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

  • Conclusions changed
  • Review
  • Intervention

Authors

  • Sachin Sud,

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

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  • Maneesh Sud,

    1. University of Toronto, Department of Medicine, Toronto, Ontario, Canada
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  • Jan O Friedrich,

    1. 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
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  • Hannah Wunsch,

    1. Mailman School of Public Health, Columbia University, Department of Anesthesiology, College of Physicians and Surgeons; Department of Epidemiology, New York, NY, USA
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  • Maureen O Meade,

    1. McMaster University, Department of Clinical Epidemiology and Biostatistics, Hamilton, Ontario, Canada
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  • Niall D Ferguson,

    1. University Health Network and Mount Sinai Hospital, University of Toronto, Interdepartmental Division of Critical Care Medicine, Toronto, Ontario, Canada
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  • Neill KJ Adhikari

    1. 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
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Abstract

Background

High frequency oscillation is an alternative to conventional mechanical ventilation that is sometimes used to treat patients with acute respiratory distress syndrome, but effects on oxygenation, mortality and adverse clinical outcomes are uncertain. This review was originally published in 2004 and was updated in 2011.

Objectives

To determine clinical and physiological effects of high frequency oscillation (HFO) in patients with acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) compared to conventional ventilation.

Search methods

We electronically searched CENTRAL (Ovid), MEDLINE (Ovid), EMBASE (Ovid), and ISI (from inception to March 2011). The original search was performed in 2002. We manually searched reference lists from included studies and review articles; 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); contacted clinical experts in the field; and searched for unpublished and ongoing trials in clinicaltrials.gov and controlled-trials.com.

Selection criteria

Randomized controlled clinical trials comparing treatment using HFO with conventional mechanical ventilation for children and adults diagnosed with ALI or ARDS.

Data collection and analysis

Three authors independently extracted data on clinical, physiological, and safety outcomes according to a predefined protocol. We contacted investigators of all included studies to clarify methods and obtain additional data. We used random-effects models in the analyses.

Main results

Eight RCTs (n = 419) were included; almost all patients had ARDS. The risk of bias was low in six studies and unclear in two studies. The quality of evidence for hospital and six-month mortality was moderate and low, respectively. The ratio of partial pressure of oxygen to inspired fraction of oxygen at 24, 48, and 72 hours was 16% to 24% higher in patients receiving HFO. There were no significant differences in oxygenation index because mean airway pressure rose by 22% to 33% in patients receiving HFO (P < 0.01).  In patients randomized to HFO, mortality was significantly reduced (RR 0.77, 95% CI 0.61 to 0.98; P = 0.03; 6 trials, 365 patients, 160 deaths) and treatment failure (refractory hypoxaemia, hypercapnoea, hypotension, or barotrauma) was less likely (RR 0.67, 95% CI 0.46 to 0.99; P = 0.04; 5 trials, 337 patients, 73 events). Other risks, including adverse events, were similar. We found substantial between-trial statistical heterogeneity for physiological (I2 = 21% to 95%) but not clinical (I2 = 0%) outcomes.  Pooled results were based on few events for most clinical outcomes.

Authors' conclusions

The findings of this systematic review suggest that HFO was a promising treatment for ALI and ARDS prior to the uptake of current lung protective ventilation strategies. These findings may not be applicable with current conventional care, pending the results of large multi-centre trials currently underway.

Résumé scientifique

Ventilation à haute fréquence versus ventilation conventionnelle pour le traitement d'une lésion pulmonaire aigüe et d'un syndrome de détresse respiratoire aigüe

Contexte

L'oscillation à haute fréquence est une alternative à la ventilation mécanique conventionnelle qui est parfois utilisée pour traiter les patients atteints d'un syndrome de détresse respiratoire aigüe, mais on ignore les effets sur l'oxygénation, la mortalité et les critères de jugement cliniques indésirables. Cette revue a été publiée à l'origine en 2004 et a été mise à jour en 2011.

Objectifs

Déterminer les effets cliniques et physiologiques de la ventilation à haute fréquence (VHF) chez les patients présentant des lésions pulmonaires aiguës (LPA) ou un syndrome de détresse respiratoire aiguë (SDRA) comparé à ceux de la ventilation conventionnelle.

Stratégie de recherche documentaire

Nous avons effectué une recherche électronique dans CENTRAL (Ovid), MEDLINE (Ovid), EMBASE (Ovid) et ISI (de l'origine à mars 2011). La recherche originale a été réalisée en 2002. Nous avons recherché manuellement des listes bibliographiques dans les études incluses et dans des articles de revues ; nous avons consulté les actes de conférences de l'American Thoracic Society (de 1994 à 2010), de la Society of Critical Care Medicine (de 1994 à 2010), de l'European Society of Intensive Care Medicine (de 1994 à 2010) et de l'American College of Chest Physicians (de 1994 à 2010) ; nous avons contacté des experts cliniques dans le domaine et avons recherché des essais non publiés et en cours sur les sites clinicaltrials.gov et controlled-trials.com.

Critères de sélection

Les essais cliniques contrôlés randomisés comparant le traitement par la VHF à une ventilation mécanique conventionnelle pour les enfants et les adultes ayant reçu un diagnostic de LPA ou de SDRA.

Recueil et analyse des données

Trois auteurs ont extrait de manière indépendante des données sur les critères de jugement cliniques, physiologiques et les critères de jugement de sécurité selon un protocole prédéfini. Nous avons contacté les chercheurs de toutes les études incluses pour obtenir des explications concernant les méthodes, ainsi que des données supplémentaires. Nous avons utilisé des modèles à effets aléatoires dans les analyses.

Résultats principaux

Huit ECR (n = 419) ont été inclus ; presque tous les patients présentaient un SDRA. Le risque de biais était faible dans six études et incertain dans deux études. La qualité des preuves pour la mortalité à l'hôpital et à six mois était modérée et faible, respectivement. Le rapport de la pression partielle d'oxygène sur la fraction d'oxygène inspiré à 24, 48 et 72 heures était de 16 % à 24 % supérieur chez les patients recevant une VHF. Il n'y a pas eu de différences significatives concernant l'index d'oxygénation, car la pression moyenne des voies respiratoires a augmenté dans une mesure de 22 % à 33 % chez les patients recevant une VHF (P <I>< </I>0,01). Chez les patients randomisés pour recevoir une VHF, la mortalité a été réduite significativement (RR 0,77, IC à 95 % 0,61 à 0,98 ; P = 0,03 ; 6 essais, 365 patients, 160 décès) et l'échec du traitement (hypoxémie, hypercapnie, hypotension ou barotraumatisme réfractaires) a été moins probable (RR 0,67,IC à 95 % 0,46 à 0,99 ; P = 0,04 ; 5 essais, 337 patients, 73 événements). Les autres risques, notamment les événements indésirables, ont été semblables. Nous avons constaté une hétérogénéité statistique importante entre les essais pour les critères de jugement physiologiques (I2 = 21 % à 95 %), mais non pour les critères de jugement cliniques (I2 = 0 %). Les résultats combinés se sont basés sur peu d'événements pour la plupart des critères de jugement cliniques.

Conclusions des auteurs

Les découvertes de cette revue systématique suggèrent que la VHF est un traitement prometteur pour les LPA et le SDRA avant la mise en œuvre des stratégies de ventilation actuelles de protection des poumons. Ces découvertes peuvent ne pas s'appliquer aux soins conventionnels actuels et sont en attente des résultats de vastes essais multicentriques actuellement en cours.

Plain language summary

High frequency oscillation for the treatment of acute respiratory distress syndrome

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are life-threatening conditions. They are characterized by acute lung inflammation causing pulmonary congestion, stiff lungs that increase the work of breathing, and reduced ability of the lungs to adequately oxygenate the blood. Survivors can have a reduced quality of life. Patients with ALI or ARDS usually require mechanical ventilation in order to prevent death. High frequency oscillation (HFO) ventilation differs from conventional ventilation in that very small tidal volumes are delivered very rapidly with each breath (3 to15 Hz, or 180 to 900 breaths per minute). HFO facilitates the re-expansion of collapsed lung tissue at a constant mean airway pressure. We performed a systematic review to determine whether HFO improves clinical outcomes (including preventing deaths) when compared to conventional mechanical ventilation of adults and children with ALI or ARDS.

We included eight randomized controlled trials enrolling 419 patients. HFO as an initial ventilation strategy reduced the risk of death in hospital by 23% in six trials enrolling 365 patients, and reduced the risk of treatment failure by 33% in five trials enrolling 337 patients. The ability of the lungs to oxygenate blood, measured at 24 to 72 hours of ventilation after randomization, was 16% to 24% better in patients receiving HFO. HFO had no effect on the duration of mechanical ventilation. The risk of adverse events, including low blood pressure or further injury to the lung due to high airway pressure, was not increased. We found substantial inconsistency for physiological outcomes such as oxygenation and carbon dioxide removal from the blood but not clinical outcomes. The quality of evidence is moderate at best for outcomes that would be most important to patients due to small numbers of trials, patients, and events. This indicates that randomized trials that are currently ongoing may change or impact these findings.

Résumé simplifié

Oscillation à haute fréquence pour le traitement du syndrome de détresse respiratoire aigüe

Les lésions pulmonaires aiguës (LPA) et le syndrome de détresse respiratoire aiguë (SDRA) sont des affections potentiellement mortelles. Elles se caractérisent par une inflammation pulmonaire aigüe provoquant une congestion pulmonaire, une rigidité pulmonaire qui rend difficile la respiration et une capacité réduite des poumons à oxygéner correctement le sang. Les survivants peuvent avoir une qualité de vie réduite. Les patients atteints de LPA ou de SDRA ont généralement besoin d'une ventilation mécanique afin de prévenir le décès. La ventilation par oscillation à haute fréquence (VHF) diffère de la ventilation conventionnelle en ce que de très faibles volumes courants sont fournis très rapidement à chaque respiration (3 à 15 Hz ou 180 à 900 respirations par minute). La VHF facilite la réexpansion des tissus pulmonaires affaissés à une pression moyenne constante des voies aériennes. Nous avons effectué une revue systématique afin de déterminer si la VHF améliorait les critères d'évaluation cliniques (notamment la prévention des décès) comparé à une ventilation mécanique conventionnelle chez les adultes et les enfants atteints de LPA ou de SDRA.

Nous avons inclus huit essais contrôlés randomisés ayant recruté au total 419 patients. La VHF, à titre de stratégie de ventilation initiale, a réduit le risque de décès à l'hôpital de 23 % dans six essais ayant recruté 365 patients et a réduit le risque d'échec du traitement de 33 % dans cinq essais ayant recruté 337 patients. La capacité des poumons à oxygéner le sang, mesurée à 24 à 72 heures de ventilation après la randomisation, a été de 16 % à 24 % supérieure chez les patients recevant une VHF. La VHF n'a eu aucun effet sur la durée de la ventilation mécanique. Le risque d'événements indésirables, notamment une faible tension artérielle ou des lésions pulmonaires supplémentaires dues à la pression élevée dans les voies aériennes, n'a pas été accru. Nous avons trouvé des incohérences importantes pour les critères d'évaluation physiologiques, tels que l'oxygénation et l'élimination du dioxyde de carbone du sang, mais pas pour les critères d'évaluation cliniques. La qualité des preuves est au mieux modérée pour les critères d'évaluation qui seraient les plus importants pour les patients en raison du petit nombre d'essais, de patients et d'événements. Cela indique que les essais randomisés qui sont actuellement en cours pourraient modifier ou affecter ces résultats.

Notes de traduction

Traduit par: French Cochrane Centre 1st March, 2013
Traduction financée par: Pour la France : Ministère de la Santé. Pour le Canada : Instituts de recherche en santé du Canada, ministère de la Santé du Québec, Fonds de recherche de Québec-Santé et Institut national d'excellence en santé et en services sociaux.

Summary of findings(Explanation)

Summary of findings for the main comparison. HFO compared to conventional mechanical ventilation for ALI and ARDS
  1. 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.

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)
⊕⊕⊕⊝
moderate 2,3
 
443 per 1000341 per 1000
(270 to 434)
6 month mortality589 per 1000 4465 per 1000
(342 to 636)
RR 0.79
(0.58 to 1.08)
148
(1 study)
⊕⊕⊝⊝
low 3
 
*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.

Background

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

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

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

Description of 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.

Figure 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)).

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Figure 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).

Figure 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.

Figure 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

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

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

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

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 Trials4291Risk Ratio (M-H, Random, 95% CI)0.77 [0.58, 1.02]
3.2 Paediatric Trials274Risk 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 Mandatory3267Risk Ratio (M-H, Random, 95% CI)0.84 [0.61, 1.16]
5.2 Lung Protective Ventilation Mandatory398Risk Ratio (M-H, Random, 95% CI)0.67 [0.44, 1.03]
Analysis 1.1.

Comparison 1 Mortality, Outcome 1 Hospital or 30-day Mortality.

Analysis 1.2.

Comparison 1 Mortality, Outcome 2 Hospital or 30-day Mortality (Bollen 2005 patients lost to follow-up excluded).

Analysis 1.3.

Comparison 1 Mortality, Outcome 3 Hospital or 30-day mortality: Adult versus paediatric trials.

Analysis 1.4.

Comparison 1 Mortality, Outcome 4 Hospital or 30-day Mortality: Low risk of bias versus unclear risk of bias.

Analysis 1.5.

Comparison 1 Mortality, Outcome 5 Hospital or 30-day Mortality: Lung protective ventilation mandatory vs. not mandatory.

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 Obstruction4 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Adverse events, Outcome 1 Treatment Failure (Intractable Hypoxia, Hypotension, Acidosis, Hypercapnea requiring discontinuation of study intervention).

Analysis 2.2.

Comparison 2 Adverse events, Outcome 2 Barotrauma.

Analysis 2.3.

Comparison 2 Adverse events, Outcome 3 Hypotension.

Analysis 2.4.

Comparison 2 Adverse events, Outcome 4 Hypotension (Shah and Mentzelopoulos included).

Analysis 2.5.

Comparison 2 Adverse events, Outcome 5 ETT Obstruction.

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]
Analysis 3.1.

Comparison 3 Ventilator dependency, Outcome 1 Duration of Mechanical Ventilation.

Comparison 4. Physiological endpoints (ratio of means)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 PaO2/FiO2 (Ratio of Means)7 Ratio of Means (Random, 95% CI)Subtotals only
1.1 Day 17323Ratio of Means (Random, 95% CI)1.24 [1.10, 1.40]
1.2 Day 25262Ratio of Means (Random, 95% CI)1.16 [0.97, 1.37]
1.3 Day 35228Ratio of Means (Random, 95% CI)1.17 [1.02, 1.35]
2 Oxygenation Index (Ratio of Means)7 Ratio of Means (Random, 95% CI)Subtotals only
2.1 Day 17352Ratio of Means (Random, 95% CI)1.11 [0.97, 1.26]
2.2 Day 26306Ratio of Means (Random, 95% CI)1.07 [0.92, 1.24]
2.3 Day 36266Ratio of Means (Random, 95% CI)1.07 [0.88, 1.29]
3 PaCO2 (Ratio of Means)8 Ratio of Means (Random, 95% CI)Subtotals only
3.1 Day 18386Ratio of Means (Random, 95% CI)0.91 [0.78, 1.07]
3.2 Day 26310Ratio of Means (Random, 95% CI)0.87 [0.72, 1.06]
3.3 Day 36267Ratio of Means (Random, 95% CI)0.98 [0.84, 1.14]
4 Mean Airway Pressure (Ratio of Means)8 Ratio of Means (Random, 95% CI)Subtotals only
4.1 Day 18389Ratio of Means (Random, 95% CI)1.33 [1.27, 1.40]
4.2 Day 26309Ratio of Means (Random, 95% CI)1.26 [1.16, 1.37]
4.3 Day 36274Ratio of Means (Random, 95% CI)1.22 [1.07, 1.39]
Analysis 4.1.

Comparison 4 Physiological endpoints (ratio of means), Outcome 1 PaO2/FiO2 (Ratio of Means).

Analysis 4.2.

Comparison 4 Physiological endpoints (ratio of means), Outcome 2 Oxygenation Index (Ratio of Means).

Analysis 4.3.

Comparison 4 Physiological endpoints (ratio of means), Outcome 3 PaCO2 (Ratio of Means).

Analysis 4.4.

Comparison 4 Physiological endpoints (ratio of means), Outcome 4 Mean Airway Pressure (Ratio of Means).

Appendices

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 value

I2 (%)

 

Day 1 (24 hours)
PaO2/FiO273231.24(1.11 to 1.40)<0.001

45

 

Mean airway pressure73311.33(1.27 to 1.40)<0.001

21

 

Oxygenation index62941.11(0.97 to 1.26)0.12

38

 

PaCO263000.91(0.78 to 1.07)0.25

91

 

Day 2 (48 hours)
PaO2/FiO252621.16(0.97 to 1.37)0.10

62

 

Mean airway pressure52621.26(1.16 to 1.37)<0.001

58

 

Oxygenation index52591.07(0.92 to 1.24)0.38

39

 

PaCO2  

 

52630.87(0.72 to 1.06)0.1695
Day 3 (72 hours)
PaO2/FiO252281.17(1.02 to 1.35)0.02

44

 

Mean airway pressure52361.22(1.07 to 1.39)0.003

78

 

Oxygenation index52281.07(0.88 to 1.29)0.51

58

 

PaCO262670.98(0.84 to 1.14)0.78

90

 

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

DateEventDescription
4 January 2013New citation required and conclusions have changed

This 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

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

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

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.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arnold 1994

MethodsMulti-centre RCT in 5 tertiary care paediatric ICUs in the United States.
Participants

70 children (weight <35 kg, mean age 2.8) with acute diffuse lung injury and impaired oxygenation.

Excluded: if <40 weeks post-conceptual age or former prematurity with residual chronic lung disease, obstructive airway disease, intractable septic or cardiogenic shock, non-pulmonary terminal diagnosis.

Interventions

3100 high-frequency oscillatory ventilator (SensorMedics). Initial settings of FiO2: 1.0, frequency of 5 to 10 Hz, mPaw of CV+(4 to 8) cm H2O, pressure amplitude of oscillation set for “adequate chest wall movement” or according to transcutaneous PCO2 sensor, bias gas flow 18 L/min.

Controls were ventilated with pressure limited conventional mechanical ventilation (Servo 900C, Siemens; Veolar, Hamilton Medical). Target blood gas values were the same as for HFO.

Crossover to the alternate ventilator was required if the patient met treatment failure criteria.

OutcomesDuration of mechanical ventilation, 30-day mortality, supplemental oxygen at 30 days, neurological events.
Notes

Patients had ARDS (86%) or pulmonary barotrauma requiring chest tube (14%). 21/62 were less than 1 year old.

12 patients excluded from the analysis due to: exclusion from the study within eight hours of enrolment. (n = 6); protocol violations (n = 4); transferred to other institution (n = 2). Open lung approach to achieve oxygenation targets used.

No specific use of lung-volume recruitment manoeuvres.

Use of sedation and paralysis was not reported.

Use of rescue therapies or co-interventions for ARDS was not reported.

Partial industry support (SensorMedics).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers (e-mail correspondence, J Arnold, 5 June 2003)
Allocation concealment (selection bias)Low risk"randomization was based on a serialized form which included the balanced block design, thus the assignment was blinded to the investigator when a patient was selected to be in the study" (A - Adequate) (e-mail correspondence, J Arnold, 5 June 2003)
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskData were available for 58 of 70 randomized patients after author contact
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes reported
Other biasUnclear risk>10% of patients (30/58) crossed over from assigned ventilator strategy. Lung protective ventilation was not mandated in the control group receiving conventional mechanical ventilation

Bollen 2005

MethodsMulti-centre RCT in 5 ICUs in 4 European cities.
Participants

61 adults (mean age 53) with ARDS.

Excluded: Patients with a non-pulmonary terminal disease, severe chronic obstructive pulmonary disease or asthma and grade 3 or 4 air leak.

Interventions

3100B high-frequency oscillatory ventilator (SensorMedics). Frequency of 5 Hz with inspiratory time of 33%, mPaw of CV+ 5 cm H2O, pressure amplitude of oscillation set according to PaCO2 and to achieve chest wall vibration.

Controls were ventilated with time cycled pressure controlled mechanical ventilation with mean tidal volume of 8-9 mL/kg ideal body weight (calculated from mean tidal volume per kg of ideal body weight on day 1, 2, 3). General physiological targets were provided, including limitation of peak inspiratory pressure to 40 cmH2O, but more detailed ventilation procedures and methods of weaning were according to standard protocols of the investigating centres.

Crossover to the alternate ventilator was required if the patient met treatment failure criteria.

OutcomesCumulative survival without mechanical ventilation or oxygen dependency at 30 days; mortality at 30 days; therapy failure; crossover rate; and persisting pulmonary problems defined as oxygen dependency or still being on a ventilator at 30 days. Data for ventilator settings and arterial blood gases were also available for the first three days.
Notes

7/61 patients were reported lost to follow-up at 30 days; ICU mortality, but not 30-day mortality, was available for 3/61 patients after author contact.

Trial was terminated early for slow recruitment.

No specific use of lung-volume recruitment manoeuvres.

Use of sedation and paralysis was not reported.

Use of rescue therapies or co-interventions for ARDS was not reported.

Partial industry support (SensorMedics).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerized randomization
Allocation concealment (selection bias)Low riskSealed opaque envelopes (A - Adequate) (email correspondence, C. Bollen, June 26, 2009)
Incomplete outcome data (attrition bias)
All outcomes
Unclear risk30-day mortality available for 58/61 patients; ICU mortality, but not 30-day mortality, was available for 3/61 after author contact
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes were reported.
Other biasUnclear risk>10% of patients (11/61) crossed over from assigned ventilator strategy. Lung protective ventilation was not mandated in the control group receiving conventional mechanical ventilation

Demory 2007

MethodsSingle centre RCT in France.
Participants28 adults (mean age 49) with ARDS and PaO2/FiO2 <150 and PEEP ≥5 cm H2O.
Interventions

3100B high-frequency oscillatory ventilator (SensorMedics). Initial settings were FiO2 1.0, frequency of 5 Hz with inspiratory time of 33%, mPaw of CV+ 5 cm H2O (but ≤ plateau pressure), pressure amplitude of oscillation = PaCO2 during conventional mechanical ventilation (max 110).

Controls were ventilated with volume-assist control with tidal volume 6-7 mL/kg predicted body weight. PEEP was adjusted according to the ARDSNet protocol.

OutcomesPhysiologic data including PaO2/FiO2, OI, venous admixture.
Notes

All patients received conventional mechanical ventilation in the prone position for 12 hours prior to HFO or conventional mechanical ventilation in the supine position.

Duration of HFO was limited to 12 hours; therefore we included only physiologic data (PaO2/FiO2 and OI) in pooled analyses

Recruitment manoeuvres were performed at HFO initiation, but not during conventional mechanical ventilation.

Sedation and paralysis were applied equally to both treatment groups.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated list of random numbers (e-mail correspondence, L Papazian, 9 August 2011)
Allocation concealment (selection bias)Low riskSealed opaque envelopes (A - Adequate) (e-mail correspondence, L Papazian, 9 August 2011)
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo incomplete outcome data
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes reported; authors provided additional physiologic data for this review after being contacted
Other biasLow riskNo other source of bias identified

Derdak 2002

MethodsMulti-centre (13 university-affiliated medical centres) RCT in the United States and Canada.
Participants148 adults (mean age 49) with ARDS and PEEP > 10.
Interventions

3100B high-frequency oscillatory ventilator (SensorMedics). Initial settings of FiO2 0.80-1.0, frequency of 5 Hz, mPaw of CV+5, pressure amplitude of oscillation set for “vibration down to level of mid-thigh”, bias flow of 40 L/min. Switched back to CV when FiO2 was 0.50 or less and mPaw was weaned to 24 cm H2O or less with an SaO2 of 88% or more.

Controls were ventilated using pressure control with an initial tidal volume of 6 to 10 ml/kg actual body weight, RR adjusted for pH greater than 7.15, PEEP of 10, inspiratory time 33%. Subsequent adjustment of PEEP was according to study protocol (range 10-14).

OutcomesSurvival without need for mechanical ventilation at 30 days from entry to study, 30-day mortality, six-month mortality, need for mechanical ventilation at 30 days and six months. Physiologic endpoints and other clinical outcomes were also obtained after author contact.
Notes

Designed as an equivalence trial.

Rescue therapies used in 9% of the HFO group (nitric oxide 4/75; prone position 2/75, high-dose steroids 1/75) and 16% of the CV group (nitric oxide 8/73;  prone position 3/73; high-dose steroids 4/73).

Lung-volume recruitment manoeuvres were permitted, although not protocolized.

All patients who received HFO were paralysed; paralysis was not mandatory in patients receiving CV.

Partial industry support (SensorMedics).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-based randomization with a balanced block design, balanced with respect to baseline oxygenation index > 40 (e-mail correspondence, S Derdak, T Bachmann, 20 April 2009)
Allocation concealment (selection bias)Low riskComputerized randomization program (A - Adequate) (e-mail correspondence, S Derdak, T Bachmann, 20 April 2009)
Incomplete outcome data (attrition bias)
All outcomes
Low riskMortality data for withdrawn patients (2/148) obtained after author contact
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes were reported; authors provided additional clinical and physiologic outcome data for this review after being contacted
Other biasUnclear riskLung protective ventilation was not mandatory in the control group receiving conventional mechanical ventilation

Mentzelopoulus 2007

MethodsSingle centre RCT in Greece.
Participants54 adults (mean age 57) with ARDS; PaO2/FiO2 <150, PEEP 8 cm H2O.
Interventions

3100B high-frequency oscillatory ventilator (SensorMedics). Initial settings of frequency of 4 Hz, mPaw of 3 above mean tracheal pressure measured distal to the endotracheal tube, pressure amplitude of oscillation set 30 above baseline PaCO during CV. Patients received 6-24 hr of HFO each day until PaO2/FiO2 ≥150 for >12hr on CV. All patients received tracheal gas insufflation with HFO.

Controls were ventilated using volume assist control with an initial tidal volume of 6 to 7 ml/kg predicted body weight. Subsequent adjustment of tidal volume and PEEP was according to the ARDSNet protocol.

OutcomesHospital mortality, and other clinical and physiologic outcomes were obtained after author contact.
Notes

Protocols for lung volume recruitment manoeuvres were used for both the HFO and CV group.

Steroids for ARDS were used in 20/27 and 21/27 of the HFO and CV groups respectively.

Paralysis was administered to 27/27 and 21/27 of the HFO and CV groups respectively.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated list of random numbers (e-mail correspondence, SD Mentzelopoulus, 9 April 2009)
Allocation concealment (selection bias)Low riskTelephone (A - Adequate) (e-mail correspondence, SD Mentzelopoulus, 9 April 2009)
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo incomplete outcome data
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes were reported; authors provided additional clinical and physiologic outcome data for this review after being contacted
Other biasLow risk 

Papazian 2005

MethodsSingle centre RCT in France.
Participants26 adults (mean age 51) with ARDS; PaO2/FiO2≤150, PEEP ≥5 cm H2O.
Interventions

3100B high-frequency oscillatory ventilator (SensorMedics). Initial settings of FiO2 1.0, frequency of 5 Hz with inspiratory time of 33%, bias flow of 20 L/min, mPaw of CV+ 5 cm H2O, pressure amplitude of oscillation = PaCO2 during conventional mechanical ventilation (max 110). All patients were ventilated in the prone position.

Controls were ventilated with volume-assist control with tidal volume 6 mL/kg predicted body weight. PEEP was set to 2 cm H2O above the lower inflection point of the pressure volume curve. All patients were ventilated in the prone position.

OutcomesPhysiologic data (including PaO2/FiO2 and OI), haemodynamics, and inflammatory mediators in BAL fluid and blood.
Notes

All patients were ventilated in the prone position.

Recruitment manoeuvres (45 cm H2O x 40 seconds) were performed at HFO initiation, but not during conventional mechanical ventilation.

Duration of HFO was limited to 12 hours; therefore we included only physiologic data (PaO2/FiO2 and OI) in pooled analyses.

Sedation and paralysis were applied equally to both treatment groups.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated list of random numbers (e-mail correspondence, L Papazian, 9 August 2011)
Allocation concealment (selection bias)Low riskSealed opaque envelopes (A - Adequate) (e-mail correspondence, L Papazian, 9 August 2011)
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo incomplete outcome data
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes were reported; authors provided additional physiologic outcome data for this review after being contacted
Other biasLow riskNo other source of bias identified

Samransamruajkit 2005

MethodsSingle centre RCT in Bangkok, Thailand.
Participants16 children (weight <35 kg; mean age 5) with ARDS, PEEP >5 cm H2O; FiO2 >0.6  for 12 hr to keep SaO2 >92%; OI >15 for ≥4 hr.
Interventions

SensorMedics 3100 high-frequency oscillatory ventilator. Initial settings of frequency of 4-10 Hz, mPaw of CV+(2 or 3), pressure amplitude of oscillation set for 10 above peak inspiratory pressure during CV. Switched back to CV when mPaw was weaned to approximately 18 cm H2O and patients were tolerating suctioning.

Controls were ventilated using pressure control with an initial tidal volume of 6 to 10 mL/kg actual body weight, RR adjusted for pH greater than 7.15, PEEP of 10, inspiratory time 33%. PEEP was adjusted according to the ARDS Network protocol.

OutcomesPlasma sICAM-1 measured by enzyme linked immunosorbent assay on days 1, 3, 5 and 7 of ARDS. Authors also reported duration of mechanical ventilation, daily OI and PaO2/FiO2, and hospital mortality.
Notes

No specific use of lung-volume recruitment manoeuvres.

1/7 and 0/9 children received inhaled nitric oxide in the HFO and CV groups respectively.

All patients were sedated and paralysed.

Not analysed by intention to treat. (One patient who crossed over from CV to HFO shortly after randomization and was analysed as treated; authors provided data which allowed analysis of this patient according to assigned group for clinical outcomes such as mortality and treatment failure, but not for physiologic outcomes such as OI and PaO2/FiO2).

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom numbers (e-mail correspondence, R Samransamjuajkit, 3 March 2009)
Allocation concealment (selection bias)Low riskSealed opaque envelopes (A - Adequate) (e-mail correspondence, R Samransamjuajkit, 13 March 2009)
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo incomplete outcome data
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes were reported; authors provided additional clinical and physiologic outcome data for this review after being contacted
Other biasLow risk 

Shah 2004

MethodsSingle centre RCT in the United Kingdom.
Participants28 adults (mean age 49) with ARDS.
Interventions

3100B high-frequency oscillatory ventilator (SensorMedics). Initial settings of frequency of 5 Hz, mPaw of CV+5, pressure amplitude of oscillation set for “vibration down to level of mid-thigh”. No specific criteria for transitioning to CV were reported but HFO was continued until "resolution of ARDS".

Controls were ventilated with time cycled pressure controlled mechanical ventilation with mean tidal volume of 7-8 mL/kg ideal body weight (calculated from mean tidal volume per kg of ideal body weight on day 1, 2, 3). Tidal volume and PEEP were adjusted according to the ARDS Network low tidal volume protocol.

OutcomesChanges in ventilatory parameters (PaO2/FiO2 and FiO2) over the first 72 hours of HFO or CV. Data for 30-day mortality and other outcomes were also available after author contact.
Notes

No specific use of lung-volume recruitment manoeuvres.

Protocols for sedation and paralysis were applied equally to HFO and CV groups.

No use of rescue therapies or co-interventions for ARDS.

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom draw ("sealed opaque envelopes which were drawn in a random manner by physician independent of the research team") (e-mail correspondence, S Shah, 30 Nov 2007)
Allocation concealment (selection bias)Low riskSealed opaque envelopes (A- Adequate) (e-mail correspondence, S Shah, 30 Nov 2007)
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo incomplete outcome data
Selective reporting (reporting bias)Low riskAll primary and secondary outcomes were reported; authors provided additional clinical and physiologic outcome data for this review after being contacted
Other biasLow riskNo other source of bias identified

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Carlon 1983Patient population had “acute respiratory failure” from a variety of reasons and included many patients requiring mechanical ventilation who would not necessarily fit modern criteria for ALI or ARDS.
Dobyns 2002Randomized on inhaled nitric oxide, not HFO.
Fessler 2008Randomized on frequency of oscillation, not HFO.
Hurst 1984Patients served as their own controls. Total of nine patients randomized.
Hurst 1990Patients in the study who received HFOV were only “at risk” of developing ALI/ARDS.
Mentzelopoulos 2007aRandomized on tracheal gas insufflation, not HFO. Crossover design.
Mentzelopoulos 2010Randomized on tracheal gas insufflation, not HFO. Crossover design.

Characteristics of ongoing studies [ordered by study ID]

Meade 2009

Trial name or titleThe Oscillation for ARDS Treated Early (OSCILLATE) Trial
MethodsMulti-centre RCT
ParticipantsPatients of either sex, 16 years and older; Acute onset of respiratory failure, with fewer than 2 weeks of new pulmonary symptoms; Endotracheal intubation or tracheostomy; Hypoxaemia - defined as PaO2/FiO2 < 200 mmHg on FiO2 ≥ 0.5, regardless of PEEP; Bilateral alveolar consolidation (airspace disease) seen on frontal chest radiograph.
InterventionsIntervention group: high frequency oscillatory (HFO) ventilation using a lung-open approach and an explicit protocol.
Control group: conventional ventilation using low tidal volumes, a lung-open approach and an explicit protocol, and utilising HFO only as true rescue therapy.
OutcomesHospital mortality; also 6 month mortality, quality of life at 6 months
Starting dateJune 1, 2009
Contact informationmeadema@hhsc.ca
NotesPlanned enrolment of 1200 patients

Young 2010

Trial name or titleOSCAR: High Frequency OSCillation in ARDS
MethodsMulti-centre RCT
ParticipantsPatients age ≥16 years; Weight ≥35 kg; Endotracheal intubation or tracheostomy; Hypoxaemia defined as PaO2/FiO2 ratio ≤26.7kPa (200 mmHg), with PEEP ≥ 5 cm H2O, determined on two arterial blood samples 12 hours apart; Bilateral infiltrates on chest radiograph; One or more risk factors for ARDS (including pneumonia, aspiration of gastric contents, inhalation injury, sepsis, major trauma, multiple transfusions, drug overdose, burn injury, acute pancreatitis, or shock); Predicted to require at least 48 hours of artificial ventilation from the time of randomization.
Interventions

Intervention: High Frequency Oscillatory Ventilation (HFOV)

Control: Conventional positive pressure ventilation

Outcomes30-day mortality. An economic analysis is also being carried out.
Starting dateJune 1, 2007
Contact informationOSCAR.Trial@nda.ox.ac.uk
NotesPlanned enrolment of 1006 patients.

Ancillary