Rob Mac Sweeney

Pharmacological treatments in ARDS; a state-of-the-art update

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.

Acute Lung Failure

Lung failure is the most common organ failure seen in the intensive care unit. The pathogenesis of acute respiratory failure (ARF) can be classified as (1) neuromuscular in origin, (2) secondary to acute and chronic obstructive airway diseases, (3) alveolar processes such as cardiogenic and noncardiogenic pulmonary edema and pneumonia, and (4) vascular diseases such as acute or chronic pulmonary embolism. This article reviews the more common causes of ARF from each group, including the pathological mechanisms and the principles of critical care management, focusing on the supportive, specific, and adjunctive therapies for each condition.

Treatment of acute lung injury: current and emerging pharmacological therapies.

As a syndrome of injurious pulmonary inflammation resulting in deranged respiratory physiology, acute lung injury affords numerous potential therapeutic targets. Two main pharmacological treatment strategies have arisen-the attempted inhibition of excessive inflammation or the manipulation of the resulting physiological derangement causing respiratory failure. Additionally, such interventions may allow the delivery of less injurious mechanical ventilation. An emerging approach is the use of cell-based therapy, which, rather than inhibiting the inflammatory process, seeks to convert it from an injurious process to a reparative one. This review outlines previous, current, and emerging pharmacological therapies for acute lung injury.

Mesenchymal stem cell therapy in acute lung injury: is it time for a clinical trial?

Despite decades of research, no specific pharmacological therapy to treat acute lung injury (ALI) has been identified. At present, the only effective therapies act by limiting iatrogenic injury associated with positive fluid balance1 or mechanical ventilation.2 3 As efforts to pharmacologically modulate the complex inflammatory process which leads to alveolar injury have been unsuccessful,4 focus has changed to cell based therapy, aimed at utilising stems cells which have pleiotropic effects and which respond appropriately to local signalling molecules. Stem cells have the capacity for limitless self-renewal and differentiation. Mesenchymal stem cells (MSC) are multipotent adult stem cells with the capacity to differentiate into many different cell types, including alveolar cells. There are several mechanisms through which MSCs could potentially be used for attenuating lung injury and augmenting repair.5 On the basis of the currently available data, and supported by two papers,6 7 the most important therapeutic effect of exogenously administered MSCs is probably through the paracrine secretion of mediators such as growth factors and cytokines to modulate localised inflammation and tissue repair.8 Gupta et al found treatment with MSCs improved bacterial clearance in a mouse model of gram-negative pneumonia, which was due in part to lipocalin 2 production by MSCs,6 while Curley et al showed that MSC therapy improved lung repair via a paracrine mechanism that was keratinocyte growth factor (KGF)-dependent.7 However, cell contact-dependent mechanisms, via the gap junction channel protein connexin-43, have also been described.9 The other main effect of exogenously administered MSCs is their localisation to the site of …

Effect sizes in ongoing randomized controlled critical care trials

BackgroundAn important limitation of many critical care trial designs is that they hypothesize large, and potentially implausible, reductions in mortality. Interpretation of trial results could be improved by systematic assessment of the plausibility of trial hypotheses; however, such assessment has not been attempted in the field of critical care medicine. The purpose of this study was to determine clinicians’ views about prior probabilities and plausible effect sizes for ongoing critical care trials where the primary endpoint is landmark mortality.MethodsWe conducted a systematic review of clinical trial registries in September 2015 to identify ongoing critical care medicine trials where landmark mortality was the primary outcome, followed by a clinician survey to obtain opinions about ten large trials. Clinicians were asked to estimate the probability that each trial would demonstrate a mortality effect equal to or larger than that used in its sample size calculations.ResultsEstimates provided by individual clinicians varied from 0% to 100% for most trials, with a median estimate of 15% (IQR 10–20%). The median largest absolute mortality reduction considered plausible was 4.5% (IQR 3.5–5%), compared with a median absolute mortality reduction used in sample size calculations of 5% (IQR 3.6–10%) (P = 0.27).ConclusionsFor some of the largest ongoing critical care trials, many clinicians regard prior probabilities as low and consider that plausible effects on absolute mortality are less than 5%. Further work is needed to determine whether pooled estimates obtained by surveying clinicians are replicable and accurate or whether other methods of estimating prior probability are preferred.

Prolonged glucocorticoid treatment in acute respiratory distress syndrome – Authors' reply

We were disappointed that Rob Mac Sweeney and Daniel F McAuley’s Seminar (Nov 12, p 2416) on acute respiratory distress syndrome overlooked much of the evidence for prolonged glucocorticoid treatment. The authors reference two outdated meta-analyses that have contradictory results. The basis for the inconsistency between these two meta-analyses can be explained and current evidence suggests a net benefit for glucocorticoids in acute respiratory distress syndrome. In the 1980s, on the basis of a faulty laboratory model, clinical investigations focused on 1 day administration of massive doses of methylprednisolone (120 mg/kg per day) for prevention or treatment of acute respiratory distress syndrome. Unfortunately, these obsolete trials are often combined with contemporary trials in meta-analyses despite serious inconsistencies, producing misleading results. Over the past 20 years, randomised controlled trials have instead investigated low-to-moderate daily doses (methylprednisolone equivalent ≤1 mg/kg for early acute respiratory distress syndrome, or ≤2 mg/kg for late acute respiratory distress syndrome) for 1–4 weeks; meta-analyses should focus on these randomised trials, which are relevant today. Our systematic review included triallevel and patient-level meta-analyses of eight randomised trials (n=619) investigating prolonged glucocorticoid treatment in patients with acute respiratory distress syndrome. With high certainty, glucocorticoids improved time to extubation (10·1 fewer days, 95% CI −13·1 to −7·1) and mechanical ventilationfree days at day 28 (5·8 more days, 95% CI 3·8 to 11·5), and with moderate certainty reduced in-hospital mortality by 24% (95% CI 2 to 41) for patients randomised before day 14. Importantly, avoiding sudden discontinuation of glucocorticoids after extubation is essential to preserve improvement. These results are consistent with a meta-analysis of 13 randomised trials (n=2005) investigating glucocorticoid treatment in community-acquired pneumonia, which is the leading cause of acute respiratory distress syndrome.

Beta 2 antagonism in acute respiratory failure

Post hoc analyses from the B-type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL)-II-ICU study suggest an association between beta-blocker usage at admission and improved mortality in patients treated in the intensive care unit for acute respiratory failure. Although this evidence is encouraging, there is a need for a phase 2 proof-of-concept randomized controlled trial of beta-blocker therapy in patients admitted with acute respiratory failure.