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The New England Journal of Medicine. 2013. 368(23):2159-2168.

PubMed Full text PDF Guérin C, et al. "Prone positioning in severe acute respiratory distress syndrome".. 2013. 368(23):2159-2168.

Clinical Question

Among patients with severe ARDS, does prone positioning reduce all-cause mortality at 28 days when compared to supine-only positioning?

Bottom Line

Among patients with severe ARDS (P:F ratio <150 mmHg), prone positioning reduces 28-day mortality.

Major Points

Acute respiratory distress syndrome (ARDS) is associated with a high mortality and prolonged periods of intubation. While some ground was gained through low tidal volume (Vt) ventilation (ARDSNet; 2000), low fluid volume (FACTT; 2006), and therapeutic paralysis (ACURASYS; 2010), the mortality approaches 25% even in the era of these and other lung-protective strategies.[1] Prone positioning, which seems to improve ventilation-perfusion matching through aeration of previously atelectatic dependent alveoli, has been shown in unblinded studies to improve survival particularly when used as rescue therapy in severe ARDS (ie, P:F <100 mmHg). While this finding was corroborated in a 2010 meta-analysis of seven well-designed randomized trials in severe ARDS,[2] a large randomized trial was lacking.

The 2013 Proning Severe ARDS Patients (PROSEVA) trial randomized 466 patients with severe ARDS in European ICUs to early (<36h after intubation), lengthy (goal 16 hours daily), intermittent prone positioning or to a standard supine position. Severe ARDS was defined as a P:F ratio of <150 mmHg with FiO 2 >60% and PEEP ≥5 cm H 2 O. At 28 days, the prone group had a 51% relative and 17% absolute reduction in all-cause mortality when compared to the supine group (16.0% vs. 32.8%; NNT 6). Importantly, PROSEVA incorporated low-tidal ventilation and therapeutic paralysis, suggesting that prone positioning confers a survival benefit beyond that seen with the standard of care. Adverse events more common with prone positioning included unscheduled extubation (13.3% vs. 10.9%) and ET tube obstruction (4.9% vs. 2.2%). PROSEVA did not report incidence of pressure ulcers, which have been shown to occur more frequently in prone-positioned patients.[2]

The large survival benefit in PROSEVA was markedly higher than the 16% relative risk reduction in the 2010 meta-analysis referenced earlier.[2] Some of this discrepancy may reflect prior trials' inadequate duration of prone positioning and their inclusion of less critically ill patients who are unlikely to benefit from prone positioning.[3] However, an alternative explanation stems from differences in baseline characteristics between study groups at the time of inclusion. In particular, although the prone group had a similar SAPS II score, their SOAP scores were lower (mean 9.6 vs. 10.4) and fewer prone patients received ECMO (0.8% vs. 2.6%), inhaled nitric oxide (9.7% vs. 15.7%), vasopressors (73% vs. 83%), renal replacement therapy (11% vs. 17%), and glucocorticoids (40% vs. 45%), all of which suggest that the prone group was relatively healthier than the supine group at baseline.

While PROSEVA is an imperfect study whose results are confounded by baseline between-group differences, it adds to the growing body of evidence that prone positioning improves survival in severe ARDS. This intervention should be restricted to select patients meeting this study's inclusion criteria or perhaps the more stringent criterion of ARDS with P:F ratio <100 mmHg.

Guidelines

Surviving Sepsis Campaign severe sepsis and septic shock (2016, adapted)[4]

Recommend prone over supine positioning in adults with ARDS from sepsis and a PaO2/FIO2 ratio <150 (strong recommendation, moderate quality of evidence)

Design

Multicenter, randomized, open-label trial

N=466 Supine (n=229) Prone (n=237)

Setting: 27 European ICUs

Enrollment: 2008-2011

Follow-up: 90 days

Analysis: Intention-to-treat

Primary outcome: All-cause mortality at 28 days

Population

Inclusion Criteria

Severe ARDS P:F ratio <150 mmHg FiO 2 >60% PEEP ≥5 cm H 2 O Vt 6 mL/kg

ETT in place and mechanical ventilation for <36 hours

Exclusion Criteria

ICP >30 mmHg, CPP <60 mmHg, or MAP <65 mmHg

Massive hemoptysis

Recent tracheal surgery, sternotomy, facial trauma, DVT, PPM placement

Unstable fractures of spine, femur, or pelvis

Anterior chest tube with air leak

Nitric oxide, almitrine bismesylate, or ECMO therapy

Lung transplant, pregnancy, or >20% BSA burn

Chronic O 2 or NIV therapy

or NIV therapy Other disease resulting in life expectancy <1 year

End-of-life decision

Inclusion in other research protocol in prior 30 days with mortality as endpoint

Prone positioning prior to inclusion

Baseline Characteristics

From the supine group. Comparisons are supine vs. prone when given.

Demographics: Mean age 60 years, male 66.4%

ARDS from pneumonia: 58.1%

Sepsis: 85.2% vs. 82.2% (P<0.05)

Source of admission to ICU: ED 42.8%, acute care facility 38.0%, home 11.4%, ICU 3.9%, other 3.9%

McCabe score: A 79.9%, B 19.7%, C 0.4%

SAPS II: 47

Mean SOFA score 10.4

PMH: DM 17.0%, ESRD 5.2%, liver disease 7.0%, CAD 10.5%, cancer 13.1%, COPD 12.7%, immunodeficiency 16.6%

BMI: 29

Interventions: Vasopressors: 83.0% vs. 72.6% (P<0.05) NM blockade 82.3% vs. 91.0% (P<0.05) RRT 17.1% glucocorticoids 44.9%

Ventilator settings: Vt 381 mL (6.1 mL/kg), RR 27/min, PEEP 10 cm H 2 O, FiO 2 79%

O, FiO 79% Respiratory measurements: Plateau pressure 23 cm H 2 O, compliance 35 mL/cm H 2 O

O, compliance 35 mL/cm H O PaO 2 :FiO 2 100

:FiO 100 Bloodwork: pH 7.30, PaCO 2 52 mmHg, PaO 2 80 mmHg, HCO 3 25

Interventions

Stabilization for 12-24 hours prior to enrollment

Randomized to supine or prone position Supine position: Semirecumbent position with physiologic measurements every 6 hours Prone position: Turning to prone for ≥16h, repeated daily for ≥28 days; cessation of prone positioning if: Improved oxygenation, defined as P:F ratio ≥150 mmHg with PEEP ≤10 cm H 2 O and FiO 2 ≤60% ≥4 hours after last prone session Decreased P:F ratio before 2 consecutive prone sessions of ≥20% relative to the supine ratio Complications during a prone session leading to its interruption

Both groups were kept in standard ICU beds (ie, did not use beds specific for prone-positioning)

Mechanical ventilation was modeled after the low Vt ARDSNet protocol, with end-inspiratory plateau pressure goal ≤30 and goal pH 7.20-7.45

Outcomes

Comparisons are as supine vs. prone.

Primary Outcome

28-day mortality 32.8% vs. 16.0% (HR 0.39; 95% CI 0.25-0.63; P<0.001; NNT=6) SOFA score-adjusted: HR 0.42; 95% CI 0.26-0.66; P<0.001

Secondary Outcomes

All-cause mortality at 90 days 41.0% vs. 23.6% (HR 0.44; 95% CI 0.29-0.67; P<0.001; NNT=6) SOFA score-adjusted: HR 0.48; 95% CI 0.32-0.72; P<0.001

Successful extubation at 90 days 65.0% vs. 80.5% (HR 0.45; 95% CI 0.29-0.70; P<0.001)

Time to successful extubation Survivors: 19 vs. 17 days (P=0.87) Non-survivors: 16 vs. 18 days

ICU stay duration Survivors: 26 vs. 24 days (P=0.05) Non-survivors: 18 vs. 21 days

Ventilator-free days At 28 days: 10 vs. 14 (P<0.001) At 90 days: 43 vs. 57 (P<0.001)

Pneumothorax 5.7% vs. 6.3% (HR 0.89; 95% CI 0.39-2.02; P=0.85)

Noninvasive ventilation At 28 days: 4.7% vs. 1.8% (HR 0.36; 95% CI 0.7-3.50; P=0.11) At 90 days: 1.5% vs. 1.8% (HR 1.22; 95% CI 0.23-6.97; P=1.00)

Tracheotomy At 28 days: 5.2% vs. 3.8% (HR 0.71; 95% CI 0.27-1.86; P=0.37) At 90 days: 8.1% vs. 6.4% (HR 0.78; 95% CI 0.36-1.67; P=0.59)

Additional Analyses

ECMO 2.6% vs. 0.8% (P=0.14)

Inhaled NO 15.7% vs. 9.7% (P=0.05)

Almitrine bismesylate 6.6% vs. 2.5% (P=0.04)

NM blockade 5.6 days vss. 5.7 days (P=0.74)

Sedation 9.5 vs. 10.1 days (P=0.35)

Adverse Events

Cardiac arrest 31 vs. 16 events (P=0.02)

Criticisms

Unclear if centers with less experience in prone positioning would have higher rates of complications

Unclear if an inclusion bias present as little data from excluded patients was collected

Fluid balance and catacholamine dosing were not measured or reported

Groups imbalanced based on heir SOFA score, NM blockade, vasopressor, and glucocorticoid use

Highly selected patients [3]

Significant mortality difference may have been due to a decrease in deaths due to refractory shock. There was minimal difference in deaths due to hypoxemia.

Funding

Both public and private funding.