PROSEVA Trial – Prone Positioning in Severe ARDS

As it turns out, patients with ARDS should be belly sleepers.  The PROSEVA trial, freshly published in NEJM, examined the role of prone positioning in patients with early, severe acute respiratory distress syndrome (ARDS).

Background

Prior to PROSEVA, trials examining prone positioning in ARDS generally showed improvement in surrogate physiologic parameters (eg, oxygenation), but failed to show a benefit in patient outcomes.  This French study was designed to examine patients with severe ARDS focusing on early proning for prolonged periods of time.

Study Design

• Multicenter, randomized trial in France and Spain
• Included patients with early, severe ARDS
  • “Early” was defined as being included to the trial within 36 hours of meeting ARDS criteria
  • “Severe” was defined as a PaO₂:FiO₂ ratio < 150 mm Hg (with FiO₂ of at least 60%, PEEP 5 cm H₂0, and tidal volume of 6 mL/kg ideal weight)
• All patients meeting inclusion criteria underwent a 12-24 hour “stabilization” period to verify inclusion criteria prior to randomization
• Randomized patients to either prone or supine positioning daily for up to 28 days
• Importantly, the study received no commercial support and did not use any special equipment

Intervention

• Prone positioning was conducted for at least 16 consecutive hours per day in standard ICU beds.  The patient’s head was rotated (left or right) every two hours while prone
• For those more familiar with special proning beds, check out the NEJM video demonstrating the process on a standard ICU bed
• Proning was stopped once the patient met oxygenation requirements while supine for at least four hours (PaO₂:FiO₂ ≥ 150 mm Hg with PEEP ≤ 10 and FiO2 ≤ 60%)
• Adjustments to mechanical ventilation, weaning parameters, sedation, and paralytics were protocolized in a similar manner between groups
• Of note, all ICUs included in the trial had been using this prone positioning protocol for more than 5 years.  Given the complexity and resources required for proning, this is a potential issue for external validity.

Results

• Randomized 466 patients (mean PaO₂:FiO₂ 100 mm Hg) to supine or prone positioning.  Most patients had ARDS due to pneumonia (about 60%), and most received vasopressors (73-83%), neuromuscular blockers (82-91%), and many received glucocorticoids (40-45%)
• Prone positioning significantly reduced 28-day all-cause mortality compared to supine positioning (16% vs 32.8%, HR 0.39, NNT 6, p<0.001)
• Proning also reduced 90-day mortality (23.6% vs. 41%, HR 0.44, NNT 6, p<0.001)
• Although those randomized to supine positioning may have been slightly sicker at baseline (higher SOFA score), this mortality benefit was still significant after adjustments for baseline SOFA scores
• On average, prone patients received 4±4 prone sessions lasting for 17±3 hours.  These patients were proned for 73% of the time spent on a ventilator

Discussion and Conclusions

• ARDS trials have been fraught with failed interventions (high-frequency oscillation, surfactants, inhaled prostacyclin or nitric oxide, β2 agonists, N-acetylcysteine, ketoconazole, antioxidants, omega-3 fatty acids, GM-CSF, statins, ibuprofen, liposomal prostaglandin E1, lisofylline, pentoxifylline — just to name a few), which highlights the excitement of an ARDS trial showing more than a 50% mortality benefit
• The trial was powered for a 28-day mortality rate of 60% in the control group (was actually 32.8%); however, because the effect size was so great, PROSEVA had a post-hoc statistical power of 99%
• It is unclear why previous proning trials were not favorable.  Likely suspects for benefit in PROSEVA include early intervention (within 36 hours of ARDS), selecting the most appropriate patients (using a 12-24 hour stabilization period), and the significant proportion of time spent proning (73% versus closer to 30% in other trials)
• As discussed, the biggest limitation to the trial is that the nursing staff had years of experience in proning patients.  It is unclear whether less trained staff may experience more complications during the proning process
• Proning can be done without purchasing a new bed or special equipment, and based on this trial, can reduce mortality by more than half.  A reduction of 50% in mortality is absolutely unheard of in the ARDS literature.  While the results seem “too good to be true”, it’s difficult to ignore.

Reference

Guérin C, Reignier J, Richard JC, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013;368(23):2159-68. PMID 23688302.

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