Invasive ventilatory strategies that target ultra-low tidal volumes or minimisation of driving pressure in patients receiving invasive mechanical ventilation on an intensive care unit: a systematic review and meta-analysis

Adel Elfeky; Adam J Boulton; Anna Wilson; Rachel Court; Amy Grove; Peter Auguste; Daniel Gallacher; Ewan C Goligher; Daniel F McAuley; Gavin D Perkins; Barnaby R Scholefield; Marin Thompson; Joyce Yeung; Yen-Fu Chen; Keith Couper

doi:10.3310/nihropenres.14331.1

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Systematic Review

Invasive ventilatory strategies that target ultra-low tidal volumes or minimisation of driving pressure in patients receiving invasive mechanical ventilation on an intensive care unit: a systematic review and meta-analysis

[version 1; peer review: 1 not approved]

Adel Elfeky^1,2, Adam J Boulton³, Anna Wilson¹, [...] Rachel Court^1,2, Amy Grove^1,2, Peter Auguste^1,2, Daniel Gallacher^1,2, Ewan C Goligher⁴, Daniel F McAuley^5,6, Gavin D Perkins^3,7, Barnaby R Scholefield^4,8, Marin Thompson⁹, Joyce Yeung^3,7, Yen-Fu Chen^1,2,10, Keith Couper ^3,7

Adel Elfeky^1,2, Adam J Boulton³, [...] Anna Wilson¹, Rachel Court^1,2, Amy Grove^1,2, Peter Auguste^1,2, Daniel Gallacher^1,2, Ewan C Goligher⁴, Daniel F McAuley^5,6, Gavin D Perkins^3,7, Barnaby R Scholefield^4,8, Marin Thompson⁹, Joyce Yeung^3,7, Yen-Fu Chen^1,2,10, Keith Couper ^3,7

PUBLISHED 21 Jul 2026

Author details Author details

¹ Warwick Evidence, University of Warwick Warwick Medical School, Coventry, England, UK
² Centre of Evidence and Implementation Science, University of Birmingham School of Social Policy, Birmingham, England, UK
³ Warwick Clinical Trials Unit, University of Warwick Warwick Medical School, Coventry, England, UK
⁴ Interdepartmental Division of Critical Care Medicine, University of Toronto Temerty Faculty of Medicine, Toronto, Ontario, Canada
⁵ Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, Northern Ireland, UK
⁶ Royal Victoria Hospital, Belfast, Northern Ireland, UK
⁷ Critical Care Unit, University Hospitals Birmingham NHS Foundation Trust, Birmingham, England, UK
⁸ Department of Critical Care Medicine, Hospital for Sick Children, Toronto, Canada
⁹ Patient and Public representative, University of Warwick Warwick Medical School, Coventry, England, UK
¹⁰ Department of Health and Welfare, College of City Management, University of Taipei, Taipei City, Taipei City, Taiwan

Adel Elfeky
Roles: Conceptualization, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Writing – Original Draft Preparation, Writing – Review & Editing

Adam J Boulton
Roles: Investigation, Methodology, Writing – Review & Editing

Anna Wilson
Roles: Investigation, Writing – Review & Editing

Rachel Court
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Amy Grove
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Peter Auguste
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Daniel Gallacher
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Ewan C Goligher
Roles: Conceptualization, Investigation, Writing – Review & Editing

Daniel F McAuley
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Gavin D Perkins
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Barnaby R Scholefield
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Marin Thompson
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Joyce Yeung
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Writing – Review & Editing

Yen-Fu Chen
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

Keith Couper
Roles: Conceptualization, Funding Acquisition, Investigation, Methodology, Supervision, Writing – Original Draft Preparation, Writing – Review & Editing

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Our objective was to examine the clinical and cost-effectiveness of ultra-low tidal volume ventilation (ULTV) and limited-driving pressure ventilation in adults and children receiving invasive mechanical ventilation on an intensive care unit.

Methods

We searched MEDLINE, Embase and other sources from inception to October 2025. We included randomised controlled trials comparing ULTV or driving pressure minimisation strategies to standard care. We included all full economic evaluations. Two reviewers independently identified eligible studies, extracted data, and assessed risk of bias and overall GRADE certainty of evidence. Meta-analyses were conducted with random effects models.

Results

We included 12 clinical effectiveness trials (13 trial reports) and three health economic evaluations. Seven trials compared ULTV with standard care and five compared driving pressure minimisation strategies with standard care in adult patients receiving mechanical ventilation. We identified no relevant evidence in children.

The evidence is very uncertain about the effect of ULTV strategies on duration of invasive ventilation (mean difference [MD] -1.87 days, 95% CI -5.07 to 1.33), 28-day mortality (risk ratio [RR] 1.11, 95% CI 0.97 to 1.28), or any other clinical outcomes.

The evidence is also very uncertain about the effect of driving pressure minimisation strategies on duration of invasive ventilation (MD -1.66 days, 95% CI -3.95 to 0.63) or 28-day mortality (RR 1.10, 95% CI 0.80 to 1.50), and other clinical outcomes. The certainty of evidence for all outcomes was assessed as low or very low.

Conclusions

Current evidence does not support the routine use of ULTV and driving pressure minimisation strategies. Further high-quality randomised trials are needed.

Systematic review registration

PROSPERO CRD42024554619.

Plain Language Summary

Background

Patients that become critically unwell may require invasive mechanical ventilation on an intensive care unit. We know that the way in which we deliver ventilation can affect both how likely someone is to survive and how quickly they come off the ventilator.

A key concern when delivering ventilation is that we might cause damage to the lung. Two approaches to delivering ventilation that seek to minimise this damage are:

1.
Ultra-low tidal volume- this means giving very smaller than normal breaths, each time the ventilator delivers a breath.
2.
Reducing driving pressure- this means reducing the pressure used to deliver each breath.

Aim

We did a systematic review, in which we identified all the best available studies about these two approaches, to identify whether or not they help patients get off the ventilator more quickly.

What we did

We searched several medical databases to find randomised controlled studies that analyse how well these two ventilator approaches work. We included studies in both adults and children. We combined the results of these studies and evaluated how good the evidence was.

What we found

We found 12 studies. Seven studies looked at ultra-low tidal volume and five studies looked at reducing driving pressure. We found no studies in children.

Overall, we found that the available evidence did not give a clear indication on whether either ultra-low tidal volume or reducing driving pressure helped patients recover more quickly. There is a need for further studies for both approaches.

How we worked with patients

This review was supported by a patient representative who has lived experience of being admitted to an intensive care unit and receiving invasive mechanical ventilation. They helped us frame the research question, interpret the evidence, and write this paper.

Keywords

Invasive ventilation, acute respiratory distress syndrome, tidal volume, driving pressure, systematic review

Corresponding author: Keith Couper

Competing interests: DFM reports personal fees from consultancy for Bayer, Novartis, Aptarion, MSD, Direct Biologics and Healios. Professor McAuley also reports grant funding to his institution from several funders (NIHR, Wellcome Trust, Innovate UK, Medical Research Council, and Northern Ireland Health and Social Research and Development division) for studies in patients with ARDS and COVID-19, and has a patent (US8962032) issued to his institution for a treatment for inflammatory disease. GDP, JY and KC report grant funding to their institution from the National Institute for Health and Care Research for studies in ARDS, COVID-19 and weaning from invasive mechanical ventilation. The remaining authors declare no conflicts of interest.

Grant information: This project is funded by the National Institute for Health and Care Research (NIHR) under its [Technology Assessment (HTA) Programme (grant number NIHR154798) and NIHR Doctoral Research Fellowship (NIHR303023)] The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright: © 2026 Elfeky A et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Elfeky A, Boulton AJ, Wilson A et al. Invasive ventilatory strategies that target ultra-low tidal volumes or minimisation of driving pressure in patients receiving invasive mechanical ventilation on an intensive care unit: a systematic review and meta-analysis [version 1; peer review: 1 not approved]. NIHR Open Res 2026, 6:100 (https://doi.org/10.3310/nihropenres.14331.1) First published: 21 Jul 2026, 6:100 (https://doi.org/10.3310/nihropenres.14331.1) Latest published: 21 Jul 2026, 6:100 (https://doi.org/10.3310/nihropenres.14331.1)

Introduction

There are few interventions that improve clinical outcomes in patients receiving invasive mechanical ventilation.^1–3 One such intervention is the use of a low-tidal volume ventilation strategy. The landmark ARMA trial showed in adults with acute respiratory distress syndrome (ARDS) that a lower tidal volume ventilation strategy, which involved an initial tidal volume of 6 ml/kg ideal body weight and plateau pressure < 30 cmH₂O reduced hospital mortality.² This clinical benefit is likely driven by the avoidance of lung injury associated with high ventilatory pressures.⁴

The opportunity to improve outcomes through minimisation of ventilator-induced lung injury has driven interest in other ventilation strategies that aim to further minimise tidal volumes (ultra-low tidal volumes [ULTV]) and associated pressures beyond those used in the ARMA trial. A parallel strategy is through minimising driving pressure, which has been associated with reduced mortality in observational studies.⁵ These two interventions might however drive harm through mechanisms such as respiratory acidosis and their effect may be influenced by lung mechanics.⁶

Our recent scoping review summarised all the evidence underpinning key innovative ventilation technologies. We identified an expanding body of evidence in relation to ventilatory strategies that target ultra-low tidal volumes or the minimisation of driving pressure, and a lack of recent high-quality systematic reviews or that reviews typically focused on a specific technology.^7,8 On this basis, we undertook a systematic review and meta-analysis to evaluate the clinical and cost-effectiveness of a ventilatory strategy that targets ultra-low tidal volumes or minimises driving pressure, compared with standard care, in adults and children receiving invasive mechanical ventilation on an intensive care unit.

Methods

Patient and public involvement

This review forms part of a larger evidence synthesis project exploring innovative ventilation technologies in the intensive care unit.⁹ Through that larger project, individuals with personal experience of adult and paediatric intensive care participated in an expert advisory group, which informed the decision to undertake this review and provided advice on scope and outcomes. One patient and public representative provided detailed advice throughout the conduct of the review and co-authors this manuscript.

Overview of methods

The review protocol was prospectively registered on the International Prospective register of Systematic Reviews (PROSPERO) and funded by the National Institute for Health and Care Research, (CRD42024554619).⁹ This manuscript is written in line with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement guidelines.¹⁰ A completed checklist is included in the supplementary materials.

Eligibility criteria

We included parallel group and cluster randomised controlled trials that evaluated the clinical effectiveness of a ventilatory strategy that primarily targeted either ULTV (including apnoeic ventilation) or the minimisation of driving pressure in adults (18-years or above) or children (one-month to 17-years) receiving invasive mechanical ventilation on an intensive care unit. We defined an ULTV strategy as one that targeted a tidal volume of 4 ml/kg predicted body weight (PBW) or less. We did not define a specific target for driving pressure. For health economic studies, we additionally included full economic evaluations (for example, cost-benefit, cost-effectiveness, cost-utility and cost-consequence analyses). Grey literature, including studies published only as abstracts and research letters were eligible for inclusion.

Outcomes

Our primary clinical outcome was duration of invasive mechanical ventilation. Secondary clinical outcomes included length of stay (ICU, hospital); Mortality (ICU, 28-day), health-related quality of life, ventilator-free days (28- or 30-days), reintubation rate, intervention efficacy (tidal volume, driving pressure, mechanical power), and clinically important adverse events. Our economic outcomes were costs and quality-adjusted life years gained, and incremental cost-effectiveness ratios. Our outcomes align with the core outcome set for critical care ventilation trials.¹¹

Search strategy

We searched MEDLINE (Ovid), Embase (Ovid), Cochrane Library, Science Citation Index and Conference Proceedings Citation Index- Science (Web of Science), CEA Registry, and Dissertations & Theses Global database (ProQuest) in October 2025, with no limits on publication date or language. The search strategy was iteratively developed by an information specialist. We sought additional relevant citations through engagement with clinical experts and searches of ClinicalTrials.gov, Google.co.uk (targeted searching), and the reference lists of key relevant reviews and included studies. Full details of the search are included in the supplementary materials.

Study selection and data extraction

Records retrieved from electronic database searches and other sources were imported to EndNote and then de-duplicated. The remaining records were uploaded to Rayyan review management software. The review of titles and abstracts was independently conducted by two reviewers. Full texts of each eligible article were then obtained and independently evaluated by the same two reviewers. In cases of disagreement, the two reviewers reached consensus through discussion.

Data were extracted to an Excel spreadsheet by one reviewer and then checked for accuracy by another reviewer. Discrepancies were resolved through discussion. Extracted data included study design and setting, details of the intervention and comparator group, outcomes and timepoint/method of assessment, patient characteristics, and reporting of key demographic information based on PROGRESS-PLUS criteria.¹² For economic studies, we additionally extracted details of methods (e.g., type of economic analysis), results and other key information (e.g., source of funding). We highlight cases where a completed trial has not been published. For trials that reported continuous outcomes as median and interquartile range, we estimated the mean and standard deviation using the approach described by Wan and colleagues.¹³

For duration of mechanical ventilation, we preferentially extracted data for all patients (both survivors and non-survivors) in line with the core outcome set for ventilation studies.¹¹ For the outcome of 28-day mortality, we used mortality data at similar time-points (30-day or hospital), where a study did not report 28-day mortality.

Assessment of risk of bias (quality) and evidence certainty

For randomised controlled trials, we assessed risk of bias using the Cochrane risk of bias tool version two (RoB2).¹⁴ The Consolidated Health Economic Reporting Standards (CHEERS) checklist was used to assess reporting quality of economic evaluation studies.¹⁵ The methodological quality of the economic evaluations was assessed by two commonly used tools for the appraisal of model-based¹⁶ and trial-based economic evaluations.¹⁷ Risk of bias assessments were undertaken by two reviewers independently, with discrepancies resolved through discussion or deferral to a third reviewer. The GRADE approach was used to assess the certainty of evidence for each outcome.¹⁸ GRADE assessment was undertaken by two researchers independently using GRADEpro GDT software. Further details of our approach to our GRADE assessment are included in the supplementary materials.

Strategy for data synthesis

For each pairwise comparison, we synthesised data to obtain effect size estimates, namely risk ratio (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) and 95% CI for continuous outcomes. For dichotomous outcomes, we additionally report the risk difference (RD) and 95% CI. We also calculated 95% prediction intervals for duration of ventilation and 28-day mortality.¹⁹ We used a random effects model to incorporate the assumption that different studies are estimating different, yet related, treatment effects.²⁰ We synthesised data from ULTV and driving pressure minimisation studies separately, but present on the same forest plot to facilitate comparison of treatment effects. We explored statistical heterogeneity through visual inspection of forest plots and the χ² test. The I² statistic was calculated to evaluate the proportion of total variance arising from between-study heterogeneity. We planned to use funnel plots and related methods to assess publication bias/small study effects if there was a sufficient number of studies (i.e., ten or more) included in the meta-analysis. Due to the context-specific nature of economic evaluations, we planned to summarise economic studies narratively.

We planned, where feasible, to undertake the following subgroup analyses for the primary outcome: ARDS at randomisation; baseline PaO₂/FiO₂ ratio; baseline PaCO₂; adults v children; baseline respiratory system elastance; use of extracorporeal life support strategies to facilitate achieving the target tidal volume/driving pressure; and trial risk of bias. We subsequently decided to extend these analyses to the outcome of 28-day mortality. Based on the available data, we present the planned sub-group analysis for risk of bias as a sensitivity analysis. We undertook a post-hoc sensitivity analysis in which we explored duration of ventilation in different groups (survivors and non-survivors) in line with the core outcome set.¹¹ We undertook an additional post-hoc sensitivity analyses that explored studies where target intervention treatment was delivered and a sub-group analysis of patients presenting with and without COVID-19.

Results

Our search identified 12,672 unique study records after duplicates were removed. After initial title and abstract screening, 104 full text articles were assessed for eligibility. Twelve clinical effectiveness trials (13 trial reports) and three health economic evaluations met the inclusion criteria and were included in the review. For one of the included trials (the REST trial), we included two reports (a primary results paper and long-term outcomes paper) and an economic evaluation based on findings from the trial. The PRISMA flow diagram is included as Figure 1.

Figure 1. PRISMA flow diagram outlining the study selection process.

Footnote: Two reports included in the clinical effectiveness review and one economic evaluation included in the cost-effectiveness review were related to the REST trial.

Characteristics of clinical-effectiveness trials

We included 12 clinical effectiveness trials (13 trial reports). Seven trials^21–28 compared ULTV ventilation to standard care and five compared limited driving pressure ventilation to standard care (Table 1; supplementary materials Table S1).^29–33 The precise tidal volume or driving pressure target varied across studies. Four trials used extracorporeal carbon dioxide removal (ECCO₂R) or extracorporeal membrane oxygenation (ECMO) to support intervention delivery, all of which were studies that targeted ULTV ventilation.^{21,22,24–26}

Table 1. Summary of included randomised controlled trials.

Study	Design (sample size)	Setting	Number of centres	Population	Intervention	Comparator
Ultra-low tidal volume ventilation
Bein 2013	RCT (n = 79)	Germany; Austria	Multi-centre	Adult- ARDS	ULTV (3 ml/kg/predicted body weight [PBW]) + ECCO₂R	Standard care (TV 6 mL/kg/PBW)
De Haro 2023	RCT (n = 98)	Spain; USA	Multi-centre	Adult- non-ARDS	ULTV (4 mL/kg PBW)	Standard care (TV- 8 mL/kg/PBW)
Guervilly 2022	RCT (n = 39)	France	Multi-centre	Adult- ARDS (on ECMO)	ULTV (1–2 mL/kg/PBW) + ECMO	Standard care (Pplat<25 cm H2O) + ECMO
Hermann 2024	RCT (n = 44)	Austria	Single centre	Adult- ARDS	ULTV <4 mL/kg + ECMO	Standard care including ECMO (TV <6 mL/kg/PBW)
REST trial McNamee 2021 Boyle 2022	RCT (n = 412)	UK	Multi-centre	Adult- AHRF	ULTV (≤3 mL/kg/PBW) + ECCO₂R	Standard care (TV- 6 mL/kg/PBW)
Richard 2023	RCT (n = 215)	France	Multi-centre	Adult- COVID-ARDS	ULTV- (4 mL/kg PBW)	LTV aiming for VT 6 mL/kg/PBW
Simonis 2018	RCT (n = 961)	Netherlands	Multi-centre	Adult- non-ARDS	ULTV- (4 mL/kg PBW)	Standard care (TV- 10 mL/kg/PBW)
Limited driving pressure ventilation
Costa 2024	RCT (n = 77)	Brazil	Single centre	Adult- COVID-ARDS	Driving pressure (DP) ≤ 15 cm H₂O	ARDSNet strategy
Hamama 2021	RCT (n = 110)	Egypt	Single centre	Adult- ARDS	DP ≤ 14 cm H₂O	ARDSNet strategy
Maia 2024	RCT (n = 214)	Brazil; Colombia	Multi-centre	Adult-COVID-ARDS	DP ≤14 cm H₂O	Low PEEP strategy
Romano 2020	RCT (n = 31)	Brazil	Multi-centre	Adult- ARDS	DP- 10 cm H₂O	ARDSNet strategy
Tongyoo 2024	RCT (n = 126)	Thailand	Single centre	Adult- non-ARDS	DP ≤15 cm H₂O	Standard care (TV≤8 mL/kg/PBW)

Three trials^23,28,31 specifically recruited patients who did not have ARDS, with the remaining nine trials either including only patients with ARDS or including patients both with and without ARDS. Three studies included patients with COVID-19 ARDS.^27,29,32 Most trials were conducted in Europe (n = 7) and were multi-centre (n = 8). We identified no trials in children. Trials often failed to achieve clear separation between the intervention and control group in relation to tidal volume, mechanical power, and driving pressure (supplementary materials Table S2). Key information about participant demographics, as per the PROGRESS-PLUS criteria,¹² was infrequently reported in trials (supplementary materials Table S3).

We identified eight ongoing trials. Six trials are comparing ULTV ventilation to standard care and two trials are comparing limited-driving pressure ventilation to standard care (supplementary materials Table S4).

Risk of bias assessment and certainty of evidence of clinical-effectiveness trials

Risk of bias was considered to be low in six trials.^{21,24,25,27,29,32} We deemed three trials to be at high risk of bias.^23,28,31 This was largely driven by concerns of bias arising from deviations from the intended interventions as these trials did not achieve their target tidal volume or driving pressure and there was no separation between trial arms. We deemed three trials (four trial reports) as having some concerns for risk of bias.^22,26,30,33 Risk of bias judgments for key outcomes across comparisons are presented in Figure 2. We were unable to formally assess publication bias as the number of trials identified for each outcome was less than ten. For all outcomes, GRADE certainty of evidence was ranked as low or very low (supplementary materials).

Figure 2. Risk of bias assessments.

Footnote: McNamee 2021 and Boyle 2022 are two reports of the REST trial.

Clinical outcomes

Duration of mechanical ventilation was reported in four (3 ULTV; 1 driving pressure minimisation) trials (Figure 3; supplementary materials Table S5). Two trials reported duration of mechanical ventilation in survivors only, one trial reported duration of mechanical ventilation in both survivors and all patients, and in the fourth trial, it was not stated whether duration of mechanical ventilation was reported in all patients or just survivors. For duration of invasive ventilation, the evidence is very uncertain about the effect of both ULTV strategies (MD -1.87 days, 95% CI -5.07 to 1.33; I² 77.53%; 3 trials; 1311 participants) and minimisation of driving pressure strategies (MD -1.66 days, 95% CI -3.95 to 0.63; I2 0%; 1 trial; 110 participants).

Figure 3. Effect of ultra-low tidal volume and strategies to minimise driving pressure on duration of mechanical ventilation.

Mortality at 28-days and ICU discharge was reported in 11 (6 ULTV; 5 driving pressure minimisation) and 7 (4 ULTV; 3 driving pressure minimisation) trials respectively (Figures 4 and 5; Table S5). We found that evidence is very uncertain about the effect of ULTV strategies on mortality at 28-days (RR 1.11, 95% CI 0.97 to 1.28; RD 3.4%, 95% CI -0.9% to 8.7%; I² 0%; 6 trials; 1613 participants; very low certainty evidence) and mortality at ICU discharge (RR 1.10, 95% CI 0.74 to 1.63; RD 2.6%, 95% CI -6.7% to 16.1%; I² 41.17%; 4 trials; 1084 participants). We similarly found very uncertain evidence for the effect of minimisation of driving pressure strategies on mortality at 28-days (RR 1.10, 95% CI 0.80 to 1.50; RD 3.6%, 95% CI -7.2% to 17.9%; I² 30.2%; 5 trials; 541 participants) and mortality at ICU discharge (RR 1.10, 95% CI 0.85 to 1.42; RD 4.8%, −7.2% to 20.1%; I² 19.85%; 3 trials; 355 participants).

Figure 4. Effect of ultra-low tidal volume and strategies that minimise driving pressure on 28-day mortality.

Figure 5. Effect of ultra-low tidal volume and strategies that minimise driving pressure on intensive care unit mortality.

Length of stay on ICU and in the hospital was reported in nine (5 ULTV; 4 driving pressure minimisation) and eight (5 ULTV; 3 driving pressure minimisation) trials respectively (Figures 6 and 7). The evidence is very uncertain about the effect of ULTV on ICU length of stay (MD -0.12 days, 95% CI -3.55 to 3.30; I² = 78.07%; 5 trials; 1589 participants) and hospital length of stay (MD 1.91 days, 95% CI -1.51 to 5.33; I² = 37.17%; 5 trials; 1742 participants). We similarly found that evidence is very uncertain about the effect of driving pressure minimisation strategies on ICU length of stay (MD -2.15 days, 95% CI -4.02 to −0.27; I² = 0%; 4 trials; 465 participants) and hospital length of stay (MD -0.7 days, 95% CI -4.83 to 3.43; I² = 0%; 3 trials; 355 participants).

Figure 6. Effect of ultra-low tidal volume and strategies that minimise driving pressure on intensive care unit length of stay.

Figure 7. Effect of ultra-low tidal volume and strategies that minimise driving pressure on hospital length of stay.

The evidence is also very uncertain about the effect of ULTV (MD -0.4 days, 95% CI -1.88 to 1.09 days; I² = 37.58%; 5 trials; 1581 participants) or driving pressure ministration strategies (MD 0.03 days, 95% CI -3.53 days to 3.58 days; I² = 73.94%; 5 trials; 541 participants) on number of ventilator free days to day-30 (Figure 8). One ULTV trial reported health-related quality of life.²² At 12-months, the effect of ULTV on health related quality of life was very uncertain (utility score: MD −0.004, 95% CI −0.13 to 0.12; visual analogue score MD 6.4, 95% CI −1.4 to 14.2).

Figure 8. Effect of ultra-low tidal volume and strategies that minimise driving pressure on ventilator-free days.

Across six adverse events (ventilator-associated pneumonia, barotrauma, intracranial haemorrhage, development of atelectasis, development of ARDS, reintubation), we found that evidence is very uncertain about the effect of the interventions on the rate of these events (supplementary materials figures S1 to S6). Strategies that target ULTV reduced tidal volume, driving pressure, and mechanical power (supplementary materials figures S7 to S9). In contrast, strategies that target minimisation of driving pressure did not reduce tidal volume, driving pressure, or mechanical power.

Subgroup and sensitivity analyses

Our ability to undertake sub-group analyses was limited by either an absence of evidence (e.g. studies in children), lack of reporting of relevant data in included studies, and the limited number of studies that reported our primary outcome. We undertook a post-hoc sensitivity analysis in which we analysed data for survivors only (supplementary materials figure S10). Due to the available data, we were not able to analyse ventilation duration in non-survivors.

For the outcome of 28-day mortality, our sub-group and sensitivity analyses explored use of extracorporeal support (ULTV only), ARDS status (ULTV and minimisation of driving pressure), risk of bias (ULTV and minimisation of driving pressure), COVID-19 status (minimisation of driving pressure only), and achievement of target treatment separation (ULTV and minimisation of driving pressure) (supplementary materials figures S11-S16). These analyses were consistent with our primary analysis with no evidence of differences across sub-groups. Of note, our sub-group analysis of extracorporeal support in ULTV studies compared studies that ECMO, ECCO₂R, and no extracorporeal support with the analysis finding no evidence of sub-group differences (p = 0.38).

Health economic evaluations

We included three economic analyses, all of which analysed ULTV facilitated by ECCO₂R.^34–36 Two related studies (with one being an extension of the other) undertook a model-based economic analysis,^34,35 and the other undertook a trial-based economic evaluation.³⁶ Both model-based analyses reported that ULTV was likely to be cost-effective, whilst the trial-based analysis found that ULTV was unlikely to be cost-effective. Further details of the findings of health economic studies are included in the supplementary materials (including Tables S6 to S13).

Discussion

In this systematic review, strategies that target ULTV effectively reduced tidal volume and driving pressure, but this did not translate into improvements in patient-centred clinical outcomes. Strategies that target minimisation of driving pressure did not reduce tidal volume or driving pressure and did not affect clinical outcomes, except intensive care length of stay. We found no evidence in children. Health economic evidence was limited to three studies, with the only trial-based evaluation reporting that a ULTV strategy facilitated by ECCO₂R was unlikely to be cost-effective. GRADE certainty in evidence for all outcomes was assessed as low or very low, which means that we have very little confidence in the effect estimates and the true effects could be substantially different from the estimated effects.

Across included trials, we found that the driving pressures or tidal volumes delivered in the intervention group often exceeded the protocolised target. For example, in the largest of the minimisation of driving pressure trials included in this review, the delivered tidal volume (ml/kg PBW) in the intervention group was 5.9, 6.6, and 7.4 at days one, two, and three respectively. Whilst this was significantly lower than that of the control group, it was markedly higher than the target of 4 ml/kg PBW.²⁸ This may reflect the real-world application of these interventions, but it inevitably dilutes any potential treatment effect and would bias towards the null hypothesis. In the original ARMA trial, the delivered treatment adhered closely to the protocolised treatment in both the intervention (delivered: 6.2 ml/kg/PBW; target 6 ml/kg/PBW) and control (delivered: 11.8 ml/kg/PBW; target 12 ml/kg/PBW) groups.² However, this lower target tidal volume is frequently exceeded in clinical practice. For example, in the LUNG-SAFE study, around 35% patients received a tidal volume over 8 ml/kg and 60% received a tidal volume over 7 ml/kg.³⁷

Four of the included trials used an extracorporeal strategy (ECCO₂R or ECMO) to support intervention delivery of ULTV.^{21,22,24–26} Importantly, despite potential differences in patient populations across trials that did and did not use extracorporeal strategies, our sub-group analysis that compared the three groups of ECCO₂R, ECMO and no extracorporeal strategy found no evidence of a difference in treatment effect across sub-groups. However, as there were only two or three studies in each sub-group, the analysis might be under-powered to detect these sub-group differences. Extracorporeal strategies potentially facilitate intervention delivery by obviating the potential harms of reduced minute ventilation, such as respiratory acidosis. However, such strategies carry the inherent risks associated with any extracorporeal circuit, such as infection, thrombosis, and bleeding.³⁸ The REST trial which used ECCO₂R to facilitate delivery of ULTV recorded nine cases of intracranial haemorrhage that were categorised as serious adverse events, all of which occurred in the ULTV group who were receiving systemic anticoagulation. However, across two trials, we found very low certainty evidence that ULTV did not increase the incidence of intracranial haemorrhage. A recent large observational study of 11,972 patients reported an association between a large relative reduction in PaCO₂ in the 24 hours after commencing ECMO with an increased rate of neurological complications (odds ratio 1.7, 95% CI 1.3 to 2.3).³⁹ The association between a change in PaCO2 and intracranial haemorrhage is biologically plausible, but these data provide evidence only of correlation and need to be interpreted in the context of baseline risk of developing risk of developing an intracranial haemorrhage in a critically ill patient population.^39,40

The very limited economic studies that we identified reported conflicting findings for the cost-effectiveness of ECCO₂R supported ULTV ventilation. A key difference that might have contributed to the discrepant results was estimated clinical benefits from ULTV ventilation. The two model-based studies assumed better survival and shorter duration on mechanical ventilation with ULTV ventilation based on observational evidence, but these benefits were not observed in the REST trial which provided evidence for the trial-based economic evaluation.³⁶

Our review has several important limitations. First, few studies reported our primary outcome of duration of ventilation. This outcome was determined a priori and is a clinically important outcome that reflects the proposed mechanism of the interventions. Whilst there are challenges with its interpretation due to the competing risk of death, its relevance is reflected by patients and clinicians selecting it as a core outcome in the core outcome set for invasive mechanical ventilation trials.¹¹ The infrequent reporting may reflect both that some studies were designed prior to the development of the core outcome set and sub-optimal uptake of the outcome set in critical care trials. Importantly, across all reported outcomes, we found no clear evidence of benefit or harm. Second, our review included both studies that target ULTV and minimisation of driving pressure. The decision to include both strategies was made a priori, and reflects some overlap in clinical objective across the two interventions. Nevertheless, important clinical differences meant that we analysed each intervention separately. Third, available evidence precluded some pre-planned sub-group analyses, such as baseline elastance, which might have provided key clinical insights into potential differences across physiological phenotypes. Fourth, there was heterogeneity across studies in the targeted tidal volume and driving pressure. For ULTV, we selected a threshold of 4 ml/kg. For driving pressure, we were unable to define a specific target. Underlying this are a number of assumptions, including the clinical appropriateness of targeting of a single parameter, and that there is a linear association between reductions in the parameter and clinical outcome. It is possible that different thresholds for inclusion might have influenced review findings. Fifth, the included trials recruited a heterogeneous study population (ARDS, non-ARDS, COVID, hypoxemic respiratory failure). Sixth, we identified no relevant evidence in children. Seventh, we found only three health economic studies, all of which focused on ULTV ventilation facilitated by an extracorporeal strategy. Given the additional costs associated with use of an extracorporeal strategy in relation to both the equipment and staff training, these findings may not be generalisable to interventions that do not require use of an extracorporeal strategy and which can be delivered through a conventional ventilator. Finally, in line with our review protocol, we undertook a frequentist analysis, such that, in contrast to a Bayesian analysis, we are unable to report the probability of a clinically meaningful treatment effect.

Conclusions

In conclusion, across 12 randomised controlled trials and three health economic analyses, we found that ULTV and driving pressure minimisation strategies did not meaningfully influence key clinical outcomes, with evidence certainty characterised as low or very low. This may partly be attributable to difficulty achieving the target tidal volume or driving pressure described in the protocol, which would tend to bias towards the null hypothesis. Ongoing uncertainty should drive the need for further trials, including trials in children, to better inform clinical practice.

Data availability

Underlying data

All data underlying the results are available as part of the article and no additional source data are required.

Extended data

Supplementary materials are available at Open Science Framework: “Supplementary materials- DP ULTV Review_300426.pdf” https://doi.org/10.17605/OSF.IO/SZKQN.⁴¹

This project contains the following extended data:

• Supplementary materials

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Reporting guidelines

A completed PRISMA checklist for “Invasive ventilatory strategies that target ultra-low tidal volumes or minimisation of driving pressure in patients receiving invasive mechanical ventilation on an intensive care unit: a systematic review and meta-analysis” OSF | Supplementary materials- DP ULTV Review_300426.pdf is available at Open Science Framework under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).⁴¹

DOI: https://doi.org/10.17605/OSF.IO/SZKQN

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