Summary of findings
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 (PaO
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.
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.
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
1. Hospital or 30-day mortality
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 (PaO
7. Oxygenation index (OI, defined as 100 x mean airway pressure/(PaO
8. Ventilation, measured by partial pressure of carbon dioxide (PaCO
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.
To update our previous literature search, we:
- 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
Searching other resources
In addition to the electronic search, 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); and
- 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 PaO
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 I
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.
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 PaO
We assessed any subgroup effects using a z-test for interaction.
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).
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.|
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 PaO
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 H
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 H
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
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 (I
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, I
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 PaO
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 PaO
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 PaO
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
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 PaO
The improvements in PaO
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.
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 PaCO
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.
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
- Top of page
- Summary of findings [Explanations]
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Differences between protocol and review
- Index terms
Appendix 1. Search strategies
MEDLINE (OvidSP, 1948 to March 2011)
1. Exp High-Frequency Ventilation/
2. (high adj3 oscillat$).mp.
3. 1 or 2
4. clinical trial.mp. or clinical trial.pt. or random:.mp. or tu.xs.
5. 3 and 4 [NOTE this is the same as the following command: limit 3 to “therapy (sensitivity)”]
6. (animals not humans).sh.
7. 5 not 6
8. Infants, newborn.sh.
9. 7 not 8
EMBASE (1980 to March 2011)
1. Exp High Frequency Ventilation/
2. (high adj3 oscillat$).mp.
3. 1 or 2
4. random:.tw. or clinical trial:.mp. or exp health care quality/
5. 3 and 4 [NOTE this is the same as the following command: limit 3 to "treatment (2 or more terms high sensitivity)"]
6. (animal$ not human$).sh,hw.
7. 5 not 6
9. 7 not 8
CENTRAL (Issue 1, 2011)
1. (high adj3 oscillat$).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
Last assessed as up-to-date: 1 March 2011.
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:
- no financial support for the submitted work from anyone other than their employer;
- no financial relationships with commercial entities that might have an interest in the submitted work;
- no spouses, partners, or children with relationships with commercial entities that might have an interest in the submitted work;
- 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
Medical Subject Headings (MeSH)
Acute Lung Injury [mortality; *therapy]; High-Frequency Ventilation [*methods; mortality]; Randomized Controlled Trials as Topic; Respiration, Artificial [*methods; mortality]; Respiratory Distress Syndrome, Adult [mortality; *therapy]
MeSH check words
Adolescent; Adult; Child; Child, Preschool; Humans; Infant