigh PN, Moxham J. Respiratory muscle strength and ventilatory failure in amyotrophic lateral sclerosis.
Pr
Brain : a journal of neurology. 2001;124(Pt 10):2000-2013.
14. Pinto S, Turkman A, Pinto A, Swash M, de Carvalho M. Predicting respiratory insufficiency in amyotrophic lateral sclerosis: the role of
phrenic nerve studies. Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology. 2009;120(5):941-
al
946.
15. rn
Suh MR, Kim DH, Jung J, et al. Clinical implication of maximal voluntary ventilation in myotonic muscular dystrophy. Medicine (Baltimore).
2019;98(18):e15321.
u
16. Pinto S, de Carvalho M. SVC Is a Marker of Respiratory Decline Function, Similar to FVC, in Patients With ALS. Front Neurol. 2019;10:109.
Jo
17. Varrato J, Siderowf A, Damiano P, Gregory S, Feinberg D, McCluskey L. Postural change of forced vital capacity predicts some respiratory
symptoms in ALS. Neurology. 2001;57(2):357-359.
18. Poussel M, Kaminsky P, Renaud P, Laroppe J, Pruna L, Chenuel B. Supine changes in lung function correlate with chronic respiratory failure
in myotonic dystrophy patients. Respiratory physiology & neurobiology. 2014;193:43-51.
19. Jackson C, De Carvalho M, Genge A, et al. Relationships between slow vital capacity and measures of respiratory function on the ALSFRS-R.
Amyotrophic lateral sclerosis & frontotemporal degeneration. 2018:1-7.
20. Orlikowski D, Prigent H, Quera Salva MA, et al. Prognostic value of nocturnal hypoventilation in neuromuscular patients. Neuromuscular
disorders : NMD. 2017;27(4):326-330.
21. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. American journal of respiratory and
critical care medicine. 2000;161(1):166-170.
22. Carratu P, Cassano A, Gadaleta F, et al. Association between low sniff nasal-inspiratory pressure (SNIP) and sleep disordered breathing in
amyotrophic lateral sclerosis: Preliminary results. Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology
e-Table 2. Evidence Profile- Testing for Sleep Disordered Breathing
№ of Risk of Other
Study design Inconsistency Indirectness Imprecision
studies bias considerations
Survival (follow up: range 6 months to 7 years; assessed with: Survival in months (parameters not defined); Nocturnal desaturation determined via overnight pulse oximetry:
desaturators had T90 > 10% and non-desaturators had T90 ≤ 10%.)
1 1
observational serious not serious serious b
serious c
none Comparing 20 ALS patients with and 56 ALS ⨁◯◯◯ CRITICAL
studies a
patients without nocturnal desaturation, longer VERY LOW
survival was observed in those without
nocturnal desaturation: median survival of 32
f
oo
(range 15-67) months vs 21 (range 12-40)
months, respectively.
Onset of Respiratory Failure (follow up: range 6 months to 7 years; assessed with: Respiratory failure defined as PaO2<60 mm Hg or SpO2 ≤90%; Nocturnal desaturation determined
pr
via overnight pulse oximetry: desaturators had T90 > 10% and non-desaturators had T90 ≤ 10%.)
e-
1 1
serious c
studies a
patients without nocturnal desaturation, 11 VERY LOW
(55%) patients with nocturnal desaturation
Pr
developed daytime respiratory failure compared
to 16 (28.6%) patients without desaturation
(p=0.034). During the study, the subjects with
al
desaturation had increased risk of developing
daytime respiratory failure (HR 2.479, 95% CI
1.12–5.47; p=0.030).
rn
Hospitalizations (follow up: range 6 months to 7 years; assessed with: likelihood of respiratory-related hospital admissions; Nocturnal desaturation determined via overnight pulse
u
oximetry: desaturators had T90 > 10% and non-desaturators had T90 ≤ 10%.)
Jo
1 1
serious c
studies a
patients without nocturnal desaturation, those VERY LOW
with nocturnal desaturation had a higher
likelihood of respiratory-related hospital
admissions (HR 2.411, 95% CI 1.17–4.98; p=
0.01).
Prevalence and Type of Sleep Disordered Breathing (follow up: Single night sleep study; assessed with: full-night, laboratory-based or home sleep study)
4 2-5
observational not serious d
serious e
serious f
none SDB (defined as nocturnal transcutaneous CO2 ⨁◯◯◯ IMPORTANT
studies serious >50 mmHg or >10 mmHg above baseline, VERY LOW
morning pCO2 >45 mmHg or oxygen saturation
(SaO2) <90% for more than five consecutive
minutes) was detected in 11/17 (64.7%) non-
ventilated adult Pompe Disease patients.2
SDB (defined per 2007 AASM criteria): was
f
detected in 20/51 (39.2%) adult FSHD
oo
patients: 13/20 showed pure OSA (three of
them had an AHI>20 events per hour and
needed treatment with positive airways
pr
pressure ventilation), 4/20 showed REM sleep-
related desaturations, and 3/20 showed a
mixed pattern (obstructive apneas plus REM
e-
desaturations without obstructive events).3
Pr
OSA (defined as AHI  5 events per hour) was
detected in 22/40 (55.0%) adult DM1 patients.4
SDB (defined as AHI  5 events per hour) was
al
detected in 24/58 (41%) adult myasthenia
gravis patients.5
rn
NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; SDB: Sleep disorder breathing; T90: oxygen saturation under 90%; FSHD: Facioscapulohumeral muscular
dystrophy; HR: Hazard ratio; CI: Confidence interval; DM1: Myotonic dystrophy type 1; AHI: Apnea-Hypopnea Index; AASM: American Academy of Sleep Medicine; OSA:
u
Obstructive sleep apnea; REM: Rapid eye movement
Jo
Explanations
a. Minimal outcome reporting suggests a moderate risk of bias.
b. The study assessed the prognostic value of overnight pulse oximetry for the onset of respiratory failure in ALS patients, which differs importantly from the research question
focused on the utility of testing for SDB compared to not testing for SDB on patient-important outcomes.
c. The study includes a total of 76 participants, not meeting optimal information size thresholds (>400) and suggesting imprecision.
d. Studies relied on various parameters to define SDB.
e. These studies describe the prevalence and/or type of SDB in cohorts of NMD patients, which differs importantly from the research question focused on the utility of testing for
SDB compared to not testing for SDB on patient-important outcomes.
f. All studies include fewer than 60 participants (range 11 to 58). These small samples are concerning for imprecision.
Bibliography
1. Bote SM, Martinez NP, Amarilla CE, et al. Overnight Pulse Oximetry to Determine Prognostic Factors in Subjects With Amyotrophic Lateral
Sclerosis. Respir Care. 2020;65(8):1128-1134.
2. Boentert M, Karabul N, Wenninger S, et al. Sleep-related symptoms and sleep-disordered breathing in adult Pompe disease. European
journal of neurology. 2015;22(2):369-376, e327.
3. Della Marca G, Frusciante R, Dittoni S, et al. Sleep disordered breathing in facioscapulohumeral muscular dystrophy. Journal of the
neurological sciences. 2009;285(1-2):54-58.
4. Pincherle A, Patruno V, Raimondi P, et al. Sleep breathing disorders in 40 Italian patients with Myotonic dystrophy type 1. Neuromuscular
disorders : NMD. 2012;22(3):219-224.
5. Yeh JH, Lin CM, Chiu HC, Bai CH. Home sleep study for patients with myasthenia gravis. Acta neurologica Scandinavica. 2015;132(3):191-
195.
e-Table 3a. Evidence Profile- NIV and Survival in NMD
f
oo
pr
Survival (follow up: 1 year; assessed with: median survival from randomization to death in days)
e-
1 1
randomized not not serious not serious serious a
none From a cohort of 92 ALS patients, 41 patients ⨁⨁⨁◯ CRITICAL
Pr
trials serious were randomly assigned to NIV (n=22) or MODERATE
standard care (n=19) when they developed
either orthopnea with maximum inspiratory
pressure <60% of that predicted or
al
symptomatic hypercapnia, median (range)
survival from randomization in days was 219
u rn (75-1,382) and 171 (1-878), respectively
(p=0.0062).
Survival (follow up: up to 15 years; assessed with: median survival in days from symptom onset to death; Kaplan Meier analysis)
Jo
1 2
observational serious not serious not serious not serious none For 173 ALS patients treated with NIV, 69 ⨁◯◯◯ CRITICAL
studies b
patients treated with NIV followed by TIV, 146 VERY LOW
patients not receiving ventilation, and 21
patients treated with TIV, median survival from
symptom onset in days was (no ranges
reported):
NIV 788 days

NIV/TIV 1,734 days
No Treatment 699 days
TIV 1,031 days
p=0.0001
Survival (follow up: up to 5 years; assessed with: mean survival in months from diagnosis to death; Kaplan Meier analysis)
1 3
observational not not serious not serious serious a
none For 38 ALS patients using NIV^ via BiPap for > ⨁◯◯◯ CRITICAL
studies serious 4 hours per day, 32 patients using NIV via VERY LOW
BiPap for < 4 hours per day, and 52 patients
not treated with ventilation (due to refusal of
treatment), mean (SD) survival was:
NIV > 4 h/day 35.5 (23.6) months
NIV < 4 h/day 29.2 (18.8) months
No NIV 29.4 (12.7)
f
(p=0.11 NIV >4h vs NIV <4h; p=0.01 NIV >4h
oo
vs No NIV; p=0.038 NIV <4h vs No NIV).
From the point of BiPap introduction, 50% of
pr
patients using NIV >4h/day (n=38), 19% of
patients using NIV <4h/day (n=32) and 8% of
patients who refused NIV (n=52) were alive at
e-
12 months, at 18 months 21%, 5% and 2% of
patients were alive and at 24 months 18%, 3%
Pr
and 0%, respectively. NIV > 4h/day treated
patients had a significantly increased survival
rate compared to NIV <4h/day (p=0.0039) and
untreated (p=0.0001) patients.
al
Survival (follow up: 4 years; assessed with: participants alive and cox proportional hazards model (adjusted for bulbar symptoms, type of device, use of neuroprotective agents, and
maximal expiratory pressure))
1 4
observational not not serious serious
u
c
rnserious a
none During a 4-year study of 39 ALS patients, ⨁◯◯◯ CRITICAL
studies serious 29/39 patients died, 9/29 were NIV tolerant VERY LOW
Jo
(able to sleep nightly while receiving NIV for at

least 4 consecutive hours) and 20/29 were NIV
intolerant. In patients intolerant of NIV, the
relative risk for death was 3.1-fold greater
(95% CI, 1.8-fold to 9.6-fold) than that of
intolerant patients (p<0.001). The median
duration of survival from onset of respiratory
insufficiency in intolerant and tolerant patients
was 2 and 15 months, respectively. A Cox
proportional hazards model that adjusted for
potential confounders (bulbar symptoms, type
of device, use of neuroprotective agents, and
maximal expiratory pressure) indicated that a
significant survival benefit persisted for tolerant
patients (relative risk for intolerant compared
with tolerant patients, 1.72 [95% CI, 1.03 to
3.03]; p = 0.04).
Survival (follow up: median 568 days; assessed with: median survival in days (not further defined); Cox regression model adjusted for the effects of baseline measures)
1 5
observational not not serious not serious serious d
none For 26 ALS patients treated with and tolerant ⨁◯◯◯ CRITICAL
studies serious (able to use NIV for >4h a night) of NIV, 13 VERY LOW
patients not treated with NIV due to intolerance
or refusal of treatment, and 15 ALS patients
without respiratory muscle weakness (with
similar ALS severity and age as the 39 patients
requiring NIV), median (95% CI) survival was
298 (192-404) days, 18 (11-25) days, and 370
f
(278-462) days, respectively (p=0.00001).
oo
After adjusting for blood gas oxygen tension,
untreated patients continued to have worse
survival than NIV-treated patients: HR 24.9
pr
times (95%CI 11.4-54, p<0.0001). Non-
respiratory muscle weakness patients had
better survival than the NIV group, but this
e-
difference was not significant after adjusting for
blood gas oxygen tension: HR 0.5 95% CI 0.17
Pr
-1.21, p=0.21.
Survival (follow up: 15 years; assessed with: median survival in months from disease onset to natural death; Kaplan Meier analysis)
al
1 6
observational serious not serious not serious serious a
none For 59 ALS patients treated with NIV^^ for at ⨁◯◯◯ CRITICAL
studies e
least 4h/day, 55 patients using NIV <4h/day or VERY LOW
u rn refusing NIV treatment, and 61 patients
receiving TIV, median survival (no range
provided) was 43 months, 32 months, and 78
months, respectively (p<0.001 for NIV vs no
Jo
NIV and p=0.001 for NIV vs TIV).
Survival (follow up: up to 11 years; assessed with: mean survival in months from diagnosis to death; Kaplan Meier analysis)
1 7
none For 37 ALS patients receiving NIV, 7 patients ⨁◯◯◯ CRITICAL
studies f
receiving TIV (n=6 transitioned from NIV to VERY LOW
TIV), and 70 not receiving ventilatory support,
mean survival from diagnosis was 23.3 months
(95% CI 16.7- 28.8), 72 (95%CI 14.36-129.6),
and 26.7± 4.5 (no CI reported), p=0.01. No
significant differences were found in survival
between the NIV cohort and the no ventilatory
support group (p-value not provided).
Tracheostomy-free Survival (follow up: up to 15 years; assessed with: mean survival in months from symptom onset to death or permanent assisted ventilation; Kaplan Meier
analysis)
1 8
none For 9 patients with respiratory onset ALS ⨁◯◯◯ CRITICAL
studies serious receiving NIV as bilevel NIPPV and 12 patients VERY LOW
not offered NIV, intolerant of NIV (n= 4), or
refusing NIV (n=1), mean survival from
symptom onset to permanent assisted
ventilation or death was 36.4 (16) months and
21.5 (16) months, respectively (p=0.02).
f
Tracheostomy-free Survival (follow up: up to 20 years; assessed with: Survival in months from onset of symptoms to death, date of tracheostomy, or censoring; Multivariate Cox-
oo
regression analysis adjusted for percutaneous endoscopic gastrostomy, riluzole, age of onset and gender;)
1 9
observational not not serious not serious not serious none After adjusting for age of disease onset, ⨁⨁◯◯ CRITICAL
pr
studies serious gender, use of riluzole, and use of PEG, use of LOW
NIV (n=219) compared to no NIV (n=710) in
ALS/MND patients was associated with
e-
increased survival: median survival in months:
28.63 vs 15.02, respectively; HR (95%CI) 0.72
Pr
(0.60-0.88), p=0.001.
Tracheostomy-free Survival (follow up: 10 years; assessed with: median survival from symptom onset to tracheostomy or death in years; Kaplan-Meier analysis)
al
1 10
observational not not serious not serious not serious none Median tracheostomy free survival from ⨁⨁◯◯ CRITICAL
studies serious symptom onset of patients with ALS who did LOW
u rn not undergo NIV (n=1,001) was 2.4 years
(95% CI 2.3 - 2.5), while that of the patients
who underwent NIV (n=259) was 2.8 years
(95% CI 2.5-3.0), p=0.74.
Jo
Survival (follow up: 8 years; assessed with: mean survival in months from symptom onset to death; Kaplan Meier analysis)
1 11
none For 46 ALS patients with respiratory ⨁◯◯◯ CRITICAL
studies serious insufficiency* who regularly used NIV for more VERY LOW
than 4h/day, eight (17%) were still alive at the
end of the 8-year study compared to only 9/67
(13%) patients with respiratory insufficiency
who did not use NIV. Patients using NIV had a
longer estimated mean survival 36 months
(95% CI 29– 44) months after the onset of
symptoms compared to those who refused NIV
(mean 35 months; 95% CI, 27–42 months,
p=0.004).
1-Year Survival (follow up: 1 year; assessed with: survival rates; Kaplan Meier analysis)
1 12
none For ALS patients with FVC < 75% treated with ⨁◯◯◯ CRITICAL
studies serious NIV (n=16) and patients with FVC < 75% who VERY LOW
refused or were intolerant to NIV (n=12), 1-
year survival rate was significantly higher in
the NIV cohort: 12/16 vs. 4/12; χ2 = 5.32; p =
0.02. No significant difference was found
between patients with FVC > 75% treated with
NIV (n=44) vs. patients with FVC < 75%
f
treated with NIV: 37/44 vs 12/16; χ2 = 0.408;
oo
p = 0.5.
Survival with NIV Use (follow up: up to 5 years; assessed with: survival rate; Kaplan Meier analysis)
pr
2 13,14
observational serious not serious serious h
serious a
none For 93 ALS/MND patients using NIV, the ⨁◯◯◯ IMPORTANT
studies g
median duration of survival from initiation of VERY LOW
e-
ventilation was 1.0 (95% CI 0.7-1.3) years.
One year and 5-year survival probabilities were
Pr
52% and 7%, respectively.13 For 11 NMD
patients receiving NIV, the survival rate after 2
years of ventilation use was 9.9%.14
al
NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; MND: Motor neuron disease; NIV: Noninvasive ventilation; TIV: Invasive ventilation via tracheostomy; CI:
Confidence interval; SE: Standard error; HR: Hazard ratio; FVC: Forced vital capacity
rn
^NIV offered when FVC < 50% predicted or if FVC dropped >15% within a 3-month period.
^^NIV offered when clear evidence of respiratory muscle involvement related to hypoventilation with at least 1 criterion (pCO2 ≥45 mm Hg, dyspnea at night, or %FVC <50)
u
was present.
Jo
*Respiratory insufficiency assessed by presence of at least 1 of the following: dyspnea, orthopnea, or morning headaches.
Explanations
a. The total sample size does not meet optimal information size criteria (> 400 participants/events), suggesting imprecision.
b. Minimal outcome reporting suggests a moderate risk of bias.
c. The study analyzes survival differences among NIV tolerant and NIV intolerant patients which differs importantly from the question focus on the comparative effectiveness of
NIV and no ventilation or invasive ventilation.
d. Wide CIs for median survival measures in most groups; The study is underpowered to detect an HR between patients without respiratory muscle weakness and those receiving
NIV.
e. Incomplete outcome data reporting suggests a moderate risk of bias.
f. Co-interventions among participants were not standardized and differed across the long study period; Outcome data is not fully and consistently reported.
g. One study was of unclear risk of bias due to minimal methods reporting.
h. Non-comparative studies providing descriptive data on survival with the use of NIV.
e-Table 3b. Evidence Profile- NIV and Respiratory Function in NMD
Rate of FVC Decline (follow up: Varied; assessed with: changes in rate of FVC decline after initiation of NIV)
5 observational not not serious a

not serious not serious none In 29 adolescents (mean age 14.6yo) with DMD who ⨁⨁◯◯ CRITICAL
3,9,11,12,1
studies serious b
performed a median of 6.5 lung function tests prior to LOW
5
initiating NIV and 22 who performed a median of 5 tests
following NIV initiation during a 10-year study period, the
annual mean rate of decline in FVC z-score prior to NIV
f
initiation was −0.72 z-score pa (95% CI −0.79 to 0.64, SE
oo
0.04, p < 0.01) and it significantly slowed following NIV
initiation to −0.46 z-score pa (95%CI −0.54 to 0.38, SE
0.04) p < 0.01.15
pr
For 208 ALS patients treated with NIV and followed for up to
e-
20 years, rates of FVC (slope difference^ (95%CI) 0.16
(0.04-0.29), p=0.009) decline were significantly reduced
after NIV initiation.9
Pr
In 16 NIV tolerant^^ patients with ALS and 12 NIV
intolerant patients, during one year of follow-up, among
surviving patients with baseline FVC < 75%, the median rate
al
of FVC decline following initiation of NIV was slower in
patients who tolerated NIV than in patients who did not
u rn tolerate NIV: FVC% slope change per month was 1.52 ± 0.3
in NIV treated patients and 2.81 ± 0.8 in non-NIV treated
patients (p <0.0001).12
Jo
In a study following patients for up to 5 years, ALS patients

using NIV>4h/day (n=38) showed a slower rate of FVC
decline^^^ after the initiation of NIV (before NIV vs After -
4.8 ± 2.9 vs -3.5 ± 5.3, p=0.09) compared to patients using
NIV <4h/day (n=32) (-4.5 ± 2.5 vs -5.9 ± 4.8, p=0.07) and
untreated patients (n=52) (-4.6 ± 3.0 vs -8.3 ± 5.0,
p<0.001). The rate of decline in the NIV >4h/day group was
significantly slower than the rate of decline in both the NIV
<4h/day group (p=0.02) and the untreated group
(p<0.001).3
Over an 8-year study period, FVC was continuously followed

in 111 ALS patients. For 46 patients receiving NIV, the rate
of FVC reduction (as estimated by the median of pairwise
slopes) was significantly lower than in those not receiving
ventilatory support (median two-point slope 0.149 vs 0.279,
respectively, p = 0.007).11
Rate of VC Decline (follow up: Varied; assessed with: changes in rate of VC decline or decreases in VC% predicted following initiation of NIV)
3 16-18
observational not not serious a
not serious not serious none For 71 DMD patients followed for a mean of 4 years, ⨁⨁◯◯ CRITICAL
studies serious b
compared to before initiation of NIV annual decreases in LOW
VC% predicted were significantly reduced with the use of
NIV: 4.28 vs 1.36, p<0.001, respectively.16
For 30 ALS patients treated with NIV and followed for 10

months, VC declined from baseline but a significant mean
reduction of 12.7 ± 7% was first observed at 10 months
f
after NIV initiation.17
oo
For 216 ALS/MND patients followed for up to 15 years, the
pre-NIV mean rate of VC decline was 5.1 ± 7.6% per month,
pr
decreasing to a mean rate of 2.5 ± 3.6% per month
(p<0.01) following initiation of NIV.18
e-
Rate of Maximal Inspiratory and Maximal Expiratory Decline (follow up: Varied; assessed with: change in rate of MIP and MEP or MIP% and MIP% predicted decline following
initiation of NIV)
Pr
3 9,11,16
observational not not serious a
not serious serious b
none For 208 ALS patients treated with NIV and followed for up to ⨁◯◯◯ CRITICAL
studies serious 20 years, rates of MEP (slope difference^ (95%CI): 9.14 VERY
(4.87-13.41), p<0.001) and MIP (6.12 (2.54-9.88), p=0.001 LOW
al
decline were significantly reduced after NIV initiation.9
u rn For 71 DMD patients followed for a mean of 4 years,
compared to before initiation of NIV annual decreases in MIP
% predicted (2.4 vs 1.3, p<0.001), and MEP % predicted
(1.8 vs 0.6, p<0.001) were significantly reduced after NIV
Jo
initiation.16
For 40 ALS patients followed for 8 years, decline in MIP ( -

0.159 vs - 0.247, p=0.391) and MEP (-0.112 vs -0.255,
p=0.158) decreased with the introduction of NIV, but not
significantly (as estimated by the median of pairwise
slopes).11
Rate of Sniff Inspiratory Pressure Decline (follow up: Varied; assessed with: change in rate of SNIP decline following initiation of NIV)
3 9,11,16
observational not not serious c
none For 208 ALS patients treated with NIV and followed for up to ⨁◯◯◯ CRITICAL
studies serious 20 years, the rate of SNIP decline was not significantly VERY
changed after NIV initiation: slope difference ^ (95%CI) LOW
2.03 (-2.33 to 6.39), p=0.36.9
For 71 DMD patients followed for a mean of 4 years,

compared to before initiation of NIV annual decreases in
SNIP % predicted were not significantly different after NIV
f
initiation: 0.7 vs. 1.12, p=0.35.16
oo
For 40 ALS patients followed for 8 years, the decline in SNIP
was not significantly reduced with the introduction of NIV: -
pr
0.087 vs -0.125, p=0.62.11
Dyspnea & Hypoventilation (follow up: up to 12 months; assessed with: Medical Research Council dyspnea scale (higher score=greater degree of dyspnea), Clinical hypoventilation
e-
score (higher score= greater degree of hypoventilation), Chronic Respiratory Disease Questionnaire)
Pr
2 5,14,19
observational not not serious not serious serious b
none For 11 NMD patients using NIV, the degree of dyspnea ⨁◯◯◯ CRITICAL
studies serious remained unchanged until 12 months post-NIV initiation VERY
d
when it significantly deteriorated (mean MRC dyspnea scale LOW
score 3.7 ± 0.8 to 4.3 ± 0.5 mm Hg, p = 0.002).14
al
For 58 ALS patients, within the first 3 months after NIV
u rn initiation, median CHS scores improved from 22.0 (95% CI:
19.5‐25.0) to 18.0 points (95% CI: 12.0‐23.5; p = 0.013).
No more significant changes in CHS scores were observed at
6 months after NIV initiation.19
Jo
For 26 ALS patients using NIV for 4 or more hours a night,

there was an improvement from pre-NIV in the CRDQ
Dyspnea score for the first month after initiation of NIV
(p=0.01), following which there was a return to
pretreatment dyspnea level (mean score at baseline 3.12
(SD 1.32), change in effect size at 9 months was 0.59).5
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; PA: per annum; ALS: Amyotrophic lateral sclerosis; CI: Confidence interval; DMD: Duchenne muscular dystrophy; MND:
Motor neuron disease; VC: Vital capacity; MIP: Maximum inspiratory pressure (cm H2O); MEP: Maximum expiratory pressure (cm H2O); SNIP: Sniff nasal Inspiratory pressure (cm H2O);
FVC: Forced vital capacity; MRC: Medical research council; CHS: Clinical hypoventilation score
^Mixed model analysis providing the difference in pulmonary function slopes before and after NIV initiation in L/year.
^^ Tolerance was defined as the ability to sleep nightly while receiving noninvasive positive-pressure ventilation for at least 4 consecutive hours
^^^Compared the slope of decline in %FVC before and after initiation of Bipap using a paired t-test.
Explanations
a. Evidence consistently reports reduced lung function decline with the use of NIV.
b. The included studies rely on small samples that do not meet optimal information size criteria individually suggesting imprecision.
c. Evidence consistently reports no significant changes to the rate of lung function decline with the use of NIV.
d. One study is of unclear risk of bias due to minimal patient selection and diagnosis methods reporting.
e-Table 3c. Evidence Profile- NIV and Sleep in NMD
Respiration and Gas-Exchange (follow up: 1 day to 40 months; assessed with: change in respiratory parameters during sleep with use of NIV; diagnostic sleep studies)
3 observational not not serious not serious serious a

none For 29 adolescent (mean age 14.7yo) DMD patients, a ⨁◯◯◯ CRITICAL
15,20,21
studies serious statistically significant improvement was found between VERY
the last diagnostic sleep study prior to NIV initiation and LOW
the NIV titration study for the following PSG parameters:
(median [IQR]) total AHI (8.2 [12.8]) vs (1.9 [2.8]),
f
oo
p<0.0005; Maximum TcCo2 (51.8 [8.70]) vs (46.5[6]),
p=0.004; Minimum SpO2 (83[13]) vs (90[6]),
p<0.0005.15
pr
For 15 Pompe Disease patients, initiation of NIV resulted
in significant improvement in AHI (mean ± SD 7.5±8.4
e-
vs 2.5±4.0 p<0.05), mean SpO2 (91.2±3.5 vs 94.1±1.7,
p<0.01), t < 90% (106.4±125.6 vs 20.0±39.2,
p<0.001), and mean tcCO2 (46.7±6.8 vs 39.4±4.0,
Pr
p<0.01) during the first night of treatment. Follow-up
sleep studies revealed stable normoxia and normocapnia
without deterioration of sleep outcomes for up to 40
al
months.20
In 32 DM1 patients using NIV for the first night of

u rn treatment, NIV was associated with significant reductions
from baseline (pre-NIV) in the AHI/h (16.0±14.1 vs
2.6±3.0, p<0.05) and time spent with SpO2 < 90%, min
(mean ± SD: 114.9± 129.3 vs 47.1±74.6, p<0.05).
Jo
Reductions in AHI/h remained significantly reduced from

baseline at 4.9 ± 2.4 months after initiation of NIV (n =
23/32), after 12.1 ± 5.3 months (n = 20/32), and after
19.6 ± 10.6 months (n = 12/32). Time spent with SpO2
< 90%, min remained significantly reduced at 4.9 ± 2.4
months after initiation of NIV (n = 23/32), after 12.1 ±
5.3 months (n = 20/32), but not after 19.6 ± 10.6
months (n = 12/32).21
Sleep Parameters (follow up: 1 day to 19.6 months; assessed with: sleep efficiency %, N3 sleep % TST, WASO, min, Index of sleep stage changes/h TST, arousal index/h and
respiratory arousal index/h; diagnostic sleep study)
1 21
none For 32 DM1 patients using NIV for the first night of ⨁◯◯◯ CRITICAL
studies serious treatment, NIV use did not result in significant changes in VERY
sleep parameters (sleep efficiency %, N3 sleep % TST, LOW
WASO, min, Index of sleep stage changes/h TST, arousal
index/h and respiratory arousal index/h) from baseline
(pre-NIV). Sleep parameters remained significantly
unchanged from baseline at 4.9 ± 2.4 months after
initiation of NIV (n = 23/32), after 12.1 ± 5.3 months (n
f
= 20/32), and after 19.6 ± 10.6 months (n = 12/32).21
oo
Sleep Quality (follow up: up to 12 months; assessed with: visual analog scale, Pittsburg Sleep Quality Index, time to fall asleep and nocturnal awakenings, Stanford sleepiness scale)
pr
4 observational not not serious not serious serious a
none For 58 ALS patients, compared to baseline (pre-NIV) ⨁◯◯◯ CRITICAL
1,5,17,19
studies serious within the first 3 months after NIV initiation, median VERY
PSQI score improved from 6.5 (95% CI: 5.0‐8.5) to 6.0 LOW
e-
(95% CI: 4.5‐7.0; P = 0.042) and the median SSS score
improved from 3.0 (95% CI: 2.0‐4.0) to 2.0 (95% CI:
Pr
2.0‐3.0; P = 0.004).19
For 30 ALS patients^, the percentage of patients with

improvement in sleep quality scores increased
al
significantly from baseline up to 10 months across 4
sleep quality assessment scales: Visual Analog Scale:
u rn 1wk (68%), 1 mo (80%), 4mo (71%), 7mo (75%), 10mo
(67%), all p<0.05, PSQI: 1wk (65%), 1 mo (71%), 4mo
(63%), 7mo (56%), 10mo (86%), p<0.05 at 1wk, 1mo,
10mo; time to fall asleep: 1wk (74%), 1 mo (53%), 4mo
Jo
(57%), 7mo (44%), 10mo (57%), p<0.05 at 1wk; and

nocturnal awakenings: 1wk (65%), 1 mo (71%), 4mo
(71%), 7mo (88%), 10mo (67%), p<0.05 1wk to 7mo. A
significant percentage of patients showed improvement in
daytime sleepiness as assessed by the SSS at both 1 wk
(67%) and 1 mo (64%) after NIV initiation, but not at 4
(55%), 7 (44%), or 10 (42%) months.17
For 26 ALS patients using NIV for 4 or more hours per

night, mean SAQLI scores improved significantly within 1
month of NIV initiation and significant improvement was
maintained up to 9-months (at 9-months change in effect
size of 1.89, p<0.001).5
For 22 ALS patients receiving NIV and 19 patients not

receiving ventilatory support followed for up to 12
months, the median (range) days SAQLI scores were
maintained above 75% of baseline was significantly
longer in the NIV cohort: SAQLI symptoms 192 (48-
1357) vs 46 (0-703), p=0.0013; SAQLI score 173 (25-
1357) vs 99 (0-645), p=0.031.1
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; DMD: Duchenne muscular dystrophy; DM1: Myotonic dystrophy; CI: Confidence interval;
SD: Standard deviation; AHI: Apnea hypopnea index; TcCO2: Transcutaneous carbon dioxide level; mmHg: Millimeters of mercury; SpO2: Oxygen saturation level; PSG:
Polysomnography; t < 90%: Desaturation time with SpO2 < 90% (min); TST: Total sleep time; WASO: Wake after sleep onset; N3: Slow wave; PSQI: Pittsburg sleep quality index; SSS:
Stanford sleepiness scale; SAQLI: Sleep Apnea Quality of Life Index
^Follow up decreased over time: at baseline before NIV (n=30), 1 wk (n=25), 1 mo (n=19), 4 mo (n=10), 7 mo (n=9) and 10 mo (n=7).
Explanations
a. All included studies rely on small samples that do not meet optimal information size criteria (> 400 participants/events) suggesting imprecision.
e-Table 3d. Evidence Profile- NIV and Cognitive Function in NMD

f
oo
pr
Cognitive Functioning (follow up: median 568 days; assessed with: Kendrick object learning test; List learning test; Raven's standard progressive matrices)
1 5
none For 13 ALS patients using NIV for 4 or more CRITICAL
e-
⨁◯◯◯
studies serious hours a night, the total learning score on the VERY LOW
List Learning Test showed a trend toward
Pr
improvement from a pre-NIV mean score of
43.23 (SD 13.34) to a post-NIV score of 48.38
(SD 13.05) (p=0.069). On the KOLT, the total
learning score numerically increased from a
al
mean of 43.46 (SD 8.83) to 45.92 (SD 8.83)
(p=0.086), and there was also a trend toward a
u rn significant increase in the total correct score on
the RSPM (from 46.09 [SD 8.36] to 49.18 [SD
4.54]) (p= 0.093).
Jo
Mental Fatigue (follow up: 10 months; assessed with: mental fatigue score and visual analog scale)
1 17
none For 30 ALS patients, the percentage of patients ⨁◯◯◯ CRITICAL
studies b
using NIV (n= 30 at baseline) and reporting VERY LOW
improvement in mental fatigue was not
significant at any point during follow up as
assessed with both the mental fatigue score^
(1wk (38%), 1mo (35%), 4mo (33%), 7mo
(33%), 10mo (43%)) and visual analogue scale
(1wk (58%), 1mo (41%), 4mo (40%), 7mo
(40%), 10mo (33%)).
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; SD: Standard deviation; KOLT: Kendrick object learning test; RSPM: Raven's standard
progressive matrices
^Mental fatigue subscore of the scale for assessment of fatigue (reference provided: Wessely S, Powell R: Fatigue syndromes: A comparison of chronic “postviral” fatigue with
neuromuscular and affective disorders. J Neurol Neuro-surg Psychiatry1989;52:940–8)
Explanations
a. The small sample does not meet optimal information size criteria and is concerning for imprecision.
b. Significant loss to follow up over study period.
e-Table 3e. Evidence Profile- NIV and Quality of Life in NMD
Other Impact Certainty Importance

№ of Risk of Inconsis Indirect Imprecisi consid
Study design
studies bias tency ness on eratio
ns
Quality of Life (follow up: Varied; assessed with: Short Form Health Survey, Sickness Impact Profile; Health Index)
5 observation not not not serious b

none For 22 ALS patients receiving NIV and 19 patients not receiving ventilatory support, the ⨁◯◯◯ CRITICAL
1,5,14,22,2
al studies ^ serious a
serious serious duration in median days (range) that QoL was maintained above 75% of baseline was VERY
3 significantly longer in NIV treated patients than those receiving standard care across all
components of the SF-36 measured: SF-36 Mental Component Summary 168 (45-1357) vs
LOW
f
99 (0-690), p=0.0017; SF-36 Physical Component Summary 150 (27-908) vs 81 (0-273),
oo
p=0.0014.1
For 16 ALS patients with respiratory muscle weakness receiving NIV and 11 patients with
pr
normal respiratory function not receiving NIV, the SF-36 Vitality domain score improved
significantly from baseline to 1-month post-NIV in the NIV cohort (mean score at baseline
27% (SD 12) vs mean score at 1 month 46% (SD 16), p=0.001) and the improvement was
e-
maintained through an average of 9 months of follow up (mean score 45% (SD 17)). None
of the other SF-36 domain scores (physical functioning, bodily pain, role physical, role
emotional, social functioning, general health, or mental health), changed significantly from
Pr
baseline (n=16) to 9-month post-NIV (n=4) in the NIV treated cohort. The control group
experienced a significant decline in the physical functioning domain (baseline n=11, 28% ±
32 vs 9-month, n=4 27% ± 31, p=0.028), but did not experience significant changes in any
of the other domains.22
al
For 13 NMD patients (conditions unspecified) and 16 postpolio dysfunction patients treated
with NIV and 3 NMD and 17 postpolio dysfunction patients treated with TIV followed for an
u rn undefined period of time, overall SIP scores were not significantly different in postpolio
dysfunction patients treated with tracheostomy (n=17) compared to those treated with NIV
(n=16): mean ± SD 12.9 ± 9.8 vs 14.6 ± 17.5 (p-value not provided, but noted as non-
significant), respectively. Overall SIP scores for NMD patients treated with tracheostomy
(n=3) were not significantly different from scores of those treated with NIV (n=13): 12.5 ±
Jo
5.7 vs 22.3 ± 33.1. Overall HI scores were significantly lower in postpolio dysfunction
patients treated with tracheostomy compared to those treated with NIV: 29.0 ± 2.7 vs 24.6
± 4.3, p=0.001, respectively. Overall HI scores were not significantly different in NMD
patients treated with tracheostomy compared to those treated with NIV: 23.3 ± 5.5 vs 25.8
± 2.4, respectively.23
For 26 ALS patients using NIV for 4 or more hours a night, mean QoL assessment scores
significantly improved within 1 month of NIV initiation: ESS (p 0.001), McGill QoL measure
(p<0.001), CRDQ fatigue (p <0.001), CRDQ Emotional (p <0.01), CRDQ Mastery (p <0.01),
and SF-36 Energy and Vitality (p<0.001). Improvements were maintained up to 12 months.
There was also an improvement in SF-36 Role Emotional, Mental Health, and Change in
Health domains (p=0.001). These improvements, however, were only maintained for 3
months.5
For 11 NMD patients receiving NIV for at least 4 hours a day, health-related QoL did not
change until 6 months after NIV initiation in 11 NMD patients (mean SF-36 PCS score at
baseline 32.48 ± 4.95 vs 32.5 ± 4.7 at 6 months, p<0.05). At 6 months, SF-36 PCS scores
showed a significant deterioration from that time point and thereafter (32.5 ± 4.7 to 26.7 ±
2.5, p = 0.014).14
Depression & Anxiety (follow up: Varied; assessed with: Self-reported anxiety and depression, Beck's Depression Inventory, Visual analog scale, and Mood scale, van Zerssen scale.)

№ of Risk of Inconsis Indirect Imprecisi consid
Study design
studies bias tency ness on eratio
ns
2 observation serious c
not not serious b
none In a cross-sectional survey of 47 male DMD patients receiving continuous NIV ⨁◯◯◯ CRITICAL
17,24,25
al studies serious serious and 63 receiving TIV, the number of patients self-reporting concerning anxiety VERY
(19 (40.4%) vs 31 (49.2%), respectively, p=0.59) and depression (10 (21.3%) LOW
vs 12 (19.0%), respectively, p=0.54) was not significantly different between
the cohorts.24
For 30 ALS patients receiving NIV, the percentage of patients reporting
f
improved depression scores from baseline (pre-NIV) was only significant at
oo
week 1^^ (p<0.05) as assessed with the Beck's Depression Inventory (1wk
(73%), 1mo (67%), 4mo (63%), 7mo (57%), 10mo (33%)). Percentage of
patients reporting improvement in depression was not significant for any time
pr
points using the visual analogue scale (1wk (59%), 1mo (60%), 4mo (57%),
7mo (43%), 10mo (80%)) or Mood scale, van Zerssen (1wk (70%), 1mo
e-
(53%), 4mo (33%), 7mo (38%), 10mo (14%)).17
For 27 ALS patients receiving NIV, at 1-month post initiation of NIV, no
Pr
significant differences were reported between pre-NIV and post-NIV HADS
anxiety and depression scores and Kessler psychological distress scores (mean
values not reported).25
al
Caregiver Quality of Life (follow up: 12 months; assessed with: Hospital Anxiety and Depression Score and Short Form Health Survey)
1 5
observation
al studies
not
serious
not
serious
not
serious
serious
u b rn
none For the caregivers of 21 ALS patients receiving NIV for 4 or more hours a night,
there was a significant increase in mean HADS Anxiety score from 6.0 (SD 4.4)
⨁◯◯◯
VERY
IMPORTAN
T
at baseline (pre-NIV) to 7.7 (SD 4.6) at 3 months post-NIV initiation (p<0.01), LOW
but this was not sustained. There was also an increase in the HADS Depression
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scores from a mean of 3.8 (SD 3.6) at baseline to 5.7 (SD 4.3) at 12 months,
but these were not suggestive of significant levels of stress or depression. The
SF-36 Physical Function score decreased in caregivers of NIV patients from a
baseline mean value of 84.3 (SD 20.0) to 66.1 (SD 31.4) at 12 months
(p<0.05). The SF-36 Energy and Vitality domain for caregivers of NIV patients
declined from a mean baseline of 56.7 (SD 23.8) to 34.4 (27.2) at 12 months
(p 0.05). Caregivers of untreated patients (n=7) had impaired SF-36 Physical
Function (p 0.01), SF-36 Role Physical (p<0.01), SF-36 Role Emotional (p
<0.01), SF-36 Pain (p<0.05), SF-36 Vitality (p <0.05), and HADS Depression
(p 0.05) compared with caregivers of patients established on NIV.
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; SD: Standard deviation; DMD: Duchenne muscular dystrophy; TIV: Invasive ventilation via
tracheostomy; SF-36: Short Form Health Survey; SIP: Sickness Impact Profile; HI: Health Index; HADS: Hospital Anxiety and Depression Score
^ One included study is a randomized trial.

^^ Loss to follow up increased over the study period: baseline before NIV (n=30), 1 wk (n=25), 1 mo (n=19), 4 mo (n=10), 7 mo (n=9) and 10 mo (n=7)
Explanations
a. One study is of a moderate risk of bias due to voluntary sample selection and one study is of unclear risk of bias due to minimal sample selection methods reporting and baseline
characteristics reporting.
b. All included studies relied on small samples that do not meet optimal information size criteria and are concerning for imprecision.
c. One study was a cross-sectional survey that relied on a volunteer sample; One study had an important loss to follow up over the study period.
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patients with amyotrophic lateral sclerosis: a randomised controlled trial. The Lancet. Neurology. 2006;5(2):140-147.
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with ALS. Journal of the neurological sciences. 1999;164(1):82-88.
4. Aboussouan LS, Khan SU, Meeker DP, Stelmach K, Mitsumoto H. Effect of noninvasive positive-pressure ventilation on survival in
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oo
amyotrophic lateral sclerosis. Annals of internal medicine. 1997;127(6):450-453.
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6. Hirose T, Kimura F, Tani H, et al. Clinical characteristics of long-term survival with noninvasive ventilation and factors affecting the transition
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to invasive ventilation in amyotrophic lateral sclerosis. Muscle & nerve. 2018.
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7. Sanjuan-Lopez P, Valino-Lopez P, Ricoy-Gabaldon J, Verea-Hernando H. Amyotrophic lateral sclerosis: impact of pulmonary follow-up and
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al
8. Shoesmith CL, Findlater K, Rowe A, Strong MJ. Prognosis of amyotrophic lateral sclerosis with respiratory onset. Journal of neurology,
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Berlowitz DJ, Howard ME, Fiore JF, Jr., et al. Identifying who will benefit from non-invasive ventilation in amyotrophic lateral sclerosis/motor
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neurone disease in a clinical cohort. Journal of neurology, neurosurgery, and psychiatry. 2016;87(3):280-286.
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10. Chio A, Calvo A, Moglia C, et al. Non-invasive ventilation in amyotrophic lateral sclerosis: a 10 year population based study. Journal of
neurology, neurosurgery, and psychiatry. 2012;83(4):377-381.
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Lateral Sclerosis patients with nocturnal respiratory insufficiency. Orphanet journal of rare diseases. 2009;4:10.
13. Tan GP, McArdle N, Dhaliwal SS, Douglas J, Rea CS, Singh B. Patterns of use, survival and prognostic factors in patients receiving home
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14. Tsolaki V, Pastaka C, Kostikas K, et al. Noninvasive ventilation in chronic respiratory failure: effects on quality of life. Respiration;
international review of thoracic diseases. 2011;81(5):402-410.
15. Angliss ME, Sclip KD, Gauld L. Early NIV is associated with accelerated lung function decline in Duchenne muscular dystrophy treated with
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Respiratory Pressures in Duchenne Muscular Dystrophy. Respiratory care. 2016;61(11):1530-1535.
17. Butz M, Wollinsky KH, Wiedemuth-Catrinescu U, et al. Longitudinal effects of noninvasive positive-pressure ventilation in patients with
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Neurol Scand. 2019;139(2):128-134.
20. Boentert M, Drager B, Glatz C, Young P. Sleep-Disordered Breathing and Effects of Noninvasive Ventilation in Patients with Late-Onset
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21. Spiesshoefer J, Runte M, Heidbreder A, et al. Sleep-disordered breathing and effects of non-invasive ventilation on objective sleep and
nocturnal respiration in patients with myotonic dystrophy type I. Neuromuscul Disord. 2019;29(4):302-309.
e-
22. Lyall RA, Donaldson N, Fleming T, et al. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology.
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2001;57(1):153-156.
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diseases treated with noninvasive and invasive home mechanical ventilation. Chest. 2002;122(5):1695-1700.
al
24. Boussaïd G, Stalens C, Devaux C, Segovia-Kueny S, Lofaso F, Reveillere C. Impact of Mechanical Ventilation Methods on the Life Perception
25.
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of Subjects With Duchenne Muscular Dystrophy: French Cross-Sectional Survey. Respir Care. 2020.
Morélot-Panzini C, Perez T, Sedkaoui K, et al. The multidimensional nature of dyspnoea in amyotrophic lateral sclerosis patients with chronic
u
respiratory failure: Air hunger, anxiety and fear. Respir Med. 2018;145:1-7.
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e-Table 4. Evidence Profile- Respiratory Parameters to Predict Effective Timing of the Initiation of NIV
№ of Risk of Inconsis Other
Study design Indirectness Imprecision
studies bias tency considerations
Predictive Value of Pulmonary Function Parameter for Introduction of Ventilator Use (follow up: up to 7 years; assessed with: ROC curve analysis^)
21,2 observational not not not serious serious a

none Based on data from 26 non-ventilated, 20 part-time ventilated ⨁◯◯◯ CRITICAL
studies serious serious (nocturnal NIV), and 37 continuously ventilated DMD patients, the VERY
following cut-off values for VC, RR/TV, and RR/VC to introduce part- LOW
time or continuous ventilation use demonstrated good diagnostic
accuracy (based on AUC^^)1:
Part-time Ventilator Use Requirement:

Parameter Cut-off Sensitivity % Specificity % AUC
Value*
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Vc, ml ≤770 85 89 0.896
TV/VC ≥0.3 80 73 0.806
RR/TV, ≥0.024 81 90 0.905
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breaths/ml
BITI ≥0.144 75 85 0.835
VRI ≥3.04 70 89 0.863
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RR/VC, ≥0.024 85 89 0.921
breaths/ml
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Continuous Ventilator Use Requirement:
Parameter Cut-off Value* Sensitivity % Specificity % AUC
Vc, ml ≤370 78 85 0.898
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TV/VC ≥0.48 70 80 0.789
u rn RR/TV,
breaths/ml
BITI
≥0.153
≥0.246
81
59
90
85
0.905
0.717
VRI ≥6.96 62 90 0.825
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RR/VC, ≥0.071 86 95 0.935

breaths/ml
Based on data from 110 ALS/PMA patients (87 receiving an NIV

indication^^^ during the 7-year study period), PCF had the largest
predictive value for NIV indication among the five pulmonary
parameters assessed trimonthly for up to 7 years 2:
Parameter Cut-off Sensitivity % Specificity %
Value**(95% CI)
FVC 95 (77-104) 85 22
PCF 386 (356-472) 88 36
MIP 67 (52-74) 85 27
MEP 74 (66-90) 85 38
SNIP 45 (41-59) 87 40
Sensitivity of MIP and FVC for Initiating NIV (follow up: up to 1 years; assessed with: MIP and FVC evaluated monthly)
13 observational not not not serious serious b

none Monthly assessment of MIP and FVC in a cohort of 161 ALS patients ⨁◯◯◯ CRITICAL
studies serious serious followed for up to 1 year found MIP to be a more sensitive indicator VERY
of early respiratory insufficiency than FVC: Significantly more ALS LOW
patients met MIP criterion (MIP< -60 cm H2O) than FVC criterion (
FVC<50%) for NIV initiation at baseline: 71/109 (65%) vs 9/109
(8%), p<0.0001. There were no cases in which FVC<50%
antedated MIP< -60 cm H2O and patients reached the MIP criterion
4 to 6.5 months earlier than the FVC criterion.
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Utility of Polygraphy for Initiation of NIV (follow up: Cross-sectional; assessed with: polygraphy and FVC assessment; Nocturnal hypoventilation was defined when one of the
following findings in polygraphy or arterial BGA during sleep was present: (1) SpO2 during sleep <90% for >5 min with a minimum value at least 85%, (2) SpO2 of <90% for >30% of
total sleep duration or (3) PaCO2 of >45 mm Hg during sleep or disproportionally increased PaCO2 levels compared with wakefulness.)
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1 4
observational not not not serious serious c
none Pulmonary function assessment of 131 ALS patients found ⨁◯◯◯ CRITICAL
studies serious serious polygraphy does not provide additional useful evidence for the need VERY
e-
to initiate NIV if the FVC is already <75%: Following assessment, LOW
29/131 patients did not report dyspnea and had FVC>75%. In 14 of
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these 29 (48.3%) patients, polygraph results indicated nocturnal
hypoventilation.
Predictive Value of Respiratory Function Assessment for NIV Compliance (follow up: 1-month post-NIV initiation; assessed with: ROC curve analysis)
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1 5
observational not not serious d
serious e
none Based on the analysis of 21 ALS patients treated with NIV for 1- ⨁◯◯◯ IMPORTAN
studies serious serious
u rn month, the duration of nocturnal hypercapnia obtained by
capnography exhibited a significant predictive power for good
compliance (mean use of >4 hours per day) with subsequent NIV
VERY
LOW
T
treatment, with an AUC value of 0.846 (p = 0.018). No significant

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predictive values for nocturnal pulse oximetry (Average SaO2 AUC

0.417, p=0.569) or functional scores for nocturnal hypoventilation
were found (orthopnea questionnaire AUC 0.218, p=0.054; Bulbar-
function questionnaire AUC 0.429, p=0.630).
Survival Based on Criteria Used to Initiate NIV (follow up: 1 years; assessed with: patients alive 1 year after NIV initiation)
1 4
observational not not serious f
serious c
none In a cohort of 131 ALS patients 65 initiated NIV. In 8/65 NIV was ⨁◯◯◯ IMPORTAN
studies serious serious initiated due to the presence of nocturnal hypoventilation (no VERY T
dyspnea, FVC >50% of predicted). All 8 patients were alive 1 year LOW
after initiation. In 57/65 patients NIV was initiated due to low FVC
(<50% of predicted) or the presence of dyspnea, 9/57 patients died
within 1 year after initiation of NIV. These groups (nocturnal
hypoventilation only vs low FVC or dyspnea) did not significantly
differ in terms of age, disease duration, or ALSFRS-R.
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ROC: Receiver operating characteristic; AUC: Area-under-the-curve; BITI: Breathing intolerance index; RR:
Respiratory rate; TV: Tidal volume; VC: Vital capacity; VRI: Ventilator requirement index; FVC: Forced vital capacity (% predicted value); PCF: Peak cough flow (L/min.); MIP:
Maximum inspiratory pressure (cm H2O); MEP: Maximum expiratory pressure (cm H2O); SNIP: Sniff nasal Inspiratory pressure (cm H2O); ALS: Amyotrophic lateral sclerosis;
PMA: Progressive muscular atrophy; SpO2: Oxygen saturation; PaCO2 : partial pressure of carbon dioxide
^ Proportions of true positive results and false positive results were plotted against each other for threshold values and the AUC to reflect the accuracy of the index
^Ârea under the curve (AUC): 1=perfect discrimination between non-ventilated patients and ventilated patients; 0.5= poor discrimination with 50% chance of error.
^^^ Referral to a home ventilation service (initiation of NIV) indicated when one or more of the following occurred: FVC <70%, symptoms of nocturnal hypoventilation, signs of
increased breathing activity or daytime hypercapnia (PCO2> 45 mmHg)
*Threshold cut-off values were calculated by providing the best compromise between the optimal sensitivity and specificity
** Cut off values were determined at a value where 85% of the patients received an NIV indication within 3 months
Explanations
a. The total number of patients included in the study is 83. A small sample not meeting optimal information size thresholds (n>400) suggests imprecision.
b. The total number of patients included in the study is 161. A small sample not meeting optimal information size thresholds (n>400) suggests imprecision.
c. The total number of patients included in the study is 131. A small sample not meeting optimal information size thresholds (n>400) is concerning for imprecision.
d. The study reports the utility of respiratory function testing to predicted NIV compliance, differing importantly from the research question focused on the diagnostic utility of
pulmonary parameters for NIV initiation.
e. Analysis based on a sample of 21. A small sample not meeting optimal information size (n>400) is concerning for imprecision.
f
f. Survival reported as a function of the criteria used to initiate NIV differs importantly from the research question focused on the diagnostic utility of pulmonary parameters for
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NIV initiation.
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Bibliography
1. Hamada S, Ishikawa Y, Aoyagi T, Ishikawa Y, Minami R, Bach JR. Indicators for ventilator use in Duchenne muscular dystrophy. Respiratory
e-
medicine. 2011;105(4):625-629.
2. Tilanus TBM, Groothuis JT, TenBroek-Pastoor JMC, et al. The predictive value of respiratory function tests for non-invasive ventilation in
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amyotrophic lateral sclerosis. Respiratory research. 2017;18(1):144.
3. Mendoza M, Gelinas DF, Moore DH, Miller RG. A comparison of maximal inspiratory pressure and forced vital capacity as potential criteria
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for initiating non-invasive ventilation in amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis : official publication of the World
Federation of Neurology Research Group on Motor Neuron Diseases. 2007;8(2):106-111.
rn
4. Prell T, Ringer TM, Wullenkord K, et al. Assessment of pulmonary function in amyotrophic lateral sclerosis: when can polygraphy help
u
evaluate the need for non-invasive ventilation? Journal of neurology, neurosurgery, and psychiatry. 2016;87(9):1022-1026.
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5. Kim SM, Park KS, Nam H, et al. Capnography for assessing nocturnal hypoventilation and predicting compliance with subsequent
noninvasive ventilation in patients with ALS. PloS one. 2011;6(3):e17893.
e-Table 5a. Evidence Profile- Noninvasive Ventilation Strategies: Comparative Effectiveness of Volume-Guaranteed Pressure Support, Pressure
Support Ventilation, and Assisted Pressure-Controlled Ventilation Strategies?
Breathing Pattern & Gas Exchange (follow up: 3 consecutive nights; assessed with: observed prolonged inspirations; cardio-respiratory monitoring, including SaO2 as measured by
pulse oximetry)
11 randomized serious not serious not serious serious b

none In 28 NMD patients^ using NIV in PSV-VTG, PSV, and APCV mode in ⨁⨁◯◯ CRITICAL
trials a
random order on 3 consecutive nights, a greater number of LOW
f
prolonged inspirations was observed with PSV-VTG and PSV
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compared with APCV (P=0.048 and 0.029, respectively). SaO2 was
lower during PSV-VTG than APCV, as shown by the T < 90 values
(median (IQR); 0 (0–4.2) vs 0 (0-0), p= 0.042, respectively). There
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were no significant differences in daytime ABG among the different
NIV modalities. There were also no significant differences for the
other ventilator parameters recorded (including bicarbonate
e-
concentration, oxygen desaturation index, lowest oxygen saturation).
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Patient-Ventilator Asynchrony (follow up: 3 consecutive nights; assessed with: rates of autotriggerings, ineffective efforts, inspiratory triggerdelay, prolonged inspirations observed in
different modes of NIV sessions)

none In 28 NMD patients^ using NIV in PSV-VTG, PSV, and APCV mode in CRITICAL
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⨁⨁◯◯
trials a
random order on 3 consecutive nights, IE was observed in 89% of LOW
patients during PSV-VTG, and the rate of IE exceeded 5 events/h in
u rn 54% of patients. Prolonged inspirations were identified in all patients
in all ventilation modes but were more frequent in the PSV-VTG and
PSV modes than in the APCV mode (medians (IQR): 0.5 (0.3–1.6) vs
0.6 (0.3–2.4) vs 0.3 (0.1–1.0), p = 0.048 for PSV-VTG versus APCV,
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p = 0.028 for PSV versus APCV, respectively); there was a significant

relationship between prolonged inspirations and the magnitude of
leaks in all ventilatory modes (PSV-VTG: r = 0.53, P = 0.005; PSV: r
= 0.67, P = 0.0004; APCV: r = 0.62, P = 0.0001). Inspiratory trigger
delays were recorded for each patient during all ventilatory modes
but did not correlate with leaks or polygraphic parameters.
Autotriggering was recorded in 10 patients during PSV-VTG, in 13
patients during PSV and in 14 patients during APCV.
Patient Comfort (follow up: 3 consecutive nights; assessed with: Visual analogue satisfaction scores for subjective comfort after each ventilation session (scored 0 to 10; higher score
indicates greater comfort)

trials a
random order on 3 consecutive nights, mean patient comfort scores LOW
were 7.8±1.55, 8.49±0.9, and 8.41±1.33 for PSV-VTG, PSV, and
APCV ventilation modes, respectively (no p-value provided but
authors indicate "no difference" in comfort).
Patient Preference (follow up: 3 consecutive nights; assessed with: patient-reported preference for a ventilation mode)

trials a
random order on 3 consecutive nights, 3/28 (11%) patients did not LOW
express a preference for any ventilation mode. Most patients (53%)
preferred APCV; 25% preferred PSV and 11% preferred PSV-VTG.
(APCV vs PSV, P = 0.04; APCV vs PSV-VTG, P = 0.001; PSV vs PSV-
VTG, not significant). There were no correlations among patient
comfort, polygraphic and ventilation data, or ventilator settings. The
sequence in which patients received different ventilatory modes did
f
not influence preference.
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NIV: Noninvasive ventilation; NMD: Neuromuscular disease; PSV-VTG: Volume guaranteed pressure support; PSV: pressure support ventilation; APCV: assisted pressure-
controlled ventilation; IQR: Interquartile range; ABG: Arterial blood gases; AUTO: Autotriggerings; IE: Ineffective efforts; ITD: Inspiratory triggerdelay; PI: Prolonged
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inspirations; SaO2: Oxygen saturation
^ n=22 Duchenne muscular dystrophy; n=2 Congenital muscular dystrophy; n=3 ALS; n=1 mitochondrial myopathy
e-
Explanations
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a. Randomized cross-over design and incomplete outcome data reporting suggest some risk of bias.
b. Total study sample of 28 is concerning for imprecision.
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e-Table 5b. Evidence Profile- Noninvasive Ventilation Strategies: Effectiveness of Positive End Expiratory Pressure
№ of Study Risk of
u rn Other
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Effective NIV (follow up: 2 consecutive nights; assessed with: ventilatory pattern and gas exchanges during PEEP administration compared to baseline pattern and exchanges)
1 2
none In 25 ALS patients naive to ventilatory treatment using ⨁⨁⨁◯ CRITICAL
trials serious 0 and 4cm H2O of PEEP in random order on 2 MODERATE
consecutive nights, as compared with baseline values,
among SpO2 parameters, ODI and mean SpO2 improved
with NIV at both 0 cm H2O (PEEP0) and 4 cm H2O
(PEEP4) (p< 0.05). These variables did not differ
between PEEP0 and PEEP4: ODI (no./h) mean (IQR) 1.4
(0.5-4.0) vs 2.1 (0.2-5.4), p=0.26 and SpO2m (%)
mean (SD) 93.8(1.6) vs 93.9(2.0); p=0.16,
respectively.
Sleep Architecture (follow up: 2 consecutive nights; assessed with: Measured by: TST, SE, non-REM stages, REM, AAI, SOL, and WASO)
1 2
none In 25 ALS patients naive to ventilatory treatment using ⨁⨁⨁◯ CRITICAL
trials serious 0 and 4cm H2O of PEEP in random order on 2 MODERATE
consecutive nights, considering TST, SE, N1, N2, N3,
REM, AAI, SOL and WASO significant differences were
only observed between PEEP0 and PEEP4 administration
in N3 (%TST)-median (IQR) 2.5% (0.0-18.0) vs 0.0%
(0.0-12.1); p=0.001, respectively and AAI (events/h)-
mean (SD) 13.4(5.0) vs 16.9(7.4) events; p=0.01,
f
respectively. The difference in AAI between settings was
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correlated to the difference in leaks (leaks increased
during PEEP, 41.4 ± 29.3% vs 31.0 ± 25.7%, p=
0.0007). Findings suggest, during the application of
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PEEP, sleep quality was worse, as shown by a shorter
duration of slow-wave sleep (N3) and by a higher rate of
arousals and awakenings (AAI).
e-
NIV: Noninvasive ventilation; PEEP: Positive end expiratory pressure; PEEP0: 0 cmH20 of PEEP; PEEP4: 4 cmH20 of PEEP; ODI: Number of oxygen desaturations ≥4% per hour of sleep;
SpO2: Pulse oxygen saturation; IQR: Interquartile range; ALS: Amyotrophic lateral sclerosis; TST: Total sleep time; SE: Sleep efficiency; N1: Non-REM stage 1; N2: Non-REM stage 2; N3:
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Non-REM stage 3; REM: Rapid-eye-movement; AAI: Total number of arousals and awakenings/hour of sleep; SOL: Sleep onset latency; WASO: Wake time after sleep onset
Explanations
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a. The total study sample of 25 individuals does not meet optimal information size criteria and is concerning for imprecision.
Ventilation
u rn
e-Table 5c. Evidence Profile- Noninvasive Ventilation Strategies: Comparative Effectiveness of Spontaneous and Spontaneous-Timed Modes of
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Gas Exchange (follow up: 4 consecutive nights; assessed with: minimal oxygen saturation percentage; Oxygen desaturation index per h/sleep; PtcCO2>55 mm Hg)
1 3
randomized serious not serious not serious serious b
none In 13 ALS patients using NIV in S mode ST mode in ⨁⨁◯◯ CRITICAL
trials a
random order on consecutive nights, ST mode showed LOW
better results in gas exchange (minimal SpO2%: 83 (80–
89) % vs 87 (84–89) %), ODI: 15 (5–28)/h sleep vs 7
(3–9)/h sleep, and PtcCO2>55 mm Hg: 20 (0–59) % vs 0
(0–27) % (all p< 0.05).
Sleep Architecture (follow up: 4 consecutive nights; assessed with: AAI, REM, SE, and TST)
1 3
none In 13 ALS patients using NIV in S and ST mode in random ⨁⨁◯◯ CRITICAL
trials a
order on consecutive nights, considering AAI/n per hour LOW
(23±17 vs 17±7); REM sleep % (19±11 vs 21±11); SE%
(67±12 vs 67±18) and TST/minutes (345±100 vs
339±132), no significant difference were found between
the ventilator modes.
Patient-Ventilator Asynchrony (assessed with: ineffective efforts, auto triggerings, premature termination, double triggering)
f
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1 3
none In 13 ALS patients using NIV in S and ST mode in random ⨁⨁◯◯ CRITICAL
trials a
order on consecutive nights, ineffective efforts were LOW
significantly more common during the S mode (49.4
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(18.6–131.8)/h sleep vs 9.2(2.9–37.4)/h sleep; p< 0.01).
No significant differences were found between the two
modes for premature termination, double triggering or
e-
auto triggering, and the PVA index. Obstructive
respiratory events were more frequent in the S mode (8.9
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(1.2-18.3)/h sleep vs 1.8 (0.3-4.9)/h sleep, p<.01).
Central respiratory events were also more frequent in S
mode (2.6 (0.4-14.1)/h sleep vs 0.2 (0.0-1.1)/h sleep,
p<0.01).
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NIV: Noninvasive ventilation; NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; S: Spontaneous; ST: Spontaneous-timed; SpO2%: Minimal oxygen saturation percentage;
asynchrony
PVA: Patient-ventilator asynchrony
u rn
ODI: Oxygen desaturation index; PtcCO2: Transcutaneous carbon dioxide; AAI: Arousal-awakening index; REM: Rapid eye movement; SE: Sleep efficiency; TST: Total sleep time;
Explanations
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a. The randomization process is not described, and outcome data is not fully reported suggesting some risk of bias.
b. Total sample of 13 for the outcome assessed does not meet optimal information size criteria and is concerning for imprecision.
e-Table 5d. Evidence Profile- Noninvasive Ventilation Strategies: Comparative Effectiveness of Pressure Support and Volume-Assured Pressure
Support Modes of Ventilation
№ of Impact Certainty Importance

Study Risk of Other
studie Inconsistency Indirectness Imprecision
design bias considerations
s
Respiratory Pattern (follow up: Cross-sectional; assessed with: attainment of goal tidal volume as % target tidal volume; rapid shallow breathing as ratio of respiratory rate to tidal
volume)
№ of Impact Certainty Importance

Study Risk of Other
studie Inconsistency Indirectness Imprecision
design bias considerations
s
1 4
none For 215 ALS patients using NIV in PS mode and 56 ⨁◯◯◯ CRITICAL
studies serious using NIV in VAPS mode, attainment of goal tidal VERY
volume^ was significantly lower for PS (median LOW
(IQR), 68.9% (66.2-71.5) vs 73.8% (68.8-78.9),
p=0.009, respectively), while rapid shallow breathing
(the ratio of respiratory rate to tidal volume) was
significantly greater (mean 51.5 (95% 45.5-54.6) vs
f
44.6 (95%CI 38.8-50.5), p=0.022, respectively).
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Patient-Ventilator Asynchrony (follow up: Cross-sectional; assessed with: percentage of spontaneously triggered and spontaneously cycled breaths)
pr
1 4
none For 215 ALS patients using NIV in PS mode and 56 ⨁◯◯◯ CRITICAL
studies serious using NIV in VAPS mode, the median (range) VERY
percentage of spontaneously triggered breaths was LOW
e-
83.7% (80.7-86.7) and 88.6% (83.6-93.7),
respectively (p=0.33). The median (range)
Pr
percentage of spontaneously cycled breaths was
significantly lower in the PS cohort, at 36.7% (31.6-
41.8) vs 57.9% (49.4-66.4), respectively (p=
0.0001).
al
Patient Compliance (assessed with: mean hours of NIV use per day)
1 4
observational
studies
not
serious
not serious not serious
u rn serious a
none For 215 ALS patients using NIV in PS mode and 56
using NIV in VAPS mode, there were no significant
⨁◯◯◯
VERY
IMPORTANT
differences between the cohorts in mean (95% CI) LOW

Jo
hours of NIV use per day: 6.6 (6.0-7.2) h/d for PS vs.
6.5 (5.4-7.7) h/d for VAPS, p=0.70. One hundred and
forty-five patients (67.4%) using PS were using NIV
more than 4 hours/day compared to 39 patients
(69.6%) using VAPS.
NIV: Noninvasive ventilation; NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; PS: Pressure support; VAPS: volume-assured pressure support; CI: Confidence interval;
^Goal tidal volumes were calculated as 8 ml/kg of patient’s ideal bodyweight (IBW), using the following formulas: males, 5012.3[height(inches)260]; females, 45.512.3[height(inches)260]
Explanations
a. A total sample of 215 patients using PS mode and 56 using VAPS mode does not meet optimal information size and is concerning for imprecision.
e-Table 5e. Evidence Profile- Noninvasive Ventilation Strategies: Comparative Effectiveness of Volume NIV and Pressure-Cycled NIV
Tracheostomy-free Survival (follow up: 4-year study period; assessed with: mean survival without tracheostomy in months from NIV initiation assessed with Kaplan-Meier analysis)
1 5
observational serious not serious not serious serious b
none For 62 medically stable ALS patients ventilated using volume ⨁◯◯◯ CRITICAL
studies a
NIV and 82 ALS patients ventilated using pressure-cycled NIV, VERY
f
oo
the mean survival in months from NIV initiation was 24.56 ± LOW
3.55 and 28.27 ± 3.53, respectively (p=0.53). In patients with
spinal onset, the mean survival from NIV initiation in the Vol-
NIV group was 30.82 ± 5.23 months and 31.81 ± 3.94 months
pr
in the Pres-Vol group (p=0.975); In the bulbar-onset group, the
mean survival in Vol-NIV patients was 14.86 ± 3.22 months and
e-
8.37 ± 1.53 months in Pres-NIV patients (p= 0.233).
Effective Ventilation (follow up: assessment every 3 months up to 4 years; assessed with: Nocturnal ventilation was considered effective when TST90 while using NIV was< 5%, PaCO2
Pr
using NIV <45mmHg and hypoventilation symptoms were avoided; NIV during daytime, if necessary, was considered effective if SpO2 while using NIV was >96%, PaCO2 <45mmHg,
absence of hypoventilation symptoms and there was no evidence of patient-ventilator asynchrony)
al
1 5
none For 62 medically stable ALS patients ventilated using volume ⨁◯◯◯ CRITICAL
studies a
NIV and 82 ALS patients ventilated using pressure-cycled NIV, VERY
effective ventilation was achieved in 72.4% of patients in the
u rn Vol-NIV group and 48.8% in the Pres-NIV group (p<0.001). In
those patients in whom NIV was ineffective, no statistical
LOW
differences were found between Vol-NIV and Pres-NIV patients

for baseline parameters, except for the proportion of bulbar-
Jo
onset patients (35.0% vs. 9.8%, respectively, p<0.001).

NIV: Noninvasive ventilation; NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; Vol-NIV: Volume NIV; Pres-Vol: Pressure-cycled NIV
Explanations
a. Baseline imbalances in outcome important characteristics across the study groups (partially addressed via analysis) and differences in ventilation treatment protocols across the two study
centers suggests a moderate risk of bias.
b. The total study sample of 62 patients using S mode NIV and 82 patients using ST mode NIV does not meet optimal information size and is concerning for imprecision.
Bibliography
1. Crescimanno G, Marrone O, Vianello A. Efficacy and comfort of volume-guaranteed pressure support in patients with chronic ventilatory
failure of neuromuscular origin. Respirology (carlton, vic.). 2011;16(4):672‐679.
2. Crescimanno G, Greco F, Arrisicato S, Morana N, Marrone O. Effects of positive end expiratory pressure administration during non-invasive
ventilation in patients affected by amyotrophic lateral sclerosis: A randomized crossover study. Respirology (Carlton, Vic.). 2016;21(7):1307-
1313.
3. Vrijsen B, Buyse B, Belge C, Vanpee G, Van Damme P, Testelmans D. Randomized cross-over trial of ventilator modes during non-invasive
ventilation titration in amyotrophic lateral sclerosis. Respirology (Carlton, Vic.). 2017;22(6):1212-1218.
4. Nicholson TT, Smith SB, Siddique T, et al. Respiratory Pattern and Tidal Volumes Differ for Pressure Support and Volume-assured Pressure
Support in Amyotrophic Lateral Sclerosis. Annals of the American Thoracic Society. 2017;14(7):1139-1146.
5. Sancho J, Servera E, Morelot-Panzini C, Salachas F, Similowski T, Gonzalez-Bermejo J. Non-invasive ventilation effectiveness and the effect of
ventilatory mode on survival in ALS patients. Amyotrophic lateral sclerosis & frontotemporal degeneration. 2014;15(1-2):55-61.
e-Table 6. Evidence Profile- Mouthpiece Ventilation

Importanc
Impact Certainty
f
№ of Risk of Other e
oo
Survival (follow up: up to 17 years; assessed with: tracheostomy-free survival in days from M-NIV initiation in NMD patients using M-NIV for at least 1 month)
pr
2 1,2
serious b
none Based on data from 31 ALS patients consistently using ⨁◯◯◯ CRITICAL
studies serious daytime mouthpiece (MVP) NIV (in addition to nighttime mask
e-
VERY
NIV) for at least 1-month, median tracheostomy-free survival LOW
was 286 days (range 41 to 1,769 days).
Pr
Based on data from 12 DMD patients on 24h NIV using
daytime MVP (in addition to mask NIV at night) for up to 12
years, mean survival on MVP was 5.7 years (range 0.17 to 12
al
years).2
progression)
u rn
Lung Function (follow up: up to 17 years; assessed with: change in respiratory parameters over time based on respiratory assessments every 2-6 months, depending on rate of disease
2 1,2
serious b
none In 31 ALS patients consistently using daytime mouthpiece NIV ⨁◯◯◯ CRITICAL
Jo
studies serious (in addition to nighttime mask NIV) for at least 1 month, FVC VERY
fell overtime, maximum insufflation capacity remained LOW
consistent, maximum insufflation capacity-VC difference
increased, peak cough flow and peak cough flow with lung-
volume recruitment decreased (quantitative data on the
change in parameters not reported).
In 12 DMD patients on 24h NIV using daytime MVP (in

addition to mask NIV at night) for up to 12 years, during the
period of MVP use gradual loss of lung function was observed:
FVC was reduced from 0.9L to 0.5L (p<0.02), MIPs from -29.9
to -17.7 (p<0.002), MEPs from 28.5 cmH2O to 19 cmH20
(p<0.002).2
Patient Preference for NIV Interface (follow up: Cross-sectional; assessed with: patient-reported preference for NIV interface)
Importanc
Impact Certainty
№ of Risk of Other e
2 3,4
observational serious not serious not serious serious e
none Based on interviews of 12 adults with NMD* using mouthpiece ⨁◯◯◯ IMPORTA
studies c d
ventilation (M-NIV) during daytime hours for 1 to 15 years VERY NT
and nasal BPAP during nighttime hours for 2 to 20 years, M- LOW
NIV was described as aiding in loudness, utterance duration,
clarity, and endurance of speech. But, was also described as
interfering with the flow of speech due to mouthpiece
placement issues, speech breathing coordination difficulty, and
speech-related technology interference (speech software
f
attempting to identify a word for the sounds made by the
oo
ventilator). Nasal BPAP was described as interfering with
speech in terms of nasal resonance and muffled speech.
Speaking with nasal BPAP was also described as
pr
uncomfortable and difficult to coordinate with breathing.4
Based on interviews of 10 adult men with muscular dystrophy
e-
using M-NIV during the day and nasal BPAP at night for an
average of 8 years, M-NIV, but not nasal BPAP, was reported
Pr
to improve cough effectiveness (most participants also used
breath stacking). These patients also preferred eating and
drinking with M-NIV and considered M-NIV safer for
swallowing than nasal BPAP. Greater challenges coordinating
al
breathing and swallowing were described with use of nasal
BPAP when eating (in 7/10 men who described eating and
u rn drinking while using nasal BPAP).3
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; FVC: Forced vital capacity; M-NIV: Mouthpiece noninvasive ventilation; BPAP:
Bilevel positive airway pressure
Jo
* NMD conditions include n=9 Duchenne muscular dystrophy, n=1 Becker muscular dystrophy, n=1 post-polio syndrome, and n=1 spinal cord injury
Explanations
a. This noncomparative, single cohort study differs importantly from the research question focused on the comparative effectiveness and safety of mouthpiece NIV and other NIV
modalities.
b. The total number of patients included in this analysis is 31, not meeting the minimum optimal information size threshold (>400) and concerning for imprecision.
c. Qualitative assessments of patient interviews and small, volunteer cohorts suggest a moderate risk of bias.
d. Study population includes one individual with spinal cord injury (a condition excluded from consideration by the research question inclusion criteria). The majority of included
participants have conditions aligned with the inclusion criteria for the research question suggesting borderline indirectness.
e. The total number of patients included is 22. The small sample is concerning for imprecision.
Bibliography
1. Bedard ME, McKim DA. Daytime Mouthpiece for Continuous Noninvasive Ventilation in Individuals With Amyotrophic Lateral Sclerosis.
Respiratory care. 2016;61(10):1341-1348.
2. McKim DA, Griller N, LeBlanc C, Woolnough A, King J. Twenty-four hour noninvasive ventilation in Duchenne muscular dystrophy: a safe
alternative to tracheostomy. Canadian respiratory journal. 2013;20(1):e5-9.
3. Britton D, Hoit JD, Benditt JO, et al. Swallowing with Noninvasive Positive-Pressure Ventilation (NPPV) in Individuals with Muscular
Dystrophy: A Qualitative Analysis. Dysphagia. 2020;35(1):32-41.
4. Britton D, Hoit JD, Pullen E, Benditt JO, Baylor CR, Yorkston KM. Experiences of Speaking With Noninvasive Positive Pressure Ventilation: A
Qualitative Investigation. Am J Speech Lang Pathol. 2019;28(2s):784-792.
e-Table 7. Evidence Profile- Invasive Ventilation


f
oo
Survival (TIV vs. No Ventilation) (follow up: up to 10 years; assessed with: mean or median survival determined via Kaplan-Meier Survival Analysis)
2 1,2
observational not serious a
none Based on data from 38 ALS patients receiving ⨁◯◯◯ CRITICAL
pr
studies serious home TIV and 38 ALS patients receiving VERY LOW
palliative care after the refusal of TIV, mean
survival in months during the first year of
e-
ventilation or palliative care was 10.39 (95%CI
9.36-11.43) and 0.83 (95%CI 0.60-1.06)
Pr
(p<0.0001), respectively.1
Based on data from 87 ALS patients receiving

TIV and 192 ALS patients not receiving TIV (85
al
receiving NIV) followed over 10 years, median
survival in months from disease onset to death
u rn was significantly higher in those receiving TIV:
47 (IQR 33-61) vs 31 (IQR 20-47), p=0.008,
respectively.2
Jo
Survival (TIV vs. NIV) (follow up: up to 10 years; assessed with: median or mean survival determined via Kaplan-Meier Survival Analysis)
2 3,4
observational not serious c
studies serious TIV and 92 ALS patients receiving NIV followed VERY LOW
up to 10 years, median survival in months was
longer for those receiving TIV: 19 (95%CI 7-
43) vs. 15 (95%CI 10-18), respectively (no p-
value reported). 3

TIV and 16 ALS patients receiving nocturnal NIV
associated with diurnal mouthpiece ventilation,
mean survival in days from ventilation onset
was 1088.06 and 1131.63 (p=0.27),
respectively.4
Survival (TIV vs NIV vs No Ventilation) (follow up: up to 15 years; assessed with: survival probability at 1 and 5 years and median survival in months)

2 5,6
observational serious not serious not serious not serious e
studies d
TIV, 22 ALS patients receiving NIV, and 86 ALS VERY LOW
patients receiving palliative support followed up
to 13 years, the percentage of patients
surviving 5-years after the onset of disease
were 62%, 32%, and 19%, respectively.
Median survival in months from disease onset
was 74, 48, and 32 (p<0.001 for TIV vs NIV
and for NIV vs palliative support), respectively.6
f
oo
TIV, 69 ALS patients who received NIV followed
by TIV, 173 ALS patients receiving NIV, and
pr
146 ALS patients receiving no ventilation
followed for up to 15 years, the probability of
e-
surviving 1 year after initiation of treatment
was 80% (SE 0.10), 83% (SE 0.06), 73% (SE
0.04) and 68% (SE 0.05), respectively. The
Pr
probability of surviving 5 years after the
initiation of treatment was 13% (SE 0.09), 25%
(SE 0.07), 6% (SE 0.02), and 5% (SE 0.02),
al
respectively.5
observational serious not serious

u rn
Survival (Oxygen vs TIV vs NIV) (follow up: historical cohort; assessed with: Mean survival age in years)
17 not serious serious g

none In a historical cohort of 227 patients with DMD ⨁◯◯◯ CRITICAL
studies f
the mean age of survival of those treated with VERY LOW
Jo
oxygen, TIV, and NIV were 18.1, 28.9, and
39.6 years, respectively.
Disease Progression (follow up: up to 10 years; assessed with: rate of progression as measured by the Appel ALS Rating Scale (AARS) (slow, intermediate, or rapid progression) and
by ALSFRS-R rate calculated as: ΔFS=(ALSFRS-R at onset−ALSFRS-R at time of diagnosis)/diagnostic delay (months))

1 2
observational not not serious not serious serious g
studies serious TIV and 192 non-tracheostomized patients (NT) VERY LOW
(85 receiving NIV), as measured by the AARS
52/87 tracheostomized patients (59.8%)
showed an intermediate rate of progression, as
compared to 41.2% of NT patients. Slowly
progressing patients were less likely to undergo
tracheostomy (only 12.6% were submitted to
palliative care), whereas rapidly evolving
f
oo
patients were more equally distributed among
the two groups (TIV, 27.6% vs NT, 33.8%)
(p=0.009, chi-square analysis). Measured via
ALSFRS-R, 20.7% of the TIV patients showed a
pr
slow disease progression, as compared with
30.4% of the NT; rapidly evolving patients were
e-
slightly overrepresented in the TIV group (i.e.,
44.8% TIV vs 38.1% NT), while patients with
an intermediate rate of progression were
Pr
equally distributed among the two groups (TIV,
34.5% vs NT, 31.5%). The difference between
groups did not reach significance (chi-square=
al
2.95, DF 2, p= 0.229).
Ventilatory Parameters (follow up: last 3 months of life; assessed with: change in respiratory parameters over time)
1 4
observational serious not serious
u rn
not serious serious g
none Comparing respiratory parameters in 16 ALS ⨁◯◯◯ CRITICAL
studies h
patients receiving TIV and 16 patients receiving VERY LOW
nocturnal NIV and associated diurnal
Jo
mouthpiece ventilation from the start of

ventilation to the last 3 months of life, there
was a significant improvement over the time in
paO2 and pacO2 in the group treated with TIV
compared to those treated with NIV (P>0.001,
P>0.001, respectively). None of the other
respiratory parameters evaluated (c-rP, miP,
MEP, SNIP, PCF, satO2) showed significant
improvement over time in either group.
Sleep Dysfunction (follow up: Cross-sectional; assessed with: patients with sleep dysfunction assessed via Sickness Impact Profile and the Health Index for Sleep)

1 8
observational not not serious not serious serious g
none Based on data from 17 post-polio patients ⨁◯◯◯ CRITICAL
studies serious receiving home TIV and 29 NMD patients VERY LOW
receiving NIV (n= 14 post-polio, n=15 with
other NMDs), measured via the Sickness
Impact Profile 11/17 (64.7%) of TIV and 23/29
(79.3%) of NIV patients experienced sleep
dysfunction. Measured via the Health Index for
Sleep 10/17 (58.8%) and 26/29 (89.7%) of
NIV patients experienced poor, quite poor, or
f
oo
very poor sleep.
Tracheostomy Related Deaths (assessed with: deaths related to tracheostomy procedure)
pr
2 1,3
none Based on data from 47 tracheostomized ALS ⨁◯◯◯ CRITICAL
studies serious patients, 2/29 (6.9%) deaths in the cohort were VERY LOW
e-
related to the tracheostomy procedure (1
granuloma of the tracheal wall and 1 stomal
hemorrhage).3
Pr
Based on data from 38 tracheostomized ALS
patients, 0 patients died as a result of the
al
procedure or procedure-related adverse
events.1
rn
Hospitalizations Following Tracheostomy (follow up: up to 10 years; assessed with: patients hospitalized, hospital admissions, and hospitalization following tracheostomy)
u
2 1,9
none Out of 38 ALS patients receiving home TIV, 19 ⨁◯◯◯ CRITICAL
studies serious (50%) required hospitalization during the first
Jo
VERY LOW
year of ventilation, with a total of 31 hospital
admissions; mean hospitalizations per patient
was 0.82 ±0.98 (range 0-3).1
For 41 NMD patients (n=30 ALS; n=5 muscular

dystrophies; n=3 myasthenia gravis; n=3
spinal muscular atrophy) receiving
tracheostomy-intermittent positive-pressure
ventilation for at least 24 months and followed
for up to 10 years, the mean number of
emergency hospital readmission per patient
after initiating TIV was 0.32.9
Quality of Life & Patient Satisfaction (follow up: last 3 months of life or average of 25 months after tracheostomy; assessed with: Satisfaction Profile (SAT-P) and VAS Scales (10-
point scale ranging from absent to extremely, higher score indicates greater distress))

2 4,10
none Based on data from the last 3 months of life in ⨁◯◯◯ CRITICAL
studies serious 16 ALS patients receiving TIV and 16 receiving VERY LOW
nocturnal NIV with associated diurnal
mouthpiece ventilation, as measured by the
SAT-P (lower scores indicating lower life
satisfaction), patients receiving TIV had
significantly lower mean life satisfaction scores:
30.7±1.4 vs 42.9±5.1 (p=0.001),
respectively.4
f
oo
In 13 ALS patients receiving TIV, at an average
of 25 months (range 3-55) after tracheostomy
all VAS queries showed a modest trend towards
pr
increase in distress (pain, anger, depression)
and to diminution of positive states (e.g.,
e-
optimism, will to live) compared to appraisals
immediately after tracheostomy. Most patients
continued to derive at least some satisfaction
Pr
(mean of 5.2, median and mode of 5 on the 10-
point VAS scale) and pleasure (mean of 5.5,
median and mode of 6 on the 10-point VAS
al
scale) from their daily lives.10
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; TIV: Invasive ventilation via tracheostomy; CI: Confidence interval; IQR:
rn
Interquartile range; SE: Standard error; AARS: Appel ALS Rating Scale; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; c-rP: c reactive protein;
miP: maximal inspiratory pressure; MEP: maximal expiratory pressure; SNIP: Sniff nasal inspiratory pressure; PCF: Peak cough flow; satO2: oxygen saturation; paO2: Partial
u
pressure of oxygen; pacO2: partial pressure of carbon dioxide; SAT-P: Satisfaction profile; VAS: Visual Analog Scale
Jo
Explanations
a. Survival estimates differ across studies (after accounting for differences in follow-up period).
b. Both studies include samples that do not meet optimal information size criteria, suggesting imprecision.
c. One study suggested increased survival with TIV, while the other study suggests increased survival with NIV.
d. One study included individuals that likely differed in outcome important co-interventions: One study minimally reported outcome parameters.
e. One study includes a small sample that does not meet optimal information size criteria; One study includes a total of 409 participants minimally meeting optimal information
size criteria.
f. Available care differed across cohort members as treatments changed over time which may have impacted the outcome of survival rate.
g. Small sample suggests imprecision.
h. Minimal reporting of outcome parameters made the risk of bias assessment unclear.
Bibliography
1. Sancho J, Servera E, Diaz JL, Banuls P, Marin J. Home tracheotomy mechanical ventilation in patients with amyotrophic lateral sclerosis:
causes, complications and 1-year survival. Thorax. 2011;66(11):948-952.
2. Spataro R, Bono V, Marchese S, La Bella V. Tracheostomy mechanical ventilation in patients with amyotrophic lateral sclerosis: clinical
features and survival analysis. Journal of the neurological sciences. 2012;323(1-2):66-70.
3. Fini N, Georgoulopoulou E, Vinceti M, et al. Noninvasive and invasive ventilation and enteral nutrition for ALS in Italy. Muscle & nerve.
2014;50(4):508-516.
4. Nicolini A, Parrinello L, Grecchi B, et al. Diurnal mouthpiece ventilation and nocturnal non-invasive ventilation versus tracheostomy invasive
ventilation in patients with amyotrophic lateral sclerosis. Panminerva Med. 2020;62(1):19-25.
5. Dreyer P, Lorenzen CK, Schou L, Felding M. Survival in ALS with home mechanical ventilation non-invasively and invasively: a 15-year cohort
study in west Denmark. Amyotrophic lateral sclerosis & frontotemporal degeneration. 2014;15(1-2):62-67.
6. Tagami M, Kimura F, Nakajima H, et al. Tracheostomy and invasive ventilation in Japanese ALS patients: decision-making and survival
analysis: 1990-2010. Journal of the neurological sciences. 2014;344(1-2):158-164.
7. Ishikawa Y, Miura T, Ishikawa Y, et al. Duchenne muscular dystrophy: survival by cardio-respiratory interventions. Neuromuscular disorders :
f
oo
NMD. 2011;21(1):47-51.
8. Klang B, Markstrom A, Sundell K, Barle H, Gillis-Haegerstrand C. Hypoventilation does not explain the impaired quality of sleep in postpolio
pr
patients ventilated noninvasively vs. invasively. Scandinavian journal of caring sciences. 2008;22(2):236-240.
9. Marchese S, Lo Coco D, Lo Coco A. Outcome and attitudes toward home tracheostomy ventilation of consecutive patients: a 10-year
e-
experience. Respiratory medicine. 2008;102(3):430-436.
Pr
10. Rabkin JG, Albert SM, Tider T, et al. Predictors and course of elective long-term mechanical ventilation: A prospective study of ALS patients.
Amyotrophic lateral sclerosis : official publication of the World Federation of Neurology Research Group on Motor Neuron Diseases.
2006;7(2):86-95.
al
e-Table 8a. Evidence Profile-Sialorrhea Management: Anticholinergics
u rn
Jo
№ of
Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations
studies
Sialorrhea Severity (follow up: 1 week; assessed with: Mean change in VAS 10 mm scores for saliva severity & saliva difficulty; Lower score indicates less severity/difficulty)
№ of
studies
1 1
randomized serious a
not serious not serious serious b
none For 8 ALS patients with sialorrhea randomized to ⨁⨁◯◯ CRITICAL
trial treatment with scopolamine or placebo patch for 1 LOW
week then crossed over after a 1-week washout
period, the mean severity of sialorrhea before and
after scopolamine was 54.4 ± 2.0 mm and 43.7 ±
18.7 mm, respectively (MD -10.700 95%CI -
24.9610 to 3.5610). Before and after the placebo,
it was 60.0 ± 32.1 mm and 55.6 ± 29.0 mm (MD -
f
4.400 95%CI -37.2038 to 28.4038).
oo
Concerning sialorrhea-related difficulty, the values
before and after using scopolamine were 60.0 ±
pr
28.8 and 46.3 ± 29.2 mm, respectively (MD -
13.700 95%CI -44.8001 to 17.4001). Before and
after placebo, they were 58.8 ± 31.8and 55.6 ±
e-
29.0 mm (MD -3.200 95%CI -35.8353 to
29.4353).
Pr
There were no significant differences between the
treatment groups for either mean change in
severity (p = 0.384) or mean change in saliva
al
difficulty (p = 0.388; paired t-test).
Sialorrhea Symptom Improvement (follow up: Not Reported; assessed with: Participants experiencing improvement in symptoms)
1 2
observational not not serious not serious
u rn
serious c
none For 72 ALS patients with excessive saliva ⨁◯◯◯ CRITICAL
study serious prescribed an anticholinergic (hyoscine, VERY LOW
amitriptyline, atropine, propantheline, or
Jo
glycopyrrolate), an improvement in symptoms was

recorded for 44 (61%). Of the 28/72 (39%)
patients with our symptom improvement following
an initial anticholinergic, 22 tried treatment with
another anticholinergic and 21/22 had an outcome
for symptoms recorded. 4/21 (19%) experienced
symptom improvement following the initiation of a
second anticholinergic. Eleven patients were given
a combination of two anticholinergics after a first
anticholinergic was reported to improve but not
adequately control symptoms over time with 5
(45%) reporting symptomatic improvement when
they started a second anticholinergic alongside
their initial anticholinergic.
Adverse Events (follow up: 1 weeks; assessed with: Participants experiencing AEs)
№ of
studies
1 1
randomized serious a
not serious not serious serious d
none For 10 ALS patients with sialorrhea randomized to ⨁⨁◯◯ CRITICAL
trials treatment with scopolamine or placebo patch for 1 LOW
week then crossed over after a 1-week washout
period, 2/10 (20%) developed pneumonia and
discontinued the study (authors concluded
pneumonia was unrelated to study interventions).
One patient complained of dry mouth and in this
patient, the cotton rollweight and daily oral suction
f
were markedly decreased and the VAS (severity)
oo
was improved by scopolamine. No other patient
complained of any other symptom. No remarkable
differences were observed in blood pressure, pulse,
pr
SpO2, or hematological/biochemical parameters.
Adverse Events^ (follow up: Not reported; assessed with: Participants experiencing AEs)
e-
1 2
observational not not serious not serious serious c
none For 57 ALS patients using hyoscine patches for ⨁◯◯◯ CRITICAL
Pr
study serious sialorrhea, 34 (60%) reported adverse events and VERY LOW
19 (33%) discontinued treatment due to AEs. For
25 ALS patients using amitriptyline for sialorrhea,
12 (48%) reported adverse events and 3 (12%)
al
discontinued treatment due to AEs. For 17 ALS
patients using oral glycopyrronium for sialorrhea, 4
u rn (24%) reported AEs, and 1 discontinued treatment
due to AEs.
NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; VAS: Visual analog scale; MD: Mean difference; CI: Confidence interval; AE: Adverse event ^Reported AEs include
excessive dry mouth, thickened secretions, skin reaction, confusion, drowsiness, dizziness, light headed, nausea, urinary retention, or Bulbar dysfunction.
Jo
Explanations
a. Minimal methods reporting and loss to follow up suggest risk of bias.
b. Small sample and wide CIs suggesting great benefit and harm.
c. Small sample with incomplete data reporting.
d. Small sample suggests imprecision.
e-Table 8b. Evidence Profile-Sialorrhea Management: Botulinum Toxin

Sialorrhea Improvement (follow up: range 2 weeks to 12 weeks; assessed with: Visual Analog Scale & Drooling Scales)
6 3-8
observatio seriou not serious not serious b
none For 26 ALS patients treated with BTX-A (10-20 U in 2ml saline and Dysport 30-60 ⨁◯◯◯ CRITICAL
nal studies sa serious U), 2 weeks after treatment subjective sialorrhea severity VAS scores were VERY
significantly improved: pre-treatment VAS score (mean ±SD) 7.4±1.8 vs post-
treatment 3.5±2.3, p<0.0001.5
LOW
For 5 ALS patients treated with 20 U of BTX-A 100 U in 1 ml of 0.9% saline and 5
treated with 20 U of BTX-A 100 U in 2 ml 0.9% saline, both groups showed
significant improvement from baseline on the VAS for drooling at 4 weeks post-
treatment: 1 ml dilution-mean score at baseline 76±14.3 vs 51±12.4 at 4 weeks
post-treatment, p< 0.05; 2 ml dilution-mean score at baseline 83±10.4 vs 64±16.4
f
at 4 weeks post-treatment, p< 0.05.4
oo
For 25 adult (mean age 54.36±17.09) NMD patients^ treated with BTX-A (20-30
U), the average subjective score of severity of sialorrhea (1=markedly worse to
pr
5=markedly better) was 3, 3.84 ± 0.8, and 4.28 ± 0.6 at pre-administration of
BTX-A, 4-weeks follow up, and 6-week follow up, respectively. 8
e-
For 10 ALS patients receiving BTX-A injections, at 4 weeks post-treatment mean
subjective severity (1=dry; 5= profuse) and frequency of drooling (1=never;
5=constant) scores were reduced (no p-values provided but described as
Pr
“significant”): severity scores baseline 4.2±0.6 vs 1.8±0.6 and frequency scores
3.8±0.4 vs 1.7±0.5. Significant reductions in drooling severity (mean score at 12
weeks 2.0±0.8) and frequency (2.0±0.9) were maintained at 12 weeks post-
treatment (compared to baseline, no p-values provided). 6
al
For 16 ALS patients receiving BTX-B treatment (2,500 U), at 4 weeks post-
treatment compared to pretreatment VAS sialorrhea (7.2 ± 1.3 vs 2.1 ± 2.2,
u rn p=0.001) and disability (6.2 ± 2.2 vs 1.5 ± 1.1, p=0.001) severity scores were
significantly improved. Significant improvements were maintained for both
sialorrhea severity score (at 12 weeks 5.0 ± 1.9, p=0.003) and disability severity
score (3.8 ± 1.9, p=0.001) at 12 weeks post-treatment compared to pretreatment.
3
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For 14 ALS patients treated with incobotulinumtoxinA (100 MU in both parotid

glands and 50 MU in both submandibular glands) mean Drooling Frequency Scores
(1= never drool; 4 severe drooling) were reduced at week 4 (p = 0.04), week 8 (p
= 0.02), but not after week 12. Mean Drooling Severity Scores were reduced at
week 4 (p = 0.03), week 8 (p = 0.04), and week 12 (p = 0.04) (mean scores not
reported). 7
Sialorrhea Severity (follow up: range 4 weeks to 12 weeks; assessed with: Drool Rating Scale: score 8 to 39; 8= no burden of drooling) and subjective drooling assessment)
2 9,10
randomize seriou not serious not serious b
none For 10 ALS patients receiving 1 to 2 BTX-A injections (20-50 MU), at 4 ⨁⨁◯◯ CRITICAL
d trials sc serious weeks (n=8) and 12 weeks (n=7) post-treatment, mean Drool Rating LOW
Scale scores were not significantly improved from baseline: 21.3 (3.8) vs
4 weeks 22.5 (5.3), and 12 weeks 20.8 (6.6) (no p-values reported,
described as NS). 10
For 11 ALS patients treated with BTX-B (2,500 MU) and 9 randomized to
placebo injection (2,500 MU), at 2 weeks, 82% of patients randomized
f
to BTxb (n=11) and 38% of patients receiving placebo (n=9) reported
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improvement in drooling (rated as 1= markedly worse to 5=markedly
better) (p<0.05). At 4 weeks, 90% of BTX-B patients reported
improvement compared 44% of placebo patients (p<0.05). At 8 weeks,
pr
67% of BTX-B treated patients reported improvement compared to 22%
of placebo-treated (p=0.153), and at 12 weeks 50% of BTX-B patients
(n=9) reported improvement compared to 14% of placebo (n=9) treated
e-
patients (p=NS).9
Adverse Events (follow up: range 2 weeks to 12 weeks; assessed with: Participants with adverse events)
Pr
5 3,6-
observatio seriou not serious not serious b
none For 25 adult (mean age 54.36±17.09) NMD patients^ treated with BTX- ⨁◯◯◯ CRITICAL
9
nal studies sd serious A (20-30 U) and followed for 6 weeks, no adverse events were VERY
al
^^ reported.8 LOW
u rn For 10 ALS patients treated with BTX-A (40 U) and followed for 12
weeks, no xerostomia, dysphagia, or other adverse events were
reported.6
For 14 ALS patients treated with incobotulinumtoxinA (100 MU in both

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parotid glands and 50 MU in both submandibular glands) and followed

for 12 weeks, no patients experienced changes in swallowing patterns or
any other adverse events.7
For 11 ALS patients treated with BTX-B (2,500 U) and followed for 12
weeks, there was no increased risk of aspiration pneumonia, worsening
dysphagia, or an increase in the rate of decline of vital capacity in the
treatment group.9
For 16 ALS patients treated with BTX-B (2,500 U) and followed for 12
weeks, reported adverse effects were viscous saliva (n = 5), local pain
(n = 4), increased difficulty of chewing (n = 3), respiratory infection (n
= 2), facial paresis (n = 1) and burning tingling of the eyes (n = 1).
There was a non-significant increase in the dysphagia scale at week 12.
There were no other serious adverse events, and, except for one case of
severe xerostomia, all adverse effects were considered by the patients
as mild to moderate.3
NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; CI: Confidence interval; SD: Standard deviation; BTX-A: Botulinum toxin type A; BTX-B: Botulinum toxin type B; MU:
Mouse unit; U: Unit; VAS: Visual analog scale
Âdult NMD Patients (mean age 54.36±17.09) with Duchenne muscular dystrophy n=3, myotonic dystrophy n=3, oculopharyngeal muscular dystrophy n=1, inclusion body myositis n=2,
primary lateral sclerosis n=1, ALS n=9, spinal muscular atrophy type 2 and 3 n=2, spinal-bulbar muscular atrophy n=2, and Becker’s muscular dystrophy n=2.
^^ One included study is a small (n=10) RCT comparing botulinum toxin treatment to RT of high risk of bias for variable intervention dosing and missing outcome data due to significant
loss to follow up.
Explanations
a. The majority of studies relied on unmasked subjective outcome reporting; Two studies did not provide specific dosing information (dosing range and the number of treatments); Three
studies documented potentially important differences in co-interventions.
b. Included studies relied on very small samples, concerning for precision.
c. One study is of a high risk of bias due to incomplete outcome data reporting and imbalanced loss to follow up between groups with outcome assessment dependent on patient-reported
assessments with patients unmasked to study assignment; One study is of a low risk of bias.
d. The majority of included studies of a moderate risk of bias due to subjective, unmasked outcome reporting, incomplete intervention description, and loss to follow up.
f
e-Table 8c. Evidence Profile- Sialorrhea Management: Radiation Therapy
oo
pr
e-
Sialorrhea Improvement (follow up: up to 6 months; assessed with: rate of improvement, subjective assessment of improvement, or Sialorrhea Scoring Scale)
5 11-15
observational serious not serious not serious b
none For 50 ALS patients undergoing RT of the parotid and submandibular glands- 30 CRITICAL
Pr
⨁◯◯◯
studies a
serious receiving 10 Gy in 2 fractions and 20 receiving 20 Gy in 4 fractions-, post-RT, all VERY
patients had improved per the SSS: 46 (92%) had a complete response (SSS scores 1-
3) and 4 (85) had a partial response (SSS 4-5). A significant lasting salivary reduction
LOW
was observed 6 months after RT completion: 71% complete response and 26% partial
al
response (significant SSS reduction vs baseline, p<0.00001); At baseline, all 50
patients had severe hypersalivation (mean SSS, 8; range, 6-9), In comparison with
u rn baseline values, RT induced an SSS decreased of 76%, 62%, 67%, and 65% at the end
of RT and at 1 month, 3 months, and 6 months after the end of RT, respectively
(p<0.0000001).11
For 21 ALS patients receiving RT of the parotid and submandibular glands at a mean
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dose of 19.1 Gy delivered in 5 fractions, 13 were treated with 5.5–6 MV photons and 8
were treated with 6–15 MeV electrons. During the mean follow-up of 10.4 months, half
of the patients treated with photons (6/12) reported (via interviews using the ALSFRS)
a positive response, and 87.5% of patients treated with electrons (7/8) reported a
positive response (P = 0.09).12
For 16 ALS patients receiving RT of the parotid and submandibular glands at 4-48 Gy in
1-11 fractions (7 patients were treated with electrons and 9 with photons) using a 4-
point Likert scale, 80% of patients felt improved at 1 month and 43% at 6 months
posttreatment. One month after RT, the mean ALSFRS salivation subscore improved,
although not significantly, from 0.43 ± 0.50 to 0.62± 1.08 (no p-value or 6-month data
provided).13
For 10 ALS patients receiving external electron beam RT of parotid glands at a total
dose of 1500 cGy in 3 fractions, sialorrhea improved in all patients. Most patients noted
a reduction in sialorrhea commencing by 2–4 weeks after irradiation with maximal
improvement by 6–8 weeks.14
For 19 ALS patients receiving RT of parotid glands at 12 Gy in 2 fractions with 8-14 MeV
electrons (n=5) or 250kV photons (n=14) and followed up to 3 weeks, 14 (74%) had a
satisfactory response after initial RT, 4 (21%) patients showed no improvement after
initial treatment were re-irradiated; 1 (5%) patient showed a partial improvement.15

Sialorrhea Rate (follow up: up to 3 months; assessed with: mean salivary secretion rate or Drool Rating Scale (score 8-39, 8=no burden of drooling))
3 observational not not serious not serious b

none For 18 ALS patients undergoing RT of parotid and submandibular glands at ⨁◯◯◯ CRITICAL
10,16,17
studies ^ serious serious 7.0 Gy (n=13) or 7.5 Gy in one fraction, mean parotid salivary secretion VERY
rate was 1.44± 1.31 ml/5 min 1-hour before irradiation and diminished LOW
significantly from pre-RT at both 1 day (0.62 ±0.54 ml/5 min, 43%
decrease) and 2 weeks (0.82 ± 0.9 ml/5 min, 57% decrease) after
irradiation (no p-values provided).16
f
oo
For 14 ALS patients treated with RT at 7.5 Gy for 1 fraction with 4-6 MV
photons, mean salivary secretion rate was significantly reduced after RT:
Before RT 0.57±0.81 ml/min vs 0.23±0.39 (60% reduction) 1-week post-
RT, 0.30± 0.27 (51% reduction) after 2 weeks, and 0.45±0.45 (21%
pr
reduction) at 3 months post-RT.17
e-
For 10 ALS patients receiving RT of the parotid glands with a single fraction
of 7.0 Gy delivered using a 15-MeV electron beam, at 4 weeks (n=9) and 12
weeks (n=9) post-treatment mean Drool Rating Scale scores (scores 8 to 39
Pr
with lower scores indicating lower burden of drooling) were reported as not
significantly improved from baseline: 21.2±2.8 vs 4 weeks 19.9±4.9, 12
weeks 16±3.2 (no p-values reported).10
al
Adverse Events (follow up: up to 6 months; assessed with: rate of adverse events following RT)
u rn
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8 10-17
observational serious not serious not serious b
none For 18 ALS patients undergoing RT of the parotid and submandibular glands at 7.0 Gy ⨁◯◯◯ CRITICAL
studies c
serious (n=13) or 7.5 Gy and followed for 2 weeks 1 patient experienced persistent xerostomia VERY
beginning 1 week after treatment. All patients and caregivers reported no aspiration
pneumonia during follow-up.16
LOW
For 50 ALS patients receiving RT of the parotid and submandibular glands- 30 at 10 Gy

in 2 fractions and 20 at 20 Gy in 4 fractions- followed for up to 6 months, there was no
grade 3-4 toxicity or treatment-related deaths. Grade 1-2 toxicities (mild pain,
xerostomia, saliva thickening, swallowing difficulty, taste modification) were observed in
17 patients (34%) during RT, then 4 (8%), 6 (15%), and 2 (5%) patients at 1-, 3-, and
f
6-months post-RT, respectively.11
oo
For 21 ALS patients receiving RT of the parotid and submandibular glands at a mean
dose of 19.1 Gy delivered in 5 fractions, 13 were treated with 5.5–6 MV photons and 8
pr
were treated with 6–15 MeV electrons. Among the 12 patients treated with photons, 4
(33%) experienced toxicity. The symptoms included oral pain and mucositis under
irradiation, oral pain 3 months after radiotherapy, edema that resulted in the inability to
e-
lie down properly with the head mask, or xerostomia one month after radiotherapy.
Among the eight patients treated with electrons, none experienced toxicity (p = 0.1).12
Pr
For 16 ALS patients receiving RT of the parotid and submandibular glands at 4-48 Gy in
1-11 fractions, 7 patients were treated with electrons and 9 with photons. In the
electron group, 2 (29%) patients reported slight mouth dryness and 0/7 reported pain,
edema, or erythema. In the photon group, 2 (22%) reported dryness and 1 (11%)
patient reported pain and edema requiring interruption of radiotherapy after three
al
fractions.13
u rn For 10 ALS patients receiving external electron beam RT of parotid glands at a total
dose of 1500 cGy in 3 fractions, no patients developed xerostomia, oropharyngeal
soreness, or skin changes.14
For 14 ALS patients treated with RT at 7.5 Gy for 1 fraction with 4-6 MV photons, no
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serious side-effects were observed up to 3 months post-RT.17
For 19 ALS patients receiving RT of parotid glands at 12 Gy in 2 fractions with 8-14 MeV
electrons (n=5) or 250 kV photons (n=14), 6 (32%) experienced pain and 4 (21%)
experienced xerostomia.15
For 10 ALS patients receiving RT of the parotid glands with a single fraction of 7.0 Gy
delivered using 15-MeV electron beam, immediately following RT 7/10 (70%)
experienced adverse events (viscous saliva, pain, loss of voice, swallowing difficulty,
little saliva, dry mouth) and at 4 weeks post-RT 2/10 (20%) reported adverse events
(dry mouth).10
ALS: Amyotrophic lateral sclerosis; RT: radiation therapy; Gy: Gray; MeV: Mega electron volts; MV: Megavolts; kV: Kilovolts; SSS: Sialorrhea Scoring Scale; ALSFRS: Amyotrophic lateral
sclerosis functional rating scale
^ One included study is a small (n=10) RCT comparing botulinum toxin treatment to RT of high risk of bias for variable intervention dosing and missing outcome data due to significant loss
to follow up.
Explanations
a. Two studies are of a low risk of bias; Two studies have missing outcome data due to significant loss to follow up; Two studies did not define the assessment criteria for the primary
outcome.
b. All studies relied on small samples, concerning for imprecision.
c. Five studies are of a low risk of bias; Three studies have missing outcome data due to significant loss to follow up.
e-Table 8d. Evidence Profile- Airway Clearance Techniques: Glossopharyngeal Breathing
Change in CPF (follow up: cross-sectional; assessed with: mean CPF following GPB)
1 18
none For 18 muscular dystrophy patients (mean age ⨁◯◯◯ CRITICAL
study serious 21.1±5.4yo), performing various assisted cough VERY LOW
techniques, mean CPF assisted by GPB exceeded
unassisted CPF: 262.5±72.8 vs 180±80.37 L/min
(p<0.001, 46% increase).
f
oo
Mean CPF assisted by GPB and thoracoabdominal thrust
(326.4 ±87.5 L/min) and by GPB plus independently
maneuvering a wheelchair for a table thrust (310.3±4.7
pr
L/min) also significantly exceeded unassisted CPF
(p<0.001) but were not significantly different (P= 0.07)
e-
from each other.
Lung Volume (follow up: range 7 months to 169 months; assessed with: mean maximum single-breath capacity (GPmaxSBC) and mean vital capacity (VC))
Pr
1 19
none For 21 male DMD patients (mean age 20.6 ±3.1yo) able ⨁◯◯◯ CRITICAL
study b
to GPB, mean GPmaxSBC significantly exceeded mean VERY LOW
al
VC: 824±584 vs 244±51 ml, respectively (p<0.001).
Need for Ventilator Use (follow up: range 7 months to 169 months; assessed with: Mean minutes of ventilator use required)
1 19
observational serious not serious not serious
u rn
serious a
none For 15 male DMD patients (mean age 20.6±3.1yo) ⨁◯◯◯ CRITICAL
study b
trained in and using GPB throughout daytime hours such VERY LOW
that respiratory distress and hypercapnia developed
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when ceasing GPB, GPB delayed the need for daytime

ventilator use. These patients required 5.3±1.7
mouthpiece intermittent positive-pressure ventilations
per minute (1200 ml each) when not using GPB and
3.4±1.7 ventilations per minute when using it.
CPF: Cough peak flow; DMD: Duchenne muscular dystrophy; GPB: Glossopharyngeal breathing; GPmaxSBC: maximum single-breath capacity; VC: Vital capacity
Explanations
a. Study relied on a small sample, concerning for precision.
b. Study is of a moderate risk of bias due to missing outcome data.
e-Table 8e. Evidence Profile- Airway Clearance Techniques: Mechanical Insufflation-Exsufflation
Effect of Cough Peak Flow (follow up: Cross-sectional; assessed with: change in CPF following MI-E)
11 20-30
none ⨁◯◯◯ CRITICAL
studies ^ a
VERY LOW
The majority of 10 studies reporting change in CPF suggest a statistically significant immediate improvement with the
f
use of MI-E:
oo
unassisted CPF CPF with-MI-E P value (% CPF with MI-E P value (%
increase) + MAC increase) †
Cesareo 2018 (n= 20 Median 163 [IQR 85.2] 164.6 [87] 0.86
pr
DMD)
Chatwin 2003 (n=22 169 (95%CI 129-209) 297 (246- <0.001
e-
NMD) 350)
Fauroux 2008 (n=17 162 ± 97 192 ± 99 0.02 (19%)
NMD)
Pr
Kikuchi (2018) (n=12 59 ± 34.2 198.8 ± 40.2 <0.001 (237%) 240 ± 38.4 <0.001 (307%)
DMD)
Kim 2016 (n=40 NMD) 95.7 ± 40.5 177.2 ± 33.9 <0.01 (85%) 202.4 ± <0.01 (111%)
46.6^
Mustfa 2003 (n=47 ALS)
al
Bulbar ALS (n=21) 178 ± 61 212 ± 75 <0.05 (19%)
Non-bulbar ALS (n=26) 217 ± 84 264 ± 73 <0.001 (22%)
u rn
Sancho 2004 (n= 26
ALS)
Senent 2011 (n= 16
268.2 ± 138.6
Median 84 (IQR 35-118)

225 ± 55.2
488 (243-
NR (-16%)
<0.001
ALS) 605)
Sivasothy 2001 (n=12
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NMD)
Without scoliosis (n=8) Median (range) 104 (43- 156 (61-247) <0.01 248 [110- <0.01
188) 343]
With scoliosis (n=4) Median 288 (175-367) 231 (148- NS 362 [218- NS
597) 440]
Winck 2004 (n=20 NMD)
ALS (n=13) Median 170 [IQR 128- 200 [170- <0.001
300] 352]
Other NMD (n=7) Median 180 [IQR 150- 220 [190- <0.05
275] 300]
Cough Peak Flow (CPF) measured in L/min; Mean ± SD unless otherwise noted; † Compared to unassisted CPF
For 18 adult (>18yo) NMD† patients receiving cough assistance via MI-E, MI-E and manually assisted cough (MI-E +
MAC) and Intermittent positive pressure breathing with manually assisted cough (IPPB + MAC) in a random order, all
techniques resulted in a significant increase in CPF from baseline (p<0.0001). CPF was highest with IPPB + MAC,
followed by MI-E + MAC (Wilcoxon p = 0.0108), which was higher than with MI-E alone (Wilcoxon p = 0.0297), which
was higher than the baseline condition (Wilcoxon p = 0.003).30
Effect on Vital Capacity (follow up: 1 year; assessed with: Change in mean VC (liters) from 2 years prior to MI-E introduction to 1-year post-MI-E)
1 31
observational serious not serious not serious serious d
none For 21 NMD‡ patients (mean age 16.1+6.5yo), in the ⨁◯◯◯ CRITICAL
study c
two years before the introduction of MI-E, mean VC VERY LOW
declined from 0.88±0.45 L to 0.71±0.38 L (n=14,
p=0.02) and from 0.71±0.38 L to 0.50 ±0.24 L (n=16,
p=0.057), respectively. In the first year, after initiation
of MI-E, mean VC significantly increased (n=21; 0.50 L
vs. 0.64 L, p= 0.002), an average relative increase of
28%. After the second year of regular use, this effect
f
remained stable with a further increase of VC from
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0.64 to 0.65 L (n=6).
Effect on Dyspnea (follow up: Cross-sectional; assessed with: Change in median Borg score following MI-E; Borg scale (0 =not at all breathless; 10 =maximal breathlessness))
pr
1 29
observational serious not serious not serious serious d
none For 13 adults with ALS and 7 adults with other NMDs§ ⨁◯◯◯ CRITICAL
study e
median dyspnea scores improved significantly from VERY LOW
e-
baseline after application of MI-E at 40cmH20 for 3
cycles in participants with varied NMDs (from 2.0 (IQR
Pr
0.4-3.3) to 0.75 (IQR 0-2.3), p<0.05) but not for the
ALS cohort (from 2.0 (IQR 0.8-3.5) to 1.0 (IQR 0.5-
2.0, no p-value provided).
al
Pulmonary Morbidity (follow up: Varied; assessed with: rate of pneumonia, chronic atelectasis, and chest infection)
3 32-34
observational
studies ^^
not
serious
not serious not serious
u rn
serious b
none For 62 children (mean age at MI-E initiation 11.3yo)
with NMD¶ initiating and using MI-E for a mean of 13.4
months, caregivers reported 5 children experienced a
⨁◯◯◯
VERY LOW
CRITICAL
reduction in the frequency of pneumonia and 4 children

Jo
experienced an improvement in chronic atelectasis. 32
For 19 ALS patients using NIV plus MI-E for at least 2

sessions per day and followed up 12.3 person-years,
6/19 (31.6%) experienced 19 episodes of chest
infection with a mean duration of symptoms per
infection of 3.9 days. 33
Comparing 48 ALS patients prescribed MI-E and/or

breath stacking 3 times per day and 60 patients not
prescribed a device over 12 months there was no
difference in rate of chest infections, 28 vs 27,
respectively (p=0.17).
Hospitalization (follow up: Varied; assessed with: rate and/or risk of hospitalization)
3 33,35,36
observational serious f
not serious not serious serious b
none For 11 NMDƒ patients (aged 16-64) and respiratory ⨁◯◯◯ CRITICAL
studies ^^ tract infection using MI-E compared to 16 historical VERY LOW
age-matched controls with NMD and respiratory tract
infection who received chest physical treatments alone,
no difference was observed in mean days hospitalized
between the 2 groups studied: 20.5±20 d vs 19.8 ±17
d, p = 0.93, respectively.36
f
For 37 NMD¥ patients (mean age 19.8 yo) using MI-E
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at home with medical histories up to 20 years pre-MI-E
and up to 5 years post-MI-E, the relative risk of
hospital separations before MI-E initiation was 1.82
pr
(95% CI 0.76-4.38), and the relative risk of ED
presentations before MI-E was 1.76 (95%CI 1.10-
2.84).35
e-
For 19 ALS patients using NIV plus MI-E daily for 2
Pr
sessions and followed for 12.3 person-years, there
were 6 episodes of hospitalization.33
Adverse Events (follow up: Varied; assessed with: rate of adverse events with MI-E use)
al
4 observational not not serious not serious serious b
none For 11 patients (aged 16-64) with NMDƒ and ⨁◯◯◯ CRITICAL
22,29,32,36
studies serious
u rn respiratory tract infection using MI-E, 1 episode of
stomach distension and 1 mild nosebleed were
reported.36
VERY LOW
Jo
For 62 children (mean age at MI-E initiation 11.3 yo)

with NMD¶ using MI-E for mean of 13.4 months, 2
children discontinued MI-E due to abdominal pain and
other chest discomfort. One child experienced
premature ventricle contractions upon initial use but
continued use after the resolution of the acute
respiratory failure episode.32
For 20 adult NMD§ patients undergoing one application

of 6 cycles of MI-E at each 15 cm H2O, 30 cm H2O,
and 40 cm H2O of pressure, no stomach distension,
vomiting, blood-streaked sputum or chest pain were
reported.29
For 17 children (mean age 11±4 yo) with NMD«

undergoing one MI-E application of 6 cycles at each 15,
30, and 40 cm H2O of pressure, no episodes of
stomach distention, gastroesophageal reflux, or chest
pain were reported.22
Patient Comfort (follow up: Varied; assessed with: patient assessed comfort)
4 observational not not serious not serious serious b

none For 22 NMDÆ patients (aged 10-56yo), mean VAS ⨁◯◯◯ CRITICAL
21,22,27,30
studies ^^^ serious comfort scores (0=least comfortable; 10= most VERY LOW
comfortable) were higher with MI-E assisted cough
than unassisted cough: 7.3 (95%CI 6.6-8.0) vs 5.4
(95%CI 4.5-6.3), respectively.21
For 18 adult NMD† patients receiving cough assistance

via MI-E, MI-E and manually assisted cough (MI-E +
f
MAC), and Intermittent positive pressure breathing
oo
with manually assisted cough (IPPB + MAC) in a
random order, median VAS comfort ratings (0= “I
breath very badly”; 10= “I breathe very well”) were
pr
similar with all techniques: MI-E 6.4 vs MI-E + MAC
6.6 vs IPPB+MAC 7.0. Subjective cough effectiveness
was rated lower with MI-E than the other two
e-
techniques (median score for MI-E 6.4 vs 8.3 for
IPPB+MAC and 8.5 for MI-E + MAC (p<0.05 for MI-E
Pr
vs IPPB +MAC and MI-E vs MI-E + MAC).30
For 17 children (mean age 11±4 yo) with NMDs«

receiving three MI-E sessions respiratory comfort
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significantly improved from baseline following MI-E:
mean VAS 100 scores (higher score indicates greater
u rn comfort) 73±21 vs 83±19, p=.02, respectively.22
For 16 ALS patients performing a series of cough

techniques in random order, median (IQR) VAS
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comfort ratings (0=least comfortable; 10= most

comfortable) were higher with MI-E assisted cough
than unassisted cough: 7 (3-8) vs 5 (4-7), respectively
(reported “not significant”, no p-value provided).27
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; DMD: Duchenne muscular dystrophy; MI-E: Mechanical insufflation exsufflation; MAC:
Manually assisted cough; IQR: Interquartile range; VAS: Visual analog scale
^ Evidence base includes 4 prospective and/or randomized controlled trials. All trials were of a moderate to high risk of bias. The initial certainty rating of high for trials was considered when
assessing overall risk of bias in the evidence base.
^^ Evidence base includes one crossover trial of a high risk of bias.
^^Êvidence base includes one randomized controlled trial of a moderate risk of bias. The initial certainty rating of high for trials was considered when assessing overall risk of bias in the
evidence base.
† NMD cohort includes n=9 DMD; n=1 Becker's muscular dystrophy; n=2 Acid maltese deficiency; n=2 Spinal amyotrophy; n=1 congenital muscular dystrophy; n=1 Ulrich syndrome; n=2
gamma-sarcglycanopathy.
‡ NMD cohort includes n=10 DMD, n=4 spinal muscular atrophy; n=4 congenital myopathy w/o diaphragm weakness; n=3 congenital myopathy with diaphragm weakness.
§ Other NMD cohort includes n=4 Myotonic dystrophy; n=1 DMD; n=2 other muscular dystrophies.
¶ NMD cohort includes n=17 DMD; n=21 spinal muscular atrophy; n=12 myopathy; n=12 other non-specific NMD.
ƒ NMD cohort includes n=2 ALS, n=1 LGMD; n=4 DMD; n=3 SMA; n=1 FSHMD; Historical control cohort includes n=2 LGMD; n=7 DMD; n=6 ALS; n=1 congenital myopathy.
¥ More than half (55.6%) of the NMD cohort had a diagnosis of muscular dystrophy; The remaining participants had a variety of NMD diagnoses including spinal muscular atrophy (SMA),
limb girdle MD, congential myopathies, arthrogryposis multiplex congenital and congenital MD.
« NMD cohort includes n=4 DMD; n=4 spinal muscular atrophy; n=9 other congenital myopathy n=9.
Æ NMD cohort includes n=10 spinal muscular atrophy; n=6 DMD; n=3 poliomyelitis; n=3 other congenital muscular dystrophies
Explanations
a. Three studies are of a low risk of bias; Eight studies are of moderate to high risk of bias for the inclusion of participants in varying stages of disease and/or minimal methods reporting,
and/or unmasked outcome assessment.
b. All included studies relied on small samples and the total number of participants across studies is concerning for precision.
c. Study is of a moderate risk of bias for missing outcome data.
d. Study relies on a small sample.
e. Study is of a moderate risk of bias due to the inclusion of participants in varying stages of disease and missing outcome data.
f. Studies are of a moderate risk of bias due to the inclusion of participants in varying stages of disease and minimal compliance with the intervention.
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e-Table 8f. Evidence Profile- Airway Clearance Techniques: Manually Assisted Cough

Effect on Cough Peak Flow (follow up: Cross-sectional; assessed with: change in CPF following MAC)
18,21,23- a
14 observational not not serious not serious serious none The majority of studies indicate a significant increase in ⨁◯◯◯ CRITICAL
25,27,28,37-43
studies ^ serious cough peak flow with MAC and with MAC combined with VERY LOW
LVR:
unassisted CPF CPF with P value (% CPF MAC + P value (%
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MAC increase) LVR† increase)‡
Bianchi 2014 (n= 18 MD) Physiotherapist 243.3 ± 77.0 NR (35%)
Thoracoabdominal Thrust 180 ± 80.37
Self-Thoracoabdominal Thrust 240.3 ± 71.7 NR (34%)
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Brito 2009 (n=28 DMD) Chest Compressions 171 ± 67 231 ± 81 <0.001(35%) 292 ± 86 <0.001 (71%)
Chatwin 2003 (n=22 NMD) Physiotherapy Assisted Mean 169 (95%CI 129- 188 (146-229) NR (11%)
209)
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Ishikawa 2008 (n= 61 DMD) Abdominal Thrust 204 ± 75 <0.0001 302 ± 78 <0.0001 (119%)
138 ± 70
(48%)
Kan 2018 (n=28 NMD) MAC by physiotherapists 185 ±59 NS (2%)
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181 ± 61
MAC by caregivers 181± 63 NS (0)
Kang 2005 (n=51 DMD) Abdominal Thrust 217.7 ± 65.9 250.6 ± 66.2 NS (15%)
Kang 2006 (n=32 DMD) Abdominal Thrust 212 ± 52 246 ± 49 <0.001 (16%) 286 ± 41 <0.001 (35%)
Kikuchi 2018 (n= 12 DMD) 59 ± 34.2 112.9 ± 31.8 <0.001 (91%)
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Kikuchi 2019 (n=24 NMD) Thoracoabdominal Thrust
Air stacking + MAC (n=15) Median (range) 75 (0, 120 (50, 215) NR
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No Air Stacking MAC (n=9)
Kim 2016 (n=40 NMD) Abdominal Thrust
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Mustfa 2003 (n= 47 ALS) Abdominal Thrust
215)
Median 120 (80, 230)
95.7 ± 40.5
105 (0, 245)
155.9 ± 53.1^
NR
NR (63%)
Bulbar ALS (n=21) 178±61 197±63 <0.01 (11%)

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Non-bulbar ALS (n=26) 217±84 244±83 <0.001 (13%)

Senent 2011 (n= 16 ALS) Abdominal thrust Median (range) 84 (35, 104 (80–140) NR 284 (146– NR
118) 353)
Sivasothy 2001 (n=12 NMD) Thoracoabdominal Thrust
Without scoliosis (n=4) Median (range) 104 (43- 185 (93-355) <0.01
188)
With scoliosis (n=8) Median (range) 288 (175- 193 (185-287) NS
367)
Toussaint 2009 (n=179 NMD)
Muscular Dystrophy (n=127)
Thoracic MAC 209 ± 71 <0.001 (28%)
163 ± 81
Abdominal-thoracic MAC 210 ± 70 <0.001 (29%)
SMA (n=26)
Thoracic MAC 225 ± 73 <0.001(14%)
198 ± 78
Abdominal-thoracic MAC 245 ± 73 <0.001 (24%)
Other NMDs (n=26)
Thoracic MAC 197 ± 78 NS ( -1%)
199 ± 84
Abdominal-thoracic MAC 197 ± 85 NS ( -1%)
Cough Peak Flow (CPF) measured in in L/min; NR: Not reported; NS: reported as “not significant” without p-value provided; MIC: maximum insufflation capacity; ^ MAC
following a MIC maneuver; †MAC + air stacking combined; ‡ Compared to unassisted CPF
Patient Comfort (follow up: Cross-sectional; assessed with: mean VAS scale comfort ratings (0=least comfortable; 10=most comfortable))

21,27 a
2 observational not not serious not serious serious none For 22 NMD patients (aged 10-56 yo) performing a series of ⨁◯◯◯ CRITICAL
studies ^^ serious cough techniques, mean VAS comfort scores (0=least VERY LOW
comfortable; 10= most comfortable) were higher with MAC
than unassisted cough: 5.9 (95%CI 5.2-6.7) vs 5.4 (95%CI
4.5-6.3), respectively.21
For 16 ALS patients performing a series of cough techniques

in random order, median (IQR) VAS comfort ratings
(0=least comfortable; 10= most comfortable) were higher
with MAC cough than unassisted cough: 8 (7-8) vs 5 (4-7),
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respectively (noted as not significant, no p-value
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provided).27
NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; DMD: Duchenne muscular dystrophy; MI-E: Mechanical insufflation exsufflation; MAC:
Manually assisted cough; IQR: Interquartile range; VAS: Visual analog scale; CI: Confidence interval; IQR: Interquartile range
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^ Evidence base includes 5 prospective and/or randomized controlled trials. All trials were of a moderate to high risk of bias. The initial certainty rating of high for trials was considered when
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assessing overall risk of bias in the evidence base.
^^ Evidence base includes a prospective trial. The trial was of a moderate risk of bias. The initial certainty rating of high for trials was considered when assessing overall risk of bias in the
evidence base.
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Explanations
a. All included studies relied on small samples, concerning for imprecision.
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e-Table 8g. Evidence Profile- Airway Clearance Techniques: Lung Volume Recruitment

№ of Study Risk of Indirectnes Imprecisio
Inconsistency consider
studies design bias s n
ations
Effect on Cough Peak Flow (follow up: Varied; assessed with: change in CPF following LVR)
a b
13 observation serious not serious not serious serious none ⨁◯◯◯ CRITICAL
18,19,37,
al studies ^ VERY LOW
38,43-51
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Studies by Brito et al., Bianchi et al., Cleary et al., Ishikawa et al., Toussaint, et al., and Del Amo Castrillo, et al. demonstrate a statistically significant immediate improvement in PCF
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with LVR. In contrast, Cleary et al. does not note significant improvement at 15 or 30 minutes post-LVR. Marques et al. and Bach et al. report significant improvement in unassisted and
assisted PCF after longer-term, regular LVR use. In contrast, neither McKim et al, Katz et al, or Kaminska et al. report significant differences in assisted and/or unassisted PCF after
regular LVR use:
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uCPF uCPF P value (% aCPF Mean aCPF P Value (% Duration of Study
Pre-LVRa Post-LVRb increase) Pre-LVRc Post-LVRd increase)
Bach 2007 (n=74 DMD) 145±112 164 ± 76 <0.001 (13) 250±84 289 ± 91 <0.001 (16) 7-169 months
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Bianchi 2014 (n=18 MD) 180 ± 80.37 271.4 ± 71.6 <0.001 (51) 243.3 ± 77.0 326.4 ± 79.5 <0.001 (34) Cross-sectional
Brito 2009 (n=28 DMD) 171±67 225±80 <0.001 (32) 231±81 292±86 <0.001 (26) Cross-sectional
Cleary 2013 (n=29 ALS)
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15 minutes post-LVR 251.35 ±118.55 305.00±140.70 <0.001 (21) - - - Cross-sectional
30 minutes post-LVR 251.35 ±118.55 295.38±122.99 <0.001 (18) - - -
Ishikawa 2008 (n=61 DMD) 138±70 236±68 <0.0001 (71) 204±75 302±78 <0.0001 (48) Cross-sectional
Kaminska 2015 (n=18 NMD) 373.1± 126.0 Mean change 12.5 0.62 - - - 3 months
(95%CI -14.4, 39.4)
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Katz 2016e (n=16 DMD) 90 (60-115) 90 (70-108) NR 200 (145-243) 205 (140-240) NR 1.7-16.1 years
Marques 2014 (n=18 NMD) 257.8±84.3 277.9±90.2 <0.0001 (8) 272.7±82.9 299.8±98.2 <0.0001 (10) 4-6 months
McKim 2012 (n=21 DMD) 144.8±106.9 128.3±80.1 0.235 (-11) 232.8±103.3 216.1±91.0 0.514 (-8) 3.75 years (median)
Toussaint 2016 (n=52 DMD)
Ventilator (n=27)
Reses bag (n=25)
132±55
125±55
u rn 199±NR
186±NR
<0.001 (51)
<0.001 (49)
-
-
-
-
-
-
Cross-sectional
Cough Peak Flow (CPF) in Liters/minute; a. baseline unassisted CPF before LVR initiation; b. CPF after use of LVR but unassisted by any other means (abdominal thrusts, etc.); c.
assisted CPF before LVR initiation; d. CPF with use of LVR and additional assistance (abdominal thrusts, etc.); e. Median/Interquartile Range
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For 46 NMD† patients (aged 7-85yo) using daily air stacking for 6 months to 24 years, the increase in lung volumes by air stacking to approach MIC combined with abdominal thrust
resulted in CPF of 4.3 ± 1.7 liters/sec by comparison with unassisted CPF of 2.5 ± 2.0 liters/sec (p < 0.001).44
For 20 adult (aged 22-71yo) NMD§ patients testing breath stacking during volumetric NIV and volumetric cough mode in random order, CPF was significantly higher using breath stacking
than at baseline (p=0.004; baseline median/IQR CPF 176/68 L/min median post-treatment CPF not provided).51
For 15 adult (aged 23-85yo) NMD¶ patients performing air stacking and 9 not performing air stacking, assisted CPF was higher than unassisted CPF using a manually assisted coughing
approach in the air stacking group and lower in the non-air stacking group: air stacking unassisted CPF median L/min 75 vs assisted 120; non-air stacking unassisted 120 vs assisted
105 (no p-values provided).43
Effect on Forced Vital Capacity (follow up: Varied; assessed with: change in FVC after LVR)
45-49 c b
al studies VERY LOW

ations
Studies by Cleary et al. and Marques et al. report small increases in FVC after immediate and longer-term use of LVR. In contrast, Kaminska et al. reports a significant
decrease in FVC with 3 months of LVR use:
Mean FVC Mean FVC P value Duration of

Pre-LVRa Post-LVRb (% increase) Study
Cleary 2013 (n=29 ALS)
15 minutes post-LVR 2.23±0.93 2.30±0.92 0.77 (3) Cross-sectional
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30 minutes post-LVR 2.23±0.93 2.25±0.95 0.94 (0.9)
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Kaminska 2015 (n= 17 NMD) NR Mean change -0.082 (95%CI -0.159, -0.005), p=0.04 3 months
Marques 2014 (n=18 NMD) 1.78±0.60 1.83±0.63 0.81(3) 4-6 months
Forced vital capacity (FVC) in Liters; a. baseline FVC before initiating LVR; b. FVC after using LVR; NR: Not reported
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For 21 adult (>18yo) DMD patients using LVR for a median of 3.75 years, decline of FVC percent-predicted was significantly slower after the initiation of LVR. Prior to LVR
the mean annual decline in FVC percent-predicted was 4.7 percent-predicted a year, and after initiation of LVR was 0.5 percent-predicted a year (89% improvement in
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rate of decline, p< 0.000).49
For 16 DMD patients (aged 8 to 33yo) using LVR for a median of 6.1 years, the mean rate of decline of FVC decreased from 4.5% predicted per year before LVR to 0.5%
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predicted per year after therapy: a difference of 4% per year 95%CI 3.2-4.8, p<0.001.47
Effect on Maximal Insufflation Capacity (follow up: Varied; assessed with: change in MIC after LVR)
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44,47- d b
50
al studies VERY LOW
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Studies by Katz et al. and Marques et al. identified small increases in MIC over the study period:
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Mean MIC ± SD Pre-LVRa Mean MIC ± SD Post-LVRb Study Duration
Katz 2016 (n=16 DMD) Median 1.3 (IQR 0.8-4.0) Median 1.6 (IQR 1.2-1.8) 1.7-16.1 years (6.1y median)
Marques 2014 (n=18 NMD) 2.046±0.634 2.057±0.673 4-6 months
Maximum insufflation capacity (MIC) in Liters; a. baseline FVC before initiating LVR; b. FVC after using LVR; IQR: Interquartile range
For 46 NMD† patients (aged 7-85yo) using daily air stacking for 6 months to 24 years, mean MIC and LIC increased 462 ± 260 and 365 ± 289 ml, respectively, despite a
decrease in mean VC of 209± 97 ml.44
For 21 adult (>18yo) DMD patients using LVR for a median of 3.75 years, from LVR initiation to the end of follow up (median 45 months) MIC increased by 1.8±11.9
percent- predicted (p=0.51).49
In the 24 adult (>18yo) DMD patients able to perform air stacking via a ventilator and in the 22 adult DMD patients able to perform air stacking via resuscitator bag both
techniques resulted in MIC values greater than spontaneous FVC in both groups (mean within-group change: +672 mL, P<0.001 for the home-ventilator group and +537
mL, P <0.001 for the resuscitator-bag group).50
Pulmonary Morbidity (follow up: 12 months; assessed with: rate of chest infection and subsequent hospitalization)
33 e f
1 randomized serious not serious not serious serious none For 21 ALS patients using NIV and breath-stacking via an LVR bag at least 2 times a day for ⨁⨁◯◯ CRITICAL
trial 2-3 cycles of 3-5 breaths per session (15/21 compliant with NIV & LVR), 7/21 patients LOW
experienced a total of 13 episodes of chest infection over the 12-month study period. The
mean duration of symptoms per chest infection was 6.9 days and 46% of chest infections
resulted in hospitalization.

ations
Survival (follow up: 12 months; assessed with: participants alive)
33 e f
1 randomized serious not serious not serious serious none For 21 ALS patients using NIV and breath-stacking via an LVR bag at least 2 times a day for ⨁⨁◯◯ CRITICAL
trial 2-3 cycles of 3-5 breaths per session (15/21 compliant with NIV & LVR), 13/21 (61.9%) were LOW
alive at 12 months.
Quality of Life (follow up: 3 to 12 months; assessed with: Sickness Impact Profile, Short Form 36 Physical & Mental Component scores)
33,46 b
2 observation not not serious not serious serious none For 19 adult NMD‡ patients using LVR 2 to 4 times a day for 3 months, mean quality of life CRITICAL
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⨁◯◯◯
g
al studies serious scores did not significantly change from baseline: SIP (baseline 19.8±10.4 vs 19.7±10.1,
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VERY LOW
p=0.58); PCS (baseline 30.2±6.9 vs 31.3±7.6, p=0.46); MCS (baseline 48.9±12.5 vs
50.0±11.9, p=0.57).46
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For 21 ALS patients using NIV and breath-stacking via an LVR bag at least 2 times a day for
2-3 cycles of 3-5 breaths per session (15/21 compliant with NIV & LVR), MCS and SAQLI sym
scores were maintained above 75% of baseline for a median of 329 and 280 days,
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respectively.33
Acceptability (follow up: 3 months; assessed with: patients rating LVR as acceptable on a 5-point scale from "highly acceptable" to "absolutely not acceptable")
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46 f
1 observation not not serious not serious serious none For 19 adult NMD‡ patients using LVR 2 to 4 times a day for 3 months, 10 subjects rated the ⨁◯◯◯ IMPORTANT
al study serious technique as “highly acceptable,” 7 rated it as “acceptable for the most part,” and 2 were “not VERY LOW
sure.”
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NMD: Neuromuscular disease; NIV: Noninvasive ventilation; ALS: Amyotrophic lateral sclerosis; DMD: Duchenne muscular dystrophy; LVR: Lung volume recruitment; PCF: Peak cough
flow; CPF: Cough peak flow; FVC: Forced vital capacity; MIC: Maximum insufflation capacity; LIC: Lung insufflation capacity
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^ Evidence base includes three cross-over trials and one randomized, parallel group trial. The initial certainty rating of high for these studies was considered when rating the overall risk of
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bias.
^^ Evidence base includes one randomized, parallel group trial comparing air stacking via ventilator to air stacking with resuscitator bag.
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† NMD cohort includes n=53 DMD; n=6 myotonic; n=55 other myopathies, n=31 SMA; n=76 ALS; n=25 post-polio; n= 36 "miscellaneous" neuromuscular conditions.
§ NMD cohort includes n=7 DMD, n=6 spinal amyotrophy, n=1 Ulrich syndrome, n=1 acid maltase deficiency, n=1 vacuolar myopathy, n=1 poliomyelitis, n=2 gamma-sarcoglycanopathy,
n=1 Becker muscular dystrophy.
¶ NMD cohort includes n= 10 DMD; n=6 ALS; n=8 MD1; n=1 limb-girdle muscular dystrophy; n=1 oculopharyngeal muscular dystrophy; n=1 polymositis; n=1 Parkinson disease; n=1
multiple system atrophy; n=1 perry syndrome; n=1 spinocerebellar degeneration; n=1 Lafora disease.
‡NMD cohort includes ALS n=8; post-polio syndrome n=10; and myotonic dystrophy n= 6.
Explanations
a. Four of the 12 studies are of a low risk of bias; The remaining studies are of moderate risk of bias due to minimal methods reporting, missing outcome data, and baseline imbalances.
b. All studies rely on small samples, concerning for imprecision.
c. Two studies are of a low risk of bias; Three studies are of a moderate risk of bias due to important baseline imbalances or missing outcome data.
d. Two studies are of a low risk of bias; three studies are of a moderate risk of bias for a minimal description of prognostic factors, and/or missing outcome data, and/or important baseline
differences.
e. Minimal compliance with assigned intervention may have impacted outcomes of interest.
f. Study relied on a small sample, concerning for imprecision.
g. One study, a randomized trial, is of a high risk of bias due to minimal compliance with the assigned LVR intervention. Not further downgraded here due to the downgrading of the
evidence base to low as categorized as observational. The second observational study is of a moderate risk of bias due to missing outcome data.
e-Table 8h. Evidence Profile- Airway Clearance Techniques: High Frequency Chest Wall Oscillations
Lung Function (follow up: 12 weeks; assessed with: Mean change from baseline; two-sample t test for significance for symptoms and pulmonary function tests)
1 52 randomized serious a not serious not serious serious b none For 19 ALS patients receiving HFCWO twice daily for 10-15 minutes (range 5 to 25 Hz) ⨁⨁◯◯ CRITICAL
trial and 16 ALS patients not receiving HFCWO, at 12 weeks mean FVC predicted declined in LOW
both groups: mean decline for HFCWO group (n=16) was 6.3% vs 5.1% in the untreated
group (p= 0.784). O2 saturation also declined in both groups: mean decrease for HFCWO
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group (n=18) was 0.28 vs 0.25 decrease in the untreated group (p=0.951). Mean PEF
increased 21.8 L/min in the HFCWO group but decreased 23.5 L/min in the untreated
group (p 0.179).
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Dyspnea (follow up: 12 weeks; assessed with: Mean change from baseline; ALSFRS-RS scoring)
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1 52 randomized serious a not serious not serious serious a none For 19 ALS patients receiving HFCWO twice daily for 10-15 minutes (range 5 to 25 Hz) ⨁⨁◯◯ CRITICAL
trial and 16 ALS patients not receiving HFCWO, at 12 weeks based on ALSFRS-RS scoring LOW
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36.8% of the HFCWO group and 37.5% of the untreated group showed worsening
dyspnea scores (p=0.968). HFCWO treated patients (n=19) experienced a mean
decrease in self-reported breathlessness score on a subjective scale (-1.28, indicating
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improvement) compared to untreated patients(n=16) who experienced a mean increase
in breathlessness score, indicating worsening (0.84; p=0.021).
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Symptom Improvement (follow up: 12 weeks; assessed with: modified Borg Visual Analog Scale)
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trial and 16 ALS patients not receiving HFCWO, at 12 weeks treated patients reported a LOW
mean increase in nocturnal symptoms scores on a modified VAS scale of 0.26 (indicating
improvement) while untreated patients reported a mean decrease of -0.55 (indicating
worsening), p=0.35). Based on ALSFRS-RS scores, 5.3% of the HFCWO group and
6.3% of the untreated group showed worsening respiratory insufficiency scores (p=0.90).
Adverse Events (follow up: 12 weeks; assessed with: Rate of adverse events)
trial and 16 ALS patients not receiving HFCWO, during the 12-week study period, 1/16 (6%) LOW
patient in the untreated group was hospitalized, one patient from each group had
emergency department visits, and 3/19 (16%) from the HFCWO group and 4/16 (25%)
from the no treatment group were placed on antibiotics for pulmonary-related
complications.
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Healthcare Use (follow up: study period 2007 to 2011; assessed with: Total medical claims costs per member per month)
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1 53 observational serious c not serious serious d not none Based on data from 426 individuals (mean age 29.9±22.0) with NMDs^, total medical ⨁◯◯◯ CRITICAL
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study serious claims costs (excluding pharmacy costs) per member per month in the 6-months VERY
preceding HFCWO use was $10,470.02. The total medical claims cost per member per LOW
month after HFCWO initiation was $8,521.49: $1,949 (18.6%) less, p=0.002.
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Hospitalizations (follow up: Study period 2007 to 2011; assessed with: Inpatient admissions)
1 53 observational serious c not serious serious d

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not
rn none Based on insurance claims data from 426 individuals (mean age 29.9±22.0) with NMDs^, ⨁◯◯◯ CRITICAL
study serious compared to the 6-month period before HFCWO treatment initiation, inpatient hospital VERY
admissions (reported per 1,000^^) were significantly lower following HFCWO: 1,401 vs LOW
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1,118; -20.2%, p=0.004).

NMD: Neuromuscular disease; ALS: Amyotrophic lateral sclerosis; HFCWO: High frequency chest wall oscillation; FVC: Forced vital capacity; PEF: Peak expiratory flow; ALSFR-
RS: ALS Functional Rating Scale respiratory subscale.
^Study sample included n=56 with multiple sclerosis; n= 171 with quadriplegia; and n=29 with diaphragm disorder; n=257 diagnosed with motor neuron diseases, spinal muscular atrophy, enzyme deficiency or polio.
^^ Data were reported as uses per 1,000, which is defined as uses per eligible member month multiplied by 12,000. This is intended to reflect the number of uses 1,000 members would experience over 12 months.
Explanations
a. The study is of a moderate risk of bias due to inadequate allocation concealment and incomplete outcome data reporting.
b. Small sample is concerning for precision.
c. This study based on retrospective insurance claims data is of a moderate risk of bias due to reliance on; unvalidated diagnostic codes and incomplete outcome reporting.
d. The patient population included conditions, such as multiple sclerosis, diaphragm disorder, and unspecified quadriplegia not aligned with the research question.
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dystrophy. American journal of physical medicine & rehabilitation. 2007;86(4):295-300.
20. Cesareo A, LoMauro A, Santi M, Biffi E, D'Angelo MG, Aliverti A. Acute Effects of Mechanical Insufflation-Exsufflation on the Breathing
Pattern in Stable Subjects With Duchenne Muscular Dystrophy. Respiratory care. 2018;63(8):955-965.
21. Chatwin M, Ross E, Hart N, Nickol AH, Polkey MI, Simonds AK. Cough augmentation with mechanical insufflation/exsufflation in patients
with neuromuscular weakness. The European respiratory journal. 2003;21(3):502-508.
22. Fauroux B, Guillemot N, Aubertin G, et al. Physiologic benefits of mechanical insufflation-exsufflation in children with neuromuscular
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diseases. Chest. 2008;133(1):161-168.
23. Kikuchi K, Satake M, Kimoto Y, et al. Approaches to Cough Peak Flow Measurement With Duchenne Muscular Dystrophy. Respiratory care.
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24. Kim SM, Choi WA, Won YH, Kang SW. A Comparison of Cough Assistance Techniques in Patients with Respiratory Muscle Weakness. Yonsei
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25. Mustfa N, Aiello M, Lyall RA, et al. Cough augmentation in amyotrophic lateral sclerosis. Neurology. 2003;61(9):1285-1287.
26. Sancho J, Servera E, Diaz J, Marin J. Efficacy of mechanical insufflation-exsufflation in medically stable patients with amyotrophic lateral
sclerosis. Chest. 2004;125(4):1400-1405.
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on Motor Neuron Diseases. 2011;12(1):26-32.

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subjects, patients with chronic obstructive pulmonary disease (COPD), and patients with respiratory muscle weakness. Thorax.
2001;56(6):438-444.
29. Winck JC, Goncalves MR, Lourenco C, Viana P, Almeida J, Bach JR. Effects of mechanical insufflation-exsufflation on respiratory parameters
for patients with chronic airway secretion encumbrance. Chest. 2004;126(3):774-780.
30. Lacombe M, Del Amo Castrillo L, Bore A, et al. Comparison of three cough-augmentation techniques in neuromuscular patients: mechanical
insufflation combined with manually assisted cough, insufflation-exsufflation alone and insufflation-exsufflation combined with manually
assisted cough. Respiration; international review of thoracic diseases. 2014;88(3):215-222.
31. Stehling F, Bouikidis A, Schara U, Mellies U. Mechanical insufflation/exsufflation improves vital capacity in neuromuscular disorders. Chronic
respiratory disease. 2015;12(1):31-35.
32. Miske LJ, Hickey EM, Kolb SM, Weiner DJ, Panitch HB. Use of the mechanical in-exsufflator in pediatric patients with neuromuscular disease
and impaired cough. Chest. 2004;125(4):1406-1412.
33. Rafiq MK, Bradburn M, Proctor AR, et al. A preliminary randomized trial of the mechanical insufflator-exsufflator versus breath-stacking
technique in patients with amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration. 2015;16(7-8):448-
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34. Tattersall R, Murray D, Heverin M, et al. Respiratory measurements and airway clearance device prescription over one year in amyotrophic
lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21(1-2):70-77.
35. Mahede T, Davis G, Rutkay A, et al. Use of mechanical airway clearance devices in the home by people with neuromuscular disorders:
effects on health service use and lifestyle benefits. Orphanet journal of rare diseases. 2015;10:54.
36. Vianello A, Corrado A, Arcaro G, Gallan F, Ori C, Minuzzo M. Mechanical insufflation-exsufflation improves outcomes for neuromuscular
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37. Brito MF, Moreira GA, Pradella-Hallinan M, Tufik S. Air stacking and chest compression increase peak cough flow in patients with Duchenne
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38. Ishikawa Y, Bach JR, Komaroff E, Miura T, Jackson-Parekh R. Cough augmentation in Duchenne muscular dystrophy. American journal of
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39. Kan AF, Butler JM, Hutchence M, Jones K, Widger J, Doumit MA. Teaching Manually Assisted Cough to Caregivers of Children With
Neuromuscular Disease. Respiratory care. 2018;63(12):1520-1527.
40. Kang SW, Kang YS, Moon JH, Yoo TW. Assisted cough and pulmonary compliance in patients with Duchenne muscular dystrophy. Yonsei
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43. Kikuchi K, Satake M, Terui Y, Kimoto Y, Iwasawa S, Furukawa Y. Cough peak flow with different mechanically assisted coughing approaches
under different conditions in patients with neuromuscular disorders. Phys Ther Res. 2019;22(2):58-65.
44. Bach JR, Mahajan K, Lipa B, Saporito L, Goncalves M, Komaroff E. Lung insufflation capacity in neuromuscular disease. American journal of
physical medicine & rehabilitation. 2008;87(9):720-725.
45. Cleary S, Misiaszek JE, Kalra S, Wheeler S, Johnston W. The effects of lung volume recruitment on coughing and pulmonary function in
patients with ALS. Amyotrophic lateral sclerosis & frontotemporal degeneration. 2013;14(2):111-115.
46. Kaminska M, Browman F, Trojan DA, Genge A, Benedetti A, Petrof BJ. Feasibility of Lung Volume Recruitment in Early Neuromuscular
Weakness: A Comparison Between Amyotrophic Lateral Sclerosis, Myotonic Dystrophy, and Postpolio Syndrome. PM & R : the journal of
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47. Katz SL, Barrowman N, Monsour A, Su S, Hoey L, McKim D. Long-Term Effects of Lung Volume Recruitment on Maximal Inspiratory Capacity
and Vital Capacity in Duchenne Muscular Dystrophy. Annals of the American Thoracic Society. 2016;13(2):217-222.
48. Marques TB, Neves Jde C, Portes LA, Salge JM, Zanoteli E, Reed UC. Air stacking: effects on pulmonary function in patients with spinal
muscular atrophy and in patients with congenital muscular dystrophy. Jornal brasileiro de pneumologia : publicacao oficial da Sociedade
Brasileira de Pneumologia e Tisilogia. 2014;40(5):528-534.
49. McKim DA, Katz SL, Barrowman N, Ni A, LeBlanc C. Lung volume recruitment slows pulmonary function decline in Duchenne muscular
dystrophy. Archives of physical medicine and rehabilitation. 2012;93(7):1117-1122.
50. Toussaint M, Pernet K, Steens M, Haan J, Sheers N. Cough Augmentation in Subjects With Duchenne Muscular Dystrophy: comparison of Air
Stacking via a Resuscitator Bag Versus Mechanical Ventilation. Respiratory care. 2016;61(1):61‐67.
51. Del Amo Castrillo L, Lacombe M, Bore A, et al. Comparison of two cough-augmentation techniques delivered by a home ventilator in
subjects with neuromuscular disease. Respiratory care. 2019;64(3):255‐261.
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52. Lange DJ, Lechtzin N, Davey C, et al. High-frequency chest wall oscillation in ALS: an exploratory randomized, controlled trial. Neurology.
2006;67(6):991-997.
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e-Appendix 4. Narrative Evidence Summaries
Use and Timing of Pulmonary Function Tests
The advantages of using PFTs in following NMD patients lie in their ability to be standardized easily using
guidelines and to be performed at low cost, even in low resource areas.1 PFTs have been shown to correlate
with functional status in spinal muscular atrophy2, upper extremity function in Duchenne muscular dystrophy
(DMD)3, respiratory failure, need for tracheostomy, and survival in ALS.4,5 However, no clinical research on
the frequency of pulmonary function testing is currently available. The frequency of testing has been advised in
general based on professional assessment of the rate of advancement of individual diseases.
In a retrospective cohort of 23 Becker muscular dystrophy patients, a 1% decline of SVC was noted at a median
interval of one year.6 Longitudinal studies in ALS suggest important changes in vital capacity occur rapidly. In
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a study of longitudinal decline of PFTs in patients with ALS, 65 subjects whom had at least 3 serial PFTs
between baseline and 10 months showed decline during the 10-month interval.7 In a phase 3 study of EH301 in
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ALS, there was a statistically significant decline of 2.6% in FVC% in the 10 subjects in the placebo arm over 4
months.8 In a phase 3 randomized clinical trial of tirasemtiv in ALS patients there was a 14.4% decline in SVC
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in the placebo group and 13.4% decline in the treatment group over 6 months suggesting that a 6 month interval
may be a useful clinical endpoint in this group of patients.9 In 893 placebo treated patients with ALS, the
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average decline of SVC from baseline through 1.5 years of follow-up was -2.7% per month and improved
outcomes were noted when the rate of decline was slower than 1.5% points in the first 6 months.5 Similarly, in a
phase 3 study of topiramate with 296 patients with ALS, subjects in the placebo arm had a -2.46% decline in
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FVC% when measured at 3 month intervals for 12 months.10

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Observational studies have identified several PFT parameters as diagnostic of respiratory failure progression
and predictors of survival, predominantly in patients with amyotrophic lateral sclerosis (ALS).4,5 PFTs have also
been shown to correlate with functional status in other NMDs such as spinal muscular atrophy2 and with other
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markers of disease progression such as upper extremity function in DMD.3

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Certain PFT parameters have been associated with respiratory weakness (SVC, FVC and FEV1)11-13,
hypoventilation (FVC, FEV1 and MVV)14-17, and respiratory failure progression (rate of SVC and FVC decline)
5,11,18
in NMD patients. (e-Table 1b). A study of 232 ALS patients with pulmonary function testing at baseline
and at 6-month follow-up showed that a decrease in SVC and FVC was predictive of functional delays
measured by ALSFRS score. In this study subjects had monthly decays of 0.89 ± 0.91 for ALSFRS, 2.18 ±
2.6% for SVC and 2.23 ± 2.69% for FVC.11
Survival
The studies of survival were limited by the fact that the studies explored the predictive value of pulmonary
function testing to assess survival while our research question focused on the utility of PFT testing on disease
progression.
SVC decline
Two observational studies reviewed the effect of slow vital capacity (SVC) in predicting survival. In one study
analyzing data from the placebo treated group of 2 large clinical trials and a trial database of 893 ALS patients
with a mean SVC of 90.5% , the rate of decline of SVC was -2.7 to -3.1% per month.5 When the rate of decline
in the first 6 months was slower by 1.5%, it was associated with a 22% reduction in risk of respiratory
insufficiency or death after 6 months and a 23% risk reduction for death at any point after 6 months. In a second
observational study of 469 patients with definite/probable ALS, FVC and SVC were strongly correlated (r2 =
0.981) and a 1% decrease in FVC or SVC was associated with a 2% increased probability of dying.18 A similar
correlation between FVC and SVC was reported in another study by the same group.11
Pulmonary function decline

In an observational study of 256 patients with ALS, SVC, maximum inspiratory end-expiratory pressure’s (MIP,
MEP), sniff nasal inspiratory pressure (SNIP), and peak cough flow (PCF) were measured at baseline and every
4 months, risk of death was significantly associated with decline in pulmonary function and respective of the PFT
parameter.19 When VC, MIP/SNIP, and MEP (% of predicted) decreased by 10%, or PCF decreased by 50 L/min,
the risk of death was multiplied by 1.31 (95% CI 1.21–1.41), 1.48 (1.32–1.66), 1.54 (1.32–1.79), and 1.32 (1.19–
1.75), respectively.
Respiratory impairment and survival

In other neuromuscular diseases such as Type 2C and 2D limb girdle muscular dystrophies (LGMD), PFT
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parameters were associated with respiratory events such as acute respiratory failure and the need for home
mechanical ventilation (HMV) but were not associated with mortality.20 In this small study of 34 patients with
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LGMD, median age was 30 years and over a period of 6 years of follow-up 38% of the subjects had respiratory
events, 14% cardiac events and 20% died.
Respiratory Function Tests to Predict Mortality at 2 Years

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In a study of 80 patients with ALS followed for 2 years, rate of decline of seated FVC and supine FVC had a
strong correlation with survival as did base line seated and supine FVC values.4 Normal values of these tests at
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baseline was associated with a two-year survival in majority of patients.
FVC decline
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In an observational study of 469 patients with definite/probable ALS, FVC and SVC were strongly correlated (r2
= 0.981) and a 1% decrease in FVC or SVC was associated with a 2% increased probability of dying.18 In a study
of 80 patients with ALS followed for 2 years, rate of decline of seated FVC and supine FVC had a strong
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correlation with survival as did base line seated and supine FVC values.4 In this study change in FVC was not
associated with survival as it had a significant, negative correlation with supine FVC . Most of the subjects with
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diaphragmatic weakness shown by abnormal supine FVC values had a change in FVC less than 10%. In a small
study of 34 patients from Japan while differences in decline in FVC by >= 14% per year versus those with < 14%
per year was associated with survival on univariate analysis, when compared to all the factors significant in
univariate analysis including age, duration of onset, cough flow decline by more or less than 25%, only duration
of onset of less or more than 2 years and cough flow decline of more or less than 25% were statistically
significant.21
In 73 ALS patients followed for 6 months, median monthly decline in FVC was 1.71% (range -0.16 to -3.46%)
and median decline in peak cough expiratory flow 6.06 (-7.14 to -14.9) L/m.22 In this study monthly decline in
FVC% (HR 0.89 95%CI 0.79-1.00, p=0.05) and supine FVC% (HR 0.89 95%CI 0.81-0.99, p=0.03) were
significantly associated with survival.
In 97 ALS patients from the placebo arm of a 12-month topiramate study assessed at 3-month intervals, FVC%
and ALS Functional Rating Scale (ALSFRS) declined in a linear fashion during the 1-year study period, and their
rate of decline predicted 1-year ALS survival in univariate and multivariate models.23 In this study arm in grip
strength measurements were not associated with survival.
In 139 patients with ALS followed for 50 months, the median rate of decline of FVC was 97 ml (IQR 52-170 ml)
or 2.4% (IQR 1.4-4.4%) of predicted every 30 days.24 Patients with the rate of decline of less than 97 ml or 2.4%
per month had a higher rate of survival (mean survival years 2.0±1.4 vs 1.0±0.8, p<0.05) or time from BiPAP
initiation (1.9±1.5 vs 1.0±0.9 yrs., p<0.05) compared to those with a faster decline.
In 36 ALS patients 11 with FVC % predicted of 86.2 +/- 25.8 survived for more than 5 years while 25 with FVC
% predicted of 54.7 +/- 24.7 for less than 5 years (p 0.004).25
In Duchenne muscular dystrophy (DMD), 58 patients with the median age of 10.5 years were followed for 7.5
years, the median rate of decline in FVC was -8% (range 2-39%) predicted /year.26 In this study when comparing
individuals dying before and after the median time of survival (20.5 yrs.), only the change in percentage of
predicted FVC per year (p < 0.0003) and maximal FVC were predictive of survival (p<0.0005).
Cough Peak Flow

In a small study of 34 patients from Japan while differences in decline in FVC by >= 14% per year versus those
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with < 14% per year was associated with survival on univariate analysis, when compared to all the factors
significant in univariate analysis including age, duration of onset, cough flow decline by more or less than 25%,
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only duration of onset of less or more than 2 years and cough flow decline of more or less than 25% were
statistically significant.21 In this study CPF decline rate significantly correlated with the decline in ALSFRS-R
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bulbar score (P < 0.0001) and FVC (P < 0.0001).
Respiratory function and events

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Respiratory Parameters to Predict Hypoventilation
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In 199 patients with ALS, 24 with hypoventilation defined by hypercapnia (pCO2 > 45 mmHg), all patients had
forced vital capacity (FVC); maximal static inspiratory and expiratory pressures (PImax and PEmax); mouth
inspiratory pressure at 100 ms (P0.1); amplitude of motor responses from phrenic nerve stimulation recorded 16
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In a logistic regression analysis including these variables only FVC and phrenic nerve amplitude in bulbar patients
and phrenic nerve amplitude) for spinal-onset patients were associated with hypoventilation.
In 36 patients with ALS followed for 26 months, PFTs were recorded monthly for the first 3 months and then
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every 1-3 months.14 Chronic hypoventilation was defined as FVC less than 50% or paCO2 more than 45 mm Hg
or oxygen saturation less than 80 percent for 5 consecutive minutes. Median FVC was 87% (IQR 72-104%) and
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declined by 10% up to 6 months (IQR 2-49%). This study showed no correlation between FVC percent at baseline
and FVC slope during the first 3 months and presence of hypoventilation.
In 81 ALS patients respiratory muscle strength was evaluated to predict hypoventilation defined as pCO2 more
than or equal to 45 mmHg.15 Vital capacity, MIP, MEP, maximum sniff esophageal pressure, trans diaphragmatic
sniff pressure and nasal sniffs pressure and cough gastric pressure were measured. No parameter tested had
significant predictive power for hypercapnia in 16 patients with significant bulbar weakness. In 65 patients
without significant bulbar involvement sniff trust diaphragmatic pressure had the greatest predictive power to
predict hypercapnia (OR 57).
In 50 patients with myotonic muscular dystrophy type I (DM1) FVC, FEV1, and MVV demonstrated a significant
negative correlation with hypercapnia, whereas MIP and MEP did not.17 The study showed negative correlation
of FVC (Pearson coefficient -0.298, p=0.04), % predicted FVC (-0.362, p=0.01),FEV1(-0.301, p=0.03), %
predicted FEV1(-0.345,p=0.01), MVV (-0.291, p=0.04), and % predicted MVV (-0.353, p=0.01) with
hypercapnia was shown via bivariate correlation for each parameter, and ratios of their measured values to
predicted values.
FVC to Predict Respiratory Weakness.
A study of 232 patients with ALS with pulmonary function testing at baseline and 6 months later showed that
FVC in SVC correlated at study entry (r2 = 0.98, p < 0.01) and decreases in SVC and FVC were predictive of
functional delays measured by ALSFRS score.11 In this study subjects had monthly decays of 0.89 ± 0.91 for
ALSFRS, 2.18 ± 2.6% for SVC and 2.23 ± 2.69% for FVC.
In a study comparing between supine and erect FVC in 38 patients with ALS and 15 controls, the average decrease
in FVC from erect to supine was 15.6% (range 0-45%) in patients with ALS and 6.2 percent in controls.13 the
greatest difference between supine and erect a percentage was noted in patients with dyspnea(19.6% p<0.074),
orthopnea (21.4%, p < 0.018) and fatigue (26.3% p < 0.001).
Changes in supine FEV1 to predict respiratory weakness

Postural changes in pulmonary function were studied in 58 patients with myotonic dystrophy type I and showed
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that both FEV1 and FVC were significantly decreased in the supine position compared to sitting position by 64.1
± 18.3% versus73.0 ± 20.0% and 67.3 ± 22.3% versus 73.5 ± 19.7% of predicted values, respectively (p <
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0.0001).12 In this study a decrease in FEV1 by >20% in the supine position was predictive of ventilatory
restriction defined as vital capacity and total lung capacity less than 80% , hypoxemia defined as PaO2 <
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80mmHg, and hypercapnia defined as paCO2 > 45 mmHg.
SVC and respiratory symptom progression

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In 893 ALS patients with a mean SVC of 90.5% , the rate of decline of SVC was -2.7 to -3.1% per month.5 When
the rate of decline in the first 6 months was slower by 1.5% per month in the first six months , risk reductions for
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events after 6 months were 19% for decline in the ALSFRS-R respiratory subdomain or death after 6 months,
22% for first onset of respiratory insufficiency or death after 6 months, 23% for first occurrence of tracheostomy
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or death after 6 months, and 23% for death at any time after 6 months (P < .001 for all).
A study of 232 patients with ALS with pulmonary function testing at baseline and 6 months later showed that
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decreases in SVC and FVC were predictive of functional delays measured by ALSFRS score.11 In this study
subjects had monthly decays of 0.89 ± 0.91 for ALSFRS, 2.18 ± 2.6% for SVC and 2.23 ± 2.69% for FVC.
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In 453 placebo treated ALS patients from the EMPOWER trial, the median SVC was 88% at baseline.27 In this
study, patients with SVC values below the median (n = 154) had significantly worsening orthopnea and
respiratory insufficiency and a trend towards worsening dyspnea measured by the revised ALS functional rating
scale, at week 48 than those at or above the median (n = 205). Orthopnea was noted in 39% (vs. 25.9% p 0.0081)
and respiratory insufficiency in 36.4% (vs. 17.1% p < 0.0001) and dyspnea in 35.7% (vs. 27.3%, ns) in those with
SVC values below the median. At week 48, subjects with baseline percent predicted SVC values below median
(<88% predicted) were also significantly more likely to have a change in ALSFRS-R respiratory subdomain score
from 12 to below 12 (40.9% vs. 30.2%; p <0.0358) and a change in ALSFRS-R respiratory subdomain score from
10 or greater to below 10 (41.6% vs. 24.4%; p<0.0005) compared with subjects with baseline percent predicted
SVC values at or above the median.
Respiratory parameters to predict ventilation

In an observational study of 124 neuromuscular disease patients excluding ALS (majority myotonic dystrophy
type 1 n=48, spinal muscular atrophy n= 13 and Duchenne or Becker muscular dystrophy n= 9) who had
transcutaneous CO2 recordings and were followed for a median period of 2.5 years (IQR 1.6-4.1), mechanical
ventilation was initiated in 51 patients and 4 patients died.28 Nocturnal peak transcutaneous CO2 >= 49 mmHg
was the best predictor of initiation of home mechanical ventilation with the hazard ratio of 2.6 (95% CI 1.4-4.6)
in a multivariate analysis adjusting for lung function parameters.
In other neuromuscular diseases such as Type 2C and 2D limb girdle muscular dystrophies (LGMD), PFT
parameters were associated with respiratory events such as acute respiratory failure and the need for home
mechanical ventilation OR 6.80 (95% CI 1.4–32.4, p 0.025) but were not associated with mortality.20
Sleep disordered breathing
Predictive value of respiratory parameters for sleep hypoventilation

In 19 patients with Duchenne muscular dystrophy, (age >= 12 yrs.), FEV1 <40% was a sensitive (91%) but not
specific (50%) indicator of sleep hypoventilation (TST < 90% of >= 2%); a PaCO2 of >= 45 mm Hg was an
equally sensitive (91%) but more specific (75%) indicator while a base excess of >= 4 mmol/L was highly specific
(100%) but less sensitive (55%).29 Introduction of noninvasive ventilation during sleep (n=8) was associated with
a significant reduction in awake pO2 despite a further decline in FEV1.
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Predicted value of SNIP for sleep disordered breathing
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In an observational study of 31 ALS patients, maximal sniff-inspiratory pressure (SNIP) was compared to FVC
as a marker of sleep-disordered breathing.30 21 patients with SNIP < 60 cm H2O showed a linear correlation
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between SNIP and reduce nocturnal oxygen saturation (n = 21; r = 0.449; p = 0.04). There was a negative
correlation between SNIP and time spent with oxygen saturation < 90% (r =– 0.584; p = 0.0054) and
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oxyhemoglobin desaturation index (events/hour) (r= –0.458; p =0.0368). The authors concluded that SNIP < 60
cm H2O might be considered an early predictor of sleep-disordered breathing in ALS.
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Regarding prediction of survival, an observational study measured SVC, maximum inspiratory end-expiratory
pressures (MIP, MEP), sniff nasal inspiratory pressure (SNIP), and peak cough flow (PCF) at baseline and
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every 4 months in 256 ALS patients.19 The risk of death was significantly associated with a decline in
pulmonary function irrespective of the parameter. When VC, MIP/SNIP, and MEP (% of predicted) decreased
by 10%, or PCF decreased by 50 L/min, the risk of death increased 1.31 (95% CI 1.21–1.41), 1.48 (1.32–1.66),
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1.54 (1.32–1.79), and 1.32 (1.19–1.75) times respectively. In a study of 80 ALS patients followed-up for 2
years, the rate of decline of seated and supine FVC had a strong correlation with survival as did baseline seated
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and supine FVC values.4 Furthermore, normal baseline values of these tests were associated with a two-year
survival of the majority of patients. In a study of 34 ALS patients from Japan, cough flow decline of ≥ 25% was
also associated with shorter survival. 21
Testing for Sleep Related Breathing Disorders
In a study of 65 patients with Pompe’s disease, 17 had sleep studies available, SDB and nocturnal
hypoventilation were present in 65%.31 Similarly, a study of 51 patients with facioscapulohumeral muscular
dystrophy (FSHMD) investigated the prevalence of SDB and found 20 (39%) of the patients had positive PSG
findings.32 Patients presenting PSG evidence for SDB were rarely symptomatic and otherwise would not have
been detected. An Italian study of a random sample of 40 patients with Myotonic dystrophy type 1 reported that
22 (55%) patients had OSA, despite the absence of clinical symptoms. Apnea hypopnea index and oxygen
desaturation were also strongly correlated.33
Additionally, an observational study of 76 subjects with ALS reported that hypoxemia (defined as oxygen
saturation of < 90% for >10% of the recording) detected with ONO predicted respiratory failure and overall risk
of hospitalization and survival.34 As this study was performed in ALS, it may not be relevant to other NMDs,
particularly in pediatric NMD’s where CO2 measurements have been required to better assess respiratory
impairment.35
Use of Noninvasive Ventilation
Fourteen articles, including one RCT, reported survival as an outcome for ALS patients on NIV.36-49 In a cohort
of 92 ALS patients, 41 patients were randomly assigned to NIV (n=22) or standard care (n=19) when they
developed either orthopnea with MIP <60% of that predicted or symptomatic hypercapnia. The median survival
benefit was 205 days (p=0.006).
Eleven observational studies with predominantly DMD, ALS and mixed NMD patients, studied the impact of
NIV on respiratory function and reported mixed results regarding NIV initiation reducing decline in respiratory
function.36,38-40,44,46,47,50-53
Seven observational studies in DMD, ALS, Pompe’s and Myotonic Dystrophy patients evaluated the impact of
NIV on sleep quality and respiration and all but one showed significant benefit.36,40,51,53-56 Two observational
studies40,51 showed benefits in total learning score or mental fatigue after NIV initiation in ALS patients.
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Finally, 7 studies reported mixed results on improvements in quality of life, depression, anxiety, or caregiver
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quality of life after NIV initiation in ALS, DMD and mixed NMD populations.36,40,49,57-60
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Respiratory Parameters for Initiation of NIV
In a study of monthly pulmonary function in ALS patients followed for up to 1 year, 65% met the MIP criterion
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and 8% met the FVC criterion for NIV initiation (p<0.0001). Patients reached the MIP criterion 4 to 6.5 months
earlier than the FVC criterion.61 In 110 ALS/PMA patients, PCF was the strongest predictor of NIV initiation
and sniff nasal inspiratory pressure (SNIP) showed the greatest decline prior to NIV.62
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In DMD, the ratios of respiratory rate to tidal volume (RR/TV) and to vital capacity (RR/VC), and the vital
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capacity (VC) demonstrated good diagnostic accuracy for the introduction of part-time or continuous
ventilation.63 In 21 ALS patients treated with NIV for 1-month, the duration of nocturnal hypercapnia predicted
good compliance (mean use of >4 hours per day) with subsequent NIV treatment.64
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In a retrospective study of 131 ALS patients, 65 (50%) initiated NIV of which 8/65 had NIV due to nocturnal
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hypoventilation. All 8 patients were alive 1 year later. In 57/65 patients, NIV was initiated due to low FVC or
dyspnea, 9/57 patients died within 1 year after NIV initiation. These groups did not differ in terms of age,
disease duration, or ALSFRS-R. From the 131, 29 (22%) did not report dyspnea and had FVC>75%, yet 14/29
(48%) had nocturnal hypoventilation that would justify NIV.65
Noninvasive Ventilation Strategies

In a randomized trial during 3 consecutive nights, neither pressure targeted (pressure support or pressure-
controlled ventilation) nor volume targeted NIV mode (volume guarantee pressure support) was superior in
terms of efficacy of gas exchange or patient-ventilator interaction in 28 NMD patients with chronic
hypoventilation.66 Tracheostomy-free survival was also shown to be similar in stable ALS patients ventilated
using either volume cycled NIV (62 patients) or pressure cycled NIV (82 patients) in a 4-year follow-up
observational study.67 Regarding mode settings, in a randomized cross-over trial of 13 ALS patients using NIV
in S mode and ST mode in random order on 4 consecutive nights, ST mode achieved better gas exchange,
patient-ventilator synchrony (ineffective efforts) and respiratory events (obstructive and central).68 Although a
set back-up rate may address decreased triggering, setting a sufficient fixed inspiratory time may address the
issue of decreased spontaneous cycling as reported in an observational study of 215 ALS patients using NIV in
either PS or VAPS mode.69 In two randomly determined nights using NIV with and without 4cmH20 of PEEP
in patients with ALS, the administration of PEEP increased unintentional leaks, patient–ventilator dyssynchrony
and sleep fragmentation and increased nocturnal heart rate variability.70 The effect on gas exchange was equal.
Though statistically significant, differences were small and clinical significance is uncertain.
Mouthpiece Ventilation
For 31 ALS patients consistently using daytime mouthpiece NIV and nighttime mask NIV for at least 1-month,
median tracheostomy-free survival from MPV initiation was 286 days (range 41 to 1,769 days) and was longer
in those with peak cough flow with lung volume recruitment of more than 180 L/m (637 vs. 240 days). The
tracheostomy-free survival from initiation of NIV was 648 days (range 176 –2,188),exceeding that from studies
that did not include MPV.71 In this cohort, FVC fell overtime, maximum insufflation capacity remained
consistent, maximum insufflation capacity-VC difference increased, PCF and PCF with LVR decreased
(quantitative data on the change in parameters not reported).71 Similarly, for 12 DMD patients using daytime
mouthpiece NIV and nighttime mask NIV for up to 12 years, mean survival was 5.7 years.72 In this cohort FVC,
MIP and MEP fell overtime.
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Based on interviews of 10 adult men with muscular dystrophy using MPV during the day and nasal BPAP at
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night, MPV, but not nasal BPAP improved cough effectiveness. Greater challenges coordinating breathing and
swallowing were described with use of nasal BPAP when eating (in 7/10 men who described eating and
drinking while using nasal BPAP).73
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Based on interviews of 12 adults with various NMD using MPV during daytime hours for 1 to 15 years and
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nasal BPAP during nighttime hours for 2 to 20 years, MPV was described as aiding in loudness, utterance
duration, clarity, and endurance of speech. However, it was also described as interfering with the flow of speech
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due to the need for pauses between breaths, mouthpiece placement issues, speech breathing coordination
difficulty, and speech-related technology interference (speech software attempting to identify a word for the
sounds made by the ventilator).74
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Invasive Home Mechanical Ventilation

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Several observational studies suggest invasive home MV via tracheostomy is associated with increased survival
in patients who choose this route compared to either no or palliative care. In a 10-year prospective study, 38
patients with ALS choosing invasive home MV via tracheostomy had a mean survival of 10.4 months compared
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to 0.83 months in 38 patients refusing this option (p<0.0001).75 Similarly, 87 ALS patients receiving invasive
home MV had a median survival of 47 months compared to 31 months in 192 ALS patients who chose no
respiratory support or NIV (p=0.008).76 Forty-four percent of the comparison group used NIV >4 hrs/day at the
time of death, however, data is not available on this subset to directly compare to the tracheostomy group.
Overall, this evidence suggests implementation of invasive home MV in ALS is associated with prolonged
survival with the obvious confounding effect of providing true life support with MV.
Observational studies comparing invasive home MV to NIV to no or palliative ventilatory support in ALS
suggest that both modalities are associated with prolonged survival with invasive home MV associated with a
longer survival. ALS patients receiving invasive home MV, NIV, and palliative support had median survival
periods of 74 months, 48 months, and 32 months from disease onset, respectively (p<0.001 for TIV vs. NIV and
NIV vs palliative).77 A single center cohort study in ALS reported improved 1 and 5 year survival with invasive
home MV either initially (n=21; 80% and 13%) or following NIV (n=69; 83% and 25%) versus NIV only
(n=173; 73% and 6%) or palliative care (n=146; 68% and 5%).37 A direct comparison study reports median
survivals of 19 months (95%CI 7-43) vs 15 months (95%CI 10-18) in invasive home MV and NIV groups
respectively (no p value reported).78 Invasive home MV is also associated with better gas exchange and sleep
quality compared to NIV.76,79 However, another study suggests ALS patients using invasive home MV (n=16)
and NIV (n=16) have similar mean survival rates at 1088 and 1132 days, respectively (p=<0.3).79 Patients on
invasive home MV had significantly lower life satisfaction scores than NIV patients (30.7±1.4 versus 42.9±5.1,
p=0.001).79
Tracheostomy placement is relatively safe with a pooled death rate related to the procedure of 2 deaths in 85
patients .37,75 A small study of quality of life in invasive home MV patients suggests that while many aspects of
patients’ lives worsen with increasing distress, most patients maintain the ability to have some satisfaction and
pleasure in their daily lives.80 Given the overall impact of ALS on patient lives, it is important to note that some
satisfaction can be maintained with prolonged ventilation.
Additionally, although outside the scope of this PICO question, it is important to note that several observational
studies have reported long term survival with 24 hours a day NIV in patients with NMD using a combination of
NIV via nasal/facial interface at night and mouthpiece ventilation during the daytime and as such, prolonged
hours of NIV use alone, should not be the reason to consider home MV. 72,81 The panel felt that this decision
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should be individualized based on patient satisfaction and goals. As an additional point, while extubation
protocols are outside the scope of this guideline, NMD specific extubation protocols should be considered for
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intubated patients being transitioned off the ventilator.82
Airway Clearance Techniques
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Anticholinergics re
In a study of 10 ALS patients with sialorrhea randomized to scopolamine or placebo patch for 1 week then
crossed over after a 1-week washout period, sialorrhea and sialorrhea-related difficulty were assessed and saliva
volume was derived from a cotton roll weight after oral placement for 5 min.83 There were no differences
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between treatment groups for mean change in sialorrhea severity sialorrhea-related difficulty, or cotton roll
weight. 83
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In another multicenter retrospective cohort study, salivary outcomes were available in 72 ALS patients with
excessive saliva who were prescribed an anticholinergic (hyoscine, amitriptyline, atropine, propantheline, or
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glycopyrrolate).84 Improved symptoms were recorded for 44 (61%). Of the 28/72 (39%) patients without
symptom improvement following an initial anticholinergic, 22 tried another anticholinergic and 4 of 21 with a
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recorded outcome (19%) experienced improvement. Eleven patients were given a combination of two
anticholinergics after a first anticholinergic was reported to incompletely control symptoms, with 5 (45%)
reporting symptomatic improvement with the combination. In 99 patients using an anticholinergic for
sialorrhea, 50 (51%) reported adverse events and 23 (23%) discontinued treatment due to adverse events.84
Botulinum Toxin
Seven of 8 studies demonstrated subjective improvements in salivary frequency or severity using a visual
analog scale (VAS).85-92 All but one study evaluated ALS patients while one enrolled subjects with a variety of
NMDs.91 The single RCT demonstrated reduced drooling at 2 and 4 weeks but not at 8 and 12 weeks, the
insignificant results, possibly being due to beta error.88 Only 5 studies reported adverse events 4 of which
indicated no adverse events; dysphagia, xerostomia, swallowing changes, aspiration or change in vital
capacity.85,88-91 One study (n = 16) reported adverse events, each involving small numbers: viscous saliva (n =
5), local pain (n = 4), increased difficulty of chewing (n = 3), respiratory infection (n = 2), facial paresis (n = 1)
and burning tingling of the eyes (n = 1), which aside from one more severe case of xerostomia were felt to be
fairly mild to moderate in severity.85
Radiation Therapy
Based on data from 50 ALS patients undergoing RT of the parotid and submandibular glands (30 receiving 10
Gy in 2 fractions and 20 receiving 20 Gy in 4 fractions), all patients showed improvement per the Sialorrhea
Scoring Scale (SSS): 46 (92%) had a complete response (SSS scores 1-3) and 4 (85%) had a partial response
(SSS 4-5). A significant lasting salivary reduction was observed 6 months after RT completion: 71% complete
response and 26% partial response (significant SSS reduction vs baseline, p<0.00001). At baseline, all 50
patients had severe hypersalivation (mean SSS, 8; range 6-9), In comparison with baseline values, RT induced
an SSS decreased of 76%, 62%, 67%, and 65% at the end of RT and at 1 month, 3 months, and 6 months after
the end of RT, respectively (p<0.0000001).93
Based on data from 18 ALS patients undergoing RT of parotid and submandibular glands at 7.0 Gy (n=13) or
7.5 Gy in one fraction, mean parotid salivary secretion rate was 1.44 ± 1.31 ml/5 min 1-hour before irradiation
and diminished from pre-RT at both 1 day ( 43% decrease) and 2 weeks ( 57% decrease) after irradiation (no p-
values provided).94
Based on data from 50 ALS patients receiving RT of the parotid and submandibular glands: 30 at 10 Gy in 2
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fractions and 20 at 20 Gy in 4 fractions- followed for up to 6 months, there was no grade 3-4 toxicity or
treatment-related deaths. Grade 1-2 toxicities (mild pain, xerostomia, saliva thickening, swallowing difficulty,
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taste modification) were observed in 17 patients (34%) during RT, then 4 (8%), 6 (15%), and 2 (5%) patients at
1-, 3-, and 6-months post-RT, respectively.1 In another study, 10 ALS patients received RT of the parotid glands
with a single fraction of 7.0 Gy delivered using 15-MeV electron beam, immediately following RT 7/10 (70%)
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experienced adverse events (viscous saliva, pain, loss of voice, swallowing difficulty, little saliva, dry mouth)
and at 4 weeks post-RT 2/10 (20%) reported adverse events (dry mouth).92
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Glossopharyngeal Breathing (GPB)
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Two observational studies evaluated the efficacy of GPB in adults with NMD.95,96 Bianchi et al. demonstrated
that PCF was significantly improved by 46% with GPB as compared to the unassisted PCF (p< 0.001). Peak
cough flow from GPB with and without thoracoabdominal thrust was not significantly different (p=0.07).96 In a
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study of 21 patients with DMD, mean maximum single-breath capacity exceeded mean VC (p<0.001) in those
able to do GPB. In a subset of the 21 individuals with DMD, 15 patients used MPV during the day; the duration
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of daytime ventilation needed was significantly lower when using GPB versus when not using it (3.4± 1.7 per
minute vs 5.3 ± 1.7 ventilations per minute).95
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Mechanical Insufflation-Exsufflation
Seventeen studies, including 4 prospective studies or RCTs, evaluated the effect of MI-E on PCF, VC, dyspnea
relief, reduction of pulmonary morbidity, hospitalization, adverse events and patient comfort. Ten observational
studies assessed change in PCF before and following MI-E.97-106 Most studies reporting change in PCF suggest
a statistically significant immediate improvement with the use of MI-E in NMD (e-Table 8e). An additional
study comparing unassisted PCF to PCF following MI-E alone or MI-E with manually assisted cough also
reports significant improvement following MI-E and MI-E with assisted cough.107
A single study assessed change in mean VC (liters) from 2 years prior to MI-E introduction to 1-year post-MI-
E.108 This showed that for 21 mixed NMD patients already with severe reductions in VC in the two years
before the introduction of MI-E, mean VC declined >20%. In the first year after initiation of MI-E, mean VC
significantly increased (p= 0.002) an average relative increase of 28%. After the second year of regular use, this
effect remained stable (n=6).
One cross-sectional study of 20 NMD patients assessed dyspnea changes and showed significant improvement
from baseline after application of MI-E at 40 cmH20 for 3 cycles in most NMD participants, but not for the
ALS cohort.106
Three studies assessed effects of MI-E on pulmonary morbidity.109-111 For 62 children with NMD (mean age at
MI-E initiation 11.3 yrs.) initiating and using MI-E for an average of 13.4 months, caregivers reported 5
children experienced a reduction in the frequency of pneumonia and 4 children experienced an improvement in
chronic atelectasis.109 For 19 ALS patients using NIV plus MI-E for at least 2 sessions per day and followed for
12.3 person-years, 6/19 (31.6%) experienced 19 episodes of chest infection with a mean duration of symptoms
per infection of 3.9 days.110 When comparing 48 ALS patients prescribed MI-E and/or breath stacking 3 times
per day and 60 patients not prescribed a device over 12 months, there was no difference in the rate of chest
infections, 28 vs 27, respectively (p=0.17).111
The rate and/or risk of hospitalization was evaluated in 3 studies.109-111 In 11 mixed NMD patients (aged 16-64
yrs.) with respiratory tract infection while using MI-E compared to 16 historical age-matched controls with
NMD and respiratory tract infection who received chest physical treatments alone, no difference was observed
in mean days hospitalized. 112 In a larger group of 37 mixed NMD patients (mean age 19.8 yrs.) using MI-E at
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home with medical histories up to 20 years pre-MI-E and up to 5 years post-MI-E, the relative risk of
hospitalization before MI-E initiation was 1.82 (95% CI 0.76-4.38), and the relative risk of ED presentations
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before MI-E was 1.76 (95%CI 1.10-2.84).113 There were 6 episodes of hospitalization in 19 ALS patients using
NIV plus MI-E daily for 2 sessions and followed for 12.3 person-years.110
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The description of adverse events varied in terms of population ages and description of events.99,106,109,112 In a
study of 20 adults with mixed NMD undergoing one application of 6 cycles of MI-E at each 15 cm H2O, 30 cm
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H2O, and 40 cm H2O of pressure, no stomach distension, vomiting, blood-streaked sputum or chest pain were
reported.106 In a case series of 11 patients (aged 16-64) with NMD and respiratory tract infection using MI-E, 1
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episode of stomach distension and 1 mild nosebleed were reported.112 The larger review from 62 children (mean
age at MI-E initiation 11.3 yrs.) with mixed NMD using MI-E for a mean of 13.4 months, 2 children
discontinued MI-E due to abdominal pain and another due to chest discomfort.109 One child experienced
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premature ventricular contractions upon initial use but continued use after the resolution of the acute respiratory
failure episode.109 The smaller study in 17 children (mean age 11±4 yrs.) with mixed NMD undergoing one MI-
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E application of 6 cycles at each 15, 30, and 40 cm H2O of pressure, no episodes of stomach distention,
gastroesophageal reflux, or chest pain were reported.99
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There were 4 studies on patient comfort with the use of MI-E.98,99,104,107 In a study of 22 NMD patients (aged
10-56 yrs.), mean VAS comfort scores (0=least, 10= most comfortable) were significantly but mildly higher
with MI-E assisted cough.98 In the second study of 18 adult patients with mixed NMD, multiple modalities
were compared.107 Patients received either cough assistance via MI-E, MI-E and manually assisted cough (MI-E
+ MAC), or intermittent positive pressure breathing with manually assisted cough (IPPB + MAC) in - random
order. The median VAS comfort ratings (0= “I breathe very badly”; 10= “I breathe very well”) were similar
with all techniques. Subjective cough effectiveness was rated somewhat lower with MI-E than the other two
techniques (p<0.05 for MI-E vs IPPB +MAC and MI-E vs MI-E + MAC).107 For the third study, 16 ALS
patients a series of cough techniques in random order, .The median VAS comfort ratings were higher with MI-
E assisted cough than unassisted cough, but the difference was not statistically significant.104 The fourth study
was done in 17 children (mean age 11±4 yrs.) with various NMDs receiving 3 MI-E sessions (43), respiratory
comfort significantly improved from baseline following MI-E: mean VAS 100 scores (higher p=.02) .99
Manually Assisted Cough

The MAC therapeutic effect is short term but repeatable and the procedure is neither difficult nor painful for
most. Fourteen studies evaluated the effect of manually assisted cough (MAC) on PCF and patient
comfort.96,98,100-102,104,105,114-120 Most studies indicated a significant increase in PCF with MAC or MAC
combined with LVR. The MAC was provided by physiotherapists and/or caregivers and administered variable
techniques, including abdominal, thoracic, and/or thoraco-abdominal thrusts.
The patient comfort during MAC was evaluated in 2 observational studies using VAS comfort ratings, one in a
mixed NMD population and the other in ALS.98,104 The mean VAS comfort scores were higher with MAC than
unassisted cough but the differences were not significant.98,104
Lung Volume Recruitment (LVR)

All studies reviewed demonstrated significant initial increases in LVR-assisted PCF or MIC compared to
spontaneous values.95,96,114,115,119,121-128 Two studies in patients with DMD, demonstrated increases in PCF of 61
to 120% and VC of 60 to 160% (MIC) with LVR.125,127 A study of 29 ALS patients demonstrated significant
improvements in spontaneous PCF 15 and 30 minutes after a session of LVR suggesting that even spontaneous
cough may improve immediately after LVR.122 Although not included in the evidence tables, one controlled
physiological study demonstrated significant improvements in respiratory system compliance up to an hour
after a single LVR session.129 Manual assistance with abdominal and/or thoracic compression may also further
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augment PCF.96,114,115,119 Some cohorts studied over time demonstrated early increases in spontaneous VC and
PCF as a result of continued daily LVR use and while absolute values decreased with time (months to years),
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important MIC-VC and unassisted vs. assisted PCF differences, remained.125,126 In a study of 21 patients with
DMD who used LVR (median of 3.75 yrs.), the rate of decline of FVC percent-predicted was significantly
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reduced after the initiation of LVR. Prior to LVR the mean annual decline in FVC percent-predicted was 4.7
percent-predicted a year, and after initiation of LVR was 0.5 percent-predicted a year (p< 0.000).127
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The single RCT comparing the effect of LVR vs. MI-E in 40 ALS patients with no placebo arm, was limited by
inadequate power to provide conclusions.110 No baseline measures of LVR or MI-E effectiveness were reported.
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Hospitalizations were equivalent in each group. Median survival in the breath-stacking group was 535 days and
266 days in the MI-E group (p = 0.34).
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Only 2 included studies evaluated the impact of LVR on quality of life. One included 19 NMD patients and
found no change in SIP, Physical or Mental Component scores (SF36) during LVR follow up,124 while the
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other, in 21 ALS patients, demonstrated that those compliant with LVR maintained MCS and sleep apnea
quality of life (SAQLI) scores above 75% baseline in a rapidly progressive illness, for 329 and 280 days
respectively.110 Two studies evaluated subjective experience. One involving patients with ALS, myotonic
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dystrophy and post-polio syndrome, evaluated the acceptability of LVR therapy and found that 17 of 19
indicated that LVR was either “highly acceptable or acceptable for the most part”, suggesting it does not pose a
significant burden.124 The other comparing a ‘volumetric cough mode’ with regular volume ventilator breath-
stacking found similar comfort and cough effectiveness.123 No adverse events were reported in any of these
trials though in the broader literature, there have been isolated reports of pneumothorax associated with LVR or
the combination of LVR and MI-E.130
In conclusion, low quality evidence suggests that regularly increasing lung volumes and expiratory cough flows
with LVR have immediate and long-term effects on VC, MIC and assisted cough flows. Regular LVR may have
a positive impact on clinical outcomes. Further RCTs are required to provide more objective measures of
adherence and identify those who may benefit most.
High Frequency Chest Wall Oscillation

One RCT,131 and an observational study132 evaluated the effect of HFCWO on lung function, dyspnea, symptom
improvement, adverse events, reduction of pulmonary morbidity, healthcare, hospitalization, and healthcare
costs (e-Table 8h).
The 12-week randomized trial enrolled 46 patients (58 + 10 years; 21 men, 25 women) who received HFCWO
twice daily for 10-15 minutes (range 5-25 Hz). Thirty-five completed the trial, 19 used HFCWO and 16 were
untreated. The study was not powered for significance and there was no stated primary outcome measure. The
baseline lung function parameters showed that the mean VC was 66 ± 14% and the mean O2 saturation was 95 ±
2% and the groups were similar at baseline. There were no significant differences in FVC change, peak
expiratory flow, capnography, or oxygen saturation. In a subgroup of patients with FVC between 40-70%
predicted, FVC showed a significant mean decrease in untreated patients but not in HFCWO patients.131
The dyspnea relief was based on the Amyotrophic Lateral Sclerosis Functional Rating Scale- respiratory
subscale (ALSFRS-RS). The scoring showed a similar, approximately 37%, worsening dyspnea in both groups
(p=0.97). The HFCWO treated patients (n=19) experienced a mean symptom decrease with the self-reported
breathlessness score on a subjective scale indicating improvement, compared to untreated patients who
experienced a mean increase in breathlessness score, indicating worsening (p=0.02). Cough was significantly
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different at night (p = 0.05) as it increased in the HFCWO group but decreased in the untreated group such that
HFCWO patients awakened more frequently at night than untreated patients. Fatigue was a major limiting
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factor in more than 50% of all patients but there was no difference in the mean change in fatigue between the
two groups after 12 weeks.131
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Follow up of these patients showed that 1 of the 16 (6%) patients in the untreated group were hospitalized, one
patient from each group had emergency department visits, and 3 of the 19 (16%) from the HFCWO group and 4
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of the 16 (25%) from the no treatment group were placed on antibiotics for pulmonary-related complications.131
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Respiratory Management of Patients with Neuromuscular Weakness: An American

To appear in: CHEST

Received Date: 30 November 2022

Respiratory Management of Patients with Neuromuscular Weakness: An American College of

Conflicts of Interest: see e-Appendix 1

30 mouthpiece ventilation, transition to home mechanical ventilation, salivary secretion

65 SNIP = Sniff Nasal Inspiratory Pressure

67 TcCO2 = transcutaneous carbon dioxide

143 secretion management.

167 Sialorrhea Management

187 therapy (RT) (conditional recommendation, very low certainty of evidence).

232 resources and shared decision-making.

322 Appraisal Review Tool for systematic reviews.19-22

324 Data Analysis

409 Screening for Respiratory Failure and Sleep-Related Breathing Disorders

462 Use of Non-invasive Ventilation

502 Additional Comments / Implementation Recommendations

514 Non-invasive Ventilation Strategies

539 low certainty of the evidence.

582 Evidence and Evidence-to-Decision

635 glossopharyngeal breathing (GPB), mechanical insufflation-exsufflation (MI-E), manually

675 with an LVR maneuver.137

754 workshop: Developing best practice guidelines for management of mouthpiece

757 9. Chatwin M, Toussaint M, Goncalves MR, et al. Airway clearance techniques in

797 evidence to recommendation-determinants of a recommendation's direction and

800 Accessed January 10, 2021. https://gradepro.org/. 2021.

846 respiratory and critical care medicine. 2001;164(12):2191-2194.

884 Pediatric pulmonology. 2017;52(4):524-532.

887 rehabilitation. 2001;82(1):123-128.

889 in adults with Pompe disease. European Respiratory Journal. 2012;39(6):1545-1546.

929 of respiratory and critical care medicine. 2015;191(9):979-989.

931 positive-pressure ventilation on survival in amyotrophic lateral sclerosis. Annals of

968 amyotrophic lateral sclerosis. Muscle & nerve. 2018.

971 neurological sciences. 1999;164(1):82-88.

1055 Canadian respiratory journal. 2013;20(1):e5-9.

1060 115. Klang B, Markstrom A, Sundell K, Barle H, Gillis-Haegerstrand C. Hypoventilation does

1142 techniques in neuromuscular patients: mechanical insufflation combined with manually

1147 exploratory randomized, controlled trial. Neurology. 2006;67(6):991-997.

1191 Versus Mechanical Ventilation. Respiratory care. 2016;61(1):61‐67.

ventilation with NMD following non-invasive ventilator symptom Case-

Airway Patients Selected airway No airway Secretion Cohort,

QoL, patient review,

1212 Table 2. Certainty of Evidence

1213 Table 3. CHEST Grading System

Strong Benefits We are moderately Recommendation can apply

recommendation, clearly confident in the effect to most patients in most

or vice versa estimate of the effect, but have an important impact

is substantially different. estimate of effect and may

Strong Benefits Our confidence in the effect Recommendation can apply

Weak Benefits We are moderately Best action may differ

and burden well change the estimate.

(conditional) the estimates confidence in the effect equally reasonable. Higher

Anticholinergic An initial trial of an inexpensive oral Relatively inexpensive and

Salivary gland Limited data, doses not defined. Long-lasting relief,

Glossopharyngeal Hypoventilation Positive pressure Low cost

Mechanical Reduced cough Alternating positive Expensive MI-E

assist device) alternative artificial airway. assistance.