Abstract: We identified nine relevant RCTs, which enrolled a total of 2165 participants (10 publications). All recruited participants suffered from disorders of lung function causing moderate to severe hypoxaemia and requiring mechanical ventilation, so they were fairly comparable, given the heterogeneity of specific disease diagnoses in intensive care. Risk of bias, although acceptable in the view of the review authors, was inevitable: Blinding of participants and carers to treatment allocation was not possible (face-up vs face-down). Primary analyses of short- and longer-term mortality pooled from six trials demonstrated an RR of 0.84 to 0.86 in favour of the prone position (PP), but findings were not statistically significant: In the short term, mortality for those ventilated prone was 33.4% (363/1086) and supine 38.3% (395/1031). This resulted in an RR of 0.84 (95% confidence interval (CI) 0.69 to 1.02) marginally in favour of PP. For longer-term mortality, results showed 41.7% (462/1107) for prone and 47.1% (490/1041) for supine positions, with an RR of 0.86 (95% CI 0.72 to 1.03). The quality of the evidence for both outcomes was rated as low as a result of important potential bias and serious inconsistency. Subgroup analyses for mortality identified three groups consistently favouring PP: those recruited within 48 hours of meeting entry criteria (five trials; 1024 participants showed an RR of 0.75 (95% CI 0.59 to 94)); those treated in the PP for 16 or more hours per day (five trials; 1005 participants showed an RR of 0.77 (95% CI 0.61 to 0.99)); and participants with more severe hypoxaemia at trial entry (six trials; 1108 participants showed an RR of 0.77 (95% CI 0.65 to 0.92)). The quality of the evidence for these outcomes was rated as moderate as a result of potentially important bias. Prone positioning appeared to influence adverse effects: Pressure sores (three trials; 366 participants) with an RR of 1.37 (95% CI 1.05 to 1.79) and tracheal tube obstruction with an RR of 1.78 (95% CI 1.22 to 2.60) were increased with prone ventilation. Reporting of arrhythmias was reduced with PP, with an RR of 0.64 (95% CI 0.47 to 0.87). We found no convincing evidence of benefit nor harm from universal application of PP in adults with hypoxaemia mechanically ventilated in intensive care units (ICUs). Three subgroups (early implementation of PP, prolonged adoption of PP and severe hypoxaemia at study entry) suggested that prone positioning may confer a statistically significant mortality advantage. Additional adequately powered studies would be required to confirm or refute these possibilities of subgroup benefit but are unlikely, given results of the most recent study and recommendations derived from several published subgroup analyses. Meta-analysis of individual patient data could be useful for further data exploration in this regard. Complications such as tracheal obstruction are increased with use of prone ventilation. Long-term mortality data (12 months and beyond), as well as functional, neuro-psychological and quality of life data, are required if future studies are to better inform the role of PP in the management of hypoxaemic respiratory failure in the ICU.

Plain-language summary: We identified and included in this review randomized controlled trials of adults that compared conventional mechanical ventilation in the face-down versus the face-up position. Reports from nine trials of 2165 participants (10 publications) show that prone ventilation did not appear to be of benefit for all participants requiring ventilation but identified some situations in which it may improve survival. One group of participants with the most severe lung damage appeared to have reduced mortality, as did participants who received treatment early and for prolonged periods. Complications were described. The most common of these were pressure sores and tracheal tube blockage or obstruction. Low blood pressure and abnormal heart rhythms were also seen. Clinicians need to be aware of these and to take preventative actions when possible. The application of prone position to all participants in intensive care who have low oxygen levels is not warranted, but some particular groups of participants, for example, those with especially low oxygen levels, would benefit from prone positioning. Further clinical trials would assist in clarifying potential benefits for such patient groups but further trials may not take place because of the very large treatment benefit observed in the most recent clinical trial of participants with very low oxygen levels. In the absence of new trials, meta-analysis of individual patient data may facilitate further assessment. The quality of the evidence for primary outcomes of this systematic review was low as a result of serious inconsistency and important potential bias. The evidence is current to 31 January 2014. We reran searches in CENTRAL, MEDLINE, EMBASE, CINAHL and LILACS in June 2015. Five new studies of potential interest were added to the list of "Studies awaiting classification" and will be incorporated into formal review findings during the review update.