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Base de datos Cochrane de Revisiones Sistemáticas Revisión - Intervención

Técnicas de estimulación de la tos para personas con trastornos neuromusculares crónicos

Declaraciones de intereses de los autores

Versión publicada: 22 abril 2021 Historial de versiones

https://doi.org/10.1002/14651858.CD013170.pub2
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Antecedentes

Las personas con trastornos neuromusculares pueden presentar una tos débil e improductiva que les predispone a complicaciones respiratorias. Las técnicas de estimulación de la tos tienen como objetivo mejorar la efectividad de la tos y la eliminación de la mucosidad, reducir la frecuencia y la duración de las infecciones respiratorias que requieren ingreso hospitalario y mejorar la calidad de vida.

Objetivos

Determinar la eficacia y la seguridad de las técnicas de estimulación de la tos en niños y adultos con trastornos neuromusculares crónicos.

Métodos de búsqueda

El 13 de abril de 2020 se hicieron búsquedas de ensayos controlados aleatorizados (ECA), cuasialeatorizados y ensayos aleatorizados cruzados (cross‐over) en el registro especializado del Grupo Cochrane Neuromuscular (Cochrane Neuromuscular Group), así como en CENTRAL, MEDLINE, Embase, CINAHL y ClinicalTrials.gov.

Criterios de selección

Se incluyeron los ensayos que compararon técnicas de estimulación de la tos con ningún tratamiento, técnicas alternativas o una combinación de ellas en niños y adultos con trastornos neuromusculares crónicos.

Obtención y análisis de los datos

Dos autores de la revisión, de forma independiente, evaluaron la elegibilidad de los ensayos, extrajeron los datos y evaluaron el riesgo de sesgo. Los desenlaces principales fueron el número y la duración de las hospitalizaciones no programadas por exacerbaciones respiratorias agudas. La certeza de la evidencia se evaluó con el método GRADE.

Resultados principales

La revisión incluyó 11 estudios con 287 adultos y niños, de entre tres y 73 años de edad. La deficiente información publicada de los estudios cruzados y la poca información adicional proporcionada por los autores limitaron mucho la cantidad de análisis que se pudieron realizar.

Los estudios compararon la tos asistida manualmente, la insuflación mecánica, la respiración dirigida manual y mecánica, la insuflación‐exuflación mecánica, la respiración glosofaríngea y técnicas combinadas de tos no asistida e intervenciones alternativas o simuladas. Ninguno de los estudios incluidos informó sobre los desenlaces principales de esta revisión (número y duración de los ingresos hospitalarios no programados) ni enumeró los "eventos adversos" como medidas de desenlace principales o secundarias.

La evidencia indica que una serie de técnicas de estimulación de la tos podrían aumentar el flujo máximo de tos en comparación con la tos no asistida (199 participantes, ocho ECA), pero la evidencia es muy incierta. Podría haber poca o ninguna diferencia en los desenlaces del flujo máximo de tos entre las técnicas alternativas de estimulación de la tos (216 participantes, nueve ECA).

No hubo evidencia suficiente para determinar el efecto de las intervenciones sobre las medidas de intercambio gaseoso, la función pulmonar, la calidad de vida, el funcionamiento general, o la preferencia y la satisfacción de los participantes.

Conclusiones de los autores

Existen muchas dudas sobre la eficacia y la seguridad de las técnicas de estimulación de la tos en niños y adultos con trastornos neuromusculares crónicos y se necesitan más estudios.

PICO

Population
Intervention
Comparison
Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Seguridad y efectividad de las técnicas de tos asistida en personas con trastornos neuromusculares crónicos

Pregunta de la revisión

Se revisó la evidencia sobre la seguridad y la efectividad de las técnicas utilizadas para la tos asistida en personas con trastornos neuromusculares crónicos (técnicas de estimulación de la tos).

Antecedentes

Las personas con trastornos neuromusculares (enfermedades relacionadas con los nervios que afectan a los músculos) pueden tener dificultades para toser y eliminar la mucosidad de las vías respiratorias, lo que las pone en riesgo de asfixia, infecciones respiratorias recurrentes y enfermedad pulmonar persistente. Las técnicas de estimulación de la tos, como la tos asistida manualmente, la ventilación con ambú (una bolsa autoinflable de uso habitual en la reanimación), Cough Assist mecánico (un dispositivo que elimina las secreciones aplicando una presión positiva en las vías respiratorias y cambiando rápidamente a una presión negativa), la respiración glosofaríngea (un método de respiración para ayudar a la persona a tomar un mayor volumen de aire) y la retención de aire en los pulmones (se realizan varias inspiraciones seguidas, una tras otra sin exhalar) pretenden mejorar la efectividad de la tos, con el objetivo final de reducir el número o la gravedad (o ambos) de las infecciones respiratorias, y mejorar la capacidad de las personas para realizar las actividades cotidianas (capacidad funcional) y la calidad de vida.

Métodos

Se realizó una extensa búsqueda en bases de datos de estudios sobre técnicas de estimulación de la tos en niños y adultos con trastornos neuromusculares crónicos. Se seleccionaron los estudios que asignaron al azar a las personas al/los tratamiento/s o al orden de tratamientos, ya que este tipo de estudio proporciona la mejor evidencia.

Resultados y calidad de la evidencia

Se encontraron 11 estudios con 287 personas y varias técnicas de estimulación de la tos. Un estudio midió los efectos a largo plazo del tratamiento, pero sólo se publicó como un resumen, sin información suficiente para analizar con precisión sus resultados. Muchos de los estudios incluidos tenían problemas con la forma en que se realizaron, con la forma en que se informaron sus hallazgos, o con ambas cosas, lo que dificultó la interpretación completa de sus resultados. Ninguno de los estudios informó acerca de los desenlaces considerados más importantes para tomar decisiones sobre la efectividad y la seguridad de las técnicas de estimulación de la tos. Por ejemplo, los estudios no informaron sobre el número ni la duración de los ingresos hospitalarios no programados por infecciones respiratorias, la supervivencia, la capacidad funcional ni la calidad de vida. No fue posible determinar la seguridad de las técnicas de estimulación de la tos. Algunos estudios indican que las técnicas de estimulación de la tos podrían ser mejores que la tos no asistida, pero los resultados son muy inciertos. No hubo suficiente evidencia para mostrar si alguna de las técnicas fue mejor que otra para mejorar el esfuerzo de la tos.

Conclusiones y recomendaciones

Los resultados de esta revisión no proporcionaron información suficiente para tomar decisiones acerca de cuándo y cómo utilizar técnicas de estimulación de la tos en personas con trastornos neuromusculares crónicos. Actualmente existe evidencia de certeza muy baja a favor y en contra de la efectividad y la seguridad de las técnicas de estimulación de la tos en personas con enfermedades neuromusculares crónicas y se necesitas más estudios.

La evidencia está actualizada hasta el 13 de abril de 2020.

Authors' conclusions

Implications for practice

The results of this review do not provide sufficient certainty of evidence to guide clinical practice, as we were unable to address important short‐ and long‐term clinically relevant outcomes, including measures of safety. There is very low‐certainty evidence that a range of cough augmentation techniques may increase peak cough flow (PCF) above that of unassisted cough; however, there is insufficient certainty of evidence to determine whether any one technique is superior to another technique or combination of techniques in this regard. The evidence is currently very uncertain about the safety and effectiveness of cough augmentation techniques in adults and children with chronic neuromuscular disease (NMD). Considering that respiratory decompensation in people with NMD may occur as a consequence of the inability to clear secretions during cough (Toussaint 2018), and given the very low‐certainty evidence supporting the effect of cough augmentation techniques on PCF, practitioners may continue to implement this therapy in people with chronic NMD and respiratory muscle weakness, as recommended previously (Chatwin 2018; Toussaint 2018). However, as there is no moderate or high certainty evidence for the superiority of any cough augmentation technique/s, the choice of techniques may take other factors into account, including cost, patient preference and ability, therapist knowledge and proficiency, and equipment availability. Further, there is insufficient evidence to inform safe and effective frequency or dosage of cough augmentation techniques in the management of people with respiratory muscle weakness caused by chronic NMD.

Implications for research

Further research is required to establish the safety and efficacy of cough augmentation techniques in people with NMDs, for both long‐term maintenance use, and during respiratory exacerbations or acute obstructive episodes, for 'rescue' use. We need future studies to measure longer‐term, clinically relevant outcomes that will inform the effects of interventions on morbidity, mortality, and health‐related quality of life. We also need systematic reporting of adverse events to obtain safety data, and reporting on participant choice of techniques. Studies comparing dosage and frequency regimens would be useful in this regard. Choice of comparators would depend on local standard of care. Sham treatment or non‐intervention controls may be difficult to support ethically over the long term, but comparative studies of different interventions could be ethically justifiable, as there is clearly equipoise between intervention types. Given the diversity of NMD and of age groups affected, we need studies that either focus on a specific age group or condition, or provide sufficient data for subgroup analyses in systematic reviews.

In terms of study design, long‐term parallel‐group RCTs provide the best evidence, but NMDs are rare and attaining sufficient sample size is often difficult. Researchers should therefore be encouraged to consider multisite collaborative studies to reach sufficient sample sizes for adequate power, and to allow meaningful subgroup analyses. It is particularly important to consider paediatric and adult data separately, owing to the anatomical and physiological differences between these participant groups, which likely translate into different safety and efficacy profiles.

For short‐ and medium‐term outcomes such as immediate change in PCF, cross‐over trials may be useful, as smaller samples may yield equivalent power to a parallel‐group RCT. Importantly, comprehensive reporting of data from cross‐over trials will allow for systematic review synthesis and analysis (Elbourne 2002; Nolan 2016). This includes providing full details on methods (including allocation concealment, sequence generation, washout periods, and carry‐over effects) and either individual level data (including allocation information) or appropriately summarised, separate data for both periods (Elbourne 2002). Our findings support the recommendation that minimum standards for the transparent reporting of cross‐over trials are urgently needed (Mills 2009), as currently the results of many of these trials are essentially lost, because they cannot be included in important meta‐analyses to inform clinical practice.

Involvement of people living with or affected by NMDs when designing clinical trials can ensure that outcome measures and interventions are appropriate and responsive to their needs and experiences. Cost‐effective analyses are also warranted to relate the potential benefits of interventions with financial, physical, and social costs or harms.

Summary of findings

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Summary of findings 1. Cough augmentation therapy compared with an alternative cough augmentation technique or combination of techniques for people with neuromuscular diseases

Cough augmentation compared with an alternative cough augmentation technique or combination technique

Patient or population: participants with chronic neuromuscular diseases

Settings: –

Intervention: cough augmentation

Comparison: alternative cough augmentation technique

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Alternative cough augmentation technique

Cough augmentation

Number of unscheduled hospital admissions for 'maintenance therapy'

Not reported

Duration of hospital stay (days) for 'rescue' therapy

Not reported

PCF

Follow‐up: < 1 day ('rescue' and 'maintenance' therapy)

8 RCTs (198 participants) studied various cough augmentation techniques or combinations of techniques.

  • Reported that MI‐E, mechanical exsufflation, MAC, mechanical insufflation, manual and mechanical breathstacking, glossopharyngeal breathing, mechanical insufflation + MI‐E, MAC + MI‐E, and MAC + breathstacking may increase PCF above unassisted cough.

  • 2 cross‐over RCTs (26 participants) reported no change in PCF with MAC compared to unassisted cough.

  • 1 cross‐over RCT reported no difference in PCF with mechanical insufflation compared to unassisted cough (22 participants).

Repeated measures data were reported and could not be meta‐analysed.

—

198 (8 RCTs (7 cross‐over, 1 parallel group)

⊕⊝⊝⊝
Verylowa

Cough augmentation may improve PCF compared to unassisted cough, but the certainty of evidence was very low.

See Table 1 for details.

Any adverse events

Follow‐up: < 1 day or 1–2 days ('rescue and maintenance therapy)

4 cross‐over RCTs (64 participants) compared various cough augmentation techniques or combinations of techniques (including mechanical insufflation, mechanical exsufflation, MI‐E, MAC, MAC + manual breathstacking, MI‐E + MAC, MAC + manual breathstacking, MAC + mechanical insufflation).

  • 0 trials reported serious adverse events.

  • 3 trials reported no adverse events occurred. In most trials it was unclear whether adverse effects were systematically investigated.

  • 1 cross‐over RCT (8 participants) reported fatigue as an adverse event, measured on a 10‐point ordinal VAS. Fatigue was reported to increase from baseline in the MAC + M‐IE group, with no change in the MAC group. No data were provided for the control group or the separate periods of cross‐over. The mean postintervention fatigue score for both periods of the cross‐over trial was 5.1 (SD 2.6).

—

64 (4 cross‐over RCTs)

⊕⊝⊝⊝
Verylowb

We are unable to draw a conclusion as the certainty of evidence is very low. See Table 2; Table 3 for details.

Quality of life for 'maintenance' therapy

No study measured or reported quality of life.

Participant preference or satisfaction for 'rescue' and 'maintenance' therapy

No study measured or reported participant preference or satisfaction.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MAC: manually assisted cough; MI‐E: mechanical insufflation‐exsufflation; PCF: peak cough flow; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation; VAS: visual analogue scale.

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

aDowngraded three levels – twice for study limitations – all studies were at high risk of bias in at least one domain and unclear in several. Data were based on repeated (dependent) measurements from seven cross‐over and one parallel‐group RCTs. We also downgraded the evidence for imprecision – all studies had a small sample size, wide CI, or both. The outcome was measured less than one day after the intervention, rather than in the medium and long term as specified.
bDowngraded three levels – twice for study limitations – all studies were at high risk of bias in at least one domain and unclear in several. Data were based on repeated (dependent) measurements from seven cross‐over and one parallel‐group RCTs. We also downgraded the evidence for imprecision – all studies had a small sample size.

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1. Summary of findings: cough augmentation therapy, short‐term outcomes – details of PCF by comparison

Mean difference in PCF post intervention‐baseline (L/min)

Comparison (experimental vs control/alternative therapy/sham therapy)

Summary of results

Illustrative comparative risks

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Control/comparator

Experimental

Manual breathstacking vs mechanical breathstacking

Follow‐up: < 1 day

No evidence of a difference between manual and mechanical breathstacking in the change of PCF.

The mean PCF difference in the comparison group was 67 (SD 73) L/min

The mean PCF difference in the experimental group was 61 (SD 72) L/min

MD 6.00 (–33.43 to 45.43)

52 (1)

⊕⊕⊝⊝
Lowa

Based on 1 short‐term RCT with high risk of performance and detection bias and unclear allocation concealment (Toussaint 2016).

Glossopharyngeal breathing vs manual breathstacking

Follow‐up: < 1 day

No evidence of a difference between glossopharyngeal breathing and manual breathstacking in the change of PCF.

The mean PCF difference in the comparison group was
72.86 (SD 61.84) L/min

The mean PCF difference in the experimental group was
32.14 (SD 26.44) L/min

MD –40.72 (–90.54 to 9.10)

14 (1)

⊕⊝⊝⊝
Verylowb

Based on first‐period data from 1 cross‐over RCT with unclear allocation concealment, very small sample size, imprecision of results (wide CI), and substantial risk of performance and detection bias (Torres‐Castro 2016).

Mechanical insufflation + MAC vs MI‐E

Follow‐up: < 1 day

Mechanical insufflation + MAC produced a greater change in PCF compared to MI‐E alone.

The mean PCF difference in the comparison group was 53.4 (SD 51) L/min

The mean PCF difference in the experimental group was
124.8 (SD 38.4) L/min

MD 71.40 (18.08 to 124.72)

11 (1)

⊕⊝⊝⊝
Verylowc

Based on first‐period data of 1 cross‐over RCT with very small sample size, imprecision of results (wide CIs), and substantial risk of performance and other biases (Lacombe 2014).

MI‐E + MAC vs MI‐E

Follow‐up: < 1 day

No clear evidence of a difference between MI‐E + MAC compared to MI‐E alone in the change in PCF.

The mean PCF difference in the comparison group was 53.4 (SD 51) L/min

The mean PCF difference in the experimental group was 106 (SD 50.4) L/min

MD 52.80 (–0.32 to 105.92)

54 (2)

⊕⊝⊝⊝
Verylowc

Analysis based on first‐period data of 1 randomised cross‐over study with very small sample size (n = 14), imprecision of results (wide CIs), and substantial risk of performance and other biases (Lacombe 2014).

Study reported significantly higher PCF with MI‐E + MAC compared to MI‐E alone

N/A

The second study was a cross‐over RCT with high risk of performance, detection and other bias (Kim 2016).

Separate period data were not reported, precluding analysis and assessment of precision.

MI‐E + MAC vs mechanical insufflation + MAC

Follow‐up: < 1 day

There was no evidence of a difference in PCF change between MI‐E + MAC and mechanical insufflation + MAC.

The mean PCF difference in the comparison group was
124.8 (SD 38.4) L/min

The mean PCF difference in the intervention groups was
106 (SD 50.4) L/min

MD 18.60 (–34.46 to 71.66)

11 (1)

⊕⊝⊝⊝
Verylowc

Based on the first‐period data of 1 randomised cross‐over study design with very small sample size, imprecision of results (wide CIs), and substantial risk of performance and other biases (Lacombe 2014).

MAC vs mechanical insufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

Both studies reported no evidence of a difference in PCF between interventions.

N/A

26 (2)

⊕⊝⊝⊝
Verylowc

Based on 2 cross‐over RCTs with small sample sizes (Chatwin 2003: n = 4; Sivasothy 2001: n = 22).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Mechanical insufflation + MAC vs MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

Reported no evidence of a difference in PCF between interventions.

N/A

4 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 4 participants eligible for this review (Sivasothy 2001).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E vs MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

MI‐E reported to produce a higher PCF than MAC.

N/A

22 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 22 participants (Chatwin 2003).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E vs mechanical exsufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

MI‐E reported to produce a higher PCF than mechanical exsufflation.

N/A

22 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 22 participants (Chatwin 2003).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E vs mechanical insufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with MI‐E than with mechanical insufflation.

N/A

22 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 22 participants (Chatwin 2003).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Manual breathstacking + MAC vs MI‐E

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with MI‐E than with MAC + breathstacking.

N/A

40 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 40 participants (Kim 2016).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E + MAC vs manual breathstacking + MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with MI‐E + MAC than with MAC + breathstacking.

N/A

40 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 40 participants (Kim 2016).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MAC vs manual breathstacking + MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with manual breathstacking + MAC than with MAC alone.

N/A

28 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 28 participants (Brito 2009).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Manual breathstacking vs manual breathstacking + MAC

Follow‐up: < 1 day

We were unable to draw a conclusion
 

PCF reported to be higher with manual breathstacking + MAC than with manual breathstacking alone.
 

N/A
 

28 (1)
 

⊕⊝⊝⊝

Verylowc

Based on 1 cross‐over RCT with 28 participants (Brito 2009).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Mechanical breathstacking vs mechanical insufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with mechanical insufflation compared to mechanical breathstacking. Not quantitatively reported.

N/A

20 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 20 participants (Del Amo Castrillo 2019).

Data were presented graphically only and could not be precisely extracted from figures provided.

Separate period data were not reported or available, precluding analysis and assessment of precision.

CI: confidence interval; MD: mean difference; MAC: manually assisted cough; MI‐E: mechanical insufflation‐exsufflation; min: minute; n: number of participants; N/A: not available; PCF: peak cough flow; RCT: randomised controlled trial; SD: standard deviation.

aDowngraded twice because results come from a single short‐term RCT at high risk of bias.
bDowngraded three times based on a single randomised cross‐over study design with very small sample size, imprecision of results (wide CIs), and high risk of performance and detection bias.
cDowngraded three times based on a single randomised cross‐over study design with very small sample size, imprecision of results (wide CIs), and substantial risk of performance and other biases.

Open in table viewer
2. Study results grouped by outcome measures and interventions – cough augmentation therapy compared to alternative individual cough augmentation therapies

Outcome measure

Unassisted cough

MI

ME

MI‐E

MAC

Manual BS

Mechanical BS

Sham BS

GPB

Between‐group comparison

PCF

(L/min)
 
 

Chatwin 2003 (n = 22)

Mean (95% CI)

169

(129 to 209)a

182 (

147 to 217)

235

(186 to 284)

297

(246 to 350)

188

(146 to 229)

—

—

—

—

ME vs unassisted cough: P < 0.01

MI‐E vs unassisted cough: P < 0.001

MI‐E vs ME: P < 0.001

Toussaint 2016 (n = 52)

Mean ± SD baseline to after intervention

—

—

—

—

—

125 ± 52 to 186 ± 50; P < 0.001; n = 25

132 ± 55 to 199 ± 48; P = 0.001; n = 27

—

—

P = 0.33

Del Amo Castrillo 2019 (n = 20)

Median/IQR

176/68a

Data not reported

—

—

—

—

Data not reported

—

—

P < 0.001 comparing MI to baseline (favouring MI)

P < 0.001 comparing MI to BS (favouring MI)

P = 0.004 comparing BS to baseline (favouring BS)

Torres‐Castro 2016 (n = 14)

MD ± SD (95% CI) baseline to after interventionb

—

—

—

—

—

72.86 ± 61.84 (15.67 to 130.05); P = 0.02

—

—

32.14 ± 26.44 (7.69 to 56.59); P = 0.018

P = 0.14

Transcutaneous oxygen saturation

(%)

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

96 ± 3.2 to 96 ± 3

—

96 ± 3.6 to 96 ± 2.5

—

NS

Tidal volume (mL)

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

277 ± 131 to 310 ± 148; P < 0.001

—

303 ± 141 to 289 ± 128; NS

—

Significance levels not reported

Maximum inspiratory or insufflation capacity (L or mL)

Toussaint 2016 (n = 52)

mean ± SD, L

—

—

—

—

—

1.344 ± 0.520; n = 25

1.481 ± 0.477; n = 27

—

—

Mechanical vs manual BS: MD 0.14, 95% CI –0.13 to 0.41; P = 0.3

Del Amo Castrillo 2019 (n = 20)

median (IQR), L

—

1.630

(1.247 to 1.870)

—

—

—

—

1.320

(1.085–1.755)

—

—

P = 0.12

Torres‐Castro 2016 (n = 14)

MD between baseline vital capacity and postintervention maximum inspiratory capacityb

mean ± SD (95% CI), mL

—

—

—

—

—

435.0 ± 364.5

(98.61 to 772.82); P = 0.02

—

—

454.29 ± 408.16 (76.80 to 831.77); P = 0.03

MD 19.29, 95% CI –386.09 to 424.67; P = 0.93

Minute ventilation

(L/min)

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

6.8 ± 3.1 to 8.0 ± 3.5; P < 0.001

—

7.4 ± 4.9 to 6.9 ± 3.3; NS

—

Significance levels not reported

Maximal expiratory pressure

(cmH2O)
 

Toussaint 2016 (n = 52)

Mean ± SD

—

—

—

—

—

26 ± 9

28 ± 10

—

—

P = 0.45

Respiratory rate

(breaths/minute)
 
 

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

27 ± 9.2 to 28 ± 10.6; P < 0.05

—

26 ± 10.3 to 26 ± 10.4; NS

—

Significance levels not reported

Ability to perform breath stacking

(%)
 

Toussaint 2016 (n = 52)

—

—

—

—

—

88

89

—

—

P = 0.9

Number of insufflations to maximal insufflation capacity

(n)

Toussaint 2016 (n = 52)

Mean ± SD

—

—

—

—

—

1.8 ± 0.6

2.6 ± 0.6

—

—

P < 0.001

Comfort, distress, and strength of cough

(VAS 10‐point score)

Chatwin 2003 (n = 22)

Mean (95% CI)

5.4 (4.5 to 6.3)a

5.8 (4.8 to 6.8)

(NS)

6.9 (5.3 to 7.0)

(NS)

7.3 (6.6 to 8.0)

(NS)

5.9 (5.2 to 6.7)

(NS)

—

—

—

—

Separate VAS scores not presented

Significance levels not reported

Comfort

(VAS 10‐point score)

Del Amo Castrillo 2019 (n = 20)

Median (IQR)

—

6.4 (5.2 to 7.6)

—

—

—

—

6.5 (3.9–7.4)

—

—

P = 0.31

Subjective cough effectiveness (VAS 10‐point score)

Del Amo Castrillo 2019 (n = 20)

Median (IQR)

—

6.0 (4.85 to 8.2)

—

—

—

—

6.2 (5.1–7.1)

—

—

P = 0.17

BS: breathstacking; CI: confidence interval; GPB: glossopharyngeal breathing; IQR: interquartile range; PCF: peak cough flow; MAC: manually assisted cough; MD: mean difference; ME: mechanical exsufflation; MI: mechanical insufflation; MI‐E: mechanical insufflation/exsufflation; min: minute; n: number of participants; NS: not significant; SD: standard deviation; VAS: visual analogue scale.
aBaseline value – not a randomly assigned control.
bUsing raw first‐period data provided by the author on request.

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3. Study results grouped by outcome measures and interventions – comparison of individual and combination cough augmentation therapies with alternative individual and combination interventions

Outcome measure

Unassisted cough

MI

MI‐E

MAC

Manual BS

MAC + MI

MAC + manual BS

MAC + MI‐E

Between‐group differences

PCF

(L/min)

Sivasothy 2001 (n = 4)

Median (range)

288 (175 to 367)a

231 (148–597)

—

193 (185–287)

—

362 (218–440)

—

—

NS

Brito 2009 (n = 28)

Mean ± SD

171 ± 67a

—

—

231 ± 81

225 ± 80

—

292 ± 86

—

Manual BS vs unassisted cough: P < 0.001

Manual BS vs MAC: NS

MAC + BS vs unassisted cough: P < 0.001

MAC vs MAC + BS: P < 0.05

Manual BS vs MAC + BS: P < 0.05

Lacombe 2014 (n = 18)

Mean ± SD 

—

—

Absolute valueb:

210.6 ± 52.8

MD from baselineb:

53.4 ± 51.0; n = 7

—

—

Absolute valueb:

225 ± 83.4

MD from baselineb:

124.8 ± 38.4; n = 4

—

Absolute valueb:

210.6 ± 50.4

MD from baselineb: 106.2 ± 50.4; n = 7

Comparison of MDs (intervention – baseline):

MI + MAC vs MI‐E alone:

MD 71.4, 95% CI 18.08 to 124.72); P = 0.009

MI‐E + MAC vs MI‐E alone: MD 52.8, 95% CI –0.32 to 105.92; P = 0.05

MI‐E + MAC vs MI + MAC:

MD –18.6, 95% CI –71.61 to 34.41; P = 0.49

Kim 2016 (n = 40)

Mean ± SD

95.7 ± 40.5

—

177.2 ± 33.9

—

—

—

155.9 ± 53.1

202.4 ± 46.6

MAC + manual BS vs unassisted cough: P < 0.01

MI‐E vs unassisted cough: P < 0.01

MI‐E vs MAC + manual BS: P < 0.01

MI‐E + MAC vs unassisted cough: P < 0.01

MI‐E + MAC vs MAC + manual BS: P < 0.01

MI‐E + MAC vs MI‐E alone: P < 0.01

Transcutaneous oxygen saturation

(%)

Chatwin 2009 (n = 8)

Mean 

—

—

—

Data not reported

—

—

—

Data not reported

NS difference in group means

Transcutaneous carbon dioxide tension

(%)

Chatwin 2009 (n = 8)

Mean

—

—

—

Data not reported

—

—

—

Data not reported

NS difference in group means

Maximum inspiratory or insufflation capacity

(L)

Lacombe 2014 (n = 18)

mean ± SD

—

—

1.55 ± 0.34b; n = 7

—

—

1.43 ± 0.34b; n = 4

—

1.39 ± 0.43b; n = 7

Comparison of means:

MI‐E vs MI + MAC: MD –0.12, 95% CI –33.44 to 33.20; P = 0.99

MI‐E vs MI‐E + MAC: MD –0.16, 95% CI –0.57 to 0.25; P = 0.44

MI+ MAC vs MI‐E + MAC: MD 0.04, 95% CI –0.42 to 0.50; P = 0.86

Cough expiratory volume

(L)

Sivasothy 2001 (n = 4)

Median (range)

0.9 (0.5–1.1)a

0.7 (0.3–1.3)

—

0.5 (0.41–1.01)

—

0.6 (0.4–1.01)

—

—

NS

Heart rate

(beats per minute)

Chatwin 2009 (n = 8)

Not specified

—

—

—

Data not reported

—

—

—

Data not reported

NS

Effective cough time

(ms)

Lacombe 2014 (n = 18)

Mean ± SD

—

—

Absolute valueb:

70 ± 79

MD from baselineb:

54 ± 95; n = 7

—

—

Absolute valueb:

93 ± 111

MD from baselineb:

93 ± 111; n = 4

—

Absolute valueb:

22 ± 47

MD from baselineb:

20 ± 42; n = 7

MI‐E vs MI + MAC: MD 39.0, 95% CI –90.56 to 168.56; P = 0.56

MI‐E vs MI‐E + MAC: MD –34.00, 95% CI –110.95 to 42.95; P = 0.39

MI + MAC vs MI‐E + MAC:

MD 73.00, 95% CI –40.14 to 186.14; P = 0.21

Peak value time

(ms)

Sivasothy 2001 (n = 4)

Median (range)

44 (40–50)a

45 (30–60)

—

50 (35–55)

—

50 (45–120)

—

—

NS

Treatment time after 30 minutes

(min)

Chatwin 2009 (n = 8)

Median (range)

—

—

—

17 (0–35)

—

—

—

0 (0–26)

P = 0.03

Auscultation score

(VAS 10‐point score)

Chatwin 2009 (n = 8)

MD ± SD before to after intervention

—

—

—

3.4 ± 2.0 to 2.3 ± 2.2; P = 0.007

—

—

—

2.9 ± 1.9 to 1.8 ± 2.0; P = 0.02

Significance level not reported

Secretions

(VAS 10‐point score)

Chatwin 2009 (n = 8)

MD ± SD before to after intervention

—

—

—

4.4 ± 2.5 to 3.0 ± 1.4; P = 0.03

—

—

—

4.0 ± 2.2 to 1.7 ± 0.4; P = 0.03

Significance level not reported

Comfort

(VAS 10‐point score)

Chatwin 2009 (n = 8)

Baseline to after intervention 

—

—

—

Data not reported

(NS)

—

—

—

Data not reported (NS)

Data presented graphically only.

Significance level not reported

Lacombe 2014 (n = 18)

Median (IQR)

—

—

Original report:

6.4 (5.5 to –7.0)

b5.7 (0.9)

—

—

Original report: 7.0 (6.0–8.5)

b5.9 (1.15)

—

Original report: 6.6 (5.8–8.0)

b6.8 (.7)

NS

Subjective cough effectiveness

(VAS 10‐point score)

Sivasothy 2001 (n = 4)

Not reported

Not reported*

Not reported

—

Not reported

—

Not reported

—

—

Participants did not report benefit of any intervention.

Lacombe 2014 (n = 18)

Median (IQR) 

—

—

Original report: 6.4 (4.8–8.2)

b7.2 (2.4)

—

—

Original report: 8.3 (7.2–9.0)

b7.1 (0.8)

—

Original report: 8.5 (6.2–9.0)

b8.0 (1.95)

Original report:

MI‐E + MAC vs MI‐E: P < 0.05

MAC + MI vs MI‐E: P < 0.05

Breathlessness

(VAS 10‐point score)

Chatwin 2009 (n = 8)

Baseline to after intervention score

—

—

—

Data not reported

(NS)

—

—

—

Data not reported

(NS)

Data presented graphically only.

Significance level not reported

Mood

(VAS 10‐point score)

Chatwin 2009 (n = 8)

Baseline to after intervention score 

—

—

—

Data not reported

(NS)

—

—

—

Data not reported

(NS)

Data presented graphically only.

Significance level not reported

Fatigue

(VAS 10‐point score)

Chatwin 2009 (n = 8)

MD ± SD before to after intervention 

—

—

—

Data not reported (NS)

—

—

—

3.2 ± 2.2 to 5.1 ± 2.6

(P = 0.005)

Incomplete reporting.

Significance level not reported

BS: breathstacking; CI: confidence interval; GPB: glossopharyngeal breathing; IQR: interquartile range; PCF: peak cough flow; MAC: manually assisted cough; MD: mean difference; ME: mechanical exsufflation; MI: mechanical insufflation; MI‐E: mechanical insufflation/exsufflation; min: minute; n: number of participants; NS: not significant; SD: standard deviation; VAS: visual analogue scale.

aBaseline value – not a randomly assigned control.

bUsing raw first‐period data provided by the author on request.

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Summary of findings 2. Cough augmentation therapy compared with standard care for people with neuromuscular diseases

Cough augmentation therapy compared with standard care for people with neuromuscular disease

Patient or population: participants with chronic neuromuscular diseases

Settings: –

Intervention: cough augmentation therapy

Comparison: standard care

Outcome

Summary of results

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Number of unscheduled hospital admissions for 'maintenance' therapy

No study reported the number of unscheduled admissions.

1 parallel‐group RCT of manual breathstacking compared to standard care (67 participants) planned to measure these outcomes; however, only an abstract is available and data are not fully reported (Katz 2019).

Lack of quantitative data precludes assessment of precision.

Duration of hospital stay (days) for 'rescue' therapy

No study reported the duration of hospital stay.

Quality of life for 'maintenance' therapy

No study reported quality of life

Peak cough flow for 'rescue' or 'maintenance' therapy

No study reported peak cough flow

Any adverse events for 'rescue' and 'maintenance' therapy

Follow‐up: 2 years

1 parallel‐group RCT reported that no adverse events had occurred during the 2‐year study, but this outcome was not quantitatively reported and it was unclear how it was measured.

67 (1 study)

⊕⊝⊝⊝
Verylowa

We are unable to draw a conclusion.

Quality of life for 'maintenance' therapy

No study reported quality of life.

1 parallel‐group RCT of manual breathstacking compared to standard care (67 participants) planned to measure quality of life; however, only an abstract is available and data are not fully reported (Katz 2019).

Participant preference or satisfaction for 'rescue' or 'maintenance' therapy

No study measured or reported participant preference.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RCT: randomised controlled trial.

GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aDowngraded three times, twice for study limitations and once for imprecision. Data were from one parallel‐group RCT, with high risk of performance and reporting bias. This outcome was not quantitatively reported and unclear how it was measured. Lack of quantitative data precludes assessment of precision but the trial was small (67 participants).

Background

Description of the condition

A range of chronic neuromuscular disorders (NMDs) have been described in adults and children, including muscular dystrophies, congenital and metabolic myopathies, neuromuscular junction disorders, peripheral neuropathies, and anterior horn cell diseases (Gozal 2000). People affected by chronic NMDs are at risk of progressive respiratory insufficiency (breathing difficulties that worsen over time), primarily from a combination of respiratory muscle weakness and chest wall abnormalities (Boitano 2006; Finder 2010; Gozal 2000; Panitch 2009).

Many people with NMDs experience progressive respiratory insufficiency with advancing age. Infants with NMDs generally have normal lungs and normal mucociliary clearance mechanisms at birth, although pulmonary mechanics may be affected from baseline, depending on the underlying NMD (Panitch 2017). Chest deformities may develop from infancy, particularly with severe forms of spinal muscular atrophy (SMA), because of respiratory muscle weakness and chronic paradoxical chest wall or abdominal movement during breathing (or both), in conjunction with an initially very compliant chest wall (Panitch 2009; Panitch 2017; Papastamelos 1996). Respiratory muscle weakness causes chronic shallow breathing; the inability to take a sufficiently deep breath to sigh or yawn, which is required to maintain full lung expansion; an ineffective cough with secretion retention; and progressive loss of lung compliance (Fauroux 2008; Panitch 2009; Panitch 2017). Progressive thoracic deformities such as scoliosis, kyphosis, and spinal rigidity, together with fibrosis of the intercostal muscles, may further impact on lung function with a progressive decrease in chest wall compliance and ultimately a restrictive pattern of respiratory disease (Fauroux 2008; Gozal 2000; Panitch 2009; Wang 2007). Bulbar weakness and glottic dysfunction, as typically seen in children with SMA type 1 and other severe NMDs, also impact on the ability to cough effectively as well as increasing the risks of aspiration (Boitano 2006; Chatwin 2018; Toussaint 2018).

An effective cough is essential to clear pulmonary secretions from the airways (Panitch 2017). If the cough is ineffective, as is often the case in people with chronic NMD and respiratory muscle weakness, short‐term inability to clear secretions may lead to acute respiratory insufficiency and respiratory failure, while long‐term retention of secretions leads to a vicious cycle of obstruction, infection, inflammation, increased work of breathing, recurrent acute respiratory tract infections, and ultimately chronic lung disease and respiratory failure (Chatwin 2018; Homnick 2007; Panitch 2017). Respiratory tract infection with altered sputum viscosity and volume, difficult or ineffective swallowing (dysphagia), and gastro‐oesophageal reflux with chronic aspiration can all exacerbate secretion retention in people with NMD and respiratory muscle weakness (Farrero 2013; Finder 2010; Iannaccone 2007).

An effective cough requires: a sufficiently deep inspiration; brief closure of the glottis with simultaneous contraction of expiratory respiratory muscles to increase intrathoracic pressure; and finally the abrupt opening of the glottis at the start of the expiratory phase to produce a rapid, forceful flow of air from the lungs (Boitano 2006; Chatwin 2018; Farrero 2013; Panitch 2017; Toussaint 2018). Any or all these phases may be affected in people with NMD (Bach 2003; Boitano 2006; Finder 2010; Rokadia 2015).

Adults have a normal peak expiratory cough flow (PCF) range between 360 L/minutes and 1200 L/minutes (Anderson 2005; Leiner 1963; Mayer 2017; Tzeng 2000). Bach 1996 suggested that adults require a PCF greater than 160 L/minute for an effective cough. Furthermore, it has been suggested that adults with NMD require a PCF of more than 270 L/minute when well, to account for the expected decline in cough flows during intercurrent respiratory infections (Bach 1997). Cough augmentation may, therefore, be indicated if PCF falls below 270 L/minute in adults and adolescents with NMD (Toussaint 2018). In children with NMDs, an absolute PCF of less than 160 L/minute has been shown to be predictive of severe disease, but age or size‐adjusted reference values are not available (Dohna‐Schwake 2006). It must be noted that the normal range of PCF in young children is highly variable, with healthy children only able to achieve PCFs of 160 L/minute on the 5th percentile by six years of age (Bianchi 2008). Therefore, for children over the age of 12 years (when children attain adult PCF (Bianchi 2008), use of the adult values of 160 L/minute and 270 L/minute PCF cut‐offs may be appropriate (Hull 2012), but the corresponding levels in younger children are as yet unclear and this warrants further investigation.

Most episodes of respiratory failure in people with NMD are likely to be caused by ineffective coughing during intercurrent chest infections (Bach 2003; Boentert 2017; Chatwin 2018). The identification of the most effective, safe measures to optimise cough efficacy and promote secretion clearance is, therefore, vital to optimising pulmonary function, preventing morbidity, and improving the quality of life in people with chronic NMD (Toussaint 2018).

Description of the intervention

Many airway clearance techniques are used in clinical practice in people with chronic NMD. Some techniques aim to move secretions from the peripheral to the more central airways (secretion mobilisation techniques), while others aim to clear secretions from the central airways (cough augmentation techniques) (Chatwin 2018; Toussaint 2018). Secretion mobilisation and an effective cough are both needed for effective secretion clearance (Farrero 2013; Finder 2010).

Manual techniques to assist peripheral secretion mobilisation in adults and children with chronic NMD include positioning, chest wall shaking, percussion and vibrations (Chatwin 2018; Finder 2010; McCool 2006; Toussaint 2018; Wang 2007). Other secretion mobilisation techniques that have been suggested for people with NMD include the active cycle of breathing and forced expiratory techniques; autogenic drainage; positive expiratory pressure therapy; oscillatory positive pressure therapy; intermittent positive pressure breathing (IPPB); chest wall strapping; intrapulmonary percussive ventilation, and high‐frequency chest wall oscillation (Anderson 2005; Bott 2009; Chatwin 2018; Douglas 1981; Finder 2010; Hull 2012; Toussaint 2003; Toussaint 2018). Active breathing exercises, such as the active cycle of breathing and positive expiratory pressure therapy, are effort dependent and, therefore, may not be useful in people with severe respiratory muscle weakness (Finder 2010; Hull 2012), unless concomitant ventilatory support is given (Chatwin 2018; Toussaint 2018).

Cough augmentation for proximal secretion clearance can be performed using manual or mechanical methods, alone or in combination, to support different components of the cough (Chatwin 2018; Finder 2010; Panitch 2017; Toussaint 2018). These may also be done in different body positions to optimise secretion clearance (Marques 2020). Techniques such as breath‐ or airstacking, glossopharyngeal breathing (GPB), and mechanical or manual single‐breath insufflations (blowing air into the lungs), augment inspiration to achieve sufficient inspiratory lung volumes before a cough (Bott 2009; Chatwin 2018; Toussaint 2018). People can achieve lung insufflation using positive pressure devices including ventilators (invasively or non‐invasively) and IPPB devices, with set pressure or volume limits, or both. They may achieve breathstacking independently (with glottic closure) or through use of an external self‐inflating manual resuscitator bag with a one‐way valve, if needed, to prevent air leak (Chatwin 2018; Toussaint 2018). For breathstacking, a person takes or receives multiple inspiratory breaths, without exhalation between breaths, until they achieve maximal insufflation capacity (MIC) (Bach 2007; Chatwin 2018; Marques 2014; Toussaint 2018). Thereafter, the individual releases the breath in a spontaneous or assisted forced expiratory manoeuvre or cough (Chatwin 2018; Marques 2014). MIC refers to the maximum tolerable inspiratory lung volume (Bach 2007; Chatwin 2018; Kang 2000). GPB or 'frog breathing,' which does not use any external equipment, requires the person with NMD to actively 'gulp' air into the lungs by opening and closing the glottis until MIC is reached (Bach 2007; Chatwin 2018; Nygren‐Bonnier 2009; Toussaint 2018).

Mechanical exsufflation (forcible expulsion of air from the lungs by artificial means) and manually assisted cough (MAC), the latter achieved by manually compressing the thorax, abdomen, or both, aim to improve expiratory flow rates by rapidly increasing intrathoracic pressure (Anderson 2005; Chatwin 2018; Finder 2010; Panitch 2017; Toussaint 2018).

Mechanical insufflation‐exsufflation (MI‐E) supports both insufflation and exsufflation, using a device that delivers a preset positive pressure into the airways for a set duration during inspiration (insufflation), immediately followed by an abrupt change to a preset negative exsufflation pressure, thereby simulating a cough with high expiratory flow rates (Anderson 2005; Chatwin 2018; Fauroux 2008; Morrow 2013; Panitch 2017; Toussaint 2018).

How the intervention might work

Both inspiratory and expiratory cough augmentation techniques aim to optimise cough efficacy by improving PCF when respiratory muscles are too weak to independently achieve sufficient flow rates for secretion clearance. The mechanism by which PCF is affected varies among different cough augmentation techniques (Chatwin 2018; Toussaint 2018).

Inspiratory cough augmentation techniques aim to augment inspiratory lung volumes to those required for an effective cough (MIC). By increasing inspiratory volume, these techniques enhance expiratory flow bias (creating higher expiratory than inspiratory air flow) during a spontaneous or assisted cough, thereby effectively mobilising and clearing secretions (Chatwin 2018). Inhaling a large volume of air before the compressive and expiratory phases of the cough optimises the length–tension relationship of expiratory muscles and may generate higher intrathoracic pressures and PCF (Boitano 2006; Chatwin 2018).

Expiratory cough augmentation techniques, whether manual or mechanical, aim to assist the weak expiratory muscles in generating sufficient intrathoracic pressures thereby increasing the expiratory flow generated during the cough. The overall aim is to increase PCF enough to effectively clear secretions from the central airways (Boitano 2006; Chatwin 2018; Toussaint 2018).

Some investigators have suggested that combining inspiratory and expiratory cough augmentation techniques could optimise cough clearance in people with NMD (Boitano 2006; Chatwin 2018; Hull 2012; Toussaint 2018; Trebbia 2005).

Why it is important to do this review

Cough augmentation techniques are considered essential to prevent pulmonary morbidity and progression to respiratory failure in people with NMD (Bach 2003; Chatwin 2018). In addition, they prevent acute respiratory failure, improve work of breathing, and relieve distress caused by retained secretions in the short term. However, it is still unclear which technique(s) offer the greatest clinical benefit with the least risk of harm.

Any application of positive pressure to the airways carries a risk of complications including abdominal distention, discomfort, gastro‐oesophageal reflux, cardiovascular effects such as changes in blood pressure and cardiac arrhythmia, and pneumothorax (Chatwin 2018; Homnick 2007; Morrow 2013; Toussaint 2018). Pneumothorax has been described in adults following the use of MI‐E (Suri 2008), breathstacking (Westermann 2013), and long‐term non‐invasive positive pressure ventilation (Vianello 2004). There may be greater risk of barotrauma and volutrauma in infants and young children with NMD compared to older children or adults, considering their different respiratory anatomy and physiology. Application of positive pressure will affect the lungs differently according to, for example, lung volumes and respiratory system compliance and resistance, all of which vary with age and NMD condition (Gattinoni 2003; Gattinoni 2010). The effects of MAC may be altered by chest wall compliance, which is almost twice that of controls in infants with NMD (Papastamelos 1996), and may be substantially reduced in adults with NMD, particularly in the case of chest wall deformities (Gozal 2000; Panitch 2009). During MI‐E specifically, applied insufflation volume is not usually measured in clinical practice, and a rapid swing to negative pressure follows insufflation. The combination of high applied tidal volume and atelectrauma (lung injury caused by repeated expansion and collapse of lung units) has been associated with lung injury in the context of invasive mechanical ventilation (Albuali 2007; Saharan 2010). The safety of MI‐E and other insufflation techniques is unclear in this regard and warrants further research.

Some cough augmentation techniques recommended in international guidelines for the treatment of people with NMD require equipment or expertise that are not readily available in lower‐resourced environments (Bott 2009; Chatwin 2018; Finder 2004; McCool 2006; Rosière 2009; Toussaint 2018; Wang 2007; Wang 2010), while cheaper and more readily available techniques may be equally effective (Anderson 2005; Finder 2010). Currently, people living with NMD and their caregivers generally manage their airway clearance according to perceived need, and clinical management is responsive to changes in the patient's condition (Toussaint 2018). The management approach also depends on availability of equipment and local expertise, which may vary substantially at a global level (Toussaint 2018). It is not yet clear what people with NMD and their caregivers prefer when considering the choice of cough augmentation technique, and this warrants investigation.

To advocate for the best and most appropriate treatment in different sociogeographical contexts, it is necessary to first determine which cough augmentation technique(s), dosages and frequencies are effective and safe for use in people with chronic NMD, using clinically relevant outcome measures.

Objectives

To determine the efficacy and safety of cough augmentation techniques in adults and children with chronic neuromuscular diseases.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs), quasi‐RCTs, and randomised cross‐over trials. We considered quasi‐RCTs (those in which participants were allocated using methods that were partly systematic, such as by case record number, date of birth, or alternation) were considered for inclusion, considering the likely paucity of high‐level RCTs in the field. We included studies reported as full text and those published as abstract only. There were no language restrictions.

Types of participants

We included adults, adolescents, and children with a diagnosis of chronic NMD that may affect the muscles of respiration.

Owing to age‐related changes in respiratory anatomy and physiology, we planned to stratify participants according to age. For the purposes of this review, 'infants' referred to children under the age of one year; 'children' from one to 13 years of age; and 'adolescents/adults' over the age of 13 years. We chose this cut‐off, as peak cough flow normally reaches adult levels above 12 years of age (Bianchi 2008). We also planned to stratify participants according to whether the intervention was 'rescue' therapy (i.e. intercurrent acute chest infection in a person with chronic NMD) or maintenance therapy, where possible.

We excluded people with the following comorbidities/characteristics.

  • Amyotrophic lateral sclerosis/motor neuron disease (ALS/MND), which is the focus of another review.

  • Acute NMD with likelihood of resolution (e.g. Guillain‐Barré syndrome).

  • Spinal cord injuries.

  • Neonates in the first month of life, as they are pathophysiologically and anatomically a unique patient group warranting a separate review.

We considered studies with mixed eligible and non‐eligible population groups for inclusion, but only extracted data for participants meeting eligibility criteria for synthesis and analysis. Where separate data were not available, we contacted trial authors to obtain subgroup data. Where we could not obtain additional data, we presented results for all participants narratively, noting the mixed nature of the population.

Types of interventions

We included trials comparing any cough augmentation technique or combination of techniques, whether provided as maintenance therapy or for treatment of intercurrent respiratory tract infection, with no treatment (unassisted cough), alternative cough augmentation techniques, or combinations thereof. We allowed co‐interventions if they were provided to each group equally.

Cough augmentation techniques included, but were not limited to, the following alone or in combination):

  • manual or mechanical insufflation;

  • air‐ or breathstacking;

  • GPB ('frog' breathing);

  • MI‐E;

  • mechanical exsufflation;

  • and MAC.

Types of outcome measures

In formulating primary and secondary outcome measures, we differentiated between cough augmentation techniques used for 'rescue' therapy (e.g. during intercurrent respiratory exacerbations) and maintenance therapy.

In addition to the formal outcome measures listed below, we planned to informally include any valid measure of economic comparison between cough augmentation techniques relative to health outcomes.

The outcomes listed here were not eligibility criteria for this review, but rather outcomes of interest within included studies.

Primary outcomes

  • Number of unscheduled hospital admissions for episodes of acute respiratory exacerbations over one year for 'maintenance' therapy.

  • Duration of hospital stay (days) for 'rescue' therapy.

Secondary outcomes

  • Peak cough flow (PCF) measured before and after intervention for 'rescue' therapy and measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy.

  • Any adverse events, including, but not limited to: pneumothorax, rib fractures, lung injury, aerophagia/abdominal distension, and death for both 'maintenance' and 'rescue' therapy.

  • Measures of gaseous exchange (e.g. oxygen saturation in arterial blood (SaO2) and expired carbon dioxide (CO2; end tidal carbon dioxide; ETCO2)) measured before and after the intervention for 'rescue' therapy, and measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy.

  • Pulmonary function measured by forced expiratory volume in one second (FEV1), forced vital capacity (FVC), vital capacity (VC), and peak expiratory flow rate (PEFR), over the short term (less than three months); medium term (between three months and one year); and long term (one year and longer), for 'maintenance' therapy. Where possible, values were presented as percentages predicted according to age, gender, and height; or as Global Lung Function Initiative multiethnic norm‐referenced Z score values (Quanjer 2012).

  • Quality of life measured by any validated measure over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy.

  • Validated measures of function, including measures of perceived exertion, exercise tolerance, and motor function measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy.

  • Participant preference for, or satisfaction with, specific cough augmentation techniques, expressed as a proportion or percentage of the sample (preference) or any validated measure (satisfaction) for both 'rescue' and 'maintenance' therapy.

Search methods for identification of studies

Electronic searches

On 10 January 2019 and 13 April 2020, the Information Specialist searched the following databases.

  • Cochrane Neuromuscular Specialised Register via the Cochrane Register of Studies (CRS‐Web; Appendix 1).

  • Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies (CRS‐Web; Appendix 2).

  • MEDLINE OvidSP (1946 to 10 April 2020; Appendix 3).

  • Embase OvidSP (1974 to 2020 Week 15; Appendix 4).

  • Cumulative Index of Nursing and Allied Health Literature (CINAHL) EBSCOhost (1937 to 13 April 2020; Appendix 1).

We also searched the following trials registries.

  • WHO International Clinical Trials Registry Platform (ICTRP; inaccessible on 13 April 2020; Appendix 2).

  • US National Institutes for Health Clinical Trials Registry (ClinicalTrials.gov; Appendix 3).

We searched all databases from their inception to the search date, and imposed no restriction based on language of publication, or by publication status (abstract only, 'in press,' 'grey' literature, full text, etc.).

Searching other resources

We searched reference lists of all primary studies and review articles for additional references. We also searched relevant manufacturers' websites for trial information and we searched for errata or retractions from included studies. We further performed handsearches for conference proceedings.

Data collection and analysis

Selection of studies

Using Covidence (Covidence), two review authors (BM and AH) independently screened titles and abstracts of all the studies identified from the search for inclusion criteria, and coded them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve.' We retrieved the full‐text study reports/publications, and two review authors (AH and LC) independently screened the full text and identified studies for inclusion, as well as identifying and recording reasons for exclusion of the ineligible studies. We resolved any disagreement through discussion and planned, if required, to consult a third review author as arbiter (BM). We identified and excluded duplicates and collated multiple reports of the same study so that each study rather than each report was the unit of interest in the review. We recorded the selection process in sufficient detail to complete a PRISMA flow diagram (Moher 2009).

Data extraction and management

We used a data extraction form for study characteristics and outcome data, which we piloted on one study in the review. One review author (BM) extracted study characteristics from included studies. We extracted data on:

  • study design and setting;

  • characteristics of participants (e.g. disease severity and age);

  • eligibility criteria;

  • intervention details;

  • outcomes assessed;

  • source(s) of study funding;

  • conflicts of interest among investigators.

Two review authors (AH and LC) independently extracted outcome data from included studies. We noted in the Characteristics of included studies table if outcome data were not reported in a usable way, and planned to resolve disagreements by consensus or by involving a third review author if necessary (MT). One review author (BM) transferred data into Review Manager 5 (Review Manager 2020). A second author checked the outcome data entries (AH). Another review author (MZ) spot‐checked study characteristics for accuracy against trial reports.

If reports required translation, it was planned that the translator would extract data directly using a data extraction form, or authors would extract data from the translation provided. Where possible a review author planned to check numerical data in the translation against the study report.

Assessment of risk of bias in included studies

Two review authors (LC and AH) independently assessed risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020a). We made summary assessments of the risk of bias for each important outcome (across domains) within and across studies comparing the same interventions. We resolved any disagreements by discussion or by involving another review author (BM) where necessary. We assessed the risk of bias according to the following domains.

  • Random sequence generation.

  • Allocation concealment.

  • Blinding of participants and personnel.

  • Blinding of outcome assessment.

  • Incomplete outcome data.

  • Selective outcome reporting.

  • Other bias.

We graded each potential source of bias as high, low, or unclear, and provided a quote from the study report together with a justification for our judgement in the 'Risk of bias' table. We planned to summarise the 'Risk of bias' judgements across different studies for each of the domains listed. We considered blinding separately for different key outcomes where necessary. If information on risk of bias had been related to unpublished data or correspondence with an author, we planned to note this in the 'Risk of bias' table.

When considering treatment effects, we considered the risk of bias for the studies that contributed to that outcome.

Assessment of bias in conducting the systematic review

We conducted the review according to the published protocol, and reported any deviations in the 'Differences between protocol and review' section (Morrow 2018).

Measures of treatment effect

We planned to analyse all data for 'rescue' and maintenance therapy using cough augmentation techniques separately. We planned to analyse dichotomous data as risk ratios (RRs) and continuous data as mean difference (MD) when studies used the same scale, or standardised mean difference (SMD) for results across studies with outcomes that were conceptually the same but measured in different ways. We reported 95% confidence intervals (CI). Where studies reported standard errors of the means (SEMs), we planned to convert these to standard deviations (SDs) where possible. We entered data presented as a scale with a consistent direction of effect.

We planned to calculate a Peto odds ratio (Peto OR) and corresponding 95% CI for rare adverse events. In the case of statistically significant results, we planned to calculate the risk difference (RD) and 95% CI and the number needed to treat for an additional beneficial outcome or for an additional harmful outcome as appropriate.

We planned to undertake meta‐analyses only where this was meaningful (i.e. where treatments, participants, and the underlying clinical questions were similar enough for pooling to be meaningful). We reported the types of cough augmentation techniques and different underlying conditions which could not be pooled separately (if the number of trials permitted).

We planned to describe skewed data reported as medians and interquartile ranges (IQRs).

Unit of analysis issues

We only included first‐period data from cross‐over trials for purposes of analysis, when sufficient data were available (Elbourne 2002; Higgins 2020b). Long‐term studies with multiple repeated measures of outcome could be included, in which case we planned to define outcomes based on the specified time points (Higgins 2020b).

Where multiple trial arms were reported in a single trial, we planned to only include the treatment arms relevant to the review topic. If two comparisons (e.g. treatment A versus no treatment and treatment B versus no treatment) were combined in the same meta‐analysis, we planned to follow guidance in Section 23.3.4 of the Cochrane Handbook for Systematic Reviews of Interventions to avoid double‐counting (Higgins 2020b). Our preferred approach was to halve the control group.

Dealing with missing data

We attempted to contact investigators or study sponsors to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study was available as an abstract only; where only pooled data or estimates of results were presented; and where separate period data were not presented for cross‐over studies). Where this was not possible, we considered the studies adequate if more than 85% of the participants were included in the outcome analysis or if fewer participants were analysed, but sufficient measures were taken to ensure or demonstrate that this did not bias the results. Where this was unclear, we planned to conduct an intention‐to‐treat analysis from extrapolated data. If we suspected that missing data may have introduced serious bias, we planned to explore the impact of including such studies in the overall assessment of results by a sensitivity analysis. 

Assessment of heterogeneity

We planned to use the I2 statistic to measure heterogeneity among the trials in each analysis. We planned to avoid the use of absolute cut‐off values, but to interpret the I2 statistic in relation to the size and direction of effects and strength of evidence for heterogeneity (e.g. P value from the Chi2 test, or CI for the I2 statistic). 

We planned to use the rough guide to interpretation as outlined in Chapter 9 of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2017), as follows:

  • 0% to 40%: might not be important;

  • 30% to 60%: may represent moderate heterogeneity;

  • 50% to 90%: may represent substantial heterogeneity;

  • 75% to 100%: considerable heterogeneity.

If we had identified substantial unexplained heterogeneity, we planned to report it and explore possible causes with prespecified subgroup analysis.

Assessment of reporting biases

If we had been able to pool more than 10 trials, we planned to create and examine a funnel plot to explore possible small‐study biases.

Data synthesis

We were unable to pool more than one study in any meta‐analysis due to inadequate presentation of results, as well as clinical and methodological heterogeneity. Where we could not source additional information, and there was insufficient information supplied, we reported the individual results as described in the original trials in qualitative, tabular, and narrative form. If the included trials had been similar enough to combine them, we would have performed a statistical pooling of effect measures using a random‐effects model, as this is more conservative, and explore possible causes of heterogeneity by subgroup analyses if there were sufficient studies to do so. We reported the results for each review outcome measure and comparison separately, where possible. We compiled the review using Review Manager 5 (Review Manager 2020).

Subgroup analysis and investigation of heterogeneity

We planned to carry out the following subgroup analyses.

  • Infants versus children.

  • Children versus adolescents or adults, or both.

We planned to use the following outcomes in subgroup analyses.

  • Number of hospital admissions over one year (for maintenance use).

  • Duration of hospital stay (days) for 'rescue' use.

We planned to use the formal test for subgroup interactions in Review Manager 5 (Review Manager 2020). Owing to inadequate data, we were unable to conduct subgroup analyses, and this is recommended for future versions of the review.

Sensitivity analysis

We planned the following sensitivity analyses, but could not conducted them owing to insufficient data. This should be considered for future versions of this review.

  • Repeat the analysis excluding unpublished studies (if there were any).

  • Repeat the analysis excluding studies with high risk of bias (e.g. randomised versus quasi‐randomised). We planned to rate studies at overall high risk of bias if there was a high risk of bias for one or more key domains (Higgins 2020a).

  • In the case of including one or more very large study, repeat the analysis excluding these to determine to what extent they dominated the results.

  • Repeat the analysis using different statistical models (fixed‐effect versus random‐effects).

Reaching conclusions

We based our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We avoided making recommendations for practice and our implications for research suggest priorities for future research and outline what the remaining uncertainties are in the area.

Summary of findings and assessment of the certainty of the evidence

We planned to create separate 'Summary of findings' tables for 'rescue' and 'maintenance therapy' using cough augmentation techniques, using GRADEpro GDT software, presenting the following outcomes.

  • Number of unscheduled hospital admissions for episodes of respiratory exacerbations over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy.

  • Duration of hospital stay (days) for 'rescue' therapy.

  • PCF measured before and after intervention(s) for 'rescue' and maintenance therapy and measured over the medium term (between three months and one year) and long term (one year and longer) for maintenance therapy.

  • Any adverse events measured over the short term, medium term (three months to one year), and long term (one year or longer) ('rescue' and maintenance therapy).

  • Quality of life measured by any validated measure over the medium term (between three months and one year) and long term (one year and longer) (maintenance therapy).

  • Participant preference for, or satisfaction with specific cough augmentation techniques ('rescue' and maintenance therapy), measured over the short term, medium term (three months to one year) and long term (one year or longer).

However, based on the included studies, we chose to rather present separate 'Summary of findings' tables for the comparison between cough augmentation technique(s) and alternative cough augmentation technique(s) and for the comparison between cough augmentation technique(s) and standard of care, for the above outcome measures.

Two review authors (BM and AH) independently assessed the certainty of the body of evidence (studies that contributed data for the prespecified outcomes) using the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias). We used methods and recommendations described in Chapters 11 and 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Schünemann 2017a; Schünemann 2017b). We resolved any disagreements by discussion or by involving another review author (LC) where necessary. We considered RCTs as high‐certainty evidence if the five factors above were not present to any serious degree, but could downgrade the certainty to moderate, low, or very low. We downgraded evidence once if a GRADE consideration was present to a serious degree, twice if very serious, and three times based on several GRADE concerns. We justified all decisions to downgrade or upgrade the certainty of evidence using footnotes, and made comments to aid readers' understanding of the review where necessary.

Results

Description of studies

See Characteristics of included studies, Characteristics of excluded studies, and Characteristics of ongoing studies tables.

Results of the search

The literature search identified 390 papers (see Figure 1 for study flow diagram): 20 from the Cochrane Neuromuscular Specialized Register, 142 from CENTRAL, 81 from MEDLINE, 55 from CINAHL, and 92 from EMBASE.

Figure 1
Study flow diagram.

Study flow diagram.

From ClinicalTrials.gov, we identified 76 potentially relevant ongoing clinical trials and 64 ongoing trials from ICTRP, from which we identified five studies for possible inclusion in future reviews (NCT01518439; NCT02651805; NCT03355105; NCT04081116; PACTR201506001171421) (see Characteristics of ongoing studies table).

We identified one study through other methods, after reviewing the published study protocol (Katz 2019). After removing duplicates, we reviewed the titles and abstracts of 281 papers, and identified a further two duplicates in this process. We selected 17 studies for full‐text review and excluded six of these studies, with reasons (Bianchi 2014; Kang 2000; Silva 2012; Toussaint 2003; Toussaint 2009; Winck 2004; see Characteristics of excluded studies table). Eleven studies met the inclusion criteria for the review (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Katz 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016).

Included studies

Ten included studies were full published articles (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016), while one study was a congress abstract, with detailed methodology published on ClinicalTrials.gov (Katz 2019). Full details of the Katz 2019 study results were not available, and attempts to contact the author were unsuccessful.

Region and setting

Three included studies were from the UK (Chatwin 2003; Chatwin 2009; Sivasothy 2001); three from Europe (two from France (Del Amo Castrillo 2019; Lacombe 2014) and one from Belgium (Toussaint 2016)); two from Canada (Jenkins 2014; Katz 2019); one from Brazil (Brito 2009); one from Korea (Kim 2016); and one was from Chile (Torres‐Castro 2016). Ten were short term (i.e. two days or less in duration) studies of the immediate effects of cough augmentation techniques in a hospital or clinic setting (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016). One two‐year study investigated the long‐term effects of maintenance interventions performed outside the hospital setting (Katz 2019).

Study design

Two studies were prospective parallel‐group RCTs (Katz 2019; Toussaint 2016). Toussaint 2016 was a single‐centre, short‐term trial of a single intervention (52 participants); while the study by Katz 2019 was a long‐term multicentre study conducted over two years (67 participants). Katz 2019 further used a minimisation technique to allocate participants to intervention arms to ensure between‐group matching. With minimisation, allocation of the next participant depends wholly or partly on the characteristics of participants already enrolled in the trial, with only the first participant being truly randomised (Altman 2005). Minimisation is considered a valid alternative to ordinary randomisation, and has the advantage of better balancing intervention groups, especially in smaller trials (Altman 2005). Sufficient data for analysis were available for Toussaint 2016; however, the abstract of Katz 2019 did not provide sufficient data for analysis.

Most studies were cross‐over trials in which all participants received every intervention in random order, in a single session, with variable washout periods between interventions (Brito 2009; Chatwin 2003; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016). One study was a randomised cross‐over trial conducted over two days, in which eight participants were randomly assigned to receive MI‐E for one treatment session and no MI‐E for a second treatment session, with a reverse cross‐over the following day (Chatwin 2009). Only the first part of Jenkins 2014 was randomised, a second substudy involved systematically assigned interventions and, therefore, we did not include it in this review. Torres‐Castro 2016 and Lacombe 2014 provided additional first‐period data on request, which could be analysed. The remaining cross‐over trials did not present separate first‐period data, or make these data available, precluding meta‐analysis (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Sivasothy 2001).

Participants

Participants were adults and children (total 287) with a variety of NMDs ranging in age from three to 73 years. Four studies included adults only: Lacombe 2014 included 18 adults aged 21 to 68 years; Toussaint 2016 included 52 adults with a mean age of 25.3 (SD 5.1) years (27 participants) in the mechanical breathstacking group and 24.7 (SD 5.7) years (25 participants) in the manual stacking group; Del Amo Castrillo 2019 included 20 adults aged 21 to 71 years; and Sivasothy 2001 included four adults with respiratory muscle weakness and scoliosis secondary to NMD, aged 44 to 66 years. Katz 2019 included 67 children and adolescents aged six to 16 years (median 11.4 years) and Torres‐Castro 2016 included 14 children and adolescents aged from nine to 18 years. The remaining studies had mixed child, adolescent, and adult populations: Chatwin 2003 included eight children and adolescents aged 10 to 17 years, and 14 adults aged 18 to 56 years. Chatwin 2009 included two children aged four and 12 years, and six adults aged 21 to 44 years. Jenkins 2014 included 13 children and adolescents with NMDs aged four to 18 years, and one adult aged 19 years. Kim 2016 did not report separate paediatric and adult data, but enrolled 40 participants with a mean age of 20.9 (SD 7.2) years. Similarly, Brito 2009 included 28 participants over 10 years old (mean 20, SD 4 years), and did not report separate data for children, adolescents, and adults. Reports provided insufficient information to enable subgroup analysis for different age groups or comorbid conditions.

Conditions

Duchenne muscular dystrophy (DMD) was the most commonly reported condition (207 participants), with three studies only including participants with DMD (Brito 2009; Katz 2019; Toussaint 2016). The other studies included a range of NMDs including DMD (Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016); SMA (39 participants) (Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016); poliomyelitis or postpolio syndrome (six participants) (Chatwin 2003; Del Amo Castrillo 2019; Sivasothy 2001); congenital muscular dystrophy (CMD) (four participants) (Chatwin 2003; Lacombe 2014); congenital myopathy (five participants) (Chatwin 2009; Kim 2016; Torres‐Castro 2016); Becker muscular dystrophy (BMD) (three participants) (Del Amo Castrillo 2019; Jenkins 2014; Lacombe 2014); gamma‐sarcoglycanopathy (four participants) (Del Amo Castrillo 2019; Lacombe 2014); acid maltase deficiency (three participants) (Del Amo Castrillo 2019; Lacombe 2014), and other NMDs, including Ulrich Syndrome (two participants) and facio‐scapulo‐humeral muscular dystrophy, vacuolar myopathy, congenital fibre type disproportion (myopathy), limb girdle muscular dystrophy, Charcot‐Marie‐Tooth Type 1 disease, progressive muscular dystrophy, and myasthenia gravis (one participant each) (Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014).

Two studies included comparative participant groups without NMD (Chatwin 2003; Sivasothy 2001), healthy controls (Chatwin 2003; Sivasothy 2001), or controls with chronic obstructive pulmonary disease (COPD) (Sivasothy 2001), which were not eligible for inclusion in this review. Therefore, we only included data for the groups of participants with NMD. Jenkins 2014 also included participants with other central nervous system (CNS) disorders (including cerebral palsy (two participants), and seizure disorder, spinal cord injury, Rett syndrome, encephalomalacia, hypoxic brain injury, Batten disease, and Cri‐du‐Chat syndrome (one participant each)), but did not provide separate data for participants with NMDs versus CNS disorders. Similarly, Torres‐Castro 2016 included one participant with spinal cord injury, but it was not possible to analyse participants with NMD separately. Sivasothy 2001 included seven of eight participants in a non‐scoliotic participant group with ALS; therefore, we did not include this group's data in the review. We only included and described data from the participant group with eligible NMD and scoliosis (four participants) in this review (Sivasothy 2001).

One study investigated participants admitted to hospital with acute respiratory tract infections, thereby receiving 'rescue' therapy (Chatwin 2009); while one other study investigated the effects of a two‐year course of cough augmentation therapy as maintenance therapy (Katz 2019). Jenkins 2014 included both inpatients and outpatients but did not distinguish between results obtained with rescue and maintenance therapy. This study did not report participants' respiratory infection status, although participants requiring oxygen therapy were excluded (Jenkins 2014). Eight studies specifically investigated stable participants without intercurrent infection (Brito 2009; Chatwin 2003; Del Amo Castrillo 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016).

There were insufficient data to allow for subgroup analysis among different conditions, participant ages, and therapy circumstances ('rescue' or maintenance therapy).

Interventions

Studies compared cough augmentation techniques to alternative and combination techniques (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016); standard or conventional management (Katz 2019); spontaneous unassisted cough (Kim 2016); or sham interventions (Jenkins 2014). Ten studies reported a change in outcome measurements from baseline or preintervention unassisted cough to intervention‐assisted cough, but unassisted cough in these studies was not a randomly assigned intervention (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Katz 2019; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016). A summary of interventions and main results is presented in Table 2; Table 3; and Table 4, and descriptions of the interventions are fully described in the Characteristics of included studies table.

Open in table viewer
Table 4. Study results grouped by outcome measures and interventions – cough augmentation therapy compared to standard care

Outcome measure

Study identifier

Sample size

Data presentation

Unassisted cough

Manual BS

Standard care

Between‐group differences

Number and duration of unscheduled hospital and ICU admissions

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

Unassisted PCF

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

Health‐related quality of life

Katz 2019

n = 67

Pediatric Quality of Life Inventory score

—

Not reported

Not reported

No results reported

FVC

Katz 2019

n = 67

Median

% predicted

85.5 (entire cohort)a

4.1% change

6.4% change

Adjusted MD 2.0, 95% CI –8.2 to 12.3

Time to 10% decline in FVC

Katz 2019

n = 67

Not reported

—

Data not reported

Data not reported

Manual BS vs standard care: P = 0.5

Maximal inspiratory or insufflation capacity

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

MEP

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

MIP

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

Number and duration of outpatient oral antibiotic courses

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

BS: breathstacking; CI: confidence interval; FVC: forced vital capacity; ICU: intensive care unit; MD: mean difference; MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; n: number of participants; PCF: peak cough flow.

aBaseline value – not a randomly assigned control

Cough augmentation techniques included mechanical insufflation (Chatwin 2003; Del Amo Castrillo 2019; Sivasothy 2001); mechanical exsufflation (Chatwin 2003); MI‐E (Chatwin 2003; Kim 2016; Lacombe 2014); MAC (Brito 2009; Chatwin 2003; Chatwin 2009; Sivasothy 2001); manual or ventilator‐assisted breathstacking, or both (Brito 2009; Del Amo Castrillo 2019; Jenkins 2014; Katz 2019; Torres‐Castro 2016; Toussaint 2016); GPB (Torres‐Castro 2016); and breathstacking plus MAC (Brito 2009; Kim 2016); MAC plus MI‐E (Chatwin 2009; Kim 2016; Lacombe 2014); and mechanical insufflation plus MAC (Del Amo Castrillo 2019; Lacombe 2014; Sivasothy 2001).

One RCT conducted over two years compared conventional treatment (which could have included chest physiotherapy or peripheral airway clearance techniques, or both; nutritional support; antibiotics; non‐invasive ventilation (NIV) and systemic steroids) to conventional treatment plus twice daily lung volume recruitment/breathstacking, using a self‐inflating resuscitation bag with a one‐way valve (Katz 2019). Measures of adherence to the intervention were not reported (Katz 2019). One randomised cross‐over trial conducted over two days compared standardised airway clearance therapy (with MAC and ventilator‐assisted active cycle of breathing technique) with and without MI‐E (Chatwin 2009). Ventilator tidal volumes and pressures applied for the thoracic expansion component of the active cycle of breathing technique and preinsufflation part of the cough were not reported (Chatwin 2009). Toussaint 2016 compared mechanical breathstacking using a home mechanical ventilator to manual breathstacking with a resuscitation bag. Del Amo Castrillo 2019 compared standard, mechanical breathstacking using a home ventilator to augmented mechanical insufflation using the ventilator's volumetric cough mode, which provides a programmable intermittent deep breath set at a percentage of the baseline tidal volume. Torres‐Castro 2016 compared manual breathstacking (using a resuscitation bag and one‐way valve) to GPB. Brito 2009 compared MAC to manual breathstacking (using a resuscitation bag) and manual breathstacking plus MAC; Chatwin 2003 compared baseline maximal unassisted cough to 1. standard "physiotherapy assisted cough;" 2. cough after supported inspiration by a non‐invasive positive pressure ventilator (mechanical insufflation); 3. exsufflation‐assisted cough with negative pressure initiated manually at end‐inspiration; 4. insufflation‐assisted cough using a mechanical in‐exsufflator; and 5. mechanical exsufflation‐assisted cough with negative pressure delivered immediately preceding the cough effort. Chatwin 2003 did not clearly describe the method of performing "standard physiotherapy‐assisted cough," but we presumed it to include or be equivalent to MAC. Jenkins 2014 compared involuntary manual breathstacking using a self‐inflating resuscitator bag and one‐way valve, to sham breathstacking; Kim 2016 compared unassisted cough, MAC performed after manual breathstacking to maximal inspiratory capacity, MI‐E and MI‐E plus MAC; Lacombe 2014 compared mechanical insufflation (using a positive pressure ventilator) plus MAC, MI‐E plus MAC and MI‐E alone; and Sivasothy 2001 compared MAC alone to mechanical insufflation (delivered using an MI‐E device) and to mechanical insufflation plus MAC.

Studies applied MAC using pressure to the abdomen (Chatwin 2009; Jenkins 2014; Kim 2016), chest (Brito 2009), or both abdomen and chest (Sivasothy 2001); while Lacombe 2014 used abdominal, thoracic, or thoraco‐abdominal compression according to participant comfort. Chatwin 2003 did not describe the therapist's hand position for "physiotherapy assisted cough," but, in the study's literature review, MAC is mentioned as forming part of standard physiotherapy treatment and we assumed that the techniques were equivalent (Chatwin 2003).

Studies applied insufflation‐assisted cough mechanically using a non‐invasive positive pressure ventilator (Chatwin 2003; Del Amo Castrillo 2019; Lacombe 2014) or MI‐E devices (Sivasothy 2001). Ventilators used for insufflation were a bilevel positive airway pressure ventilator (BiPAP: Respironics Inc. Murraysville, North Carolina, USA or Breas MedicalSweden), with insufflation pressures titrated to participant comfort (Chatwin 2003); a ventilator equipped with volumetric cough mode (Astral 150, Resmed, Saint‐Priest, France) (Del Amo Castrillo 2019); and an Alpha 200C ventilator (Air Liquide, France), set to provide IPPB with a low inspiratory trigger and gradually increased inspiratory pressure to the highest tolerated value, to a maximum of 40 cmH2O, with inspiratory flow set according to patient comfort (Lacombe 2014). Sivasothy 2001 used a "CoughAssist" MI‐E device (JH Emersen, Cambridge, Massachusetts, USA) to provide insufflation, in which two cycles of both insufflation and exsufflation (set at +20 cmH2O/–20 cmH2O) were followed by a third insufflation and maximal spontaneous cough, which was measured without assistance or exsufflation support (Sivasothy 2001).

Exsufflation‐assisted cough was applied using a "CoughAssist" MI‐E device (JH Emersen, Cambridge, Massachusetts, USA) with the negative pressure applied manually at the end of inspiration (Chatwin 2003). Exsufflation pressures were titrated for participant comfort and reported to have a mean of –15 (SD 9) cmH2O (Chatwin 2003).

Five studies applied breathstacking using a manual resuscitation bag and face mask interface (Brito 2009; Jenkins 2014; Katz 2019; Torres‐Castro 2016; Toussaint 2016). Brito 2009, Jenkins 2014, Katz 2019, and Torres‐Castro 2016 specified use of a unidirectional valve during manual breathstacking. Brito 2009 and Jenkins 2014 applied three consecutive stacking breaths without exhalation before the maximum exhalation or cough, while Katz 2019 and Torres‐Castro 2016 did not specify the required number of stacked breaths to reach maximal insufflation. Toussaint 2016 individualised the number of successive inspirations for each participant, but participants were typically instructed to take "two to three successive insufflations" without breathing out in‐between. Jenkins 2014 applied sham breathstacking using the same technique as involuntary resuscitation bag breathstacking, but in the absence of a directional valve. Toussaint 2016 specified using a 2 L resuscitator bag (Resutator 2000, Dräger, Germany), while other studies did not specify the size of the resuscitator bag used.

Toussaint 2016 and Del Amo Castrillo 2019 applied mechanical breathstacking using volume‐cycled home mechanical ventilators and nasal mask (Toussaint 2016) or face mask (Del Amo Castrillo 2019) interfaces. Del Amo Castrillo 2019 specified that consecutive inspiratory‐hold insufflations were performed until participants felt their lungs were fully expanded or until the insufflation pressure plateau was 50 cmH2O.

Two studies delivered mechanical insufflation/exsufflation‐assisted cough using the CoughAssist device manufactured by JH Emerson Co (Cambridge, Massachusetts, USA) (Chatwin 2003; Lacombe 2014), and two studies used the Philips Respironics (Murraysville, Pennsylvania, USA) (Chatwin 2009; Kim 2016). All four studies reporting MI‐E used a full‐face mask interface (Chatwin 2003; Chatwin 2009; Kim 2016; Lacombe 2014). Insufflation pressures ranged from +15 (SD 3) cmH2O (Chatwin 2003, titrated for patient comfort); through +20 cmH2O (range 15 cmH2O to 35 cmH2O) (Chatwin 2009, titrated for patient comfort); up to +40 cm H2O (Kim 2016; Lacombe 2014). Exsufflation pressures ranged from –40 cmH2O (Kim 2016; Lacombe 2014); –20 cmH2O (range –20 cmH2O to –40 cmH2O) (Chatwin 2009); to –15 (SD 9) cmH2O (Chatwin 2003). Kim 2016 set the MI‐E device to deliver ± 40 cmH2O pressures as standard, while Lacombe 2014 reported gradually increasing or decreasing insufflation/exsufflation pressures to the highest or lowest tolerated values. All studies used the MI‐E device in manual mode (Chatwin 2003; Chatwin 2009; Kim 2016; Lacombe 2014). Chatwin 2003 and Lacombe 2014 did not describe insufflation/exsufflation and pause times, while Chatwin 2009 used an insufflation time of two seconds to four seconds and exsufflation time of four seconds to five seconds and Kim 2016 used an insufflation time of three seconds and exsufflation time of two seconds. Only Kim 2016 reported a three‐second pause between cycles. Lacombe 2014 set insufflation flow (and therefore insufflation time) according to participant comfort. Chatwin 2003 and Lacombe 2014 did not describe the number of MI‐E cycles delivered, while Kim 2016 applied five cycles of insufflation and exsufflation.

Torres‐Castro 2016 included GPB, in which participants were instructed to perform successive air "swallowing" manoeuvres, until they achieved maximum volume.

Outcomes

Ten studies reported only short‐term outcome measures of interventions, mostly in the context of single treatment sessions (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016). Only one studies planned to report on this review's primary outcome measures (number of unscheduled hospital admissions and duration of hospital stay) in 67 participants; however, the results of this outcome measure were not reported in the published abstract and, therefore, could not be included in qualitative or quantitative analysis (Katz 2019). Although some studies reported our secondary short‐term outcome measures of PCF and gaseous exchange, measured before and after intervention, we note that only one study measured them in the context of 'rescue' therapy, in eight participants (Chatwin 2009).

Objective outcomes measured in the included studies were: PCF (265 participants) (Brito 2009; Chatwin 2003; Del Amo Castrillo 2019; Katz 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016); FVC and time to reach a 10% decline in FVC (67 participants) (Katz 2019); physiological variables of heart rate (eight participants) (Chatwin 2009); transcutaneous oxygen saturation (31 participants) (Chatwin 2009; Jenkins 2014); transcutaneous carbon dioxide tension (PtcCO2) (eight participants) (Chatwin 2009); respiratory rate (23 participants) (Jenkins 2014); cough expiratory volume and peak value time (four participants) (Sivasothy 2001); treatment time (eight participants) (Chatwin 2009); oesophageal or gastric pressures (four participants) (Sivasothy 2001); tidal volume (23 participants) (Jenkins 2014); inspiratory or insufflation capacity (171 participants) (Del Amo Castrillo 2019; Katz 2019; Lacombe 2014; Torres‐Castro 2016; Toussaint 2016); effective cough time (time with PCF of more than 3 L/second) (18 participants) (Lacombe 2014); maximal expiratory pressure (MEP) (119 participants) (Katz 2019; Toussaint 2016); maximal inspiratory pressure (MIP) (67 participants) (Katz 2019); and the number of insufflations to reach MIC (52 participants) (Toussaint 2016).

Subjective outcome measures were: scores on a visual analogue scale (VAS) for participant comfort (46 participants) (Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Lacombe 2014); distress (22 participants) (Chatwin 2003); breathlessness (eight participants) (Chatwin 2009); fatigue (eight participants) (Chatwin 2009); mood (eight participants) (Chatwin 2009); secretion production (eight participants) (Chatwin 2009); and cough effectiveness or strength (42 participants) (Chatwin 2003; Del Amo Castrillo 2019; Lacombe 2014). Chatwin 2009 (eight participants) measured auscultation score. Sivasothy 2001 asked four participants to report whether the intervention had aided, impaired, or had no effect on their cough. None of the included studies included standardised, valid measures of function, or participant preference.

Katz 2019 planned to measure health‐related quality of life, using the Pediatric Quality of Life Inventory (PedQL) Score in 67 participants; however, this outcome was not reported in the published abstract.

None of the studies listed adverse events as a primary or secondary outcome. Chatwin 2003 (22 participants) and Sivasothy 2001 (four participants) reported there had been no adverse events. Kim 2016 (40 participants) reported that the interventions were "well tolerated." Chatwin 2009 (eight participants) reported fatigue as an adverse effect of MI‐E.

It was unclear whether serious adverse events such as pneumothorax were systematically investigated in any of the studies.

Potential conflicts of interest

Chatwin 2009 disclosed a relationship with a healthcare company that manufactured ventilation equipment, although the nature of the relationship and the relevance to this study was unclear. Del Amo Castrillo 2019 disclosed a relationship with ResMed France, the company who manufacture the ventilator device with volumetric cough mode used in their study. The exact nature of the relationship was unclear. Katz 2019 declared relationships with a pharmaceutical company, but it was unclear whether these relationships would have constituted a source of bias. Jenkins 2014 and Brito 2009 declared their funding source, which, in both studies, was unlikely to constitute a conflict of interest. Chatwin 2003, Lacombe 2014, Sivasothy 2001, Torres‐Castro 2016, and Toussaint 2016 did not declare funding sources or other potential conflicts of interest. Kim 2016 declared no financial conflicts of interests, but other interests were not declared.

Excluded studies

We excluded six studies (see Characteristics of excluded studies table): four due to incorrect study design (Bianchi 2014; Kang 2000; Toussaint 2009; Winck 2004); one because of the incorrect population (Silva 2012), and one did not describe a cough augmentation technique and we excluded it based on studying the incorrect intervention (Toussaint 2003).

Kang 2000 investigated the relationships between VC, MIC, and both unassisted and assisted PCF (using manual insufflation versus unassisted or spontaneous PCF in two groups of participants with MIC greater than or equal to their VC). The study was not designed to determine effectiveness of the cough augmentation interventions, and neither the allocation nor order of intervention was randomised.

Toussaint 2009 conducted a prospective cross‐sectional observational study investigating three cough augmentation techniques (MAC, breathstacking, and breathstacking with MAC) in 179 clinically stable participants with a range of NMDs. Breathstacking as well as breathstacking plus MAC was only conducted in a subgroup of 60 participants receiving NIV.

Winck 2004 conducted a prospective observational study to evaluate the tolerance of three different MI‐E pressures (+15 cmH2O to –15 cmH2O, +30 cmH2O to –30 cm H2O, and +40 cmH2O to –40 cm H2O) in a heterogeneous sample of people with NMD (seven participants), ALS (13 participants), and COPD (nine participants). Data for each participant group were provided separately. The MI‐E pressures were increased systematically for each participant, without randomisation of order.

Silva 2012 studied the effect of MAC alone or in association with increased positive end‐expiratory pressure (PEEP) and inspiratory time on peak expiratory flow and respiratory mechanics in mechanically ventilated participants diagnosed with head trauma, stroke, congestive heart failure, and ventilator‐associated pneumonia. The study did not include participants with NMD.

Toussaint 2003 conducted a randomised cross‐over study comparing mucous clearance techniques with and without intrapulmonary percussive ventilation (IPV), in eight participants with DMD (five with mucous hypersecretion). IPV is considered a peripheral airway clearance technique, not a proximal clearance (cough augmentation) technique, and we determined the intervention ineligible for this review.

Bianchi 2014 conducted a prospective observational study on 18 participants (aged 21.1 (SD 5.4) years) with muscular dystrophy, comparing unassisted PCF to augmented PCF using various interventions, including GPB; a self‐induced thoracic or abdominal thrust (by independently manoeuvring a wheelchair into a table); assistant‐delivered MAC; breathstacking; and combination techniques. There was no randomisation or allocation to different interventions or order of interventions, and this study was ineligible for inclusion in this review.

Risk of bias in included studies

See Figure 2, Figure 3, and the Characteristics of included studies table.

Figure 2
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Figure 3
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

Eight studies provided no details about the method of randomisation (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001). Katz 2019 used a minimisation technique, but provided no details of the minimisation methodology. Therefore, we judged these studies at unclear risk of bias for the generation of randomisation sequence. Toussaint 2016 conducted an RCT that randomised participants to receive one of the two interventions by means of a coin toss. Torres‐Castro 2016 described using freely available software to generate random number lists. We judged these two studies at low risk of selection bias. None of the included studies described allocation concealment, leading to a judgement of unclear risk of selection bias for all included studies.

Blinding

Considering the nature of cough augmentation interventions, it is highly unlikely that participant or clinician blinding would have been possible, leading to a high risk of performance bias in 10 studies (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Katz 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016).

Jenkins 2014 used a sham intervention as a control, but it was unclear if blinding was successfully achieved. Both involuntary breathstacking and sham interventions were performed in the same way except for the presence or absence of a valve. It was unclear if the masks looked identical, with a sham valve, or whether the valve was simply not added to the mask circuit for the sham intervention. Therefore, the risk of performance bias for participants was unclear. Considering therapists applying the intervention would likely have known whether a one‐way valve was applied or not, we judged the risk of personnel (therapist) performance bias as high. Overall, therefore, we judged the risk of performance bias in Jenkins 2014 as unclear.

Owing to insufficient methodological information, it was unclear whether six studies blinded outcome assessors, which we judged at unclear risk of detection bias (Chatwin 2003; Chatwin 2009; Jenkins 2014; Katz 2019; Lacombe 2014; Sivasothy 2001). Five studies measured outcomes while investigators were performing the study interventions, and, therefore, outcome assessment could not have been blinded, leading to a high risk of detection bias (Brito 2009; Del Amo Castrillo 2019; Kim 2016; Torres‐Castro 2016; Toussaint 2016).

Incomplete outcome data

All participants completed the interventions, or were appropriately accounted for, in eight studies, leading to a judgement of low risk of attrition bias (Brito 2009; Chatwin 2003; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Toussaint 2016). In two studies, it was unclear whether all included participants completed all outcome measurements, as this was not explicitly stated in the text (Chatwin 2009; Katz 2019). In one study, three participants were excluded after screening, but the trial authors did not provide clear reasons for exclusion (Torres‐Castro 2016). We judged the risk of attrition bias for these three studies as unclear (Chatwin 2009; Katz 2019; Torres‐Castro 2016).

Selective reporting

We judged three studies at high risk of reporting bias (Brito 2009; Chatwin 2009; Katz 2019). Brito 2009 did not present all stated baseline measurements (SpO2; expired CO2) but fully reported the primary outcome of PCF. Chatwin 2009 presented no data for the primary physiological outcome measures of peripheral capillary oxygen saturation (SpO2), heart rate, and PtcCO2. In addition, the study only presented VAS scores for comfort, breathlessness, and mood as graphs, and we could not extract the data precisely. Katz 2019 presented selected outcome measures in the published abstract, while the published protocol presented several primary and secondary outcome measures that were not reported in the abstract. Efforts to obtain missing data for these studies were unsuccessful.

We judged three studies at unclear risk of reporting bias (Chatwin 2003; Lacombe 2014; Sivasothy 2001). Chatwin 2003 did not report separate VAS scores of patient comfort, distress, and strength of cough. Lacombe 2014 presented several outcome measures graphically, with specific values not reported for PCF, inspiratory capacity, and effective cough time. Sivasothy 2001 did not clearly describe the study's primary and secondary outcome measures and did not mention a trial registration number, so the review authors could not confirm the outcome measures by checking the predescribed protocol. The report did not present gastric and oesophageal pressures; however, the trial authors acknowledged this and ascribed it to a measurement problem owing to collapse of balloons in the control groups. The trial authors did not fully report the subjective outcome measure of cough effectiveness, but simply stated that participants did not report any benefit of any assisted cough interventions. Sivasothy 2001 fully reported other measured outcomes.

The other five studies reported all the prespecified primary and secondary outcome measures and we judged these studies at low risk of reporting bias (Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Torres‐Castro 2016; Toussaint 2016).

Other potential sources of bias

We judged one study at low risk of other biases (Toussaint 2016), and two studies at unclear risk (Katz 2019; Torres‐Castro 2016). Torres‐Castro 2016 did not explicitly identify primary and secondary outcomes and Katz 2019 provided insufficient information to judge the risk of other biases. We judged eight studies at high risk of other bias, considering they were all short‐term cross‐over trials with no analysis of carry‐over effect, and no separate period reporting in the primary publication (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001). A short‐term cross‐over study design may not be the most appropriate for studies on conditions such as NMD, which require long‐term follow‐up. Also, none of these studies considered the potential confounder of learning effect on outcome measurement, and this may have influenced the results. 'Learning effect' refers to participants improving their ability to perform or co‐ordinate the outcome assessment (e.g. PCF technique) through practice and learning, rather than showing an objective improvement in the actual outcome being measured. Lacombe 2014 and Torres‐Castro 2016 provided separate baseline data for group allocation; for the other cross‐over studies it was unclear whether groups were well balanced at baseline, or whether the groups were treated the same except for the intervention (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001). Other potential confounders in studies included: presence of comorbid conditions (Brito 2009; Del Amo Castrillo 2019; Katz 2019); oral/bulbar control (Chatwin 2003; Jenkins 2014; Sivasothy 2001; Torres‐Castro 2016); heterogeneity of included conditions or ages, or both (Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Torres‐Castro 2016); and concomitant use of NIV (Katz 2019; Kim 2016).

Effects of interventions

See: Summary of findings 1 Cough augmentation therapy compared with an alternative cough augmentation technique or combination of techniques for people with neuromuscular diseases; Summary of findings 2 Cough augmentation therapy compared with standard care for people with neuromuscular diseases

One study was a short‐term RCT (Toussaint 2016), the main results of which are presented in Analysis 1.1 and Analysis 1.2. Katz 2019 conducted a long‐term RCT; however, the published abstract provided insufficient data. Attempts to contact the author were unsuccessful, and we could not perform any additional analysis.

Eight studies applied every intervention to every included participant in a single session, in random order (Brito 2009; Chatwin 2003; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016). Therefore, each participant received several interventions. None of these published reports presented individual responses to each intervention, which could have allowed secondary analysis. However, Torres‐Castro 2016 and Lacombe 2014 provided additional individual data on request, allowing separate first‐period analysis of one our secondary outcome measures, PCF (Analysis 2.1; Analysis 3.1; Analysis 4.1; Analysis 5.1). Meta‐analysis and pooling of the results of the remaining six studies was not possible, owing to the repeat counting that occurred, which would cause unit‐of‐analysis errors from the unaddressed correlation between the estimated intervention effects of multiple comparisons (Higgins 2020b). The two‐day cross‐over study by Chatwin 2009 also did not report data separately for the two periods of the study, precluding inclusion in a meta‐analysis. All the reported quantitative results of the included studies are presented in Table 2; Table 3; and Table 4. The main results for studies comparing cough augmentation technique(s) with alternate cough augmentation technique(s) are summarised in summary of findings Table 1 and results for studies comparing cough augmentation technique(s) with standard of care are presented in summary of findings Table 2.

Cough augmentation therapy compared with alternative cough augmentation therapy

Ten studies compared cough augmentation therapies to alternative individual or combination cough augmentation therapies (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016). See summary of findings Table 1.

Primary outcomes
1. Number of unscheduled hospital admissions for episodes of acute respiratory exacerbations over one year, for 'maintenance' therapy

No studies reported number of hospital admissions for episodes of acute respiratory exacerbations over one year, for 'maintenance use.'

2. Duration of hospital stay (days) for 'rescue' therapy

No studies reported duration of hospital stay (days) for 'rescue' use.

Secondary outcomes
1. PCF measured before and after intervention for 'rescue' therapy and measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy

PCF was the most common outcome, measured in eight studies with 198 participants (Brito 2009; Chatwin 2003; Del Amo Castrillo 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016). These studies reported the immediate effect on PCF of the cough augmentation techniques, whether for acute or maintenance use (summary of findings Table 1; Table 1). We considered the certainty of evidence for this outcome very low, downgrading twice for very serious study limitations (risk of bias) and once for imprecision (all studies had a small sample size, wide CIs, or both).

Manual versus mechanical breathstacking

Toussaint 2016 compared PCF (the primary outcome) with mechanical breathstacking compared to manual breathstacking. The mean (± SD) PCF increased in the mechanical breathstacking group from 132 (SD 55) L/minute to 199 (SD 48 L/min) (within‐group P = 0.001) compared to the manual breathstacking group, in which PCF increased from 125 (SD 52) L/min to 186 (SD 50 L/min) (within‐group P < 0.001). This study reported no evidence of a difference between the two intervention groups in the PCF change (between‐group MD 6.00 L/minute, 95% CI –33.43 to 45.43; P = 0.3; 52 participants; Analysis 1.1). The conclusion of lack of difference between resuscitator bag and ventilator breathstacking on PCF was based on a low‐certainty evidence, double downgraded as results were from a single study (Toussaint 2016), with substantial risk of bias due to lack of blinding of personnel, participants, or assessors; and unclear allocation concealment.

Glossopharyngeal breathing versus manual breathstacking

Torres‐Castro 2016 provided data for the first cross‐over period, which could be analysed. This study compared PCF at baseline and after either GPB or breathstacking using a self‐inflating resuscitator bag, in adults with DMD. In the first period of cross‐over, mean PCF in the manual breathstacking group increased from 162.86 (SD 77.4) L/min to 235.71 (SD 125.01) L/min (MD 72.86 (SD 61.84) L/minute, 95% CI 15.67 to 130.05; within‐group P = 0.02); while PCF in the GPB group increased from 167.14 (SD 42.71) L/min to 199.29 (SD 52.95) L/min (MD 32.14 (SD 26.44) L/min, 95% CI 7.69 to 56.59; within‐group P = 0.02). There was no evidence of a difference in the change of PCF between groups (between‐group MD –40.72, 95% CI –90.54 to 9.10; P = 0.14; 14 participants; Analysis 2.1). The conclusion that GPB and manual breathstacking have a similar effect on PCF was based very low‐certainty evidence, triple downgraded based on data extracted from a single randomised cross‐over study design (Torres‐Castro 2016), with unclear allocation concealment, very small sample size, imprecision of results (wide CIs), and substantial risk of performance and detection bias.

MI‐E versus mechanical insufflation plus MAC

Lacombe 2014, in adults with a range of NMD, provided separate allocation data for the first period of cross‐over, which could be analysed. The first period of cross‐over reported increases from baseline with both MI‐E and mechanical insufflation plus MAC. Mean PCF increased from 157.2 (SD 64.2) L/min (unassisted cough) to 210.6 (SD 52.8) L/min with MI‐E alone (MD 53.4 (SD 51.0) L/min) and from 100.8 (SD 69) L/min to 225 (SD 83.4) L/min with mechanical insufflation plus MAC (MD 124.8 (SD 38.4) L/min). Mechanical insufflation plus MAC produced a greater change in PCF compared to MI‐E alone (between‐group MD 71.40 L/minute, 95% CI 18.08 to 124.72; P = 0.009; 11 participants; Analysis 3.1).

MI‐E versus MI‐E plus MAC

Lacombe 2014 compared baseline unassisted PCF to PCF produced with MI‐E and MI‐E plus MAC. The study reported increases from baseline with both interventions. In the first period of cross‐over, mean PCF increased from 157.2 (SD 64.2) L/min (unassisted cough) to 210.6 (SD 52.8) L/min with MI‐E alone (MD 53.4 (SD 51.0) L/min) and from 104.4 (SD 41.4) L/min to 210.6 (SD 50.4) L/min with MI‐E plus MAC (MD 106.2 (SD 50.4) L/min). There was a slightly greater increase in PCF with MI‐E plus MAC compared to MI‐E alone (between‐group MD 52.80, 95% CI –0.32 to 105.92; P = 0.05; 14 participants; Analysis 4.1).

Kim 2016 reported increased PCF with both MI‐E and MI‐E plus MAC compared to unassisted cough, in children and adolescents with DMD. The PCF generated with MI‐E plus MAC was greater than with MI‐E alone. Separate data for the two periods of cross‐over were not available for analysis.

MI‐E plus MAC versus mechanical insufflation plus MAC

In the first period of cross‐over RCT, Lacombe 2014 reported that mean PCF increased from 101 (SD 69) L/min (baseline unassisted cough) to 225 (SD 83) L/min with mechanical insufflation plus MAC (MD 124 (SD 38.4) L/min); and from 104 (SD 41) L/min to 211 (SD 50) L/min with MI‐E plus MAC (MD 106 (SD 50.4) L/min). There was no evidence of a difference in the change in PCF from baseline between the MI‐E plus MAC and mechanical insufflation plus MAC (between‐group MD –18.60, 95% CI –34.46 to 71.66; P = 0.49; 11 participants; Analysis 5.1).

MAC versus mechanical insufflation

Sivasothy 2001 reported no evidence of a change from baseline PCF measurement with MAC or mechanical insufflation in four adults with NMD and scoliosis, and no evidence of between‐group differences. The very small sample size eligible for inclusion in this review limited the interpretation of these results. Separate data for the two periods of cross‐over were not available for analytical purposes.

Chatwin 2003 reported no evidence of a difference in PCF between "physiotherapy‐assisted cough" (MAC) and mechanical insufflation‐assisted cough using a non‐invasive ventilator device in 22 participants. Moreover, there was no evidence of a difference between PCF with unassisted cough and either MAC or mechanical insufflation alone. Separate data for the two periods of cross‐over were not available for analytical purposes.

MAC versus mechanical insufflation plus MAC

Sivasothy 2001 reported no evidence of a change from baseline PCF measurement with MAC or MAC plus mechanical insufflation, in four adults with NMD and scoliosis. There was no evidence of a difference in PCF change between interventions. The very small sample size eligible for inclusion in this review limited the interpretation of these results. Separate data for the two periods of cross‐over were not available for analytical purposes.

MI‐E versus MAC

In 22 adults and children with NMD presenting with severe respiratory muscle weakness (MIP 25 (SD 16) cmH2O; MEP 26 (SD 22) cmH2O), Chatwin 2003 reported that MI‐E assisted cough produced a higher PCF than MAC, while only MI‐E increased PCF significantly above baseline unassisted cough. Separate data for the two periods of cross‐over were not available for analytical purposes.

MI‐E versus mechanical exsufflation‐assisted cough

In 22 adults and children with NMD and severe respiratory muscle weakness, Chatwin 2003 reported that MI‐E‐assisted cough produced a higher PCF than exsufflation‐assisted cough, while both interventions produced a higher PCF than unassisted cough. Separate data for the two periods of cross‐over were not available for analytical purposes.

MI‐E versus mechanical insufflation

Chatwin 2003, in 22 participants, reported that MI‐E‐assisted cough produced a higher PCF than mechanical insufflation‐assisted cough, while only MI‐E increased PCF significantly above baseline unassisted cough. Separate data for the two periods of cross‐over were not available for analytical purposes.

MI‐E versus manual breathstacking plus MAC

Kim 2016 reported increased PCF with MAC plus breathstacking and MI‐E, compared to unassisted cough, in 40 children and adolescents with DMD. The PCF generated with MI‐E was significantly higher than with MAC plus breathstacking. Separate data for the two periods of cross‐over were not available for analytical purposes.

MI‐E plus MAC versus manual breathstacking plus MAC

Kim 2016 reported significantly increased PCF with both MAC plus breathstacking and MI‐E plus MAC compared to unassisted cough in 40 participants. The PCF generated with the MI‐E plus MAC produced greater PCF than manual breathstacking plus MAC. Separate data for the two periods of cross‐over were not available for analytical purposes.

MAC versus manual breathstacking

Brito 2009 reported that, in 28 adults with DMD, PCF increased with MAC and manual breathstacking compared to unassisted cough. There was no difference between PCF generated with MAC compared to manual breathstacking. Separate data for the two periods of cross‐over were not available for analytical purposes.

MAC versus manual breathstacking plus MAC

Brito 2009 reported that PCF increased with both MAC and MAC plus breathstacking, compared to unassisted cough, in 28 adults with DMD. PCF was higher when using manual breathstacking plus MAC compared to MAC alone. Separate data for the two periods of cross‐over were not available for analytical purposes.

Manual breathstacking versus manual breathstacking plus MAC

In 28 adults with DMD, PCF increased significantly with both manual breathstacking and manual breathstacking plus MAC, compared to unassisted cough. PCF was higher when using manual breathstacking plus MAC compared to manual breathstacking alone (Brito 2009). Separate data for the two periods of cross‐over were not available for analytical purposes.

Mechanical breathstacking versus mechanical insufflation

Del Amo Castrillo 2019 reported that, in 20 adults with NMD, both mechanical breathstacking (using a ventilator) and mechanical insufflation using a ventilator's volumetric cough mode were associated with an increase in PCF, but that mean PCF was higher with mechanical insufflation (using volumetric cough mode) than with mechanical breathstacking (P < 0.01). Data were presented graphically, and we could not extract data precisely from the figures provided. Attempts to contact the author for additional data were unsuccessful.

2. Any adverse events, including, but not limited to: pneumothorax, rib fractures, lung injury, aerophagia/abdominal distension, and death for both 'maintenance' and 'rescue' therapy

Chatwin 2009 recorded fatigue using a VAS, in eight adults and children with a range of NMD conditions, but did not report other adverse events. Reporting for the outcome measure of fatigue was, however, incomplete, with fatigue VAS values only reported for the intervention MAC plus MI‐E, and there were no data for MAC alone (Chatwin 2009). In the latter group, fatigue was only reported as being not significantly different before to after intervention, while with MAC plus MI‐E, mean fatigue VAS increased from 3.2 (SD 2.2) before the intervention to 5.1 (SD 2.6) after the intervention (P = 0.005; see Table 3). Separate data for the two periods of cross‐over were not available for analytical purposes. The lack of comparable data makes meaningful conclusions difficult. The evidence was very‐low certainty due to very serious study limitations and imprecision due to the small study size (eight participants).

None of the included studies specified adverse events as primary or secondary outcome measures, and six studies with 155 participants did not report on this outcome measure (Brito 2009; Del Amo Castrillo 2019; Jenkins 2014; Lacombe 2014; Torres‐Castro 2016; Toussaint 2016). Chatwin 2003 (22 participants) reported that no adverse events occurred during the study, and that participants tolerated the interventions well. Kim 2016 (40 participants) also reported that all three interventions were "well tolerated" and Sivasothy 2001 (four participants) reported that no adverse events had occurred. Although the studies reported no serious adverse events, it was unclear whether these were systematically investigated. We downgraded the body of evidence for adverse effects three times to very‐low certainty – twice for very serious study limitations and once for imprecision (see summary of findings Table 1).

3. Measures of gaseous exchange measured before and after the intervention for 'rescue' therapy, and measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy

None of the studies investigated the medium‐ or long‐term effects of cough augmentation techniques on measures of gaseous exchange. Chatwin 2009 (eight participants) measured the short‐term effects of interventions on physiological variables of heart rate, transcutaneous oxygen saturation, and PtcCO2 in adults and children with NMD; however, this study did not provide separate data for the interventions. Instead it simply reported that there was no difference between intervention groups for these physiological parameters. Jenkins 2014 (23 participants) reported that there was no difference in the change of transcutaneous oxygen saturation from before to after manual breathstacking using a resuscitator bag compared to sham breathstacking (see Table 2).

4. Pulmonary function measured by FEV1, FVC, VC, and PEFR, over the short term (less than three months); medium term (between three months and one year), and long term (one year and longer) for 'maintenance' therapy

None of the studies reported pulmonary function.

5. Quality of life measured by any validated measure over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' use

None of the studies reported quality of life.

6. Validated measures of function, including measures of perceived exertion, exercise tolerance, and motor function measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy

Chatwin 2009 measured the level of perceived breathlessness with MI‐E plus MAC and MAC alone, using a 10‐point VAS, in eight adults and children. The validity of the scale was not determined, and data were not presented for separate interventions. It was simply reported that there were no significant changes from baseline to after intervention (see Table 3).

7. Participant preference for, or satisfaction with, specific cough augmentation techniques, expressed as a proportion or percentage of the sample for both 'rescue' and 'maintenance' therapy

None of the studies reported participants preference or satisfaction.

8. Other outcome measures

We presented data for other outcome measures in Table 2 and Table 3.

8.1. Tidal volume

One study, with 23 participants, reported an increase in tidal volume from before to after intervention with manual breathstacking using a resuscitation bag (P < 0.0001) compared to a no change with sham breathstacking (Jenkins 2014). Authors did not report between‐group significance levels, and as separate cross‐over period data were not available, these could not be calculated.

8.2. Maximum inspiratory or insufflation capacity

Four studies measured maximal inspiratory or insufflation capacity in 104 participants (Del Amo Castrillo 2019; Lacombe 2014; Torres‐Castro 2016; Toussaint 2016).

8.2.1. Manual breathstacking versus mechanical breathstacking

Toussaint 2016 reported that mean MIC achieved by participants performing manual breathstacking was 1.344 (SD 0.520) L compared to 1.481 (SD 0.477) L for those performing breathstacking using a ventilator (between‐group MD 0.14 L, 95% CI –0.13 to 0.41; P = 0.3; 52 participants; Analysis 1.2). Therefore, there was no evidence of a difference between manual and mechanical breathstacking in achieved MIC.

8.2.2. Glossopharyngeal breathing versus manual breathstacking

Torres‐Castro 2016 reported the change from baseline VC to postintervention MIC. The published article reported that the median MIC achieved with manual breathstacking was 290 mL (IQR 168 to 567) greater than was achieved using GPB (P = 0.002); however, on analysing the provided separate first‐period data, the MD in postintervention MIC between groups was calculated as 90 mL (P = 0.76). There was no evidence of between‐groups difference in the MIC change from baseline to after intervention, with an MD from baseline to postintervention MIC in the breathstacking group of 435.0 (SD 364.5) mL compared to 454.29 (408.16) mL in the group receiving GPB (between‐group MD 19.29 mL, 95% CI –386.09 to 424.67; P = 0.9; 14 participants; Analysis 2.2).

8.2.3. MI‐E versus mechanical insufflation plus MAC

First‐period data provided on request by Lacombe 2014 compared mean inspiratory capacity between MI‐E alone (1.55 (SD 0.34) L) and mechanical insufflation plus MAC (1.43 (SD 0.34) L). There was no evidence of a difference in inspiratory capacity achieved between interventions (MD –0.12 L, 95% CI –33.44 to 33.20; P = 0.99; 11 participants; Analysis 3.2).

8.2.4. MI‐E versus MI‐E plus MAC

Lacombe 2014 provided first‐period data for mean inspiratory capacity with MI‐E alone (1.55 (SD 0.34) L) and MI‐E plus MAC (1.39 (SD 0.43) L). There was no evidence of a difference in inspiratory capacity achieved between the interventions (between‐group MD –0.16, 95% CI –0.57 to 0.25; P = 0.44; 14 participants; Analysis 4.2).

8.2.5. Mechanical insufflation plus MAC versus MI‐E plus MAC

First‐period data for mean inspiratory capacity for mechanical insufflation plus MAC (1.43 (SD 0.34) L) and MI‐E plus MAC (1.39 (SD 0.43) L) showed no evidence of difference between interventions (between‐group MD 0.04, 95% CI –0.42 to 0.50; P = 0.86; 11 participants; Analysis 5.2) (Lacombe 2014).

8.2.6. Mechanical breathstacking versus mechanical insufflation

Del Amo Castrillo 2019 reported no difference in inspiratory capacity between breathstacking using a ventilator compared to mechanical insufflation using the ventilator's volumetric cough mode in 20 participants (P = 0.12). Separate cross‐over period data were not available, precluding analysis.

8.3. Minute ventilation

One study reported minute ventilation in 23 participants (Jenkins 2014). Minute ventilation increased from baseline with breathstacking using a manual resuscitation bag (P < 0.001) compared to a non‐significant change with sham breathstacking. Authors did not report between‐group significance levels, and, as separate period data were not available for the cross‐over RCT, these could not be calculated.

8.4. Maximal expiratory pressure

Toussaint 2016 reported that mean maximal expiratory pressure was 26 (SD 9) cmH2O in the group receiving resuscitator bag breathstacking compared to 28 (SD 10) cmH2O in those receiving ventilator breathstacking (MD 2.00 cmH2O, 95% CI –3.16 to 7.16; 52 participants).

8.5. Cough expiratory volume

One study reported cough expiratory volume in four participants (Sivasothy 2001). Median cough expiratory volumes were not different between mechanical insufflation, MAC, and MAC plus mechanical insufflation. The small sample size and lack of separate period data limit interpretation of these results.

8.6. Respiratory rate

Jenkins 2014 (23 participants) reported respiratory rate increased from 27 (SD 9.2) breaths/min to 28 (SD 10.6) breaths/min (P < 0.05) with manual breathstacking using a resuscitator bag compared to a non‐significant change from 26 (SD 10.3) breaths/min to 26 (SD 10.4) breaths/min with sham breathstacking. Between‐groups significance levels were not provided, and separate period data were not available, precluding analysis.

8.7. Heart rate

Chatwin 2009 (eight participants) reported heart rate; however, although the trial authors reported that there were no differences in heart rate between standard airway clearance therapy with and without MI‐E, data and significance levels were not reported. Attempts to obtain additional data were unsuccessful.

8.8. Effective cough time (time with PCF greater than 3 L/sec or greater than 180 L/min)

One study reported effective cough time in 18 participants (Lacombe 2014). Based on first‐period data received from the author on request, the MD in effective cough time from baseline with MI‐E alone was 54 (SD 95) ms; 93 (SD 111) ms with mechanical insufflation plus MAC; and 20 (SD 42) ms with MI‐E plus MAC. Although the trial authors reported, based on the combined cross‐over data, that the increase in effective cough time was smaller with MI‐E alone than with both the combined techniques using MAC, on analysis of separate first‐period data, there was no evidence of differences between any intervention: MI‐E versus mechanical insufflation plus MAC (MD 39.0 ms, 95% CI –90.56 to 168.56; P = 0.56; 11 participants); MI‐E versus MI‐E plus MAC (MD –34.00 ms, 95% CI –110.95 to 42.95; P = 0.39; 11 participants); and mechanical insufflation plus MAC versus MI‐E plus MAC (MD 73.00 ms, 95% CI –40.14 to 186.14; P = 0.21; 14 participants).

8.9. Peak value time (time from onset of expiratory flow to peak expiratory cough flow)

One study reported peak value time (Sivasothy 2001). In four participants, median peak value time was reported not to be significantly different between mechanical insufflation, MAC, and MAC plus mechanical insufflation. Separate first‐period data were not available, precluding analysis.

8.10. Ability to perform breathstacking

One study compared the ability to breathstack using a resuscitator bag (manual breathstacking) compared with ventilator (mechanical) breathstacking (Toussaint 2016). There was no evidence of a difference in the ability to breathstack between groups, with 88% in the resuscitator bag group versus 89% in the ventilator group being able to perform the technique (RR 0.93, 95% CI 0.21 to 4.17; P = 0.33; 52 participants).

8.11. Number of insufflations to achieve MIC

Toussaint 2016 reported that a mean of 1.8 (SD 0.6) insufflations were required to reach MIC with manual breathstacking using a resuscitator bag compared to a mean of and 2.6 (SD 0.6) insufflations with mechanical breathstacking using a ventilator (between‐group MD 0.80 insufflations, 95% CI 0.47 to 1.13; P < 0.001; 52 participants).

8.12. Subjective outcome measures

One study reported auscultation score, measured using a 10‐point VAS (eight participants) (Chatwin 2009). Auscultation VAS decreased significantly with both MAC (P = 0.007) and MAC plus MI‐E (P = 0.02). Between‐groups significance levels were not reported, and we could not obtain separate period data, precluding analysis.

Chatwin 2003 (22 participants) reported a combined outcome of comfort, distress, and cough strength. The trial authors reported that there were no changes from baseline in VAS results on a 10‐point scale for any intervention (MAC, mechanical insufflation, mechanical exsufflation, or MI‐E). Between‐group significance levels were not reported, and we could not obtain separate period data, precluding analysis.

Chatwin 2009 (eight participants) reported participants' perceived presence of secretions, using a 10‐point VAS, improved from before to after intervention with standard therapy including MAC (P = 0.03) and with standard therapy with MAC plus MI‐E (P = 0.03). Between‐group significance levels were not reported, and we could not obtain separate period data, precluding analysis.

Three studies (46 participants) reported participant comfort using a 10‐point VAS (Chatwin 2009; Del Amo Castrillo 2019; Lacombe 2014). Chatwin 2009 (eight participants) presented results graphically only, and data could not be extracted from the figures. Lacombe 2014 (18 participants) reported no significant differences in subjective comfort between MI‐E, mechanical insufflation plus MAC, and MI‐E plus MAC, but did not present significance levels. Del Amo Castrillo 2019 (20 participants) reported no significant difference in comfort VAS between ventilator breathstacking and mechanical insufflation using the ventilator's volumetric cough mode.

Two studies (38 participants) reported subjective cough effectiveness (Del Amo Castrillo 2019; Lacombe 2014). Aggregate results from the cross‐over study by Lacombe 2014 (18 participants) suggested a significant difference in perceived cough effectiveness between MI‐E alone and MI‐E plus MAC (P < 0.05, favouring MI‐E plus MAC) and between mechanical insufflation plus MAC and MI‐E alone (P < 0.05, favouring mechanical insufflation plus MAC). Median values provided for the first period of cross‐over study by Lacombe 2014 (see Table 3), however, suggested a possible difference between MI‐E and MI‐E plus MAC, and no evidence of a difference between MI‐E and mechanical insufflation plus MAC in perceived cough effectiveness (measured using a 10‐point VAS). There were insufficient data to confirm the size or precision of the effect. Del Amo Castrillo 2019 (20 participants) reported no difference in perceived cough effectiveness with mechanical breathstacking compared to mechanical insufflation using volumetric cough mode (P = 0.17). Separate period data could not be obtained for this study, precluding analysis.

One study measured participant mood using a 10‐point VAS (eight participants) (Chatwin 2009). The report only presented data graphically and results could not be extracted accurately from the figures. The study reported that no within‐groups changes from baseline to after either intervention: standard treatment with MAC, or standard treatment with MAC plus MI‐E. No between‐group values or significance levels were reported, and attempts to obtain additional information were unsuccessful.

None of the studies provided cost‐effectiveness analyses, and we could not evaluate it as part of this review.

Cough augmentation therapy compared to standard of care

One study, in 67 children and adolescents with DMD, compared twice daily manual breathstacking compared to standard care, over two years (Katz 2019). Reported outcomes are presented in Table 4 and summary of findings Table 2.

Primary outcomes
1. Number of unscheduled hospital admissions for episodes of acute respiratory exacerbations over one year for 'maintenance' therapy

The study did not report number of hospital admissions for episodes of acute respiratory exacerbations over one year, for 'maintenance use.'

2. Duration of hospital stay (days) for 'rescue' therapy

The study protocol by Katz 2019 included, as a secondary outcome measure, the number and duration of hospital admissions over two years in 67 participants. However, the published abstract did not present these outcome data. Attempts to contact the author were unsuccessful.

Secondary outcomes
1. PCF measured before and after intervention for 'rescue' therapy and measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy

The study did not report PCF.

2. Any adverse events, including, but not limited to: pneumothorax, rib fractures, lung injury, aerophagia/abdominal distension, and death for both 'maintenance' and 'rescue' therapy

Katz 2019 did not include adverse events as a primary or secondary outcome measure but reported that no adverse events had occurred (67 participants; very low‐certainty evidence).

3. Measures of gaseous exchange measured before and after the intervention for 'rescue' therapy, and measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy

The study did not report measures of gaseous exchange.

4. Pulmonary function measured by FEV1, FVC, VC, and PEFR, over the short term (less than three months); medium term (between three months and one year); and long term (one year and longer) for 'maintenance' therapy

Katz 2019 measured change in FVC (as percentage predicted) over two years from baseline. Change in FVC among participants in the breathstacking group was 4.1% compared to 6.4% in the conventional treatment group (adjusted MD 2.0%, 95% CI –8.2 to 12.3; 67 participants). Sufficient data, including number of participants per group, separate allocation baseline data, and SD of the mean, were not available for analysis. This study also reported that the time to 10% decline in FVC% predicted was not significantly different between groups (P = 0.5) but did not provide data, precluding analysis. We may be able to include complete results from this study in analysis in updates of this review, if data become available.

5. Quality of life measured by any validated measure over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy

Katz 2019 planned to report health‐related quality of life using the PedsQL 4.0. However, the published abstract did not report this outcome measure, and attempts to contact the author for additional data were unsuccessful. If data become available, we may be able to include health‐related quality of life data in updates of this review.

6. Validated measures of function, including measures of perceived exertion, exercise tolerance, and motor function measured over the medium term (between three months and one year) and long term (one year and longer) for 'maintenance' therapy

The study did not report validated measures of function.

7. Participant preference for, or satisfaction with, specific cough augmentation techniques, expressed as a proportion or percentage of the sample for both 'rescue' and 'maintenance' therapy

The study did not report participant preference or satisfaction.

8. Other outcome measures

We presented data for other outcome measures in Table 4.

Katz 2019 included MIC, MEP, MIP, and the number and duration of outpatient oral antibiotic courses as additional outcome measures in the published protocol (67 participants). However, these data were not reported in the published abstract and attempts to contact the author were unsuccessful. Results from this study may be able to be included in updates of this review, if data become available.

Discussion

Summary of main results

Eleven studies involving 287 children, adolescents, and adults, with a variety of NMDs, met this review's inclusion criteria. Sample sizes in individual studies ranged from four to 67 eligible participants; 10 studies were full‐text articles and one was in abstract form.

Included studies compared a range of cough augmentation technique(s) to alternative interventions (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016); standard care (control) (Katz 2019); unassisted cough (Kim 2016), or sham intervention (Jenkins 2014), for several outcome measures. Most studies compared intervention‐assisted cough outcomes with preintervention or baseline measurements of unassisted cough (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Katz 2019; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016). Only one study was of long‐term duration, lasting two years (Katz 2019), but there were limited data presented in abstract format only. One study was a two‐day cross‐over trial (Chatwin 2009), while the remainder measured the immediate effects of single intervention sessions. Only two studies were prospective RCTs (Katz 2019; Toussaint 2016), the remaining nine were short‐term randomised cross‐over trials (Brito 2009; Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019; Jenkins 2014; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016). Two cross‐over studies provided first‐period data (Lacombe 2014; Torres‐Castro 2016), which constitutes a major limitation of this review. The large number of inadequately reported results from cross‐over studies, and the limited information provided by authors on request, severely restricted the number of analyses that could be performed.

Cough augmentation techniques aim to improve cough efficiency, with potential for both short‐ and long‐term effects on pulmonary morbidity. During acute respiratory exacerbations, cough augmentation techniques aim to clear obstructed secretions to prevent the progression to respiratory failure, improve work of breathing and gaseous exchange, and potentially reduce the need for hospital admission and, if admitted, reduce the length of stay. In the longer term, regular use of cough augmentation is hoped to reduce the incidence or severity (or both) of respiratory tract infections requiring unscheduled hospitalisation. Although one long‐term RCT planned to measure this review's primary outcome measures of number and duration of hospital admissions (Katz 2019), the published abstract of the study did not report these outcomes and attempts to contact the author for additional data were unsuccessful, therefore, these data could not be included in this review. None of the other included studies measured or reported on this review's primary outcomes. Therefore, the evidence is very uncertain about the efficacy of any cough augmentation technique for reducing the number or duration (or both) of hospital admissions for respiratory exacerbations in people with NMD (see summary of findings Table 1; summary of findings Table 2).

Clinically important secondary outcomes of this review were selected for their utility in measuring the safety of cough augmentation techniques and their effect on cough efficiency (PCF), gas exchange (oxygenation and carbon dioxide clearance), as well as objective and subjective measures of pulmonary and general function, quality of life, and participant preference or satisfaction. Only three studies provided sufficient data for analysis of one of this review's secondary outcome measures of PCF (Lacombe 2014; Torres‐Castro 2016; Toussaint 2016). None of the included studies provided sufficient data for analysis of any of this review's other secondary outcome measures. Therefore, the evidence is very uncertain about the effect of cough augmentation techniques on measures of safety, gaseous exchange, pulmonary function, quality of life, general function, or participant preference or satisfaction.

Although four studies reported that no adverse events had occurred (Chatwin 2003; Katz 2019; Kim 2016; Sivasothy 2001), none of the included studies listed "adverse events" as primary or secondary outcome measures. Chatwin 2009 reported that fatigue increased in participants receiving MAC plus MI‐E, with no change in fatigue in those receiving MAC alone; however, there were insufficient data for analysis (summary of findings Table 1). The evidence is therefore very uncertain about the safety of any of the included cough augmentation interventions.

One RCT with 67 participants planned to measure the long‐term effect of manual breathstacking on PCF (Katz 2019); however, this outcome measure was not reported in the published abstract and data could not be included in this review (summary of findings Table 2).

Eight studies with 198 participants compared the PCF generated with various cough augmentation techniques to baseline unassisted cough, as a repeated measure for each participant (Brito 2009; Chatwin 2003; Del Amo Castrillo 2019; Kim 2016; Lacombe 2014; Sivasothy 2001; Torres‐Castro 2016; Toussaint 2016). All but two cross‐over RCTs with small sample sizes (Chatwin 2003; Sivasothy 2001), showed significant increases in PCF with cough augmentation therapy from baseline. However, "unassisted cough" in all studies, except for Kim 2016, was measured at baseline or before intervention, and was not a randomly assigned control intervention. Kim 2016 did not provide separate period data. Therefore, there is only very low‐certainty evidence that manual and mechanical breathstacking; GPB; MI‐E; mechanical exsufflation; MAC; MAC plus MI‐E; MAC plus breathstacking; and mechanical insufflation may all increase PCF above unassisted cough (Table 2; Table 3; Table 1).

Based on one single‐centre, short‐term RCT (52 participants), with high risk of performance and assessor bias, and unclear allocation concealment (Toussaint 2016), there was low‐certainty evidence that manual breathstacking using a resuscitation bag may result in little to no difference in PCF in the short‐term, compared to mechanical breathstacking (using a ventilator). Further results from RCTs are very likely to have an important impact on our confidence in the estimate of effect and are likely to change this estimate (Table 1).

Based on the results of the first‐period data of one short‐term, randomised cross‐over study (14 participants) (Torres‐Castro 2016), there may be little to no difference in the short‐term outcome of PCF between GPB compared with manual breathstacking (Table 1). Considering the very small sample size of this single study, and high risk of performance and detection bias, we are very uncertain about this estimate, and sufficiently powered RCTs to compare the effects of these interventions on PCF are warranted.

Based on the first period results of one short‐term, randomised cross‐over study with small sample size (18 participants), very wide CIs, and substantial risk of performance and other biases (Lacombe 2014), there is very low‐certainty evidence that, in adults with chronic NMD, mechanical insufflation plus MAC may improve PCF more than MI‐E alone in the short term. The evidence suggests little to no difference in the change in PCF between MI‐E plus MAC and mechanical insufflation plus MAC. We are very uncertain about these estimates, and further adequately powered RCTs are required to confirm or refute these results (Table 1).

Aggregate results of short‐term cross‐over trials, without provision of separate period data, reported little to no difference in PCF between MAC and manual breathstacking (Brito 2009), or among MAC, mechanical insufflation, and MAC plus mechanical insufflation (Sivasothy 2001). Higher PCF was reported with MI‐E compared to mechanical exsufflation (Chatwin 2003) and MAC plus manual breathstacking (Kim 2016); with MAC plus manual breathstacking compared to either MAC or manual breathstacking individually (Brito 2009); with MAC plus MI‐E compared to MI‐E alone (Kim 2016) and MAC plus manual breathstacking (Kim 2016); and mechanical insufflation compared to mechanical breathstacking (Del Amo Castrillo 2019). Overall, the evidence suggests there may be little to no difference between alternate cough augmentation interventions in improving PCF (Table 1). The evidence for this is, however, very uncertain.

Two cross‐over studies measured the short‐term effect of interventions on gaseous exchange. Chatwin 2009 reported there was no difference in transcutaneous oxygen saturation and PtcCO2 between MAC and MAC plus MI‐E; Jenkins 2014 reported no difference in transcutaneous oxygen saturation between manual and sham breathstacking. One long‐term RCT measured pulmonary function (FVC) (Katz 2019); however, there were insufficient data, precluding analysis. This study reported no change in FVC or change in the time to 10% decline in FVC between participants receiving manual breathstacking compared to standard care. One study planned to report the long‐term effects of interventions on health‐related quality of life (Katz 2019); however, no data were available. The evidence is therefore very uncertain about the effect of any cough augmentation technique on gaseous exchange or health‐related quality of life.

Other outcome measures were variably reported in included studies. Based on aggregated reported results of three cross‐over studies (Chatwin 2003; Chatwin 2009; Del Amo Castrillo 2019), and first‐period data from one cross‐over study (total 68 participants) (Lacombe 2014), there was no evidence of superior participant comfort with any cough augmentation technique. Although no study reported participant preference, short‐term perceived cough effectiveness was reported in the aggregate results of three cross‐over studies with 42 participants (Del Amo Castrillo 2019; Lacombe 2014; Sivasothy 2001). Lacombe 2014 reported that perceived effectiveness was higher with MAC plus MI‐E compared with MI‐E alone. The potential greater efficacy of combined cough augmentation techniques compared with single techniques requires attention in future RCTs.

Four studies with 104 participants reported maximal insufflation or inflation capacity (MIC) (Del Amo Castrillo 2019; Lacombe 2014; Torres‐Castro 2016; Toussaint 2016), with three studies (84 participants) providing sufficient data for analysis (Lacombe 2014; Torres‐Castro 2016; Toussaint 2016). Based on these studies, there may be little to no difference in MIC with MAC, MI‐E, and MAC plus MI‐E; manual breathstacking versus GPB; mechanical versus manual breathstacking; or mechanical breathstacking versus mechanical insufflation (using volumetric cough mode).

Overall completeness and applicability of evidence

We identified 11 studies for inclusion in this review, nine of which were short‐term cross‐over studies of which only two provided separate first‐period data for analysis. These methodological limitations substantially impact on the internal and external validity of this review. We found only one long‐term trial for maintenance therapy; however, complete data were not available for inclusion in this review. None of the included studies reported clearly on the short‐ or long‐term effects of cough augmentation interventions on clinically relevant outcomes of morbidity and safety, and this study could not, therefore, address the objective of this review in determining the efficacy and safety of cough augmentation techniques for adults and children with chronic NMD and respiratory muscle weakness. Furthermore, none of the studies compared different dosages or frequencies of application of any cough augmentation technique and the evidence is therefore very uncertain regarding optimal safe and effective prescription of cough augmentation techniques in people with NMD.

Participant numbers were generally small, with no possibility of subgroup analyses for different age groups or conditions. As seen in Table 2; Table 3; and Table 4, studies compared a variety of interventions, with variable techniques, and a wide range of outcome measures. Studies were conducted in Europe (three), the UK (three), Canada (two), Korea (one) and South America (two). External generalisability to other geographical regions and socioeconomic contexts cannot be determined. None of the studies provided any estimate of cost‐effectiveness.

Quality of the evidence

Key limitations of included studies were: study design; small sample sizes; unreliable or clinically irrelevant outcome measures; and unclear to high risk of bias, specifically related to poorly reported methods of allocation concealment, randomisation sequence generation, insufficient blinding of participants and personnel, and insufficient reporting of data. The overall certainty of the evidence of included studies was low or very low, with most being short‐term randomised cross‐over trials, in which participants received two or more interventions in randomly assigned order, with undetermined and untested carry‐over effects (Mills 2009) and, in all but three studies, insufficient information to allow data analysis. In several studies, the investigators compared cough augmentation techniques and unassisted cough; however, unassisted coughing was not a randomly assigned controlled intervention except in one study (Kim 2016), and definitive conclusions regarding efficacy of interventions cannot therefore be made.

Cross‐over study designs are considered suitable for evaluating interventions with a temporary effect in participants with stable or chronic conditions (Nolan 2016), and may, therefore, be appropriate for measuring outcome measures such as PCF, a secondary outcome of interest for this review. However, short‐term cross‐over designs are generally not the most appropriate for measuring longer‐term health‐related outcomes of chronic life‐limiting and progressive conditions such as NMDs. The immediate effects of an intervention may not translate into longer‐term benefit, and results of such studies must, therefore, be interpreted with caution. The decision to include cross‐over trials in this review was based on the knowledge that this is the most common study design used among this population group, likely owing to various factors including the fact that NMDs are rare conditions, and generally a smaller overall sample size is needed for cross‐over compared to parallel‐group RCTs (Nolan 2016). In addition, well‐conducted cross‐over trials may yield more precise results than parallel‐group designs, owing to lower variability with individual compared to between‐participant responses (Elbourne 2002). The inability to pool or individually analyse data from most cross‐over trials limits the validity of this review. It is not considered methodologically acceptable to simply treat cross‐over trials as parallel‐group RCTs for the purposes of systematic reviews and meta‐analysis (Elbourne 2002).

Blinding of participants and research personnel is generally not possible for interventions such as cough augmentation techniques, increasing the risk of bias of studies. Limited available information regarding methodology (e.g. allocation concealment, washout periods, and randomisation sequence generation) further increased the risk of bias in included studies. The publications of all included cross‐over trials presented results as though from parallel‐group RCTs, and we judged the data unsuitable for meta‐analysis (Elbourne 2002).

The body of evidence included in this review did not allow any clear conclusions to be reached regarding the efficacy or safety of cough augmentation techniques in people with chronic NMD.

Potential biases in the review process

There were no major deviations from the published protocol in conducting this review. Our literature search was comprehensive, and included searches for unpublished material through trial registration platforms and congress abstract reports. There were no geographical, time, or language constraints to this review. However, it is possible that some studies may have been overlooked, particularly if published in non‐peer reviewed journals or presented at small or regional congresses. Further, we cannot control for inherent publication bias.

We contacted the corresponding authors of included studies, where appropriate, to obtain missing results or additional information but most did not respond and only one author was able to provide all the necessary information. We could not obtain missing data on the primary outcomes of this review, as measured by Katz 2019, and this may have substantially impacted on this review, which is an unavoidable source of bias. We hope that these data will be available for future versions.

Agreements and disagreements with other studies or reviews

A previous Cochrane systematic review concluded that there was insufficient evidence for or against the use of MI‐E as a cough augmentation technique in people with NMD, for efficacy and safety outcome measures (Morrow 2013). This review was also unable to present moderate or high certainty evidence for or against the safety or efficacy of either MI‐E or any other cough augmentation technique in people with NMD. Further, the evidence from this review suggests there may be little to no difference between any alternate cough augmentation technique, for a range of short‐ or long‐term outcome measures.

A previous 'state of the art' narrative review systematically reviewed the evidence‐base for airway clearance techniques (including both peripheral and proximal techniques) in adults and children with NMD, including participants with ALS (Chatwin 2018). The review reported on all study designs, including case studies and retrospective audits. Chatwin 2018 suggested that all cough augmentation techniques, including MAC, single‐breath assisted inspiration (manual insufflation), breathstacking, GPB, and MI‐E effectively increase PCF, as is also suggested in this review, based on very low‐certainty evidence. Chatwin 2018 also suggested that combining a technique augmenting inspiration with one that enhances expiration may further increase cough efficacy; however, this review demonstrated that the evidence for better cough efficiency with combination compared to single techniques is very uncertain and further research is warranted in this regard. Based largely on observational studies, Chatwin 2018 recommended using MI‐E preferentially for weaker patients with NMD. This recommendation is not supported or refuted by the results of this review. The review by Chatwin 2018 was limited by the lack of defined review objectives, the inclusion of all study types, and the lack of a risk of bias or GRADE assessments for the included studies. Owing to the differing purpose, methodologies, and reporting, direct agreements or disagreements between reviews cannot be made.

Study flow diagram.

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Figure 1

Study flow diagram.

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Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Comparison 1: Manual versus mechanical breathstacking (BS), Outcome 1: Peak cough flow

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Analysis 1.1

Comparison 1: Manual versus mechanical breathstacking (BS), Outcome 1: Peak cough flow

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Comparison 1: Manual versus mechanical breathstacking (BS), Outcome 2: Maximal insufflation capacity

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Analysis 1.2

Comparison 1: Manual versus mechanical breathstacking (BS), Outcome 2: Maximal insufflation capacity

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Comparison 2: Glossopharyngeal breathing (GPB) versus manual breathstacking (BS), Outcome 1: Peak cough flow

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Analysis 2.1

Comparison 2: Glossopharyngeal breathing (GPB) versus manual breathstacking (BS), Outcome 1: Peak cough flow

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Comparison 2: Glossopharyngeal breathing (GPB) versus manual breathstacking (BS), Outcome 2: Inspiratory capacity

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Analysis 2.2

Comparison 2: Glossopharyngeal breathing (GPB) versus manual breathstacking (BS), Outcome 2: Inspiratory capacity

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Comparison 3: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation (MI) plus manually assisted cough (MAC), Outcome 1: Peak cough flow

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Analysis 3.1

Comparison 3: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation (MI) plus manually assisted cough (MAC), Outcome 1: Peak cough flow

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Comparison 3: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation (MI) plus manually assisted cough (MAC), Outcome 2: Inspiratory capacity

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Analysis 3.2

Comparison 3: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation (MI) plus manually assisted cough (MAC), Outcome 2: Inspiratory capacity

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Comparison 4: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation‐exsufflation (MI‐E) plus manually assisted cough (MAC), Outcome 1: Peak cough flow

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Analysis 4.1

Comparison 4: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation‐exsufflation (MI‐E) plus manually assisted cough (MAC), Outcome 1: Peak cough flow

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Comparison 4: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation‐exsufflation (MI‐E) plus manually assisted cough (MAC), Outcome 2: Inspiratory capacity

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Analysis 4.2

Comparison 4: Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation‐exsufflation (MI‐E) plus manually assisted cough (MAC), Outcome 2: Inspiratory capacity

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Comparison 5: Mechanical insufflation (MI) plus manually assisted cough (MAC) versus mechanical insufflation‐exsufflation (MI‐E) plus MAC, Outcome 1: Peak cough flow

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Analysis 5.1

Comparison 5: Mechanical insufflation (MI) plus manually assisted cough (MAC) versus mechanical insufflation‐exsufflation (MI‐E) plus MAC, Outcome 1: Peak cough flow

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Comparison 5: Mechanical insufflation (MI) plus manually assisted cough (MAC) versus mechanical insufflation‐exsufflation (MI‐E) plus MAC, Outcome 2: Inspiratory capacity

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Analysis 5.2

Comparison 5: Mechanical insufflation (MI) plus manually assisted cough (MAC) versus mechanical insufflation‐exsufflation (MI‐E) plus MAC, Outcome 2: Inspiratory capacity

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Summary of findings 1. Cough augmentation therapy compared with an alternative cough augmentation technique or combination of techniques for people with neuromuscular diseases

Cough augmentation compared with an alternative cough augmentation technique or combination technique

Patient or population: participants with chronic neuromuscular diseases

Settings: –

Intervention: cough augmentation

Comparison: alternative cough augmentation technique

Outcomes

Illustrative comparative risks* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Assumed risk

Corresponding risk

Alternative cough augmentation technique

Cough augmentation

Number of unscheduled hospital admissions for 'maintenance therapy'

Not reported

Duration of hospital stay (days) for 'rescue' therapy

Not reported

PCF

Follow‐up: < 1 day ('rescue' and 'maintenance' therapy)

8 RCTs (198 participants) studied various cough augmentation techniques or combinations of techniques.

  • Reported that MI‐E, mechanical exsufflation, MAC, mechanical insufflation, manual and mechanical breathstacking, glossopharyngeal breathing, mechanical insufflation + MI‐E, MAC + MI‐E, and MAC + breathstacking may increase PCF above unassisted cough.

  • 2 cross‐over RCTs (26 participants) reported no change in PCF with MAC compared to unassisted cough.

  • 1 cross‐over RCT reported no difference in PCF with mechanical insufflation compared to unassisted cough (22 participants).

Repeated measures data were reported and could not be meta‐analysed.

—

198 (8 RCTs (7 cross‐over, 1 parallel group)

⊕⊝⊝⊝
Verylowa

Cough augmentation may improve PCF compared to unassisted cough, but the certainty of evidence was very low.

See Table 1 for details.

Any adverse events

Follow‐up: < 1 day or 1–2 days ('rescue and maintenance therapy)

4 cross‐over RCTs (64 participants) compared various cough augmentation techniques or combinations of techniques (including mechanical insufflation, mechanical exsufflation, MI‐E, MAC, MAC + manual breathstacking, MI‐E + MAC, MAC + manual breathstacking, MAC + mechanical insufflation).

  • 0 trials reported serious adverse events.

  • 3 trials reported no adverse events occurred. In most trials it was unclear whether adverse effects were systematically investigated.

  • 1 cross‐over RCT (8 participants) reported fatigue as an adverse event, measured on a 10‐point ordinal VAS. Fatigue was reported to increase from baseline in the MAC + M‐IE group, with no change in the MAC group. No data were provided for the control group or the separate periods of cross‐over. The mean postintervention fatigue score for both periods of the cross‐over trial was 5.1 (SD 2.6).

—

64 (4 cross‐over RCTs)

⊕⊝⊝⊝
Verylowb

We are unable to draw a conclusion as the certainty of evidence is very low. See Table 2; Table 3 for details.

Quality of life for 'maintenance' therapy

No study measured or reported quality of life.

Participant preference or satisfaction for 'rescue' and 'maintenance' therapy

No study measured or reported participant preference or satisfaction.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; MAC: manually assisted cough; MI‐E: mechanical insufflation‐exsufflation; PCF: peak cough flow; RCT: randomised controlled trial; RR: risk ratio; SD: standard deviation; VAS: visual analogue scale.

GRADE Working Group grades of evidence
High quality: further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: we are very uncertain about the estimate.

aDowngraded three levels – twice for study limitations – all studies were at high risk of bias in at least one domain and unclear in several. Data were based on repeated (dependent) measurements from seven cross‐over and one parallel‐group RCTs. We also downgraded the evidence for imprecision – all studies had a small sample size, wide CI, or both. The outcome was measured less than one day after the intervention, rather than in the medium and long term as specified.
bDowngraded three levels – twice for study limitations – all studies were at high risk of bias in at least one domain and unclear in several. Data were based on repeated (dependent) measurements from seven cross‐over and one parallel‐group RCTs. We also downgraded the evidence for imprecision – all studies had a small sample size.

Figuras y tablas -
Summary of findings 1. Cough augmentation therapy compared with an alternative cough augmentation technique or combination of techniques for people with neuromuscular diseases
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Table 1. Summary of findings: cough augmentation therapy, short‐term outcomes – details of PCF by comparison

Mean difference in PCF post intervention‐baseline (L/min)

Comparison (experimental vs control/alternative therapy/sham therapy)

Summary of results

Illustrative comparative risks

Relative effect
(95% CI)

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Control/comparator

Experimental

Manual breathstacking vs mechanical breathstacking

Follow‐up: < 1 day

No evidence of a difference between manual and mechanical breathstacking in the change of PCF.

The mean PCF difference in the comparison group was 67 (SD 73) L/min

The mean PCF difference in the experimental group was 61 (SD 72) L/min

MD 6.00 (–33.43 to 45.43)

52 (1)

⊕⊕⊝⊝
Lowa

Based on 1 short‐term RCT with high risk of performance and detection bias and unclear allocation concealment (Toussaint 2016).

Glossopharyngeal breathing vs manual breathstacking

Follow‐up: < 1 day

No evidence of a difference between glossopharyngeal breathing and manual breathstacking in the change of PCF.

The mean PCF difference in the comparison group was
72.86 (SD 61.84) L/min

The mean PCF difference in the experimental group was
32.14 (SD 26.44) L/min

MD –40.72 (–90.54 to 9.10)

14 (1)

⊕⊝⊝⊝
Verylowb

Based on first‐period data from 1 cross‐over RCT with unclear allocation concealment, very small sample size, imprecision of results (wide CI), and substantial risk of performance and detection bias (Torres‐Castro 2016).

Mechanical insufflation + MAC vs MI‐E

Follow‐up: < 1 day

Mechanical insufflation + MAC produced a greater change in PCF compared to MI‐E alone.

The mean PCF difference in the comparison group was 53.4 (SD 51) L/min

The mean PCF difference in the experimental group was
124.8 (SD 38.4) L/min

MD 71.40 (18.08 to 124.72)

11 (1)

⊕⊝⊝⊝
Verylowc

Based on first‐period data of 1 cross‐over RCT with very small sample size, imprecision of results (wide CIs), and substantial risk of performance and other biases (Lacombe 2014).

MI‐E + MAC vs MI‐E

Follow‐up: < 1 day

No clear evidence of a difference between MI‐E + MAC compared to MI‐E alone in the change in PCF.

The mean PCF difference in the comparison group was 53.4 (SD 51) L/min

The mean PCF difference in the experimental group was 106 (SD 50.4) L/min

MD 52.80 (–0.32 to 105.92)

54 (2)

⊕⊝⊝⊝
Verylowc

Analysis based on first‐period data of 1 randomised cross‐over study with very small sample size (n = 14), imprecision of results (wide CIs), and substantial risk of performance and other biases (Lacombe 2014).

Study reported significantly higher PCF with MI‐E + MAC compared to MI‐E alone

N/A

The second study was a cross‐over RCT with high risk of performance, detection and other bias (Kim 2016).

Separate period data were not reported, precluding analysis and assessment of precision.

MI‐E + MAC vs mechanical insufflation + MAC

Follow‐up: < 1 day

There was no evidence of a difference in PCF change between MI‐E + MAC and mechanical insufflation + MAC.

The mean PCF difference in the comparison group was
124.8 (SD 38.4) L/min

The mean PCF difference in the intervention groups was
106 (SD 50.4) L/min

MD 18.60 (–34.46 to 71.66)

11 (1)

⊕⊝⊝⊝
Verylowc

Based on the first‐period data of 1 randomised cross‐over study design with very small sample size, imprecision of results (wide CIs), and substantial risk of performance and other biases (Lacombe 2014).

MAC vs mechanical insufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

Both studies reported no evidence of a difference in PCF between interventions.

N/A

26 (2)

⊕⊝⊝⊝
Verylowc

Based on 2 cross‐over RCTs with small sample sizes (Chatwin 2003: n = 4; Sivasothy 2001: n = 22).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Mechanical insufflation + MAC vs MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

Reported no evidence of a difference in PCF between interventions.

N/A

4 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 4 participants eligible for this review (Sivasothy 2001).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E vs MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

MI‐E reported to produce a higher PCF than MAC.

N/A

22 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 22 participants (Chatwin 2003).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E vs mechanical exsufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

MI‐E reported to produce a higher PCF than mechanical exsufflation.

N/A

22 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 22 participants (Chatwin 2003).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E vs mechanical insufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with MI‐E than with mechanical insufflation.

N/A

22 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 22 participants (Chatwin 2003).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Manual breathstacking + MAC vs MI‐E

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with MI‐E than with MAC + breathstacking.

N/A

40 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 40 participants (Kim 2016).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MI‐E + MAC vs manual breathstacking + MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with MI‐E + MAC than with MAC + breathstacking.

N/A

40 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 40 participants (Kim 2016).

Separate period data were not reported or available, precluding analysis and assessment of precision.

MAC vs manual breathstacking + MAC

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with manual breathstacking + MAC than with MAC alone.

N/A

28 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 28 participants (Brito 2009).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Manual breathstacking vs manual breathstacking + MAC

Follow‐up: < 1 day

We were unable to draw a conclusion
 

PCF reported to be higher with manual breathstacking + MAC than with manual breathstacking alone.
 

N/A
 

28 (1)
 

⊕⊝⊝⊝

Verylowc

Based on 1 cross‐over RCT with 28 participants (Brito 2009).

Separate period data were not reported or available, precluding analysis and assessment of precision.

Mechanical breathstacking vs mechanical insufflation

Follow‐up: < 1 day

We were unable to draw a conclusion.

PCF reported to be higher with mechanical insufflation compared to mechanical breathstacking. Not quantitatively reported.

N/A

20 (1)

⊕⊝⊝⊝
Verylowc

Based on 1 cross‐over RCT with 20 participants (Del Amo Castrillo 2019).

Data were presented graphically only and could not be precisely extracted from figures provided.

Separate period data were not reported or available, precluding analysis and assessment of precision.

CI: confidence interval; MD: mean difference; MAC: manually assisted cough; MI‐E: mechanical insufflation‐exsufflation; min: minute; n: number of participants; N/A: not available; PCF: peak cough flow; RCT: randomised controlled trial; SD: standard deviation.

aDowngraded twice because results come from a single short‐term RCT at high risk of bias.
bDowngraded three times based on a single randomised cross‐over study design with very small sample size, imprecision of results (wide CIs), and high risk of performance and detection bias.
cDowngraded three times based on a single randomised cross‐over study design with very small sample size, imprecision of results (wide CIs), and substantial risk of performance and other biases.

Figuras y tablas -
Table 1. Summary of findings: cough augmentation therapy, short‐term outcomes – details of PCF by comparison
Ir a la tabla de la revisión
Table 2. Study results grouped by outcome measures and interventions – cough augmentation therapy compared to alternative individual cough augmentation therapies

Outcome measure

Unassisted cough

MI

ME

MI‐E

MAC

Manual BS

Mechanical BS

Sham BS

GPB

Between‐group comparison

PCF

(L/min)
 
 

Chatwin 2003 (n = 22)

Mean (95% CI)

169

(129 to 209)a

182 (

147 to 217)

235

(186 to 284)

297

(246 to 350)

188

(146 to 229)

—

—

—

—

ME vs unassisted cough: P < 0.01

MI‐E vs unassisted cough: P < 0.001

MI‐E vs ME: P < 0.001

Toussaint 2016 (n = 52)

Mean ± SD baseline to after intervention

—

—

—

—

—

125 ± 52 to 186 ± 50; P < 0.001; n = 25

132 ± 55 to 199 ± 48; P = 0.001; n = 27

—

—

P = 0.33

Del Amo Castrillo 2019 (n = 20)

Median/IQR

176/68a

Data not reported

—

—

—

—

Data not reported

—

—

P < 0.001 comparing MI to baseline (favouring MI)

P < 0.001 comparing MI to BS (favouring MI)

P = 0.004 comparing BS to baseline (favouring BS)

Torres‐Castro 2016 (n = 14)

MD ± SD (95% CI) baseline to after interventionb

—

—

—

—

—

72.86 ± 61.84 (15.67 to 130.05); P = 0.02

—

—

32.14 ± 26.44 (7.69 to 56.59); P = 0.018

P = 0.14

Transcutaneous oxygen saturation

(%)

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

96 ± 3.2 to 96 ± 3

—

96 ± 3.6 to 96 ± 2.5

—

NS

Tidal volume (mL)

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

277 ± 131 to 310 ± 148; P < 0.001

—

303 ± 141 to 289 ± 128; NS

—

Significance levels not reported

Maximum inspiratory or insufflation capacity (L or mL)

Toussaint 2016 (n = 52)

mean ± SD, L

—

—

—

—

—

1.344 ± 0.520; n = 25

1.481 ± 0.477; n = 27

—

—

Mechanical vs manual BS: MD 0.14, 95% CI –0.13 to 0.41; P = 0.3

Del Amo Castrillo 2019 (n = 20)

median (IQR), L

—

1.630

(1.247 to 1.870)

—

—

—

—

1.320

(1.085–1.755)

—

—

P = 0.12

Torres‐Castro 2016 (n = 14)

MD between baseline vital capacity and postintervention maximum inspiratory capacityb

mean ± SD (95% CI), mL

—

—

—

—

—

435.0 ± 364.5

(98.61 to 772.82); P = 0.02

—

—

454.29 ± 408.16 (76.80 to 831.77); P = 0.03

MD 19.29, 95% CI –386.09 to 424.67; P = 0.93

Minute ventilation

(L/min)

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

6.8 ± 3.1 to 8.0 ± 3.5; P < 0.001

—

7.4 ± 4.9 to 6.9 ± 3.3; NS

—

Significance levels not reported

Maximal expiratory pressure

(cmH2O)
 

Toussaint 2016 (n = 52)

Mean ± SD

—

—

—

—

—

26 ± 9

28 ± 10

—

—

P = 0.45

Respiratory rate

(breaths/minute)
 
 

Jenkins 2014 (n = 23)

Mean ± SD before to after intervention

—

—

—

—

—

27 ± 9.2 to 28 ± 10.6; P < 0.05

—

26 ± 10.3 to 26 ± 10.4; NS

—

Significance levels not reported

Ability to perform breath stacking

(%)
 

Toussaint 2016 (n = 52)

—

—

—

—

—

88

89

—

—

P = 0.9

Number of insufflations to maximal insufflation capacity

(n)

Toussaint 2016 (n = 52)

Mean ± SD

—

—

—

—

—

1.8 ± 0.6

2.6 ± 0.6

—

—

P < 0.001

Comfort, distress, and strength of cough

(VAS 10‐point score)

Chatwin 2003 (n = 22)

Mean (95% CI)

5.4 (4.5 to 6.3)a

5.8 (4.8 to 6.8)

(NS)

6.9 (5.3 to 7.0)

(NS)

7.3 (6.6 to 8.0)

(NS)

5.9 (5.2 to 6.7)

(NS)

—

—

—

—

Separate VAS scores not presented

Significance levels not reported

Comfort

(VAS 10‐point score)

Del Amo Castrillo 2019 (n = 20)

Median (IQR)

—

6.4 (5.2 to 7.6)

—

—

—

—

6.5 (3.9–7.4)

—

—

P = 0.31

Subjective cough effectiveness (VAS 10‐point score)

Del Amo Castrillo 2019 (n = 20)

Median (IQR)

—

6.0 (4.85 to 8.2)

—

—

—

—

6.2 (5.1–7.1)

—

—

P = 0.17

BS: breathstacking; CI: confidence interval; GPB: glossopharyngeal breathing; IQR: interquartile range; PCF: peak cough flow; MAC: manually assisted cough; MD: mean difference; ME: mechanical exsufflation; MI: mechanical insufflation; MI‐E: mechanical insufflation/exsufflation; min: minute; n: number of participants; NS: not significant; SD: standard deviation; VAS: visual analogue scale.
aBaseline value – not a randomly assigned control.
bUsing raw first‐period data provided by the author on request.

Figuras y tablas -
Table 2. Study results grouped by outcome measures and interventions – cough augmentation therapy compared to alternative individual cough augmentation therapies
Ir a la tabla de la revisión
Table 3. Study results grouped by outcome measures and interventions – comparison of individual and combination cough augmentation therapies with alternative individual and combination interventions

Outcome measure

Unassisted cough

MI

MI‐E

MAC

Manual BS

MAC + MI

MAC + manual BS

MAC + MI‐E

Between‐group differences

PCF

(L/min)

Sivasothy 2001 (n = 4)

Median (range)

288 (175 to 367)a

231 (148–597)

—

193 (185–287)

—

362 (218–440)

—

—

NS

Brito 2009 (n = 28)

Mean ± SD

171 ± 67a

—

—

231 ± 81

225 ± 80

—

292 ± 86

—

Manual BS vs unassisted cough: P < 0.001

Manual BS vs MAC: NS

MAC + BS vs unassisted cough: P < 0.001

MAC vs MAC + BS: P < 0.05

Manual BS vs MAC + BS: P < 0.05

Lacombe 2014 (n = 18)

Mean ± SD 

—

—

Absolute valueb:

210.6 ± 52.8

MD from baselineb:

53.4 ± 51.0; n = 7

—

—

Absolute valueb:

225 ± 83.4

MD from baselineb:

124.8 ± 38.4; n = 4

—

Absolute valueb:

210.6 ± 50.4

MD from baselineb: 106.2 ± 50.4; n = 7

Comparison of MDs (intervention – baseline):

MI + MAC vs MI‐E alone:

MD 71.4, 95% CI 18.08 to 124.72); P = 0.009

MI‐E + MAC vs MI‐E alone: MD 52.8, 95% CI –0.32 to 105.92; P = 0.05

MI‐E + MAC vs MI + MAC:

MD –18.6, 95% CI –71.61 to 34.41; P = 0.49

Kim 2016 (n = 40)

Mean ± SD

95.7 ± 40.5

—

177.2 ± 33.9

—

—

—

155.9 ± 53.1

202.4 ± 46.6

MAC + manual BS vs unassisted cough: P < 0.01

MI‐E vs unassisted cough: P < 0.01

MI‐E vs MAC + manual BS: P < 0.01

MI‐E + MAC vs unassisted cough: P < 0.01

MI‐E + MAC vs MAC + manual BS: P < 0.01

MI‐E + MAC vs MI‐E alone: P < 0.01

Transcutaneous oxygen saturation

(%)

Chatwin 2009 (n = 8)

Mean 

—

—

—

Data not reported

—

—

—

Data not reported

NS difference in group means

Transcutaneous carbon dioxide tension

(%)

Chatwin 2009 (n = 8)

Mean

—

—

—

Data not reported

—

—

—

Data not reported

NS difference in group means

Maximum inspiratory or insufflation capacity

(L)

Lacombe 2014 (n = 18)

mean ± SD

—

—

1.55 ± 0.34b; n = 7

—

—

1.43 ± 0.34b; n = 4

—

1.39 ± 0.43b; n = 7

Comparison of means:

MI‐E vs MI + MAC: MD –0.12, 95% CI –33.44 to 33.20; P = 0.99

MI‐E vs MI‐E + MAC: MD –0.16, 95% CI –0.57 to 0.25; P = 0.44

MI+ MAC vs MI‐E + MAC: MD 0.04, 95% CI –0.42 to 0.50; P = 0.86

Cough expiratory volume

(L)

Sivasothy 2001 (n = 4)

Median (range)

0.9 (0.5–1.1)a

0.7 (0.3–1.3)

—

0.5 (0.41–1.01)

—

0.6 (0.4–1.01)

—

—

NS

Heart rate

(beats per minute)

Chatwin 2009 (n = 8)

Not specified

—

—

—

Data not reported

—

—

—

Data not reported

NS

Effective cough time

(ms)

Lacombe 2014 (n = 18)

Mean ± SD

—

—

Absolute valueb:

70 ± 79

MD from baselineb:

54 ± 95; n = 7

—

—

Absolute valueb:

93 ± 111

MD from baselineb:

93 ± 111; n = 4

—

Absolute valueb:

22 ± 47

MD from baselineb:

20 ± 42; n = 7

MI‐E vs MI + MAC: MD 39.0, 95% CI –90.56 to 168.56; P = 0.56

MI‐E vs MI‐E + MAC: MD –34.00, 95% CI –110.95 to 42.95; P = 0.39

MI + MAC vs MI‐E + MAC:

MD 73.00, 95% CI –40.14 to 186.14; P = 0.21

Peak value time

(ms)

Sivasothy 2001 (n = 4)

Median (range)

44 (40–50)a

45 (30–60)

—

50 (35–55)

—

50 (45–120)

—

—

NS

Treatment time after 30 minutes

(min)

Chatwin 2009 (n = 8)

Median (range)

—

—

—

17 (0–35)

—

—

—

0 (0–26)

P = 0.03

Auscultation score

(VAS 10‐point score)

Chatwin 2009 (n = 8)

MD ± SD before to after intervention

—

—

—

3.4 ± 2.0 to 2.3 ± 2.2; P = 0.007

—

—

—

2.9 ± 1.9 to 1.8 ± 2.0; P = 0.02

Significance level not reported

Secretions

(VAS 10‐point score)

Chatwin 2009 (n = 8)

MD ± SD before to after intervention

—

—

—

4.4 ± 2.5 to 3.0 ± 1.4; P = 0.03

—

—

—

4.0 ± 2.2 to 1.7 ± 0.4; P = 0.03

Significance level not reported

Comfort

(VAS 10‐point score)

Chatwin 2009 (n = 8)

Baseline to after intervention 

—

—

—

Data not reported

(NS)

—

—

—

Data not reported (NS)

Data presented graphically only.

Significance level not reported

Lacombe 2014 (n = 18)

Median (IQR)

—

—

Original report:

6.4 (5.5 to –7.0)

b5.7 (0.9)

—

—

Original report: 7.0 (6.0–8.5)

b5.9 (1.15)

—

Original report: 6.6 (5.8–8.0)

b6.8 (.7)

NS

Subjective cough effectiveness

(VAS 10‐point score)

Sivasothy 2001 (n = 4)

Not reported

Not reported*

Not reported

—

Not reported

—

Not reported

—

—

Participants did not report benefit of any intervention.

Lacombe 2014 (n = 18)

Median (IQR) 

—

—

Original report: 6.4 (4.8–8.2)

b7.2 (2.4)

—

—

Original report: 8.3 (7.2–9.0)

b7.1 (0.8)

—

Original report: 8.5 (6.2–9.0)

b8.0 (1.95)

Original report:

MI‐E + MAC vs MI‐E: P < 0.05

MAC + MI vs MI‐E: P < 0.05

Breathlessness

(VAS 10‐point score)

Chatwin 2009 (n = 8)

Baseline to after intervention score

—

—

—

Data not reported

(NS)

—

—

—

Data not reported

(NS)

Data presented graphically only.

Significance level not reported

Mood

(VAS 10‐point score)

Chatwin 2009 (n = 8)

Baseline to after intervention score 

—

—

—

Data not reported

(NS)

—

—

—

Data not reported

(NS)

Data presented graphically only.

Significance level not reported

Fatigue

(VAS 10‐point score)

Chatwin 2009 (n = 8)

MD ± SD before to after intervention 

—

—

—

Data not reported (NS)

—

—

—

3.2 ± 2.2 to 5.1 ± 2.6

(P = 0.005)

Incomplete reporting.

Significance level not reported

BS: breathstacking; CI: confidence interval; GPB: glossopharyngeal breathing; IQR: interquartile range; PCF: peak cough flow; MAC: manually assisted cough; MD: mean difference; ME: mechanical exsufflation; MI: mechanical insufflation; MI‐E: mechanical insufflation/exsufflation; min: minute; n: number of participants; NS: not significant; SD: standard deviation; VAS: visual analogue scale.

aBaseline value – not a randomly assigned control.

bUsing raw first‐period data provided by the author on request.

Figuras y tablas -
Table 3. Study results grouped by outcome measures and interventions – comparison of individual and combination cough augmentation therapies with alternative individual and combination interventions
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Summary of findings 2. Cough augmentation therapy compared with standard care for people with neuromuscular diseases

Cough augmentation therapy compared with standard care for people with neuromuscular disease

Patient or population: participants with chronic neuromuscular diseases

Settings: –

Intervention: cough augmentation therapy

Comparison: standard care

Outcome

Summary of results

No of participants
(studies)

Certainty of the evidence
(GRADE)

Comments

Number of unscheduled hospital admissions for 'maintenance' therapy

No study reported the number of unscheduled admissions.

1 parallel‐group RCT of manual breathstacking compared to standard care (67 participants) planned to measure these outcomes; however, only an abstract is available and data are not fully reported (Katz 2019).

Lack of quantitative data precludes assessment of precision.

Duration of hospital stay (days) for 'rescue' therapy

No study reported the duration of hospital stay.

Quality of life for 'maintenance' therapy

No study reported quality of life

Peak cough flow for 'rescue' or 'maintenance' therapy

No study reported peak cough flow

Any adverse events for 'rescue' and 'maintenance' therapy

Follow‐up: 2 years

1 parallel‐group RCT reported that no adverse events had occurred during the 2‐year study, but this outcome was not quantitatively reported and it was unclear how it was measured.

67 (1 study)

⊕⊝⊝⊝
Verylowa

We are unable to draw a conclusion.

Quality of life for 'maintenance' therapy

No study reported quality of life.

1 parallel‐group RCT of manual breathstacking compared to standard care (67 participants) planned to measure quality of life; however, only an abstract is available and data are not fully reported (Katz 2019).

Participant preference or satisfaction for 'rescue' or 'maintenance' therapy

No study measured or reported participant preference.

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; RCT: randomised controlled trial.

GRADE Working Group grades of evidence
High certainty: further research is very unlikely to change our confidence in the estimate of effect.
Moderate certainty: further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low certainty: further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low certainty: we are very uncertain about the estimate.

aDowngraded three times, twice for study limitations and once for imprecision. Data were from one parallel‐group RCT, with high risk of performance and reporting bias. This outcome was not quantitatively reported and unclear how it was measured. Lack of quantitative data precludes assessment of precision but the trial was small (67 participants).

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Summary of findings 2. Cough augmentation therapy compared with standard care for people with neuromuscular diseases
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Table 4. Study results grouped by outcome measures and interventions – cough augmentation therapy compared to standard care

Outcome measure

Study identifier

Sample size

Data presentation

Unassisted cough

Manual BS

Standard care

Between‐group differences

Number and duration of unscheduled hospital and ICU admissions

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

Unassisted PCF

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

Health‐related quality of life

Katz 2019

n = 67

Pediatric Quality of Life Inventory score

—

Not reported

Not reported

No results reported

FVC

Katz 2019

n = 67

Median

% predicted

85.5 (entire cohort)a

4.1% change

6.4% change

Adjusted MD 2.0, 95% CI –8.2 to 12.3

Time to 10% decline in FVC

Katz 2019

n = 67

Not reported

—

Data not reported

Data not reported

Manual BS vs standard care: P = 0.5

Maximal inspiratory or insufflation capacity

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

MEP

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

MIP

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

Number and duration of outpatient oral antibiotic courses

Katz 2019

n = 67

Units not specified

—

Not reported

Not reported

No results reported

BS: breathstacking; CI: confidence interval; FVC: forced vital capacity; ICU: intensive care unit; MD: mean difference; MEP: maximal expiratory pressure; MIP: maximal inspiratory pressure; n: number of participants; PCF: peak cough flow.

aBaseline value – not a randomly assigned control

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Table 4. Study results grouped by outcome measures and interventions – cough augmentation therapy compared to standard care
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Comparison 1. Manual versus mechanical breathstacking (BS)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Peak cough flow Show forest plot

1

52

Mean Difference (IV, Fixed, 95% CI)

6.00 [‐33.43, 45.43]

1.2 Maximal insufflation capacity Show forest plot

1

52

Mean Difference (IV, Fixed, 95% CI)

0.14 [‐0.13, 0.41]
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Comparison 1. Manual versus mechanical breathstacking (BS)
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Comparison 2. Glossopharyngeal breathing (GPB) versus manual breathstacking (BS)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Peak cough flow Show forest plot

1

14

Mean Difference (IV, Fixed, 95% CI)

‐40.72 [‐90.54, 9.10]

2.2 Inspiratory capacity Show forest plot

1

14

Mean Difference (IV, Fixed, 95% CI)

19.29 [‐386.09, 424.67]
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Comparison 2. Glossopharyngeal breathing (GPB) versus manual breathstacking (BS)
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Comparison 3. Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation (MI) plus manually assisted cough (MAC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Peak cough flow Show forest plot

1

11

Mean Difference (IV, Random, 95% CI)

71.40 [18.08, 124.72]

3.2 Inspiratory capacity Show forest plot

1

11

Mean Difference (IV, Fixed, 95% CI)

‐0.12 [‐33.44, 33.20]
Figuras y tablas -
Comparison 3. Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation (MI) plus manually assisted cough (MAC)
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Comparison 4. Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation‐exsufflation (MI‐E) plus manually assisted cough (MAC)

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Peak cough flow Show forest plot

1

14

Mean Difference (IV, Fixed, 95% CI)

52.80 [‐0.32, 105.92]

4.2 Inspiratory capacity Show forest plot

1

14

Mean Difference (IV, Fixed, 95% CI)

‐0.16 [‐0.57, 0.25]
Figuras y tablas -
Comparison 4. Mechanical insufflation‐exsufflation (MI‐E) versus mechanical insufflation‐exsufflation (MI‐E) plus manually assisted cough (MAC)
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Comparison 5. Mechanical insufflation (MI) plus manually assisted cough (MAC) versus mechanical insufflation‐exsufflation (MI‐E) plus MAC

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Peak cough flow Show forest plot

1

11

Mean Difference (IV, Fixed, 95% CI)

18.60 [‐34.46, 71.66]

5.2 Inspiratory capacity Show forest plot

1

11

Mean Difference (IV, Fixed, 95% CI)

0.04 [‐0.42, 0.50]
Figuras y tablas -
Comparison 5. Mechanical insufflation (MI) plus manually assisted cough (MAC) versus mechanical insufflation‐exsufflation (MI‐E) plus MAC
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