Introduction

Mechanical ventilation (MV) is a lifesaving invasive treatment strategy for critically ill patients but is associated with an increased risk of respiratory complications. The presence of an endotracheal tube limits cough effectiveness due to the glottis being held in abduction, preventing the generation of adequate intrathoracic pressures for effective cough and airway clearance.¹ The use of sedatives diminishes the cough reflex and contributes to intensive care acquired weakness due to prolonged offloading of the respiratory muscles.^1,2 Additionally, exposure to dry gases used during MV are thought to cause airway mucosal dysfunction and consequently increased sputum load and viscosity.³ This, along with an ineffective cough can lead to sputum retention, increasing the risk of complications such as atelectasis, ventilator-acquired pneumonia, and ultimately respiratory failure.^4,5

Many patients who are mechanically ventilated rely on physiotherapeutic techniques to mobilise secretions and optimise airway clearance. These include strategies such as suction, manual or ventilator hyperinflation and manual assisted cough. More recently cough augmentation devices such as mechanical insufflation-exsufflation (MI-E) have also been used in the ICU setting.⁶ Mechanical insufflation-exsufflation is a non-invasive technique that utilises positive and negative pressure to augment expiratory airflow that facilitates sputum mobilisation.⁷ Over the past two decades there has been a growing trend for the use of MI-E in ICU and an increasing evidence base for its efficacy.⁸ A substantial body of evidence exists supporting the use of MI-E in patients with neuromuscular disease⁷ and emerging evidence for its use in other populations.⁹ To date, studies have demonstrated improvements in sputum clearance, pulmonary mechanics (airway resistance and lung compliance) and promising results in the reduction of re-intubation rates.^4,10,11

Despite this, MI-E is often underutilised^12–14 with several barriers described including concerns regarding safety and the risk of adverse events, particularly associated to the use of high levels of positive pressure in patients who are critically ill.¹² The physiological effects of positive pressure such as altered cardiopulmonary dynamics are recognised and well documented.¹⁵ Targeted recruitment techniques may cause undesirable effects associated with volutrauma and barotrauma, increasing the risk of a pneumothorax.⁶ Other possible complications of positive pressure may include chest and abdominal pain, haemoptysis, gastroesophageal reflux, and abdominal distention.¹⁷ Adverse effects associated with negative pressure such as lung unit de-recruitment have also been recognised in the literature¹⁸ but not specifically with the use of MI-E. Notwithstanding this, evidence regarding the safety of using MI-E in intubated critically ill patients is sparse.^8,14 The aim of this Literature Review is to report on the occurrence of adverse events associated with MI-E in invasively ventilated critically ill patients.

Methods

Search Strategy

An electronic search was performed using the following databases: AMED, CINAHL, Cochrane Library, EMBASE, MEDLINE, SPORTDiscuss and Web of Science, from database inception to January 2023, using the search terms listed in Appendix 1. Additionally, reference lists of relevant articles were hand searched for eligible studies.

Selection Criteria

Inclusion criteria included (1) primary research, (2) adult subjects (18> years) who were invasively ventilated, (3) MI-E applied in isolation or in conjunction with other treatment interventions, (4) adverse effects of MI-E as an outcome. Studies were excluded if they were in a paediatric population, not written in English language and were editorials, opinion pieces or conference papers (not original data).

Study Selection

Study selection was carried out by all five reviewers. Three were rotational band 5 physiotherapists (CW, KW and LS). One a Consultant Physiotherapist and Clinical Doctoral Research Fellow (ES) and one a Senior Lecturer in Cardiorespiratory Physiotherapy (DH). Four reviewers (CW, KW, LS and ES) independently screened study titles and abstracts of the studies retrieved from the search. Any uncertainties were reviewed in full text. All reviewers screened all remaining full text studies and assessed for eligibility. This process was repeated by the lead author (DH) to ensure accuracy.

Data Extraction

Information regarding study characteristics including participants, interventions, outcomes, and results was extracted into a table by four authors and cross checked by one author (ES) (Table 1).

Quality Assessment

The Critical Appraisal Skills Programme (CASP) tool was utilised by four independent reviewers to assess study quality.⁹ The included studies were assessed against each question using the corresponding checklist. Results were compared and any discrepancies resolved by discussion.

Data Analysis

Descriptive statistics were used to summarise quantitative data accompanied by a narrative synthesis of findings.

Results

Study selection

The study selection process is presented in Figure 1. A total 77 studies were identified through the electronic search. After removal of duplicates (44) and studies not written in English (1), 45 titles were screened. A total of five studies were selected for inclusion. No further studies were identified via hand searching reference lists.

Study Design

Of the included studies, three studies were randomised crossover studies. There was one randomised parallel-group open label trial and one case series. Studies were conducted in Brazil (n=3), France (n=1) and Spain (n=1).

Study characteristics

A summary of the included studies is shown in Table 1.

Participants

All studies included participants who were mechanically ventilated for more than 24 or 48 hours. Three of the five studies included participants ventilated via an ETT^10,11,20 and one study included participants with ETT and tracheostomies.²¹ Participant mean age ranged from 51.4 to 75.7 years. The reason for ICU admission and diagnosis varied across studies and included surgical, medical, trauma and neurological conditions. Sample sizes ranged across studies from 13-180.

MI-E Intervention

A variety of MI-E protocols were presented across included studies. All studies applied MI-E followed by ETT or tracheostomy suction. One study applied MI-E in conjunction with Expiratory Rib Cage Compressions (ERCC).¹⁰ Coutinho et al.²² and Sánchez-García et al.²¹ provided supplementary oxygen prior to and during MI-E. One study utilised MI-E with inbuilt oscillations.²¹ Mechanical insufflation-exsufflation protocols varied across studies with some lack of detail reporting. Insufflation-exsufflation pressures ranged from ±30 to ±50 cmH₂O. Insufflation and exsufflation times ranged from 2 to 3s and 1.5 to 4s respectively. Treatments were applied by physiotherapists in three studies.^10,11,20 However, Coutinho et al.²² and Sánchez-García et al.²¹ did not detail who applied the treatment. Detail regarding clinician level of experience was not included across included studies.

Outcomes

Ten different outcomes across the five included studies were identified relating to safety and/or adverse events (respiratory and haemodynamic). Only two studies examined adverse events as a primary outcome.^21,22 One study provided further definition for a ventilatory and haemodynamic adverse event.¹¹

Occurrence of Adverse Events

No haemodynamic or ventilatory adverse events were observed in two of the five studies.^11,22 Of the studies that observed adverse events only transient changes were described.^10,20,21 No study reported clinically significant adverse events that required cessation of MI-E treatment or medical intervention.

Discussion

The aim of this review was to report on the occurrence of adverse events associated with MI-E use in invasively ventilated critically ill patients. The findings suggest that the use of MI-E in this patient group does not result in adverse events that are clinically significant. Despite all studies concluding that MI-E is safe in this population, limitations to the evidence base should be acknowledged when interpreting the results.

There was large variation in MI-E protocols across studies and a lack of detail regarding device set up, which limits the ability to draw firm conclusions regarding the link between MI-E and adverse events. Although varied, the use of insufflation and exsufflation pressures of +40/-40cmH₂O is consistent with findings from a recent scoping review by Swingwood et al.⁸ It is well documented pressures of at least +40/-40cmH₂O are required to generate higher expiratory flows.²³ However, emerging evidence suggests even higher pressures may be required in those with an artificial airway, to overcome resistance to flow.^24,25 Only one study in this review applied higher insufflation and exsufflation pressures (+50/-50 cmH₂O), which did not result in significant changes in respiratory or haemodynamic parameters.²⁰ This is consistent with the findings of Hyun, Lee, and Shin²⁵ and Mart? et al.²⁶ where no adverse events were observed when pressures of +50/-50 cmH₂O and +40 to -70cmH₂O (respectively) were utilised. It is worth noting that Mart? et al.²⁶ utilised pig models, therefore findings from this study cannot be extrapolated directly to a patient population. Whilst reassuring, studies investigating adverse events with higher pressures are limited.

To allow for more accurate representation of adverse events with different pressures perhaps standardisation of MI-E protocols would be preferable. Although this approach is thought to improve clinician confidence, arguably, one set protocol is unlikely to be effective and does not take into consideration individual risk factors that may predispose patients to adverse events occurring. Previously in the literature an individualised approach to MI-E set up has been advocated.⁷ Progressively building up pressure until efficiency is achieved allows for careful monitoring of adverse effects and is potentially safer.

There was also a wide variation in the outcomes reported across studies including heart rate, blood pressure, oxygen saturation, respiratory rate, work of breathing and arterial blood gas measurement, which again limits comparisons. Differences in the definition of an adverse event used within studies may have caused conflicting results on their prevalence. Whilst Martínez-Alejos et al.¹⁰ suggested a threshold for MI-E cessation (when arterial oxygen saturation falls below 85% or blood pressure changes of over 20% from baseline), only Ferreira de Camillis et al.¹¹ provided a clear definition for a ventilatory and haemodynamic adverse event (a decrease in oxygen saturation of 3% or drop in systolic blood pressure below 90mmHg). The remaining studies did not state at which point they determined changes in respiratory or haemodynamic parameters to be indicative of an adverse event. Therefore, the occurrence of adverse events in those studies may be under-reported. Additionally, the timepoints at which measurements were taken also varies across studies. It is worth noting that adverse events were reported as secondary outcomes in three of the five studies,^10,11,20 which again may result in the under-estimation of adverse events in this population.

Methodological quality of the included studies was assessed using the CASP tool. Overall, issues were identified relating to completeness of reporting, blinding, and a lack of pre-defined measurements. All included studies were based outside of the United Kingdom (UK) and varied in study design. Differences in ICU practices have been highlighted, in particular disparities in the management of patients who are mechanically ventilated.^27,28 Consequently, little is known about the impact of confounding factors of standard ICU care protocols. Standardisation of usual care and transparency of adjunctive interventions would mitigate potential confounders in future trials. Heterogeneity in study design limits the ability to draw comparisons across studies and make firm conclusions regarding the occurrence of adverse events with MI-E.

Strengths and limitations of this review

This review outlines the current available evidence regarding the safety of MI-E in mechanically ventilated adults. Clear inclusion and exclusion criteria were developed, and robust methodology applied. Multiple reviewers were used which was a further strength of the study methods. However, the findings of this review were limited by the paucity of studies on this topic. This review highlights that overall, there is a lack of published studies investigating the relationship between MI-E and the occurrence of adverse events, suggesting it is an under researched area. The lack of available evidence has been identified as a barrier to MI-E implementation in practice, which may be contributing to the underutilisation of the device in this population.^13,14 The absence of robust large-scale studies is not surprising given the complexity of researching patients who are critically ill, and the ethical implications of withholding vital treatment interventions.²⁹ Further publication of observational studies could strengthen conclusions regarding the safety of MI-E and increase clinician confidence in the device.

Conclusion

There are limited studies specifically investigating whether the use of MI-E results in adverse events in critically ill patients who are mechanically ventilated. In the five studies included, MI-E was reported to be safe, and its use did not result in adverse events that are clinically significant. Variations is study design, protocols and outcome measures limit direct comparisons between studies. Therefore, further research is needed with emphasis on standardisation of protocols and usual care. Larger clinical trials are needed to further evaluate the safety of MI-E on clinically important parameters that are more clearly defined. Additionally, to improve clinician confidence in practice, further research exploring the occurrence of adverse events across a range of pressures is warranted.

Key points

The use of MI-E in the acutely intubated patient does not result in adverse events that are clinically significant.

There were variations in study design, MI-E protocols and outcome measures used.

Standardisation of protocols and usual care is needed, as well as a consensus on clinically important parameters that are clearly defined.

• 1.

  McGarvey L, Rubin BK, Ebihara S, et al. Global Physiology and Pathophysiology of Cough. Chest. 2021;160(4):1413-1423. doi:10.1016/j.chest.2021.04.039
• 2.

  Jonkman AH, Jansen D, Heunks LMA. Novel insights in ICU-acquired respiratory muscle dysfunction: Implications for clinical care. Crit Care. 2017;21(1). doi:10.1186/s13054-017-1642-0
• 3.

  Lellouche F. Humidification during invasive mechanical ventilation: Hygrometric performances and cost of Humidification Systems. Humidification in the Intensive Care Unit. Published online September 23, 2011:137-155. doi:10.1007/978-3-642-02974-5_17
• 4.

  Gonçalves MR, Honrado T, Winck J, Paiva J. Effects of mechanical insufflation-exsufflation in preventing respiratory failure after extubation: A randomized controlled trial. Critical Care. 2012;16(2):R48. doi:10.1186/cc11249
• 5.

  Fernández-Carmona A, Olivencia-Peña L, Yuste-Ossorio ME, Peñas-Maldonado L. Ineffective cough and mechanical mucociliary clearance techniques. Medicina Intensiva (Engl Ed). 2018;42(1):50-59. doi:10.1016/j.medin.2017.05.003
• 6.

  Tronstad O, Martí JD, Ntoumenopoulos G, Gosselink R. An update on cardiorespiratory physiotherapy during mechanical ventilation. Semin Respir Crit Care Med. 2022;43(03):390-404. doi:10.1055/s-0042-1744307
• 7.

  Chatwin M, Toussaint M, Gonçalves MR, et al. Airway clearance techniques in neuromuscular disorders: A state of the art review. Respiratory Medicine. 2018;136:98-110. doi:10.1016/j.rmed.2018.01.012
• 8.

  Swingwood EL, Stilma W, Tume LN, et al. The use of mechanical insufflation-exsufflation in invasively ventilated critically ill adults. Respir Care. 2022;67(8):1043-1057. doi:10.4187/respcare.09704
• 9.

  Chatwin M, Wakeman RH. Mechanical insufflation-exsufflation: Considerations for improving clinical practice. Journal of Clinical Medicine. 2023;12(7):2626. doi:10.3390/jcm12072626
• 10.

  Martínez-Alejos R, Martí JD, Li Bassi G, et al. Effects of mechanical insufflation-exsufflation on sputum volume in mechanically ventilated critically ill subjects. Respir Care. 2021;66(9):1371-1379. doi:10.4187/respcare.08641
• 11.

  Ferreira de Camillis ML, Savi A, Goulart Rosa R, et al. Effects of mechanical insufflation-exsufflation on airway mucus clearance among mechanically ventilated ICU subjects. Respir Care. 2018;63(12):1471-1477. doi:10.4187/respcare.06253
• 12.

  Stilma W, van der Hoeven SM, Scholte op Reimer WJM, Schultz MJ, Rose L, Paulus F. Airway care interventions for invasively ventilated critically ill adults—a Dutch National Survey. Journal of Clinical Medicine. 2021;10(15):3381. doi:10.3390/jcm10153381
• 13.

  Swingwood E, Stilma W, Tume L, et al. The use of mechanical insufflation-exsufflation in invasively ventilated critically ill adults: A scoping review protocol. Syst Rev. 2020;9(1). doi:10.1186/s13643-020-01547-8
• 14.

  Rose L, Adhikari NK, Poon J, Leasa D, McKim DA. Cough augmentation techniques in the critically ill: A Canadian national survey. Respir Care. 2016;61(10):1360-1368. doi:10.4187/respcare.04775
• 15.

  Mahmood SS, Pinsky MR. Heart-lung interactions during mechanical ventilation: The basics. Ann Transl Med. 2018;6(18):349-349. doi:10.21037/atm.2018.04.29
• 16.

  Soni N, Williams P. Positive pressure ventilation: What is the real cost? British Journal of Anaesthesia. 2008;101(4):446-457. doi:10.1093/bja/aen240
• 17.

  Auger C, Hernando V, Galmiche H. Use of mechanical insufflation-exsufflation devices for airway clearance in subjects with neuromuscular disease. Respir Care. 2017;62(2):236-245. doi:10.4187/respcare.04877
• 18.

  Park HY, Ha SY, Lee SH, et al. Repeated derecruitments accentuate lung injury during mechanical ventilation*. Critical Care Medicine. 2013;41(12):e423-e430. doi:10.1097/ccm.0b013e3182986268
• 19.

  CASP checklists - critical appraisal skills programme. Published 2021. https://casp-uk.net/casp-tools-checklists/
• 20.

  Nunes L de C, Rizzetti DA, Neves D, et al. Mechanical insufflation/exsufflation improves respiratory mechanics in critical care: Randomized crossover trial. Respiratory Physiology & Neurobiology. 2019;266:115-120. doi:10.1016/j.resp.2019.05.008
• 21.

  Sánchez-García M, Santos P, Rodríguez-Trigo G, et al. Preliminary experience on the safety and tolerability of mechanical “insufflation-exsufflation” in subjects with artificial airway. Intensive Care Medicine Experimental. 2018;6(1). doi:10.1186/s40635-018-0173-6
• 22.

  Coutinho WM, Vieira PJC, Kutchak FM, Dias AS, Rieder MM. Comparison of mechanical insufflation–exsufflation and endotracheal suctioning in mechanically ventilated patients: Effects on respiratory mechanics, hemodynamics, and volume of Secretions. Indian Journal of Critical Care Medicine. 2018;22(7):485-490. doi:10.4103/ijccm.ijccm_164_18
• 23.

  Volpe MS, Guimarães FS, Morais CC. Airway clearance techniques for mechanically ventilated patients: Insights for optimization. Respir Care. 2020;65(8):1174-1188. doi:10.4187/respcare.07904
• 24.

  Guérin C, Bourdin G, Leray V, et al. Performance of the coughassist insufflation-exsufflation device in the presence of an endotracheal tube or tracheostomy tube: A bench study. Respir Care. 2011;56(8):1108-1114. doi:10.4187/respcare.01121
• 25.

  Hyun SE, Lee SM, Shin HI. Peak expiratory flow during mechanical insufflation-exsufflation: Endotracheal Tube Versus Face Mask. Respir Care. 2021;66(12):1815-1823. doi:10.4187/respcare.09150
• 26.

  Martí JD, Martínez-Alejos R, Pilar-Diaz X, et al. Effects of mechanical insufflation-exsufflation with different pressure settings on respiratory mucus displacement during invasive ventilation. Respir Care. 2022;67(12):1508-1516. doi:10.4187/respcare.10173
• 27.

  Burns KEA, Rizvi L, Cook DJ, et al. Ventilator weaning and discontinuation practices for critically ill patients. JAMA. 2021;325(12):1173. doi:10.1001/jama.2021.2384
• 28.

  Russotto V, Myatra SN, Laffey JG, et al. Intubation practices and adverse peri-intubation events in critically ill patients from 29 countries. Journal of American Medical Association (JAMA). 2021;325(12):1164. doi:10.1001/jama.2021.1727
• 29.

  Freitas dos Santos S, Almeida MP, Winck JC. Effects of mechanical insufflator-exsufflator in people with Spinal Cord Injury: A systematic review. Physical Therapy Reviews. 2022;28(1):18-29. doi:10.1080/10833196.2022.2141527