Acute respiratory distress syndrome: Implications of recent studies
ABSTRACTAcute respiratory distress syndrome (ARDS) remains challenging to diagnose and manage. This article reviews the new definition of ARDS and the key findings of landmark studies over the last 5 years of prone-position ventilation, high-frequency oscillatory ventilation (HFOV), extracorporeal membrane oxygenation (ECMO), and neuromuscular blockade in patients with ARDS.
KEY POINTS
- The new definition of ARDS categorizes it as mild, moderate, or severe on the basis of oxygenation, specifically, the PaO2/FiO2 ratio.
- Neuromuscular blockade and prone positioning, used early in moderate or severe cases of ARDS, have shown some promise in trials, but questions remain about their application in critically ill patients.
- Based on two large trials, HFOV is no longer recommended as a primary therapy for ARDS, but it may still be considered as a rescue therapy in patients with refractory hypoxemia.
- In light of observational studies and randomized trials, ECMO should be considered an option in cases of refractory hypoxemia.
PHARMACOTHERAPY IN ARDS
The pathogenesis of ARDS includes damage to the alveolar-capillary membrane, with leakage of protein-rich edema fluid into alveoli. This damage is propagated by a complex inflammatory response including but not limited to neutrophil activation, free-radical formation, dysregulation of the coagulation system, and extensive release of inflammatory mediators.32,33 As a consequence, there are multiple potential targets for pharmacologic therapy in ARDS.
A variety of drugs, including corticosteroids, anti-inflammatory agents, immune-modulating agents, pulmonary vasodilators, antioxidants, and surfactants, have been studied in patients with ARDS.34 But effective pharmacotherapy for ARDS remains extremely limited.
Neuromuscular blockade in early severe ARDS
Mechanical ventilation can result in injurious stretching of the lung parenchyma, either from alveolar overdistention (volutrauma) or from continual recruitment and derecruitment of unstable lung units during the ventilator cycle (atelectrauma).35 Ventilator-induced lung injury can be exacerbated by asynchronous breathing.
In theory, neuromuscular blockers could minimize patient-ventilator asynchrony and provide much better control of tidal volume and pressure in patients with ARDS. This may result in less volutrauma and atelectrauma associated with asynchronous breathing. Data also suggest that cisatracurium (Nimbex), a neuromuscular blocking agent, may have a direct effect on the amount of inflammation in lungs with ARDS.36
The ACURASYS study
The ARDS et Curarisation Systématique (ACURASYS) study37 was a randomized trial in 340 patients undergoing mechanical ventilation for severe ARDS to evaluate the impact of neuromuscular blockade within the first 48 hours in this population.
The primary outcome was the mortality rate before hospital discharge or within 90 days of study entry. Secondary outcomes included the 28-day mortality rate, the rate of intensive care unit-acquired paresis, and the number of ventilator-free days. To be included, patients had to have been mechanically ventilated for less than 48 hours and to meet the AECC criteria for severe ARDS, with a PaO2/FiO2 ratio less than 150 mm Hg.
The intervention group received a continuous infusion of cisatracurium for 48 hours, while the control patients received placebo. Muscle strength was evaluated by clinical scoring of strength in different muscle groups.
Findings. The study groups were similar at baseline.
The crude 90-day mortality rate was lower in the cisatracurium group (31.6% vs 40.7%, P = .08). Regression analysis showed an improved 90-day survival rate with the use of this neuromuscular blocker after adjustment for severity of illness and the severity of ARDS (based on degree of hypoxemia and plateau pressures) (hazard ratio for death at 90 days 0.68; 95% CI 0.48–0.98; P = .04). The rate of paresis acquired in the intensive care unit did not differ significantly between the two groups.
Conclusion. In patients with severe ARDS, giving a neuromuscular blocking agent early improved the survival rate and increased the time off the ventilator without increasing muscle weakness.
These data are in line with similar findings from two other studies published by the same group.38,39 A meta-analysis of 432 patients showed that the use of neuromuscular blockade in early severe ARDS is associated with a statistically significant effect on early mortality (relative risk 0.66, 95% CI 0.50–0.87).40 The pooled analysis of these trials did not show any statistically significant critical-illness polyneuropathy.
These results need to be interpreted carefully, as we have inadequate data to see if they generalize to different intensive care units, and the evaluation and categorization of critical-illness polyneuropathy remains to be defined.
Cisatracurium is a promising treatment for moderate to severe ARDS and merits investigation in a large confirmatory randomized controlled trial.
Other pharmacologic agents
A number of other drugs have been studied in ARDS patients, including both inhaled and intravenous beta agonists,41,42 statins,43 and nutritional supplements.44 But as with other drugs previously studied in ARDS such as corticosteroids, N-acetylcysteine, and surfactant,34 these agents showed no effect on outcomes. In fact, a recent trial of intravenous salbutamol in ARDS patients was stopped after an interim analysis because of a higher incidence of arrhythmias and lactic acidosis with this agent.42
These findings reaffirm that pharmacologic therapy needs to be carefully considered, and potential harms associated with these therapies need to be addressed before they are introduced in the care of critically ill patients.
