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Perkins GD, Mistry D, Lall R, et al. Protocolised non-invasive compared with invasive weaning from mechanical ventilation for adults in intensive care: the Breathe RCT. Southampton (UK): NIHR Journals Library; 2019 Sep. (Health Technology Assessment, No. 23.48.)

Cover of Protocolised non-invasive compared with invasive weaning from mechanical ventilation for adults in intensive care: the Breathe RCT

Protocolised non-invasive compared with invasive weaning from mechanical ventilation for adults in intensive care: the Breathe RCT.

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Chapter 1Introduction

Scientific background

The widespread use of positive-pressure ventilation in intensive care units (ICUs) can be traced back to the polio epidemic in Denmark in 1952. Among a cohort of 316 patients admitted to hospital with polio affecting the bulbar muscles, mortality fell from 80% to 23% following the introduction of early tracheostomy and positive-pressure ventilation.1 The lack of mechanical ventilators at the time required teams of medical students to work around the clock in shifts to provide positive-pressure ventilation manually. The demonstrated life-saving potential of invasive positive-pressure ventilation led to an acceleration in the development of mechanical ventilators and the birth of modern-day intensive care.2

Epidemiology of positive-pressure ventilation

Each year, an estimated 20 million people worldwide receive invasive mechanical ventilation (IMV).3 In the UK, approximately 110,000 people require IMV annually.4 In a large cohort study, the main reasons for requiring mechanical ventilation were acute respiratory failure (69%), coma (16%), acute exacerbation of chronic lung disease (10%) and neuromuscular disease (2%). The causes of acute respiratory failure were postoperative (20%), pneumonia (14%), congestive cardiac failure (10%), sepsis (9%), trauma (8%), acute respiratory distress syndrome (4.5%) and other (12%).5,6 Reports from the Intensive Care National Audit and Research Centre (ICNARC) indicate that the median duration of ventilation is 5 days [interquartile range (IQR) 3–10 days] and the median length of stay on an ICU is 7 days (IQR 4–14 days).4 Patients spend, on average, 17 days in hospital (IQR 9–31 days). Mortality during ICU admission has fallen over recent years and is currently around 28%.5,6

Weaning from ventilation

Weaning is the process of liberating a patient from mechanical ventilation. It involves transferring the work of breathing from the ventilator to the patient. Weaning accounts for 40–50% of the time a patient requires positive-pressure ventilation.7 Strategies to optimise weaning should find a balance between withdrawing ventilator support too early and unnecessarily prolonging ventilation. Premature withdrawal runs the risk of reintubation, which is associated with prolonged hospital stay, increased costs, increased tracheostomy use and increased mortality.8,9 By contrast, delayed weaning is associated with increased adverse effects, such as ventilator-associated pneumonia (VAP),10,11 sinusitis,12 upper airway damage,13 respiratory muscle weakness13 and increased mortality.14,15 The requirement for sedative and muscle relaxant drugs during mechanical ventilation may further contribute to delirium, immobility and generalised weakness.16 The observations that 10–15%7 of patients require reintubation during the weaning process and that almost half of patients with an unplanned self-extubation during the weaning period do not require reintubation17 suggest that there is scope for improvement in current weaning approaches.

Weaning involves several stages (Figure 1). After treating the underlying illness and ensuring that there are no contraindications to weaning, a spontaneous breathing trial (SBT) is undertaken.7 During a SBT, minimal support is provided from the ventilator and a combination of clinical and physiological measurements is used to determine whether or not the patient can breathe unaided.

FIGURE 1. Steps involved in liberating a patient from IMV.


Steps involved in liberating a patient from IMV. ARF, acute respiratory failure.

Patients who ‘pass’ the SBT and are considered otherwise ready for extubation have their tube removed. This group of patients, which represents two-thirds of mechanically ventilated patients, has a good prognosis, with an ICU mortality of approximately 5%.7 The one-third of patients who ‘fail’ the SBT have a reported mortality of 25–30%.7 Weaning practices after failing an initial SBT are variable. SBTs are often repeated on a daily basis until either extubation or a tracheostomy is performed.

Non-invasive ventilation as an adjunct to weaning

Non-invasive ventilation (NIV) refers to the delivery of mechanical ventilation using a mask, nasal pillows, helmet or mouthpiece interface instead of an endotracheal tube. Similar to IMV, NIV reduces the work of breathing and can improve gas exchange.18 NIV may avoid some complications associated with prolonged endotracheal intubation, such as VAP, sinusitis and ventilator-induced lung injury.19 In the context of weaning, NIV has been used to facilitate early extubation, to prevent respiratory failure after extubation in high-risk patients and as a rescue therapy when respiratory failure occurs following extubation.18

Existing knowledge

A Cochrane review examined the effectiveness of NIV for weaning from IMV across 16 randomised controlled trials (RCTs) that recruited 994 patients.20 Nine trials enrolled only patients with chronic obstructive pulmonary disease (COPD), whereas seven trials included mixed or non-COPD populations. The review found strong evidence that weaning using NIV reduced mortality [risk ratio (RR) 0.53, 95% confidence interval (CI) 0.36 to 0.80], although heterogeneity was moderate (I2 = 37%). The beneficial effect seemed limited to studies that enrolled only patients with COPD (RR 0.36, 95% CI 0.24 to 0.56) in contrast to the studies that enrolled mixed populations (RR 0.81, 95% CI 0.47 to 1.40). As shown in Table 1, NIV in this context had a number of other benefits.



Effect of non-invasive weaning on clinically relevant outcomes

Need for a trial

The generalisability of the findings from the Cochrane review20 to current UK practice is limited. There are four main reasons for this. First, the treatment pathway for an exacerbation of COPD has changed since these early trials were conducted. Many patients who would have previously received IMV for respiratory failure now have ward- or ICU-based NIV as a strategy to prevent the need for IMV.21 IMV is now reserved mainly for patients who fail a trial of NIV. The population of patients ventilated for COPD in contemporary UK practice therefore differs from that enrolled in trials ≥ 10 years ago. Second, none of the trials recruited patients from the UK. This research team’s collaboration in the International Survey of Weaning practices shows marked differences in weaning practices between countries.22 Third, 3 out of the 12 studies (comprising nearly 20% of patients) are either unpublished or published as abstracts only. This limits assessment of methodological quality, and minimal information is available about the population recruited and the interventions tested. Fourth, when it was possible to assess the methodological quality of index trials, the quality of the methods was variable and eight trials had evidence of being at high risk of bias. There was also variation in the methods used to identify patients for weaning (e.g. four trials used a unique resolution of pulmonary infection criterion, which is rarely used in UK practice) and in the approaches to titration and discontinuation of ventilator support.

Although the results of the Cochrane review20 are encouraging, the size and limitations of trials conducted to date leave uncertainty as to the clinical effectiveness and cost-effectiveness of NIV as a routine tool to facilitate weaning from mechanical ventilation. This is likely to explain the limited penetration of this weaning approach into UK ICU practice. This topic is important to the intensive care community. The need for additional trials in this area was identified by the Intensive Care Society during its Research Prioritisation Exercise in 2008.23 With these considerations it was timely to conduct a well-designed, appropriately powered randomised control trial (RCT) to examine the clinical effectiveness and cost-effectiveness of NIV-facilitated weaning in the NHS.

The UK’s National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme called for applications to examine the clinical effectiveness and cost-effectiveness of using NIV as an intermediate step in weaning patients from IMV.

The objective of the trial was defined in the commissioning brief (Table 2).



The NIHR HTA programme 10/134 commissioning brief

The Breathe trial investigators were competitively selected to conduct a pragmatic, randomised, controlled, open, multicentre, effectiveness trial to determine if the use of NIV as an intermediate step in the protocolised weaning of patients from IMV is clinically effective and cost-effective.

Copyright © Queen’s Printer and Controller of HMSO 2019. This work was produced by Perkins et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK.
Bookshelf ID: NBK546384


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