Introduction
More than half a century ago, it was well-known that ventilation of the dependent lung might be impaired in mechanically ventilated patients. Children with cystic fibrosis could expectorate thick, tenacious secretions characteristic of the disease by positioning themselves on their hands and knees. Quite often, such positioning also enabled them to breathe easier (1). Based on this observation, the prone position was proposed as a measure to recruit the dependent lung regions that are predominantly affected in acute respiratory distress syndrome (ARDS) (2).
Early studies of prone ventilation
In the early 1970s, Margaret Piehl, a registered nurse, and Robert Brown, her ICU medical officer, noted improved oxygenation with prone ventilation among ARDS patients while working in a small community hospital in Midland, Michigan. They published their seminal paper on mechanical ventilation in the prone position titled “Use of extreme position changes in acute respiratory failure” in the Critical Care Medicine journal of January 1976 (3). Their case series included five patients – three with polytrauma, and two postoperative cases, one following femoropopliteal bypass surgery and the other, after repair of an abdominal aortic aneurysm. All five patients developed severe acute respiratory distress syndrome (ARDS) and remained profoundly hypoxic despite optimization of ventilation, including increasing levels of PEEP. They used a novel rotating bed (Fig. 1) to turn their patients to the prone position. Assuming the prone position resulted in a remarkable improvement of PaO2 levels by a mean of 47 mm Hg, while all ventilatory parameters were held constant. The prone position also enabled postural drainage and suctioning out of copious secretions. The authors hypothesized that improved ventilation-perfusion matching and enhanced clearance of secretions in the prone position could explain the striking effect on oxygenation.
In 1988, Langer et al. evaluated gas exchange and hemodynamic status on assuming the prone position in 13 patients with moderate to severe ARDS. Patients who showed improvement in the PaO2 by at least 10 mm Hg were considered responders. Eight patients were considered responders and two, non-responders by this definition. In this pioneering study, the authors used CT scan of the chest to assess the impact of prone ventilation in two patients; as previously hypothesized, the posterobasal areas of the lungs revealed improved aeration with adoption of the prone position in these patients. The authors suggested a brief trial of prone ventilation in patients with severe ARDS to assess response (4).
The Gattinoni et al. trial – the turning point
By the turn of the century, the salutary effect of prone ventilation on oxygenation in ARDS was fairly established, with 60–70% showing improved PaO2 levels. However, the impact of prone position on clinical outcomes, including survival, was unknown. Gattinoni et al. sought to answer this question in a multicenter RCT conducted across 28 ICUs in Italy and two in Switzerland between 1996–1999 (5) . The study included mechanically ventilated patients with ARDS, with a PaO2 /FiO2 ratio of <200 while on at least 5 cm H2O PEEP, or a PaO2 /FiO2 ratio of <300 with a PEEP of at least 10 cm H2O. Patients were prone ventilated daily for 6 hours or more for a maximum duration of 10 days and compared with a control group who received conventional management in the supine position. There was no difference in mortality between the prone and supine groups during the ICU stay, at the end of the 10-day study period, or at 6 months.
Improved oxygenation was noted on assuming the prone position; the mean rise in the PaO2/FiO2 ratio during the study period in the prone group was 63.0 ± 66.8 compared with 44.6 ± 68.2 in the supine group (P = 0.02). The improvement in oxygenation was noted in more than 70% of patients on assuming the prone position; the effect was most pronounced in the first hour after turning prone. The incidence of non-pulmonary organ failure was similar between the two groups. Notably, on post-hoc analysis, the authors observed a significantly lower mortality with prone ventilation among patients with the lowest PaO2/FiO2 ratio, and the highest quartile of Simplified Acute Physiology Score (SAPS) scores.
The incidence of complications related to accidental removal of endotracheal tubes, lines, and intercostal drains were similar in both groups. Pressure-related injury related to the prone position were observed; however, the number of patients with new or worsening pressure sores were similar in both groups.
The Gattinoni et al. trial was the first large RCT that compared clinical outcomes with prone positioning in patients with ARDS. However, the study was limited by the relatively short duration of prone ventilation. Besides, the study included patients with mild ARDS, with a PaO2/FiO2 ratio of >300 mm Hg. The question remained whether prone positioning would improve survival in patients with more severe disease at baseline. A meta-analysis of four RCTs published later, found mortality benefit in the most severely hypoxic patients at baseline, with a PaO2/FiO2 ratio of <100 mm Hg (6). Based on this evidence, the stage was set for Guérin et al. to explore the impact of prone ventilation on clinical outcomes in patients with severe ARDS in a large RCT.
The PROSEVA trial
The PROSEVA trial was conducted across 26 ICUs in France and 1 in Spain over a three-and-a-half-year period from 2008–2011 (7). The study centers had more than 5 years of experience with prone ventilation. The study included patients with ARDS who were on mechanical ventilation for less than 36 hours on FiO2 more than 0.6, a PEEP level of at least 5 cm of water, and a PaO2/FiO2 ratio of less than 150 mm Hg. Mechanical ventilation was continued for a 12–24-hour period, followed by confirmation of the inclusion criteria prior to randomization.
Study groups
Prone ventilation was commenced within an hour of randomization and continued for at least 16 consecutive hours. In the supine group, a semi-recumbent position was maintained. In both groups of patients, volume-controlled mode of ventilation was employed, with a tidal volume of 6 ml/kg of predicted body weight. PEEP was applied according to a standard PEEP-FiO2 table. A Pplat of 30 cm H2O was targeted with the maintenance of pH between 7.20–7.45. A repeat session of prone ventilation could be carried out at any time while waiting for a 4-hour assessment. Prone ventilation could be carried out daily for up to 28 days, based on clinician discretion. Crossover from the supine group was allowed only in the presence of life-threatening hypoxemia, based on predefined criteria. Sedative agents and neuromuscular blocking agents were administered to both groups of patients as appropriate. Weaning from mechanical ventilation was based on a standard protocol.
Sample size
The sample size was calculated based on a 60% mortality at 28 days in the supine group. The authors assumed an absolute reduction in mortality of 15% with prone ventilation (60% mortality in the supine group and 45% mortality in the prone group). A sample size of 456 patients was required based on this assumption providing 90% power and a type I error rate of 5%.
Baseline characteristics
The underlying etiology was pneumonia in the majority of patients in both groups. The tidal volume, PEEP, and Pplat levels were similar at baseline. The mean PaO2/FiO2 ratio at the time of inclusion was 100 mm Hg in both groups. The PaCO2 levels were also similar. The Sequential Organ Failure Assessment score (SOFA) score and vasopressor use were higher in the supine group, while the use of neuromuscular blocking agents was higher in the prone group.
Findings
Analysis was performed based on intention to treat, with 229 patients in the supine and 237 patients in the prone group.
Patients were placed in the prone position within a mean duration of 55 minutes after randomization. The prone position was maintained for 17±3 hours at a time. The PaO2/FiO2 ratio rose with prone ventilation and was significantly higher compared to the supine group on days 3 and 5, while the PEEP was lower. The PaCO2 levels were similar between the two groups.
The primary outcome
Mortality at 28 days, the primary outcome, was significantly lower in the prone group (16% vs. 32.8%, p <0.001). The mortality difference was similar after adjusted analysis based on the SOFA score, use of vasopressors and neuromuscular blockers, which differed between the groups at baseline.
Secondary outcomes
Mortality at 90 days was significantly lower in the prone group (23.6% vs. 41%, p <0.001). Extubation by 90 days was higher, and the ICU length of stay was shorter among patients who were prone ventilated. Similarly, ventilation-free days were significantly higher at 28 and 90 days in the prone group.
Complications
The incidence of cardiac arrests was higher in the supine group (31 vs. 16). Other adverse events, including accidental extubation, endobronchial intubation, and blocked endotracheal tube were similar between the two groups.
The PROSEVA trial marked a turning point in the history of ARDS, providing robust evidence for improved survival among patients with severe ARDS who were prone ventilated. The participating centers had long-standing experience with prone ventilation. An initial 12–24-hour period of stabilization was followed, which enabled the selection of patients who were more likely to deteriorate, and experience worse outcomes. Unlike previous trials, the prone position was maintained for a longer duration of 16 hours per day. The duration of prone ventilation at the peak of illness was 73% compared with approximately 30% in previous trials. A lung-protective ventilation strategy was strictly adhered to; besides, prone ventilation was initiated expeditiously soon after randomization. The study chose the most severely hypoxic patients, with a PaO2/FiO2 ratio of >150 mm Hg, who were more likely to benefit, in contrast to the Gattinoni et al. trial of 2001 that included patients with PaO2/FiO2 ratio of <300 mm Hg.
Limitations
There were imbalances between the prone and supine groups at baseline. The SOFA score was lower among patients who underwent prone ventilation; besides, more patients received vasopressors in the supine group. This difference between groups may suggest a higher severity of illness in patients who were maintained supine. However, the improved survival with prone ventilation persisted after adjustment for baseline differences between the two groups. Only one-third of patients who were screened underwent randomization. Besides, a 12–24-hour period of stabilization allowed the exclusion of patients who showed early improvement, allowing the inclusion of a highly selective patient population. Despite these limitations, the PROSEVA trial provided robust evidence with prone ventilation among the sickest of patients with ARDS.
Summary
ARDS had witnessed a track record of failed therapies, notably nitric oxide, prostacyclin, and high-frequency oscillation. The PROSEVA trial offered a fresh ray of hope for the most severely hypoxic patients with ARDS. Although previous studies had consistently revealed improved oxygenation, none had shown improved clinical outcomes. Maintenance of the prone position for more than 16 hours at a time and inclusion of the most severely hypoxic patients at baseline were clearly important factors that led to improved outcomes in the PROSEVA trial. Besides, study centers had sufficient experience and expertise with prone ventilation, probably reducing the incidence of complications related to positioning. The PROSEVA trial remains a pioneering study that demonstrated improved survival and more ventilator-free days with prone ventilation besides improved oxygenation.
References
1. Mellins RB. Pulmonary physiotherapy in the pediatric age group. Am Rev Respir Dis. 1974 Dec;110(6 Pt 2):137–42.
2. Bryan AC. Conference on the scientific basis of respiratory therapy. Pulmonary physiotherapy in the pediatric age group. Comments of a devil’s advocate. Am Rev Respir Dis. 1974 Dec;110(6 Pt 2):143–4.
3. Piehl MA, Brown RS. Use of extreme position changes in acute respiratory failure. Crit Care Med. 1976;4(1):13–4.
4. Langer M, Mascheroni D, Marcolin R, Gattinoni L. The prone position in ARDS patients. A clinical study. Chest. 1988 Jul;94(1):103–7.
5. Gattinoni L, Tognoni G, Pesenti A, Taccone P, Mascheroni D, Labarta V, et al. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001 Aug 23;345(8):568–73.
6. Sud S, Friedrich JO, Taccone P, Polli F, Adhikari NKJ, Latini R, et al. Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis. Intensive Care Med. 2010 Apr;36(4):585–99.
7. Guérin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al. Prone positioning in severe acute respiratory distress syndrome. N Engl J Med. 2013 Jun 6;368(23):2159–68.
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