SummaryThe acute respiratory distress syndrome presents as hypoxia, bilateral pulmonary infiltrates on chest imaging, and the absence of heart failure sufficient to account for this clinical state.Management is largely supportive, focusing on protective mechanical ventilation, and the avoidance of fluid overload. Patients with severe hypoxaemia can be managed with early short-term use of neuromuscular blockade, prone position ventilation or extra-corporeal membrane oxygenation. The use of inhaled nitric oxide is rarely indicated and both β2 agonists and late steroids should be avoided. Mortality currently remains at approximately 30%.

Despite its high incidence and devastating outcomes, acute respiratory distress syndrome (ARDS) has no specific treatment, with effective therapy currently limited to minimizing potentially harmful ventilation and avoiding a positive fluid balance. Many pharmacological therapies have been investigated with limited success to date. In this review article we provide a state-of-the-art update on recent and ongoing trials, as well as reviewing promising future pharmacological therapies in ARDS.

This UK survey demonstrates screening for delirium is sporadic. Pharmacological treatment is usually with haloperidol in spite of the limited evidence to support this practice. Hypoactive delirium is infrequently treated pharmacologically.

 Extracorporeal carbon dioxide removal is an emerging therapy for the treatment of acute respiratory failure.  There is limited evidence to support the routine use of ECCO 2 R, outside of clinical trials, in patients with acute respiratory failure.  Future research should focus on veno-venous ECCO 2 R.  Further research is required to optimise the technology and identify if modifications can be made, especially to permit the use of less anticoagulation than is currently needed.  ECCO 2 R may have a role in facilitating lower tidal volume ventilation than the current standard of care in patients with acute hypoxaemic respiratory failure, but further research is required to confirm this.  In patients with acute hypercapnic respiratory failure, ECCO 2 R may be used to prevent endotracheal intubation, facilitate extubation, and act as an adjunct or alternative to non-invasive ventilation.  Clinicians are encouraged to enroll patients into clinical trials investigating the use of ECCO 2 R in acute respiratory failure, and contribute to data registries.

Randomised clinical trials (RCTs) are the gold standard for providing unbiased evidence of intervention effects. Here, we provide an overview of the history of RCTs and discuss the major challenges and limitations of current critical care RCTs, including overly optimistic effect sizes; unnuanced conclusions based on dichotomization of results; limited focus on patient-centred outcomes other than mortality; lack of flexibility and ability to adapt, increasing the risk of inconclusive results and limiting knowledge gains before trial completion; and inefficiency due to lack of re-use of trial infrastructure. We discuss recent developments in critical care RCTs and novel methods that may provide solutions to some of these challenges, including a research programme approach (consecutive, complementary studies of multiple types rather than individual, independent studies), and novel design and analysis methods. These include standardization of trial protocols; alternative outcome choices and use of core outcome sets; increased acceptance of uncertainty, probabilistic interpretations and use of Bayesian statistics; novel approaches to assessing heterogeneity of treatment effects; adaptation and platform trials; and increased integration between clinical trials and clinical practice. We outline the advantages and discuss the potential methodological and practical disadvantages with these approaches. With this review, we aim to inform clinicians and researchers about conventional and novel RCTs, including the rationale for choosing one or the other methodological approach based on a thorough discussion of pros and cons. Importantly, the most central feature remains the randomisation, which provides unparalleled restriction of confounding compared to non-randomised designs by reducing confounding to chance.