Source: Petrucci N, De Feo C. Lung protective ventilation strategy for the acute respiratory distress syndrome. Cochrane Database Syst Rev 2013;(2):CD003844.
Study Population: 1,297 patients with acute respiratory distress syndrome from six trials
Efficacy Endpoints: 28-day mortality, hospital mortality, mortality at the end of the follow-up period for each trial
Harm Endpoints: Hypercapnia, acidosis, barotrauma
Narrative: Acute respiratory distress syndrome (ARDS) is a type of acute, diffuse, and inflammatory lung injury. The Berlin definition (2012)1 includes the following ARDS criteria: 1) onset within 1 week of a known clinical insult, 2) bilateral opacities consistent with pulmonary edema, 3) respiratory failure not fully explained by cardiac failure or fluid overload, and 4) ratio of partial pressure of arterial oxygen (PaO2) to fraction of inspired oxygen (FiO2) of less than 300 mm Hg at a positive end expiratory pressure (PEEP) of 5 cm H2O. The new definition also categorizes ARDS as being mild for PaO2/FiO2 ratio of 200 to 300, moderate for PaO2/FiO2 ratio of 100 to 200, or severe for PaO2/ FiO2 ratio of less than 100 on PEEP of 5 cm H2O. Sepsis is the most common etiology for ARDS.2 Studies done before the introduction of Sepsis-3 in 2016 (which made the use of the term severe sepsis obsolete) showed that two of three cases with severe sepsis enter the health care system through the emergency department (ED). Prevalence of ARDS among medical patients in the ED has been estimated to be about 9%.2, 3 ED-based studies suggest an ARDS progression rate after admission of 27.5% in patients with severe sepsis and septic shock.4 The early onset and rapid progression of ARDS after ED admission which results in worsened outcomes suggest that time spent and treatments provided in the ED could alter the course of ARDS.
According to a prospective multicenter cohort study (LUNG SAFE trial 2016),5 which was conducted with the aim of assessing the burden of acute hypoxemic respiratory failure requiring ventilatory support with a specific focus on ARDS, reported a prevalence of 10.4% for ARDS among intensive care admissions and 23.4% among ventilated patients. In this trial, the rates of hospital mortality were 35, 40, and 46% for patients with mild, moderate, and severe ARDS, respectively. There is considerable evidence that progressive lung parenchymal injury is induced by excessive alveolar distension by large tidal volumes.5 Lung-protective strategy has been developed to reduce further damage to already injured lungs. Lung-protective strategy is often divided into three strategies that include: 1) low tidal volume (6 mL/kg), 2) plateau pressure (Pplat) <31 cmH2O, and 3) appropriate PEEP.
A Cochrane systematic review published in 2013 by Petrucci and De Feo6 examined lung-protective strategies of mechanical ventilation for ARDS. This systematic review included six randomized controlled trials comprising 1,297 patients and compared mechanical ventilation with a lower tidal volume (VT) of ≤7 mL/ kg (lung-protective ventilation) versus VT of 10 to 15 mL/kg (conventional ventilation). Lung-protective ventilation was associated with a significantly decreased 28-day mortality (relative risk [RR] = 0.74, 95% confidence interval [CI] = 0.61 to 0.88, absolute risk reduction [ARR] = 10%, number needed to treat [NNT] = 10). Hospital mortality was similarly reduced (RR = 0.80, 95% CI = 0.69 to 0.92, ARR = 8%, NNT = 12). Overall mortality at the end of the follow-up period for each trial did not reach statistical significance (RR = 0.86, 95% CI = 0.69 to 1.06). The follow-up period varied from hospital discharge to 180 days in the largest trial included in the study.6
Plateau pressure is defined as airway pressure during the end expiratory pause and roughly reflects the level of alveolar overdistension. The mortality benefit for lung-protective strategy was evident only when the control group received “higher” (>31 cm H2O) Pplat (RR = 0.74, 95% CI = 0.63 to 0.87). The mortality rate between the groups was not statistically different when control groups received a “lower” Pplat (31 cm H2O or less).6
The Cochrane analysis reported insufficient data to analyze secondary outcomes such as development of multiorgan failure, duration of mechanical ventilation and total duration of mechanical support, total duration of stay in intensive care unit and hospital, longterm mortality, long-term health-related quality of life, and long-term cognitive outcome. The only secondary outcome with sufficient data for analysis was duration of mechanical ventilation (three trials, 288 patients) which was not statistically different between the groups.
A subsequent 2013 Cochrane review7 assessed the benefits and harms of high versus low PEEP in patients with ARDS. The use of higher levels of PEEP is part of the lung-protective strategy aimed at reducing ventilator-induced lung injury. PEEP is a mechanical maneuver that exerts a positive pressure in the lung and is used primarily to correct the hypoxemia caused by alveolar hypoventilation. The optimal level of PEEP in patients with ARDS is still controversial. The Cochrane review7 analyzed seven randomized controlled trials, and the authors found no difference in in-hospital mortality for those who received mechanical ventilation with high versus low PEEP, although there was a trend toward decreased mortality. There was no significant difference between the two groups for the number of ventilator-free days, with the latter referring to the number of days between successful weaning from mechanical ventilation and day 28 after study enrollment. Higher PEEP was associated with improved oxygenation on Days 1, 3, and 7, without an increase in barotrauma risk, defined as the presence of pneumothorax on chest radiograph or chest tube insertions for known or suspected spontaneous pneumothorax.
A multilevel mediation analysis that analyzed individual data from 3,562 patients with ARDS enrolled in nine previously reported randomized trials of nine randomized controlled trials suggested that it is the driving pressure (DP = VT/CRS) that is most strongly associated with survival.8 Driving pressure looks at the change in pressure across the alveoli, focusing on the ratio of the patient’s target tidal volume and the lung compliance, and targets functional lung rather than predicted lung size. Patient survival was linked to a lower driving pressure, with VT and PEEP being linked to survival only if they led to reductions in driving pressure.8
Caveats: Despite the fact that lung-protective strategy is widely accepted as the only intervention that improves mortality in ARDS, its use in the ED has been found to be uncommon, and hence prolonged ED length of stay can result in iatrogenic lung injury from excessively high tidal volumes.2 Evidence demonstrates that potentially injurious ventilator practices are common in the ED,9, 10, 11, 12, 13 especially because ventilator-associated lung injury can occur shortly after the initiation of mechanical ventilation.9, 14, 15 Early lung-protective ventilation during vulnerable periods results in subsequent benefit even when delivered for short periods of time.9, 16, 17 A before–after study of mechanically ventilated patients in the ED conducted by Fuller et al.17 in 2017 showed that 1) lung-protective strategies can be effectively implemented in the ED; 2) the implementation of an ED-based lung-protective ventilator protocol resulted in early utilization of lung-protective strategies in the intensive care unit, which increased subsequent adherence to lung-protective ventilation in ARDS patients; and 3) the intervention was associated with a significant reduction in pulmonary complications, hospital mortality, and health care resource use.17
The 2013 Cochrane review6 of lung-protective strategies with low tidal volumes was heavily influenced by two studies, the ARDS Network 200018 and the study by Villar et al.,19 which are the only trials that showed a mortality benefit.6 Additionally, different lengths of follow-up and higher plateau pressure in control arms in two of the trials makes the interpretation of the combined results and long-term mortality difficult. Except for the one trial that reached the target sample size, all other five trials were terminated early. None of the trials reported a long-term outcome follow-up.
Lowering the tidal volume might not be without harm. Low tidal volumes can result in severe hypercapnia and acidosis which can in turn lead to increased intracranial pressure, depressed myocardial contractility, pulmonary hypertension, and depressed renal blood flow.20 The issue of adverse effects of a lower tidal volume was not addressed in the trials included in the Cochrane review. Specifically, the impact of acidosis and hypercapnia on the development of organ failure was not clear.6
Although the test of heterogeneity in the Cochrane meta-analysis6 was not statistically significant, the authors of Cochrane report that certain “hidden” heterogeneity due to clinical differences between the trials should be factored in. They also warn the readers about the fact that most of the trials did not report protocols of concomitant treatments and associated diseases (that is ventilator-associated pneumonia).6
In conclusion, the existing evidence supports the use of lung-protective strategy with low tidal volumes (6 mL/kg) and low plateau pressure (<30 mm Hg) in patients with ARDS due to mortality benefits. Despite the possibility of underreported harms, the benefits are prominent enough to justify assigning a color recommendation of green (benefit > harm) to this strategy.
The original manuscript was published in Academic Emergency Medicine as part of the partnership between TheNNT.com and AEM.
See theNNT.com's previous reviews of this topic:
Lung protective Ventilation Strategy for Intubated Patients with ARDS (Acute Respiratory Distress Syndrome), November 7, 2010
Author: Maida Hafiz, MD; Jennifer Stahl, MDSupervising Editors: Shahriar Zahtabchi, MD; Jarone Lee, MD
Published/Updated: March 4, 2019
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