Original Protocol

Amended Protocol (March 27 2009; July 01 2013)

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. We included longer‐term mortality 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. 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 cross‐over 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 participants 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, as it 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) were 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 that 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

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