Sivasothy 2001.

Study characteristics
Methods	Study design: randomised controlled cross‐over trial comparing 3 cough augmentation techniques: MAC; mechanical insufflation, and mechanical insufflation with MAC* Study grouping: cross‐over 'Rescue' vs maintenance therapy: maintenance Ethics: no mention of ethical clearance/number. All participants provided informed consent prior to participation.
Participants	Baseline characteristics* Respiratory muscle weakness participant group – with scoliosis   (separate data not presented for 2 periods of cross‐over trial) Sample size, n: 4 Diagnoses, n: previous poliomyelitis 2; DMD 1; SMA 1 Age in years, median: 57 (range 44–66) Gender (male/female), n: 3/1 MIP in cmH2O, median: 37 (range 30–49) MIP % predicted, median: 41 (range 37.6–50.7) MEP in cmH2O, median: 51 (range 17–62) MEP % predicted, median: 42 (range 36.4–67.3) FEV1 in L, median: 0.8 (range 0.65–1.25) FEV1 % predicted, median: 33 (range 28.4–40.4) FVC in L, median: 1.5 (range 0.7–1.75) FVC % predicted, median: 35 (range 15–42.9) PEFR in L/min, median: 225 (range 220–240) PEF % predicted, median: 47 (range 45.7–66.7) MVV in L/min, median: 33 (range 21–44) MVV % predicted, median: 24 (range 17.0–33.8) Inclusion criteria Static inspiratory and expiratory maximal mouth pressures < 70% predicted Respiratory muscle weakness diagnosed by a neurologist: subdivided based on presence of thoracic scoliosis diagnosed on physical examination and spinal x‐rays with a Cobb angle > 70° Exclusion criteria Presence of other respiratory disease Respiratory muscle weakness participant group ‐ without scoliosis Sample size, n: 8 Diagnoses, n: amyotrophic lateral sclerosis 7; Becker's muscular dystrophy 1 Age in years, median: 63 (range 27–73) Gender (male/female), n: 8/0 MIP in cmH2O, median: 15 (range 11–22) MIP % predicted, median: 14(range 11.9–24.9) MEP in cmH2O, median: 22 (range 16‐35) MEP % predicted, median: 19 (range 11.7‐27.6) FEV1 in L, median: 0.73 (range 0.48‐1.8) FEV1 % predicted, median: 19 (range 13.6‐43.9) FVC in L, median: 0.83 (range 0.55‐1.57) FVC % predicted, median: 18 (range 13‐42.0) PEFR in L/min, median: 123 (range 68‐150) PEF % predicted, median: 24 (range 13.1‐31.9) MVV in L/min, median: 26 (range 16‐35) MVV % predicted, median: 17 (range 11.1‐27.8) Inclusion criteria Respiratory muscle weakness diagnosed by a neurologist: subdivided based on absence of thoracic scoliosis  on physical examination and spinal x‐rays with a Cobb angle <70° Exclusion criteria Presence of other respiratory disease Chronic obstructive pulmonary disease group (COPD) Sample size, n: 8 Diagnoses, n: COPD 8 Age in years, median: 65 (range 52‐74) Gender (male/female), n: 3/5 MIP in cmH2O, median: 37 (range 18‐91) MIP % predicted, median: 44 (range 18.5‐93.3) MEP in cmH2O, median: 84(range 52‐167) MEP % predicted, median: 94 (range 74.7‐194.3) FEV1 in L, median: 0.95 (range 0.35–1.1) FEV1 % predicted, median: 37 (range 13.4–44.2) FVC in L, median: range 1.8 (range 0.77‐2.75) FVC % predicted, median: 66 (range 24.5–84.9) PEFR in L/min, median: 212 (range 110–270) PEF % predicted, median: 51 (range 24.9–66.7) MVV in L/min, median: 33 (range 19–60) MVV % predicted, median: 32 (range 16.7–66.1) Inclusion criteria Fulfilled the American Thoracic Society criteria for the diagnosis of COPD Exclusion criteria None described "Normal" volunteers Sample size, n: 9 Diagnoses, n: healthy 9 Age in years, median: 27 (range 17‐71) Gender (male/female), n: 4/5 MIP in cmH2O, median: 99 (range 59‐137) MIP % predicted, median: 115 (range 87‐151) MEP in cmH2O, median: 126 (range 104‐239) MEP % predicted, median: 118 (range 83‐228) FEV1 in L, median: 3.8 (range 1.7‐4.2) FEV1 % predicted, median: 98(range 88.3–120.1) FVC in L, median: 4.6 (range 2.1–5.9) FVC % predicted, median: 100 (range 78.3–120.8) PEFR in L/min, median: 444 (range 410–633) PEF % predicted, median: 103(range 86.9–140) MVV in L/min, median: 128 (range 75‐195) MVV % predicted, median: 107 (range 71–115) Inclusion criteria "normal" subjects non‐smokers Exclusion criteria history of respiratory, neuromuscular or cardiovascular disease Pretreatment No data were presented for different allocation groups at baseline; neither were separate data presented for the 2 periods of cross‐over.
Interventions	Intervention characteristics MAC Participant position: semi‐recumbent Technique description: performed by an experienced physiotherapist. Manual thoracoabdominal compression during the expulsive phase of the maximal voluntary cough. Hand position was optimised for participants with scoliosis by placing the hand used for thoracic compression on the hyperinflated hemithorax. Washout time: ≥ 5 min was allowed between each cough manoeuvre. Mechanical insufflation Participant position: semi‐recumbent Technique description: performed with an in‐exsufflator (JH Emerson Co, Cambridge, Massachusetts, USA) set to give 20 cmH2O inspiratory and –20 cmH2O expiratory pressure. 2 in‐exsufflation cycles were delivered and after the third insufflation, the participant was asked to make a maximal voluntary cough without the assistance of negative pressure. Washout time: ≥ 5 min was allowed between each cough manoeuvre. Mechanical insufflation with MAC Participant position: semi‐recumbent Technique description: the 2 techniques above were combined but the technique was not described separately. Washout time: ≥ 5 min was allowed each cough manoeuvre.
Outcomes	Separate first‐period data were not presented, precluding analysis. Maximal peak cough expiratory flow (PCF) Outcome type: continuous Unit of measure: L/min Measurement technique: a face mask (Hans Rudolf) was attached directly to a 4.5 cm pneumotachograph (PK Morgan), deriving PCF and CEV using an electric transducer and integrator. Fully reported CEV Outcome type: continuous Unit of measure: L Measurement: maximal volume recorded using face mask and pneumotachograph (as described above). Fully reported Peak value time Outcome type: continuous Unit of measure: ms Measurement: time from onset of expiratory flow to peak cough expiratory flow. Fully reported Oesophageal and gastric pressures (as proxies to pleural and abdominal pressure) Outcome type: continuous Unit of measure: cmH2O Measurement: using balloon manometry (PK Morgan) Not fully reported Subjective cough effectiveness Outcome type: categorical/ordinal Unit of measure: participants were asked if the assisted cough technique had aided, impaired, or had no effect on their cough. Not fully reported Adverse events: reported as none having occurred.
Identification	Sponsorship source: no sponsorship source declared. Conflict of interest: not declared Country: UK Setting: setting of data collected not well described, assumed to be the Respiratory Support and Sleep Centre/Papworth Hospital and 9 healthy volunteers that participated. Comments: none Author name: Dr P Sivasothy Institution: Respiratory Support and Sleep Centre; Papworth Hospital Email: ps247@cus.cam.ac.uk Address: Respiratory Support and Sleep Centre, Papworth Hospital, Papworth Everard, Cambridge, UK
Notes	Attempts to contact the author for additional data were not successful. *This study was reported as a non‐randomised clinical trial of parallel groups (healthy controls; 1 group with chronic obstructive pulmonary disease and 2 groups with NMD and respiratory muscle weakness – 1 with and 1 without scoliosis). Only data from the cross‐over component of the trial within the NMD group was eligible for inclusion in this review. The group with NMD and without scoliosis was further excluded, because 7/8 participants had ALS, an excluded condition in this review.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Quote: "To exclude bias the order of the treatments was randomised for each subject." Comment: unclear how randomisation was performed.
Allocation concealment (selection bias)	Unclear risk	Comment: allocation concealment was not described.
Blinding of participants and personnel (performance bias) All outcomes	High risk	Comment: neither participants nor personnel were blinded to intervention.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Comment: unclear whether the outcome assessors were blinded to group allocation.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Comment: all participants were accounted for, no dropouts or missing data.
Selective reporting (reporting bias)	Unclear risk	Comment: from the methods section, it was unclear which were the study's primary and secondary outcome measures. There was no trial registration number mentioned so we could not check the predescribed protocol. Gastric and oesophageal pressures were not presented due to the collapse of the balloons in the control groups. The subjective outcome measure of cough effectiveness was not fully reported, it was simply stated that participants did not report any benefit of any assisted cough interventions.
Other bias	High risk	Quote: "All subjects practised with both manually assisted cough and mechanical." Quote: "All subjects practised coughing while the face mask was adjusted to minimise air leaks. An investigator held the subject’s cheeks…" Comment: the following factors placed this study at high risk of other bias. Short‐term cross‐over trial design – this may not be the optimal study design for a condition such as NMD, which requires long‐term follow‐up. Unclear carry‐over effect. Separate period data were not provided for the cross‐over trial; therefore, data could not be pooled for meta‐analysis. There was no information on whether groups were treated equally, besides the intervention assigned. Participants practised all the cough augmentation techniques prior to the implementation of interventions and the assessment of PECF, CEV, PVT; therefore, learning effect might also influence the outcome. Holding the cheeks of the patients could affect the outcomes, e.g. PCF (no mention of bulbar control) – this is a possible confounder.