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High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome

  1. Sachin Sud1,*,
  2. Maneesh Sud2,
  3. Jan O Friedrich3,
  4. Hannah Wunsch4,
  5. Maureen O Meade5,
  6. Niall D Ferguson6,
  7. Neill KJ Adhikari7

Editorial Group: Cochrane Anaesthesia Group

Published Online: 28 FEB 2013

Assessed as up-to-date: 1 MAR 2011

DOI: 10.1002/14651858.CD004085.pub3


How to Cite

Sud S, Sud M, Friedrich JO, Wunsch H, Meade MO, Ferguson ND, Adhikari NKJ. High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome. Cochrane Database of Systematic Reviews 2013, Issue 2. Art. No.: CD004085. DOI: 10.1002/14651858.CD004085.pub3.

Author Information

  1. 1

    Trillium Health Center, University of Toronto, Division of Critical Care, Department of Medicine, Mississauga, Canada

  2. 2

    University of Toronto, Department of Medicine, Toronto, Ontario, Canada

  3. 3

    University of Toronto and Keenan Research Centre/Li Ka Shing Knowledge Institute, Critical Care and Medicine Departments, St. Michael's Hospital, Interdepartmental Division of Critical Care, Toronto, Ontario, Canada

  4. 4

    Mailman School of Public Health, Columbia University, Department of Anesthesiology, College of Physicians and Surgeons; Department of Epidemiology, New York, NY, USA

  5. 5

    McMaster University, Department of Clinical Epidemiology and Biostatistics, Hamilton, Ontario, Canada

  6. 6

    University Health Network and Mount Sinai Hospital, University of Toronto, Interdepartmental Division of Critical Care Medicine, Toronto, Ontario, Canada

  7. 7

    University of Toronto, and Department of Critical Care Medicine and Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Interdepartmental Division of Critical Care, Toronto, Ontario, Canada

*Sachin Sud, Division of Critical Care, Department of Medicine, Trillium Health Center, University of Toronto, Mississauga, Canada. sachinsud@aol.com.

Publication History

  1. Publication Status: New search for studies and content updated (conclusions changed)
  2. Published Online: 28 FEB 2013

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Summary of findings    [Explanations]

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

 
Summary of findings for the main comparison. HFO compared to conventional mechanical ventilation for ALI and ARDS

HFO compared to conventional mechanical ventilation for ALI and ARDS

Patient or population: patients with ALI and ARDS
Settings: Critical care units
Intervention: High frequency oscillation
Comparison: Conventional mechanical ventilation

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

Conventional mechanical ventilationHigh Frequency Oscillation

Hospital (or 30 day) mortalityTypical risk1RR 0.77
(0.61 to 0.98)
365
(6 studies)
⊕⊕⊕⊝
moderate2,3

443 per 1000341 per 1000
(270 to 434)

6 month mortality589 per 10004465 per 1000
(342 to 636)
RR 0.79
(0.58 to 1.08)
148
(1 study)
⊕⊕⊝⊝
low3

*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% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.

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.

 1 The basis of the assumed risk is a systematic review and meta-analysis of the mortality in patients with ARDS (Phua 2009).
2 The risk of bias was low in four studies, and unclear in two studies due to incomplete outcome data. In three studies control group ventilation used higher tidal volumes then currently recommended.
3 We downgraded the quality of evidence due to imprecision because of small numbers of patients and outcome events, resulting in wide confidence intervals which might include both appreciable and negligible benefit (serious limitations), or appreciable benefit and possible harm (very serious limitations).
4 The basis of the assumed risk is the control group risk.

 

Background

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Description of the condition

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions characterized by acute lung inflammation causing pulmonary congestion, hypoxaemia, and decreased pulmonary compliance. ALI is defined as a syndrome characterized by acute onset, bilateral pulmonary infiltrates on chest radiograph, no evidence of left atrial hypertension (or a pulmonary capillary wedge pressure of less than 18), and ratio of arterial oxygen tension to fraction of inspired oxygen (PaO2/FiO2) less than 300. ARDS refers to the more severely ill subset of patients in whom the PaO2/FiO2 ratio is less than 200. ALI and ARDS have a fairly high incidence (Rubenfeld 2005) and are associated with substantial mortality (Phua 2009; Rubenfeld 2005), morbidity (Angus 2001; Herridge 2003), and costs (Cheung 2006). 

 

Description of the intervention

High frequency oscillation (HFO) is an alternative ventilation technique in which very small tidal volumes are delivered at very high frequencies using an oscillatory pump while mean airway pressure is held constant. Humidified, oxygenated gas (bias flow) passes in front of a diaphragm which oscillates at high frequencies (3 to 15 Hz, or 180 to 900 breaths per minute). The mean airway pressure is determined by the rate of bias flow and by a resistance valve at the end of the bias flow circuit. Tidal volumes are much smaller during high frequency oscillation (1 to 4 mL/kg) compared to mechanical ventilation, and the constant mean airway pressure leads to smaller changes in alveolar pressure. Because tidal volumes during high frequency oscillation may be smaller than anatomic dead space, gas exchange occurs through gas mixing as opposed to bulk flow. Mechanisms of gas exchange during HFO include direct ventilation of proximal alveoli, Taylor dispersion, asymmetric velocity profiles, pendelluft, and diffusion (Slutsky 2002).

 

How the intervention might work

Mechanical ventilation is usually required for adequate tissue oxygenation (Artigas 1998) but may also perpetuate lung injury by over-distending and rupturing healthy alveoli, and by triggering a secondary inflammatory response that amplifies lung injury from repeatedly opening and collapsing lung units (Dreyfuss 1988; Gattinoni 2005; Muscedere 1994; Ranieri 1999). Lung-protective ventilation seeks to limit alveolar distension, recruit non-aerated alveoli, and prevent further alveolar collapse. Low tidal volumes with (Amato 1998; Meade 2008; Mercat 2008; Villar 2006) or without (ARDS Network 2000; Brochard 1998; Stewart 1998) high positive end-expiratory pressure may reduce ventilator induced lung injury. Nevertheless, mortality in patients with ARDS remains high (Phua 2009; Rubenfeld 2005). HFO theoretically meets the goals of a lung-protective ventilation strategy (Rimensberger 2003), with extremely small tidal volumes (1 to 4 mL/kg) and constant lung recruitment. 

 

Why it is important to do this review

Although HFO is increasingly used in some centres in patients with ARDS who do not tolerate conventional mechanical ventilation (Chan 2005; Finkielman 2006; Mehta 2004), its role, especially outside the realm of ‘rescue’ therapy, remains controversial (Ferguson 2008; Kacmarek 2008). Several observational studies (Ferguson 2005; Fort 1997; Mehta 2001) show improved oxygenation in patients with refractory hypoxaemia. An earlier systematic review of randomized controlled trials (Wunsch 2004) found only two small trials and could not draw definitive conclusions about the HFO effect on mortality. Additional studies have subsequently become available. Furthermore, in the context of recent (Dominguez-Cherit 2009; Kumar 2009) and future pandemics, there is a pressing need for evidence-based syntheses of the effects of potentially life-saving interventions for patients with ARDS. We therefore performed a systematic review and meta-analysis of randomized controlled trials comparing HFO to conventional mechanical ventilation for adults and children with ALI and ARDS to determine the effects of HFO on mortality, other clinical and physiological outcomes, and adverse events.

 

Objectives

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

The objective of this systematic review is to determine the effects of HFO compared to conventional mechanical ventilation on physiological outcomes, clinical outcomes, and mortality when used for the treatment of ALI or ARDS.

 

Methods

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Criteria for considering studies for this review

 

Types of studies

We included parallel group, randomized controlled trials (RCTs) which compared HFO to conventional mechanical ventilation for the treatment of ALI and ARDS and reported at least one of our prespecified outcomes.

 

Types of participants

We included adults or children (greater than four weeks old and 42 weeks postconception) with ALI or ARDS who were receiving conventional mechanical ventilation. We accepted authors' definitions of ALI and ARDS. In trials enrolling patients with other forms of respiratory failure, we stipulated that a minimum of 70% of patients must have ALI or ARDS to meet the inclusion criteria. We included trials that enrolled both adults and children because we believed that the physiological benefits of lung recruitment and reduction in tidal volume that occur during high frequency oscillation would be similar for both adult and paediatric ARDS (Albuali 2007; ARDS Network 2000; Hanson 2006; Miller 2008).

 

Types of interventions

We included studies in which patients were randomly assigned to two or more groups, including an experimental group that received HFO and a control group that received conventional mechanical ventilation for ALI or ARDS. We also included trials in which a secondary intervention was delivered as part of HFO, such as tracheal gas insufflation or recruitment manoeuvres, since these are applied in association with HFO in some centres. We included trials in which the duration of HFO was 24 hours or less for physiological outcome analyses but excluded them from analyses of major clinical outcomes, such as mortality.

 

Types of outcome measures

 

Primary outcomes

1. Hospital or 30-day mortality

 

Secondary outcomes

1. Six-month mortality

2. Duration of mechanical ventilation (in days, as stated by the authors)

3. Ventilator-free days to day 28 or 30 (in days, as stated by the authors)

4. Health-related quality of life at one year

5. Treatment failure, leading to crossover to the other arm or discontinuation of the study protocol. We accepted authors’ definitions of treatment failure, which could include severe oxygenation failure, ventilation failure, hypotension, or barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema)

6. The ratio of partial pressure of arterial oxygen (PaO2) to inspired fraction of oxygen (FiO2) (PaO2/FiO2 ratio) at 24, 48, and 72 hours after randomization

7. Oxygenation index (OI, defined as 100 x mean airway pressure/(PaO2/FiO2 ratio)) measured at 24, 48, and 72 hours after randomization

8. Ventilation, measured by partial pressure of carbon dioxide (PaCO2) at 24, 48, and 72 hours after randomization

9. Mean airway pressure 24, 48, and 72 hours after randomization

10. Barotrauma (as stated by the authors)

11. Hypotension (as stated by the authors)

12. Endotracheal tube obstruction due to secretions

13. Technical complications and equipment failure in patients treated with HFO (including unintentional system air leaks and problems with the oscillatory diaphragm, humidifier, and alarm systems) (Cartotto 2004; Finkielman 2006)

 

Search methods for identification of studies

We used systematic methods to identify published and unpublished RCTs comparing HFO to conventional mechanical ventilation in patients with ALI, ARDS, or other forms of hypoxaemic respiratory failure (Meade 1997).

In the previous version of this review (Wunsch 2004) we searched until 2002.

 

Electronic searches

To update our previous literature search, we:

  1. electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), MEDLINE (OvidSP) (1948 to March 2011), and EMBASE (OvidSP) (1980 to March 2011); please see Appendix 1 for search details; and
  2. searched for unpublished and ongoing trials in clinicaltrials.gov and controlled-trials.com. 

 

Searching other resources

In addition to the electronic search, we:

  1. manually searched reference lists from included studies and review articles;
  2. searched conference proceedings of the American Thoracic Society (1994 to 2010), Society of Critical Care Medicine (1994 to 2010), European Society of Intensive Care Medicine (1994 to 2010), and American College of Chest Physicians (1994 to 2010); and
  3. contacted clinical experts in the field.

 

Data collection and analysis

 

Selection of studies

Two investigators (SS, MS) who were not blinded to study authors or results (Berlin 1997) independently evaluated study eligibility and resolved differences by consensus.

 

Data extraction and management

Three review authors (SS, MS, JF), using a standardized spreadsheet, independently abstracted data on study methods, details of ventilation strategies, and study outcomes.  We resolved any disagreements remaining after author contact by consensus. 

 

Assessment of risk of bias in included studies

We abstracted data on methods of randomization and allocation concealment (Chalmers 1983), number of postrandomization withdrawals and losses to follow-up, crossovers between assigned groups, blinding of outcome assessors (Schulz 1995), and early stopping for benefit (Montori 2005). We summarized the risk of bias for individual studies using the Cochrane Collaboration ‘Risk of bias’ instrument (Higgins 2011). Since blinding of caregivers, patients, and family members was impossible in these trials, we determined whether important co-interventions (weaning, sedation, and paralysis) and use of rescue therapies for refractory respiratory failure (inhaled nitric oxide, prone positioning, steroids, and extracorporeal oxygenation) were standardized or equally applied in treatment groups. We assessed the quality of evidence for major clinical outcomes including mortality, treatment failure, and adverse events according to recommendations of the GRADE working group (Schunemann 2008).

 

Measures of treatment effect

We reported continuous outcomes using mean difference (MD), a measure of absolute change, and ratio of means (RoM), a measure of relative change (Friedrich 2008); and binary outcomes as relative risks (RR). We considered (2-sided) P < 0.05 as statistically significant and reported individual trial and summary results with 95% confidence intervals (CIs).

 

Unit of analysis issues

For clinical outcomes, the unit of analysis was patients. We did not identify any issues of 'double counting', for example the reporting of number of events instead of the number of patients who experienced an event.

For physiologic outcomes, the unit of analysis was at the study level since investigators reported the mean, standard error or standard deviation, and the number of patients with measurements. Because several trials used repeated measurements for physiologic endpoints (for example PaO2/FiO2) we chose to perform a separate meta-analysis for each of these endpoints at the prespecified times of 24, 48, and 72 hours after randomization.

 

Dealing with missing data

We contacted primary investigators of all included trials by e-mail and fax to request additional data and to clarify methodology after careful review of each study. Primary investigators provided additional clinical (Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) or physiologic (Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004) data, or clarified data or methods (Arnold 1994; Bollen 2005; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004).

 

Assessment of heterogeneity

Potential sources of clinical and methodological heterogeneity between studies included patients, ventilation strategies, and outcome definitions. Because we felt that this diversity would not support the underlying assumptions of a fixed-effect model, we used random-effects models for all pooled analyses. Random-effects models incorporate both within-study and between-study variation and typically provide wider CIs when heterogeneity is present. We assessed between-study statistical heterogeneity for each outcome using the I2 statistic (Higgins 2002; Higgins 2003) and used published guidelines for low (I2 = 25% to 49%), moderate (I2 = 50% to 74%), and high (I2 ≥ 75%) heterogeneity (Higgins 2003). We investigated potential sources of clinical and methodological heterogeneity through a priori subgroup analyses and sensitivity analyses (see Subgroup analysis and investigation of heterogeneity; Sensitivity analysis).

 

Assessment of reporting biases

We tested for publication bias statistically using the Begg’s Rank Correlation test (Begg 1994) and modified Macaskill’s regression test (Macaskill 2001). Because there were fewer than 10 included studies, we did not construct funnel plots.

 

Data synthesis

For each prespecified outcome, we employed random-effects models to perform meta-analysis with Review Manager (RevMan 5.1) where at least two trials with similar participants, interventions, and outcome definitions reported adequate data. We generated forest plots to summarize our results and reported relative risk or ratio of means with corresponding 95% CI.

We used the metabias command in STATA 9.2 (Stata 9.2) for statistical tests of publication bias. Given the low statistical power of these tests, we assumed a more liberal level of significance (P < 0.10) to indicate possible publication bias.

 

Subgroup analysis and investigation of heterogeneity

A priori, we planned three subgroup analyses to explore potential heterogeneity for the primary outcome of hospital or 30-day mortality and to test whether results were consistent for important subgroups of trials or patients.

Firstly, we hypothesized that potential methodological biases (quasi-randomization or unclear or unconcealed allocation and early termination for perceived benefit) might influence the results of our meta-analysis in favour of HFO, whereas greater than 10% crossovers between groups may bias the results against HFO. We therefore performed subgroup analyses of trials at higher risk of bias versus trials at lower risk of bias, as classified using the Cochrane Collaboration’s risk of bias tool. 

Secondly, we hypothesized that age might influence the benefit from HFO. Increasing age worsens the prognosis in ARDS and thus older patients might benefit less from HFO compared with younger patients (Brun-Buisson 2004; Flori 2005). Conversely, HFO is commonly used for neonatal respiratory distress syndrome and thus children may benefit more from HFO compared to adults (Cools 2009). We therefore performed a subgroup analysis comparing effects of HFO in trials enrolling postneonatal children (weight ≤ 35 kg, as defined in the paediatric trials) versus adults.

Thirdly, we hypothesized that the subset of patients with severe and life-threatening hypoxaemia may benefit more from HFO, recognizing that most patients with ARDS do not die of hypoxaemia (Montgomery 1985). We therefore planned a subgroup analysis of patients with a higher (≥ 150) versus lower (< 150) baseline PaO2/FiO2 ratio, but insufficient data precluded this analysis.

We assessed any subgroup effects using a z-test for interaction.

 

Sensitivity analysis

We also performed a post hoc sensitivity analysis of trials which mandated lung protective ventilation in the control group, defined as ≤ 8 mL/kg of ideal or predicted body weight, versus trials that did not mandate tidal volumes ≤ 8 mL/kg, because the use of higher tidal volumes in patients receiving conventional ventilation might bias results in favour of HFO (ARDS Network 2000; Brochard 1998; Stewart 1998).

We performed additional sensitivity analyses to test the robustness of our findings where data were incomplete or missing after author contact, which are described in the text (see Effects of interventions).

 

Results

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

 

Results of the search

We identified 2709 citations from searches of electronic bibliographic databases and four citations from other sources. We retrieved 22 studies for detailed evaluation, of which eight trials (Arnold 1994; Bollen 2005; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) met the criteria for this review. We also identified two ongoing studies that met inclusion criteria for our review (Meade 2009; Young 2010). Review authors had perfect agreement for study inclusion. 

See Figure 1.

 FigureFigure 1. Study flow diagram.

 

Included studies

The eight included trials (Arnold 1994; Bollen 2005; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) (see Characteristics of included studies) enrolled 431 patients (median 41, range 16 to148) with ALI and ARDS. Seven trials (Bollen 2005; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) enrolled patients exclusively with ARDS (n = 361), and 86% of the patients in the eighth trial had ARDS (Arnold 1994). Two trials enrolled only children (Arnold 1994; Samransamruajkit 2005). Two trials are currently published as abstracts (Mentzelopoulus 2007; Shah 2004). All trials (Arnold 1994; Bollen 2005; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) studied HFO as an initial ventilation strategy for ALI or ARDS as opposed to rescue therapy for refractory hypoxaemia. Trials enrolled patients within 48 hours of diagnosis of ARDS (Demory 2007; Papazian 2005; Samransamruajkit 2005) or shortly after initiation of mechanical ventilation, mean of less than two days (Bollen 2005; Derdak 2002) or five days (Arnold 1994; Shah 2004). All trials treated patients continuously with HFO except for one that applied HFO for six to 24 hours per day (most patients were treated for at least four days) according to a protocol until predefined criteria for resolution of severe ARDS had been met (Mentzelopoulus 2007). In two trials patients were treated for ≤ 24 hours (Demory 2007; Papazian 2005). The median baseline PaO2/FiO2 ratio was 112 (range 80 to 122) in seven trials (Arnold 1994; Bollen 2005; Demory 2007; Derdak 2002; Papazian 2005; Samransamruajkit 2005; Shah 2004). 

 

Details of high frequency oscillation

Patients received HFO for a prespecified period (Demory 2007; Papazian 2005) (n = 54), until prespecified criteria for weaning from HFO were met (Arnold 1994; Bollen 2005; Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005) (n = 349), or until clinical resolution of ARDS (Shah 2004) (n = 28). All studies standardized HFO implementation (Arnold 1994; Bollen 2005; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004). HFO was initiated with a mean airway pressure 2 to 5 cm H2O above mean airway pressure while on conventional ventilation and initial frequency set between 4 to 10 Hz. Pressure amplitude of oscillation was determined subjectively by chest wall vibration (Arnold 1994; Bollen 2005; Derdak 2002; Shah 2004) (n = 307), set according to arterial partial pressure of carbon dioxide (Demory 2007; Mentzelopoulus 2007; Papazian 2005) (n = 108), or set at 10 cm H2O above the peak inspiratory pressure during prerandomization conventional mechanical ventilation (Samransamruajkit 2005) (n = 16). Many trials described adjunctive measures during HFO, including partial endotracheal tube cuff leak for hypercarbia (Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Shah 2004) (n =284), tracheal gas insufflation (Mentzelopoulus 2007) (n = 54), and recruitment manoeuvres (Demory 2007; Mentzelopoulus 2007; Papazian 2005) (n = 108).

 

Details of conventional mechanical ventilation

All trials provided a description of conventional mechanical ventilation. Protocols for adjusting settings during conventional mechanical ventilation were described in five trials (Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Shah 2004) (n= 284). Four trials (Demory 2007; Mentzelopoulus 2007; Papazian 2005; Shah 2004) (n = 136) used low tidal volume ventilation in all patients (6 to 8 mL/kg predicted body weight (Demory 2007; Mentzelopoulus 2007; Shah 2004) or ideal body weight (Papazian 2005)), and three trials (Demory 2007; Samransamruajkit 2005; Shah 2004) (n = 72) mandated plateau pressure below 35 cm H2O. Five trials (Bollen 2005; Demory 2007; Derdak 2002; Papazian 2005; Shah 2004) (n = 291) reported a mean positive end-expiratory pressure of 12 to 14 cm H2O during the first 72 hours of conventional mechanical ventilation.

 

Excluded studies

See Characteristics of excluded studies; Characteristics of ongoing studies.

 

Risk of bias in included studies

Six trials (Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) had high methodological quality and low risk of bias, whereas the risk of bias was unclear in two studies (Arnold 1994; Bollen 2005) (see Characteristics of included studies; Figure 2; Figure 3). All trials concealed allocation and analysed clinical outcomes for patients by assigned group (Arnold 1994; Bollen 2005; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Shah 2004) or provided enough information to perform analyses according to assigned group (Samransamruajkit 2005). One trial (Bollen 2005) was terminated early because of low recruitment. Six trials (Bollen 2005; Demory 2007; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) reported no postrandomization withdrawals; in two trials 1.4% (2/148) (Derdak 2002) and 17% (12/70) (Arnold 1994) of patients were withdrawn after randomization. After contacting investigators, we obtained mortality data for withdrawn patients in one trial (Derdak 2002). There was no loss to follow-up in seven studies (Arnold 1994; Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) and only intensive care unit (ICU) but not 30-day mortality was available for 5% (3/61) of patients in one study (Bollen 2005). Five trials (Arnold 1994; Bollen 2005; Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005) reported crossovers between groups (range 4% to 52% of all randomized patients), which involved 0% to 19% of patients randomized to HFO (7/37 (Bollen 2005), 11/29 (Arnold 1994), 0/6 (Samransamruajkit 2005), 0/27 (Mentzelopoulus 2007), and 4/75 (Derdak 2002)); and 7% to 65% of patients randomized to conventional ventilation (4/24 (Bollen 2005), 19/29 (Arnold 1994), 1/10 (Samransamruajkit 2005), 2/27 (Mentzelopoulus 2007), and 9/73 (Derdak 2002)).

 FigureFigure 2. Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
 FigureFigure 3. Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

 

Effects of interventions

See:  Summary of findings for the main comparison HFO compared to conventional mechanical ventilation for ALI and ARDS

 

Mortality

In the primary analysis, including six trials that treated patients with HFO until resolution of ARDS (Arnold 1994; Bollen 2005; Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004) (n = 365), the median hospital or 30-day mortality in the control group was 48% (range 33% to 67%). HFO significantly reduced hospital or 30-day mortality (RR 0.77, 95% CI 0.61 to 0.98; P = 0.03; Figure 4). Mortality was determined at discharge from hospital (Mentzelopoulus 2007; Samransamruajkit 2005) or at 30 days after randomization (Arnold 1994; Bollen 2005; Derdak 2002; Shah 2004). In one trial (Bollen 2005), 3/61 patients were alive at discharge from the ICU and were assumed to be alive at 30 days; excluding these patients did not alter the results of the meta-analysis (RR 0.77, 0.61 to 0.98; P = 0.04;  Analysis 1.2). Subgroup analyses did not show significant differences in treatment effect among four adult (Bollen 2005; Derdak 2002; Mentzelopoulus 2007; Shah 2004) (n = 291) versus two paediatric (Arnold 1994; Samransamruajkit 2005) trials (n = 74) (P = 0.91 for interaction z-test;  Analysis 1.3); or four trials (n = 246) at low (Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004) versus two trials (n = 119) at unclear (Arnold 1994; Bollen 2005) risk of bias (P = 0.15 for interaction z-test;  Analysis 1.4). In a post hoc analysis, there was no significant difference in treatment effect among three trials (Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004) (n = 98) that mandated tidal volumes ≤ 8 mL/kg in the control group and three trials (Arnold 1994; Bollen 2005; Derdak 2002) (n = 267) that permitted higher tidal volumes (z-test for interaction P = 0.41;  Analysis 1.5). Only one trial (Derdak 2002) (n = 148) reported six-month mortality, with no significant effect of HFO (RR 0.79, 95% CI 0.58 to 1.08; P = 0.14).

 FigureFigure 4. Forest plot of comparison: 1 Mortality, outcome: 1.1 Hospital or 30-day mortality.

There was no evidence of publication bias. Neither Begg’s Rank Correlation test (P = 0.45) nor Macaskill’s regression test (P = 0.94) was significant.

 

Health-related quality of Life

No trial reported health-related quality of life. We identified one ongoing trial will report health related quality of quality of life at six months and one year (Young 2010).

 

Treatment failure and duration of mechanical ventilation

In five trials (Arnold 1994; Bollen 2005; Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005) (n = 337) HFO reduced the risk of treatment failure compared with conventional mechanical ventilation (RR 0.67, 95% CI 0.46 to 0.99; P = 0.04; Figure 5). Three trials (Arnold 1994; Bollen 2005; Derdak 2002) (n = 267) reported treatment failure according to predefined criteria. Two trials (Mentzelopoulus 2007; Samransamruajkit 2005) (n = 70) did not report this outcome but we obtained data directly from the authors. In one trial, one patient randomized to conventional ventilation with early treatment failure who crossed over to HFO because of barotrauma was analysed as treatment failure in the conventional mechanical ventilation group (Samransamruajkit 2005). When we did not count the two patients randomized to conventional ventilation in one trial (Mentzelopoulus 2007) who crossed over to HFO for only three and six hours as treatment failures, the pooled result was no longer significant (RR 0.69, 95% CI 0.46 to 1.01; P = 0.06). No trial reported blinding of outcome assessors or independent adjudication of treatment failure.

 FigureFigure 5. Forest plot of comparison: 2 Adverse events, outcome: 2.1 Treatment failure (intractable hypoxia, hypotension, acidosis, hypercapnoea requiring discontinuation of study intervention).

Neither the duration of mechanical ventilation (MD -0.8 days, 95% CI -5.4 to 3.9; P = 0.75; 4 trials, 276 patients;  Analysis 3.1) (Arnold 1994; Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005) nor ventilator-free days to day 28 (MD 2.0 days, 95% CI -0.7 to 4.7; P = 0.15; 1 trial, 54 patients) (Mentzelopoulus 2007) significantly differed between groups.

There was no evidence of statistical heterogeneity (I2 = 0%) for any clinical outcome.

 

Adverse events

We found no significant differences in the risk of barotrauma (6 trials, 365 patients;  Analysis 2.2) (Arnold 1994; Bollen 2005; Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004), hypotension (3 trials, 267 patients;  Analysis 2.3) (Arnold 1994; Bollen 2005; Derdak 2002), or endotracheal tube obstruction (4 trials, 246 patients) (Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004). Included studies varied in definitions of barotrauma: one study reported only pneumothorax (Shah 2004), three studies reported any pulmonary air leak (Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005), one study reported any pulmonary air leak that developed during the protocol (Arnold 1994), and one study reported severe air leak resulting in treatment failure (Bollen 2005). Three studies reported intractable hypotension (Arnold 1994; Bollen 2005; Derdak 2002). Two other trials reported transient hypotension related to a procedure, associated with either bronchoscopy on day one (1/15 in high frequency oscillation group and 0/13 in conventional ventilation group) (Shah 2004) or recruitment manoeuvres on days 1 to 4 (11/27 and 8/27) (Mentzelopoulus 2007). Including these data minimally changed the pooled result (RR 1.46, 95% CI 0.77 to 2.76; P = 0.24, I2 = 0%;  Analysis 2.4). Although four trials (n = 246) reported on endotracheal tube obstruction (Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004) all events occurred in a single study (Derdak 2002), precluding a pooled analysis. There were no serious technical problems during HFO in the three trials (n = 98) that provided these data (Mentzelopoulus 2007; Samransamruajkit 2005; Shah 2004). One trial (n = 54) reported minor technical problems, including water accumulation in the circuit (number of instances not reported) and unintentional air leaks (five instances in 116 uninterrupted sessions lasting 6 to 48 hours) (Mentzelopoulus 2007).

 

Physiological outcomes

Physiological outcomes for day one, day two, and day three are summarized in  Analysis 4.1 to  Analysis 4.4 and Appendix 2. Day one measurements were obtained at 24 hours except in two studies where they were obtained at 12 hours (Demory 2007; Papazian 2005). Analyses were by intention to treat except for one patient in one trial (Samransamruajkit 2005) who crossed over from conventional ventilation to HFO shortly after randomization and was analysed as treated because we were unable to obtain sufficient data (after contacting the author) to permit an intention-to-treat analysis.

At 24, 48, and 72 hours, HFO increased the PaO2/FiO2 ratio by 16% to 24% relative to conventional mechanical ventilation and increased mean airway pressure by 22% to 33%. Effects on the oxygenation index did not significantly differ between HFO and conventional ventilation. Heterogeneity was moderate for most analyses of physiological outcome (I2 = 21% to 78%) but extreme (I2 > 90%) for the pooled analyses of PaCO2, making this latter outcome difficult to interpret.

One trial included in our review combined tracheal gas insufflation and recruitment manoeuvres with HFO (Mentzelopoulus 2007). Because a separate randomized crossover trial (not included in this review due to crossover design) (Mentzelopoulos 2007a) showed that these co-interventions may improve oxygenation, we performed a sensitivity analysis in which data from Mentzelopoulus 2007 were not included in the analysis of the effect of HFO on the PaO2/FiO2 ratio. Results were similar but no longer statistically significant on day 3: RR of 1.22 (95% CI 1.05 to 1.40; P = 0.008, I2 = 48%) on day one, RR of 1.05 (95% CI 0.92 to 1.19; P = 0.48, I2 = 6%) on day two, and RR of 1.09 (95% CI 0.97 to1.22; P = 0.14, I2 = 0%) on day three.

 

Discussion

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Summary of main results

The main findings of our systematic review and meta-analysis are that HFO reduced hospital and 30-day mortality in patients with ALI or ARDS and decreased the risk of treatment failure when compared to conventional mechanical ventilation. These findings were based on small numbers of patients and trials, resulting in wide confidence intervals, and should therefore be interpreted cautiously. Although HFO had no effect on the duration of mechanical ventilation it improved oxygenation, as measured by the PaO2/FiO2 ratio, which was likely to be by increasing transpulmonary pressure and recruiting collapsed alveoli. There was no effect on oxygenation index due to the higher mean airway pressure during HFO. In contrast, the effects on PaCO2 were markedly inconsistent, with HFO increasing PaCO2 compared to conventional ventilation in some trials and decreasing it in others. The risk of adverse events was similar.

 

Overall completeness and applicability of evidence

Our primary analysis, although statistically significant, was based on relatively few patients and outcome events and has wide confidence intervals. Furthermore, tests for heterogeneity may be underpowered given the small number of trials. Similarly for the meta-analysis of treatment failure, if the two patients randomized to conventional ventilation in one trial (Mentzelopoulus 2007) who were only briefly crossed over to HFO are not counted as treatment failures, the pooled result would no longer be statistically significant (P = 0.06). In addition, the criteria for treatment failure varied across trials (Arnold 1994; Bollen 2005; Derdak 2002) or were not predefined (Mentzelopoulus 2007; Samransamruajkit 2005), and outcomes assessors were not blinded (Arnold 1994; Bollen 2005; Derdak 2002; Mentzelopoulus 2007; Samransamruajkit 2005). Limited data precluded subgroup analyses based on the degree of hypoxaemia and analyses of longer term mortality and health-related quality of life, although the finding of a non-significant 21% relative risk reduction in mortality at six months in one trial (Derdak 2002) was consistent with the pooled analyses of hospital or 30-day mortality. We found moderate to high heterogeneity for physiological endpoints, which limited their interpretability. Because of limited data, we were unable to analyse duration of mechanical ventilation separately for survivors and non-survivors to address the possibility that differences in early mortality could drive overall differences in duration of mechanical ventilation. The risk of bias was low in six studies (Demory 2007; Derdak 2002; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004) (N = 300, 72%) but remained unclear in two studies (Arnold 1994; Bollen 2005) (N = 119, 28%) despite author contact. Thus, although our findings support HFO as a promising treatment for ALI and ARDS, the overall quality of the evidence is moderate for the most important outcomes to patients, including mortality and treatment failure (see  Summary of findings for the main comparison), and ongoing trials may change the magnitude or the direction of the observed treatment effect (Schunemann 2008).

 

Quality of the evidence

See  Summary of findings for the main comparison.

 

Potential biases in the review process

Strengths of our review include methods to minimize bias, including a comprehensive literature search, triplicate data abstraction, and use of a predefined protocol outlining our hypotheses, methodological assessment of primary studies, and statistical analysis plan. We considered important clinical, physiological, and safety endpoints. Although blinding of patients, their families, and clinicians was not feasible, six of eight trials had high methodological quality and low risk of bias. Clinical outcomes were consistent across studies, including those enrolling adults and children, which strengthened the findings.

The mortality benefit of HFO may be over-estimated because the control group of three studies (Arnold 1994; Bollen 2005; Derdak 2002), including the largest trial (Derdak 2002) which dominated the pooled analyses, was exposed to higher tidal volumes (> 6 to 8 mL/kg predicted body weight) than currently recommended (ARDS Network 2000).  However, a sensitivity analysis showed a similar benefit in trials that implemented lower tidal volume lung protective ventilation in the control group. Alternatively, the higher rate of crossovers due to treatment failure in patients randomized to conventional ventilation may have reduced the measured effect of HFO. In two studies enrolling 30% of patients in the review (Arnold 1994; Bollen 2005) more than 10% of patients crossed over from their assigned mode of ventilation, highlighting an important methodological challenge facing clinical trials of HFO. Another opportunity to improve the success of future trials of HFO would be to adopt consistent protocols for its optimal application (Fessler 2008). In our review, only one study (Mentzelopoulus 2007) routinely applied recruitment manoeuvres as part of the HFO technique, and no trials attempted to maximize the frequency of oscillation in order to obtain the smallest possible tidal volume (Hager 2007).

 

Agreements and disagreements with other studies or reviews

Our findings differ from the previous systematic review (Wunsch 2004), which did not find reduced mortality or treatment failure, or improvements in PaO2/FiO2. However, we have included six additional trials of HFO compared to conventional ventilation and unpublished data provided by primary investigators, which generated additional statistical power and more precise estimates of treatment effects.

The improvements in PaO2/FiO2 that we observed are consistent with observational studies (Ferguson 2005; Fort 1997; Mehta 2001). Although HFO increased PaO2/FiO2 compared to conventional ventilation, there was no difference in oxygenation index (defined as 100 x mean airway pressure/(PaO2/FiO2 ratio)) because of the higher mean airway pressure applied during HFO. Although high airway pressure during conventional ventilation is harmful to the lungs (Ranieri 1999), the importance of the higher mean airway pressure during HFO is unclear because of its incompletely characterized relationship to alveolar pressure, which is a more important determinant of lung injury than mean airway pressure in patients with ARDS. Direct comparisons of mean airway pressure and oxygenation index between HFO and conventional ventilation may not be valid because, in contrast to conventional ventilation, mean airway pressures measured in the trachea during HFO are 6 to 8 cm H2O lower than values displayed on the ventilator (Muellenbach 2007).

The decrease in mortality observed in patients who received HFO is consistent with experimental studies in animals showing that histologic alveolar over-distension is reduced by HFO compared to conventional mechanical ventilation (Sedeek 2003), possibly because of the delivery of smaller tidal volumes (Hager 2007). Although improved oxygenation may not always be associated with improved clinical outcomes in ARDS (Bernard 2008; Slutsky 2009), from a clinical perspective HFO allows higher mean airway pressures without increasing barotrauma and may therefore safely recruit collapsed lung (Gattinoni 2006). Increased lung recruitment and reduction of alveolar over-distension may reduce ventilator induced lung injury (Gattinoni 2006; Ranieri 1999) and provide a biological rationale for the observed reduction in mortality with HFO. 

 

Authors' conclusions

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

 

Implications for practice

The risk of death in patients with ARDS is very high (Phua 2009; Rubenfeld 2005) and appears to have been stable over the past decade (Phua 2009). In our review, the median control group mortality in patients with ARDS was 48%. As a recent observational study of patients with H1N1 influenza demonstrated, a substantial proportion of patients with severe ARDS required inhaled nitric oxide, prone positioning, HFO, or extracorporeal membrane oxygenation, usually for refractory hypoxaemia (Kumar 2009). These therapies have different risk-benefit profiles (Adhikari 2007; Peek 2009; Sud 2008; Sud 2010a). Inhaled nitric oxide is expensive, has not been shown to reduce mortality, and may increase renal dysfunction (Adhikari 2007). Extracorporeal membrane oxygenation may reduce mortality but requires considerable technical expertise and is not widely available (Peek 2009). Mechanical ventilation in the prone position reduces mortality in severely hypoxaemic patients (Sud 2010a) and is inexpensive, but complications (Taccone 2009) and interference with other aspects of patient care may limit its application (Bein 2007; Leonet 2002). Our review suggests that HFO is a promising but yet unproven alternative to conventional ventilation in patients with ARDS with few complications, at least in expert centres. Because the effects on PaCO2 were very inconsistent, it may be prudent to avoid HFO in patients susceptible to elevated PaCO2 such as those with raised intracranial pressure. Our results were based on a small numbers of trials, patients, and events resulting in wide confidence intervals. As such, large ongoing multi-centre trials may change the magnitude or direction of the observed treatment effect.

 
Implications for research

The limitations of current data will be addressed to a large extent in two ongoing trials comparing HFO to conventional ventilation (see Characteristics of ongoing studies).  Each trial applies a lung-protective approach to the control group, and collectively they plan to enrol greater than 2000 patients. In the pilot phase of one of these trials, crossovers between randomly assigned ventilation strategies outside of the protocol were rare (Meade 2009). These trials will therefore compare HFO to best current conventional ventilation and will provide more precise estimates of treatment effect. One of these trials will also include an economic analysis and measure health-related quality of life (Young 2010). Pending completion of these studies, the results of this systematic review should be interpreted cautiously.

 

Acknowledgements

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

We thank all primary investigators who provided additional data for this review: Steven Derdak and Tom Bachman; Casper Bollen; Spyros Mentzelopoulos; Rujipat Samransamruajkit; and Sanjoy Shah.

We would like to acknowledge James Mapstone for contributions made to earlier versions of this systematic review (Wunsch 2004).

We would like to thank Mathew Zacharias (content editor), Marialena Trivella (statistical editor), Rodrigo Cavallazzi, Hansjoerg Waibel, Arash Afshari (peer reviewers) and Janet Wale (consumer Editor) for their help and editorial advice during the preparation of this updated systematic review.

 

Data and analyses

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
Download statistical data

 
Comparison 1. Mortality

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Hospital or 30-day Mortality6365Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.98]

 2 Hospital or 30-day Mortality (Bollen 2005 patients lost to follow-up excluded)6362Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.98]

 3 Hospital or 30-day mortality: Adult versus paediatric trials6365Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.98]

    3.1 Adult Trials
4291Risk Ratio (M-H, Random, 95% CI)0.77 [0.58, 1.02]

    3.2 Paediatric Trials
274Risk Ratio (M-H, Random, 95% CI)0.80 [0.44, 1.43]

 4 Hospital or 30-day Mortality: Low risk of bias versus unclear risk of bias6365Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.98]

    4.1 Low Risk of Bias Trials (free of selection, reporting, and attrition bias)
4246Risk Ratio (M-H, Random, 95% CI)0.70 [0.53, 0.92]

    4.2 Unclear Risk of Bias Trials (possible selection, reporting or attrition bias)
2119Risk Ratio (M-H, Random, 95% CI)1.04 [0.65, 1.66]

 5 Hospital or 30-day Mortality: Lung protective ventilation mandatory vs. not mandatory6365Risk Ratio (M-H, Random, 95% CI)0.77 [0.61, 0.98]

    5.1 Lung Protective Ventilation Not Mandatory
3267Risk Ratio (M-H, Random, 95% CI)0.84 [0.61, 1.16]

    5.2 Lung Protective Ventilation Mandatory
398Risk Ratio (M-H, Random, 95% CI)0.67 [0.44, 1.03]

 
Comparison 2. Adverse events

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Treatment Failure (Intractable Hypoxia, Hypotension, Acidosis, Hypercapnea requiring discontinuation of study intervention)5337Risk Ratio (M-H, Random, 95% CI)0.67 [0.46, 0.99]

 2 Barotrauma6365Risk Ratio (M-H, Random, 95% CI)0.68 [0.37, 1.22]

 3 Hypotension3267Risk Ratio (M-H, Random, 95% CI)1.54 [0.34, 7.02]

 4 Hypotension (Shah and Mentzelopoulos included)5349Risk Ratio (M-H, Random, 95% CI)1.46 [0.77, 2.76]

 5 ETT Obstruction4Risk Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 3. Ventilator dependency

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Duration of Mechanical Ventilation4276Mean Difference (IV, Random, 95% CI)-0.75 [-5.36, 3.85]

 
Comparison 4. Physiological endpoints (ratio of means)

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 PaO2/FiO2 (Ratio of Means)7Ratio of Means (Random, 95% CI)Subtotals only

    1.1 Day 1
7323Ratio of Means (Random, 95% CI)1.24 [1.10, 1.40]

    1.2 Day 2
5262Ratio of Means (Random, 95% CI)1.16 [0.97, 1.37]

    1.3 Day 3
5228Ratio of Means (Random, 95% CI)1.17 [1.02, 1.35]

 2 Oxygenation Index (Ratio of Means)7Ratio of Means (Random, 95% CI)Subtotals only

    2.1 Day 1
7352Ratio of Means (Random, 95% CI)1.11 [0.97, 1.26]

    2.2 Day 2
6306Ratio of Means (Random, 95% CI)1.07 [0.92, 1.24]

    2.3 Day 3
6266Ratio of Means (Random, 95% CI)1.07 [0.88, 1.29]

 3 PaCO2 (Ratio of Means)8Ratio of Means (Random, 95% CI)Subtotals only

    3.1 Day 1
8386Ratio of Means (Random, 95% CI)0.91 [0.78, 1.07]

    3.2 Day 2
6310Ratio of Means (Random, 95% CI)0.87 [0.72, 1.06]

    3.3 Day 3
6267Ratio of Means (Random, 95% CI)0.98 [0.84, 1.14]

 4 Mean Airway Pressure (Ratio of Means)8Ratio of Means (Random, 95% CI)Subtotals only

    4.1 Day 1
8389Ratio of Means (Random, 95% CI)1.33 [1.27, 1.40]

    4.2 Day 2
6309Ratio of Means (Random, 95% CI)1.26 [1.16, 1.37]

    4.3 Day 3
6274Ratio of Means (Random, 95% CI)1.22 [1.07, 1.39]

 

Appendices

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms
 

Appendix 1. Search strategies

MEDLINE (OvidSP, 1948 to March 2011)

1. Exp High-Frequency Ventilation/

2. (high adj3 oscillat$).mp.

3. 1 or 2

4. clinical trial.mp. or clinical trial.pt. or random:.mp. or tu.xs.

5. 3 and 4 [NOTE this is the same as the following command:  limit 3 to “therapy (sensitivity)”]

6. (animals not humans).sh.

7. 5 not 6

8. Infants, newborn.sh.

9. 7 not 8

 

EMBASE (1980 to March 2011)

1. Exp High Frequency Ventilation/

2. (high adj3 oscillat$).mp.

3. 1 or 2

4. random:.tw. or clinical trial:.mp. or exp health care quality/

5. 3 and 4 [NOTE this is the same as the following command: limit 3 to "treatment (2 or more terms high sensitivity)"]

6. (animal$ not human$).sh,hw.

7. 5 not 6

8. newborn/

9. 7 not 8

 

CENTRAL (Issue 1, 2011)

1. (high adj3 oscillat$).af.

 

ISI (1 March 2011)

1. High Frequency Oscillat* OR High Frequency Ventilat* (topic)

2. Random* or Random Alloc* OR Controlled Clinical Trial (topic)

 

Notes:  ‘$’, ‘:’, and ‘*’ retrieve unlimited suffix variations; the .mp. extension includes the title, original title and abstract fields in MEDLINE and EMBASE; the .af. extension includes all searchable fields.  Filters for MEDLINE (line 4) and EMBASE (line 4) are based on published sensitive strategies for retrieving randomized trials (Haynes 2005; Wong 2006).  References from these four databases were combined and duplicates were removed manually.

 

Appendix 2. Physiologic outcomes on Day 1 to 3 after randomization


Outcome

 
No of

trials

 
No of

patients

 
Treatment EffectHeterogeneity


Ratio of means*(95% CI)P valueI2 (%)

 

Day 1 (24 hours)

PaO2/FiO273231.24(1.11 to 1.40)<0.00145

 

Mean airway pressure73311.33(1.27 to 1.40)<0.00121

 

Oxygenation index62941.11(0.97 to 1.26)0.1238

 

PaCO263000.91(0.78 to 1.07)0.2591

 

Day 2 (48 hours)

PaO2/FiO252621.16(0.97 to 1.37)0.1062

 

Mean airway pressure52621.26(1.16 to 1.37)<0.00158

 

Oxygenation index52591.07(0.92 to 1.24)0.3839

 

PaCO2  

 
52630.87(0.72 to 1.06)0.1695

Day 3 (72 hours)

PaO2/FiO252281.17(1.02 to 1.35)0.0244

 

Mean airway pressure52361.22(1.07 to 1.39)0.00378

 

Oxygenation index52281.07(0.88 to 1.29)0.5158

 

PaCO262670.98(0.84 to 1.14)0.7890

 

PaO2/FiO2 = ratio of arterial partial pressure of oxygen to fraction of inspired oxygen; PaCO2 = arterial partial pressure of carbon dioxide.

*Mean value in high frequency oscillation group divided by mean value in conventional ventilation group.

Random effects models used for all meta-analyses.



 

What's new

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

Last assessed as up-to-date: 1 March 2011.


DateEventDescription

4 January 2013New citation required and conclusions have changedThis review is an update of the previous Cochrane systematic review, 'High-frequency ventilation versus conventional ventilation for treatment of acute lung injury and acute respiratory distress syndrome' (Wunsch 2004), which included two RCTs.

The previous author J Mapstone decided not to update the review. A previous author, Hannah Wunsch, and new authors Sachin Sud, Maneesh Sud, Jan O Friedrich, Maureen O Meade, Niall D Ferguson, Neill KJ Adhikari have updated this version.

We found six new trials that met our inclusion criteria (Bollen 2005; Demory 2007; Mentzelopoulus 2007; Papazian 2005; Samransamruajkit 2005; Shah 2004). Two were published as abstracts (Mentzelopoulus 2007; Shah 2004) and were included after clarifying study details with the primary investigators. Two additional trials are ongoing (Meade 2009; Young 2010).

The updated review reaches new conclusions. Pooled results from eight RCTs suggest that high frequency oscillation improves oxygenation and reduces the risk of treatment failure (refractory hypoxaemia, hypercapnoea, hypotension, or barotrauma) as well as hospital or 30-day mortality compared with conventional mechanical ventilation in patients with acute respiratory distress syndrome. The quality of evidence was moderate for patient-important outcomes due to imprecision and methodological limitations, indicating that as evidence from ongoing randomized trials becomes available, the magnitude or direction of effect may change.

4 January 2013New search has been performedIn the previous version (Wunsch 2004) the databases were searched until October 2002. In this updated version we reran the searches until 1 March 2011. We have included risk of bias and summary of finding tables, and updated the background section in this updated version.



 

Contributions of authors

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

All authors contributed to the study concept and design, revised the manuscript for important intellectual content, and approved the final version. SS conceived the study, acquired data, analysed and interpreted data, and drafted the manuscript. MS, JOF, and NKJA acquired, analysed and interpreted the data. MOM, NDF, and HW interpreted the data. NKJA and JOF contributed equally to this study. SS, JOF, NKJA are guarantors.

 

Declarations of interest

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms

All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare that all authors had:

  1. no financial support for the submitted work from anyone other than their employer;
  2. no financial relationships with commercial entities that might have an interest in the submitted work;
  3. no spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work;
  4. the following non-financial interests relevant to the submitted work: Drs Meade and Ferguson are primary investigators and Drs Friedrich and Adhikari are co-investigators for the ongoing Canadian Institutes of Health Research (CIHR) funded OSCILLATE study. CareFusion (formerly SensorMedics) is providing study oscillators to some of the hospitals involved in the OSCILLATE study for the duration of the study.

 

Differences between protocol and review

  1. Top of page
  2. Summary of findings    [Explanations]
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. Contributions of authors
  14. Declarations of interest
  15. Differences between protocol and review
  16. Index terms


Original ProtocolAmended Protocol (03 27 2009)Reason (outcome #)

Primary:

mortality

(Intensive care unit (ICU), hospital, 30 days, 60 plus days).
Primary outcomes:  

1. hospital or 30-day mortality.

 
Hospital mortality is the most common endpoint in critical care studies. ICU mortality is not a patient centred outcome. Hospital mortality and 30-day mortality are considered equivalent. Longer term mortality was included as a secondary outcome.

Secondary:

 1. total length of mechanical ventilation (high-frequency and conventional combined),

2. length of stay in the intensive care unit,

3. length of hospital stay,

4. any long-term quality of life measurements,

5. any long-term cognitive measurements,

6. cost effectiveness.
Secondary outcomes:  

1. 6-month mortality,

2. duration of mechanical ventilation (in days, as stated by the authors),

3. ventilator-free days to day 28 or 30 (in days, as stated by the authors),

4. health-related quality of life at one year,

5. treatment failure, leading to crossover to the other arm or discontinuation of the study protocol. We accepted authors’ definitions of treatment failure, which could include severe oxygenation failure, ventilation failure, hypotension, or barotrauma (pneumothorax, pneumomediastinum, subcutaneous emphysema),

6. the ratio of partial pressure of arterial oxygen (PaO2) to inspired fraction of oxygen (FiO2) (PaO2/FiO2 ratio) at 24, 48, and 72 hours after randomization,

7. oxygenation index (OI, defined as 100 x mean airway pressure/PaO2/FiO2 ratio) measured at 24, 48, and 72 hours after randomization,

8. ventilation, measured by partial pressure of carbon dioxide (PaCO2) at 24, 48, and 72 hours after randomization,

9. mean airway pressure 24, 48, and 72 hours after randomization,

10. barotrauma (as stated by the authors),

11. hypotension (as stated by the authors),

12. endotracheal tube obstruction due to secretions,

13. technical complications and equipment failure in patients treated with HFO (including unintentional system air leaks, and problems with the oscillatory diaphragm, humidifier, and alarm systems).

 
Total duration of mechanical ventilation (1) is ambiguous may be measured in two ways in critical care trials: days of mechanical ventilation or ventilator free days. Since these endpoints cannot be combined we analysed them separately. We did not analyse length of ICU stay or hospital length of stay (2, 3) as these were likely to be confounded by mortality (an intervention that improves survival will also increase ICU or hospital length of stay). Long term quality of life measurements (4) and long term cognitive measurements (5) was not precisely defined and unlikely to be reported in studies to date. We chose to analyse health-related quality of life at one year, if reported.

 

We did not analyse cost-effectiveness (6) because it is unlikely cost-effectiveness studies would be performed since this intervention has not been yet proven to be effective.

 

We included several physiologic endpoints not in the original review in order to assess the effect of HFO on oxygenation (6,7) and ventilation (8,9).

 

We included several additional safety endpoints prior to undertaking this update in order to assess potential complications of HFO (10-13).

Subgroup analyses:

none.
Subgroup analyses:

(see Subgroup analysis and investigation of heterogeneity; Sensitivity analysis).
(See text)

Search strategy:

 

(see previous version: Wunsch 2004).

 

 
Search strategy:

 

(see Appendix 1).

 

 
A more sensitive (but less specific) search strategy was designed using published sensitive strategies for retrieving randomized trials (Haynes 2005; Wong 2006). We also improved sensitivity of the search strategy by searching conference proceedings and contacting  primary investigators.



References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Arnold 1994 {published and unpublished data}
  • Arnold JH, Hanson JH, Toro-Figuero LO, Gutierrez J, Berens RJ, Anglin DL. Prospective, randomized comparison of high-frequency oscillatory ventilation and conventional mechanical ventilation in pediatric respiratory failure. Critical Care Medicine 1994;22(10):1530-9. [MEDLINE: 7924362]
Bollen 2005 {published and unpublished data}
  • Bollen CW, van Well GT, Sherry T, Beale RJ, Shah S, Findlay G, et al. High frequency oscillatory ventilation compared with conventional mechanical ventilation in adult respiratory distress syndrome: a randomized controlled trial. Critical Care 2005;9(4):R430-9. [MEDLINE: 16137357]
Demory 2007 {published and unpublished data}
  • Demory D, Michelet P, Arnal JM, Donati S, Forel JM, Gainnier M, et al. High-frequency oscillatory ventilation following prone positioning prevents a further impairment in oxygenation. Critical Care Medicine 2007;35(1):106-11. [MEDLINE: 16137357]
Derdak 2002 {published and unpublished data}
  • Derdak S, Mehta S, Stewart TE, Smith T, Rogers M, Buchman TG, et al. High-frequency oscillatory ventilation for acute respiratory distress syndrome in adults: a randomized, controlled trial. American Journal of Respiratory and Critical Care Medicine 2002;166(6):801-8. [MEDLINE: 12231488]
Mentzelopoulus 2007 {unpublished data only}
  • Malachias S, Kokkoris S, Zakynthinos S, Mentzelopoulos SD. High frequency oscillation and tracheal gas insufflations for severe Acute Respiratory Distress Syndrome: Results from a single-center, phase II, randomized controlled trial [NCT00416260]. Intensive Care Medicine 2009;35 Suppl 1:S6.
  • Mentzelopoulos SD, Malachias S, Tzoufi M, Markaki V, Zervakis D, Pitaridis M. High frequency oscillation and tracheal gas insufflation for severe acute respiratory distress syndrome. Intensive Care Medicine 2007;33 Suppl 2:S142.
Papazian 2005 {published and unpublished data}
  • Papazian L, Gainnier M, Marin V, Donati S, Arnal JM, Demory D, et al. Comparison of prone positioning and high-frequency oscillatory ventilation in patients with acute respiratory distress syndrome. Critical Care Medicine 2005;33(10):2162-71. [MEDLINE: 16215365]
Samransamruajkit 2005 {published and unpublished data}
  • Samransamruajkit R, Prapphal N, Deelodegenavong J, Poovorawan Y. Plasma soluble intercellular adhesion molecule-1 (sICAM-1) in pediatric ARDS during high frequency oscillatory ventilation: a predictor of mortality. Asian Pacific Journal of Allergy and Immunology 2005; Vol. 23, issue 4:181-8. [MEDLINE: 16572737]
  • Samransamruajkit R, Prapphal N, Deerojanawong J, Vanapongtipagorn P, Poovorawan Y. Soluble Intercellular Adhesion Molecule-1 (sICAM-1) in pediatric ARDS during high frequency oscillatory ventilation; Randomized controlled trial, a predictor of mortality. American Journal of Respiratory and Critical Care Medicine 2003;167:A999.
Shah 2004 {unpublished data only}
  • Shah SB, Findlay GP, Jackson SK, Smithies MN. Prospective study comparing HFOV versus CMV in patients with ARDS. Intensive Care Medicine 2004;30 Suppl 1:S84.
  • Shah SB, Jackson SK, Findlay GP, Smithies MN. Prospective study comparing high frequency oscillatory ventilation (HFOV) versus conventional (CMV) in patients with acute respiratory distress syndrome (ARDS) [abstract]. Proceedings of the American Thoracic Society 2005;2:A847.
  • Shah SB, Jackson SK, Findlay GP, Smithies MN. Ventilator induced lung injury comparing high frequency oscillator ventilation versus conventional mechanical ventilation [abstract]. Proceedings of the American Thoracic Society 2005;2:A251.

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Carlon 1983 {published data only}
Dobyns 2002 {published data only}
  • Dobyns EL, Anas NG, Fortenberry JD, Deshpande J, Cornfield DN, Tasker RC, et al. Interactive effects of high-frequency oscillatory ventilation and inhaled nitric oxide in acute hypoxemic respiratory failure in pediatrics. Critical Care Medicine 2002;30(11):2425-9. [MEDLINE: 12441749]
Fessler 2008 {published data only}
Hurst 1984 {published data only}
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Mentzelopoulos 2007a {published data only}
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Mentzelopoulos 2010 {published data only}
  • Mentzelopoulos SD, Malachias S, Kokkoris S, Roussos C, Zakynthinos SG. Comparison of high-frequency oscillation and tracheal gas insufflation versus standard high-frequency oscillation at two levels of tracheal pressure. Critical Care Medicine 2010;36(5):810-6. [MEDLINE: 20232047]

References to ongoing studies

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Meade 2009 {published data only}
  • Ferguson N, Mehta S, Slutsky A, Stewart T, Hand L, Zhou Q, et al. Conversion from ventilation to high frequency oscillation - physiologic responses in a pilot randomized trial. American Journal of Respiratory and Critical Care Medicine 2009;179:A3651.
  • Meade MO, Cook DJ, Mehta S, Arabi YM, Keenan S, Ronco JJ, et al. A multicentre pilot randomized trial of high frequency oscillation in acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 2009; Vol. 179:A1559.
Young 2010 {published data only}
  • Young JD. Conventional positive pressure ventilation or High Frequency Oscillatory Ventilation (HFOV) for adults with acute respiratory distress syndrome. details available at http://controlled-trials.com/ISRCTN10416500/ and http://www.duncanyoung.net/pdf/full-protocol---v7---19-oct-09.pdf [accessed 1 August 2010].

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
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References to other published versions of this review

  1. Top of page
  2. AbstractRésumé
  3. Summary of findings
  4. Background
  5. Objectives
  6. Methods
  7. Results
  8. Discussion
  9. Authors' conclusions
  10. Acknowledgements
  11. Data and analyses
  12. Appendices
  13. What's new
  14. Contributions of authors
  15. Declarations of interest
  16. Differences between protocol and review
  17. Characteristics of studies
  18. References to studies included in this review
  19. References to studies excluded from this review
  20. References to ongoing studies
  21. Additional references
  22. References to other published versions of this review
Sud 2007
  • Sud S, Adhikari N, Ferguson ND, Friedrich JO, Sud M, Meade MO. High-frequency oscillatory ventilation for ARDS: a meta-analysis. Critical Care Medicine 2007;35(12 Suppl):A225.
Sud 2010b
  • Sud S, Sud M, Friedrich JO, Meade MO, Ferguson ND, Wunsch H, et al. High frequency oscillation in patients with acute lung injury and acute respiratory distress syndrome (ARDS): systematic review and meta-analysis. BMJ 2010;340:c2327. [1468-5833: (Electronic)]
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