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The management of ARDS: what is really evidence-based? 

Introduction

Acute respiratory distress syndrome (ARDS) is the result of a diffuse inflammatory lung injury, which leads to increased pulmonary vascular permeability, increased lung weight, and loss of aerated lung tissue. (1) The causes of ARDS are multiple and include sepsis –the most common–, pneumonia, aspiration, and severe trauma. The Berlin criteria (1) define ARDS according to four key features: timing (within 1 week of a known clinical insult or new or worsening respiratory symptoms); chest imaging (presence of bilateral opacities that cannot be fully explained by effusions, lobar/lung collapse, or nodules); edema due to primary respiratory failure and not cardiac failure or fluid overload; the PaO2/FIO2 ratio. This latter feature is used to define the severity of ARDS as mild, moderate or severe. In a large observational study of 29,144 patients admitted to 459 intensive care units (ICUs) in 50 countries, 10% had ARDS. The overall mortality rate was 40%, increasing from 35% in patients with mild ARDS, to 40% in moderate and 46% in severe ARDS. (2) Although several studies have suggested a trend towards lower mortality rates over time (3-7), hospital mortality rates remain high (1, 2) and long-term morbidity is considerable. (8-10)

Many potential pharmacological agents, both inhaled (11) and systemic, have been assessed for use in patients with ARDS (table 1), but none has consistently been shown to improve mortality. As such, management essentially relies on treatment of the underlying cause, especially sepsis and limiting further lung injury by providing appropriate protective lung ventilation and avoiding highly positive fluid balances. (12) Here we will briefly consider the evidence base (or lack of) for these approaches and for some of the other therapeutic approaches that have been proposed.

Dr Vincent has no conflicts of interest to declare regarding this manuscript

Key words: acute respiratory distress syndrome

Interventions supported by evidence

Low tidal volume mechanical ventilation

The overwhelming majority of patients with ARDS require mechanical ventilation, yet mechanical ventilation can itself cause lung injury if administered incorrectly. The aim therefore, in addition to providing adequate oxygenation, is to avoid iatrogenic ventilator-induced lung injury (VILI), which further worsens prognosis. In the seminal study by the ARDS Network conducted some 20 years ago (13), mechanical ventilation with a lower tidal volume (6 ml/kg) than was traditionally used (12 ml/kg) was associated with decreased mortality and increased ventilator-free days. Other studies (14, 15), but not all (16, 17), have reported similar findings with patients managed with lower tidal volumes (4–8 ml/kg predicted body weight (PBW)) having better outcomes than patients managed with higher volumes (10-15 ml/kg PBW), especially when combined with a high positive end-expiratory pressure (PEEP). Meta-analyses widely support the beneficial effects of lower tidal volume ventilation on outcomes. (18-20) Recent guidelines from the American Thoracic Society, European Society of Intensive Care Medicine and Society of Critical Care Medicine give a strong recommendation for the use of low tidal volumes (4–8 ml/kg PBW) for all adult patients with ARDS requiring mechanical ventilation. (20) These recommendations are not specific for ARDS, and it is established that mechanical ventilation should always include small tidal volumes.

The role of PEEP is less clearcut. Higher PEEP may improve alveolar recruitment and prevent atelectrauma (21), but can also cause alveolar overdistention, reduce CO2 elimination and increase pulmonary vascular resistance. Although an individual patient data meta-analysis suggested that higher levels of PEEP may be associated with lower hospital mortality in patients with ARDS (22), a recent multicenter, randomized trial in 1010 patients reported that a strategy of lung recruitment maneuver with PEEP titration according to the best respiratory-system compliance (so-called ‘open lung approach’) was associated with increased 28-day mortality compared to a low PEEP strategy. (23) These conflicting results highlight the challenge of how best to determine optimal PEEP levels for individual patients. (24)

Prone positioning

Prone positioning has been suggested in patients with ARDS because of potentially beneficial effects on outcomes with improved ventilation–perfusion matching and more uniform lung recruitment resulting in improved oxygenation and CO2 clearance. (25) Meta-analyses reported that prone positioning was associated with reduced mortality in patients with moderate to severe ARDS and in those who were prone for more than 12 hours/day. (20, 26) In a randomized controlled study in centers experienced in using prone positioning, Guerin et al. reported that prone positioning applied for at least 16 hours/day in patients with severe ARDS (PaO2/FiO2 < 150 mmHg) was associated with significantly reduced 28-day mortality (16% vs 33%, p<0.001; hazard ratio for death 0.39 (95% confidence interval (CI), 0.25 to 0.63), with no associated complications. (27) Current guidelines thus recommend that prone positioning should be used if possible and continued for at least 12 hours/day. (20) Importantly, prone positioning can be associated with increased risks of endotracheal tube displacement and obstruction and may require higher levels of sedation. Moreover, when used for the recommended prolonged periods, it reduces the possibility of early mobilization and may increase the risk of pressure ulcers. Clearly too, it is not possible to place all patients receiving mechanical ventilation prone. Open abdominal wounds, unstable pelvic fractures, and spinal lesions render this technique impractical and, even when there are no contraindications, well-trained staff are required to implement it correctly and safely. Thus, although there is clear evidence to support prone positioning in severe ARDS, only 33% of patients with severe ARDS were reported to receive it in a recent international prevalence study. (28)

Restricted fluid administration?

A positive fluid balance in patients with ARDS has been associated with worse outcomes (29) and fluid therapy should therefore aim to avoid giving fluid excess to requirements. However, insufficient fluid administration is also associated with worse outcomes. In the Fluids and Catheters Treatment Trial (FACCT) in which a fluid-conservative strategy and a fluid-liberal strategy were compared, there was no statistically significant difference in 60-day mortality between the groups, but patients in the conservative fluid group had improved oxygenation, lower lung injury score and more ventilator-free days. (30) Importantly, however, in a long-term follow-up of a subgroup of the patients, those in the conservative management group had more severe neurological impairment (31), suggesting that although lung function may have been improved by restricting fluids, cerebral blood flow may have been impaired. As fluid requirements will vary among individuals and over time in any one patient, fluid therapy must be individualized and ongoing fluid requirements assessed repeatedly. Interestingly, a recent latent class analysis of the FACCT patients identified two phenotypes of patients with ARDS that responded differently to the randomly assigned fluid management strategies (32), supporting the need for personalized fluid strategies.

Table 1. Some of the many pharmacological interventions that have been tested in preclinical or clinical studies of acute respiratory distress syndrome (ARDS)

Systemic Inhaled
Beta-2 adrenergic agents Beta-2 adrenergic agents
Corticosteroids Corticosteroids
Statins Nitric oxide
Prostacyclin PGI2
Ketoconazole Surfactant
Pentoxifylline Heparin
N-acetylcysteine Activated protein C
Keratinocyte growth factor Hypertonic saline
Neutrophil elastase inhibitor Carbon monoxide
Cyclooxygenase inhibitors Epithelial sodium channel activators
Interferon beta-1a
Pharmaconutrition
Mesenchymal stem cells

Conclusion: limiting iatrogenicity

ARDS is not a single disease but rather a syndrome that can occur as the result of various conditions. Currently, no specific pharmacological anti-ARDS intervention has been demonstrated to improve outcomes. ARDS must therefore be managed using a combination of “gentle” ventilation, supportive care, and effective treatment of the underlying cause. Perhaps the most important aspect of current patient care is to avoid interventions that may further worsen the lung injury already present. As such, limiting tidal volumes and avoiding fluid overload are key damage limitation actions. Choice of ventilator mode does not seem to influence outcomes, but oscillatory ventilation should be avoided. (33) Administration of sedative agents and neuromuscular blocking agents appears to have beneficial effects (34), likely because this strategy limits patient/ventilator dyscoordination and thus prevents VILI. And the benefits of prone positioning are also likely related to reduced VILI as a result of the effects on lung stress and strain.

Importantly too, there can be no general algorithm for patient care – ventilator settings must be titrated for each patient’s needs to optimize oxygenation while limiting lung injury; similarly fluid administration must be adjusted according to ongoing fluid requirements to optimize tissue perfusion and limit the harmful effects of hypervolemia. ARDS is a heterogeneous disease process affecting patients of all ages and with various etiologies. As such, it is likely that some pharmacotherapeutic approaches may be effective in certain patient subgroups and not in others and the challenge for future studies will be to select more homogeneous patient groups to better target suggested therapies. Moreover, mortality should not be the only outcome assessment of such studies: morbidity outcomes, such as ventilator-free days, organ dysfunction, lengths of stay, should also be taken into consideration.

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Corresponding author:
Jean-Louis Vincent
Department of Intensive Care, Erasme Hospital
Université Libre de Bruxelles
Route de Lennik 808, 1070 Brussels, Belgium.
E-mail: jlvincent@intensive.org

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