Benedict C. Creagh-Brown

The RAGE axis in systemic inflammation, acute lung injury and myocardial dysfunction: an important therapeutic target?

BackgroundThe sepsis syndromes, frequently complicated by pulmonary and cardiac dysfunction, remain a major cause of death amongst the critically ill. Targeted therapies aimed at ameliorating the systemic inflammation that characterises the sepsis syndromes have largely yielded disappointing results in clinical trials. Whilst there are many potential reasons for lack of success of clinical trials, one possibility is that the pathways targeted, to date, are only modifiable very early in the course of the illness. More recent approaches have therefore attempted to identify pathways that could offer a wider therapeutic window, such as the receptor for advanced glycation end-products (RAGE) and its ligands.PurposeThe objectives of this study were to review the evidence supporting the role of the RAGE axis in systemic inflammation and associated acute lung injury and myocardial dysfunction, to explore some of the problems and conflicts that these RAGE studies have raised and to consider strategies by which they might be resolved.MethodsMEDLINE was searched (1990–2010) and relevant literature collected and reviewed.Results and conclusionRAGE is an inflammation-perpetuating receptor with a diverse range of ligands. Evidence supporting a role of the RAGE axis in the pathogenesis of systemic inflammation, ALI and myocardial dysfunction is compelling with numerous animal experiments showing the beneficial effects of inhibiting the RAGE axis. Despite a number of unanswered questions that need to be further addressed, the potential for inhibiting RAGE-mediated inflammation in humans undoubtedly exists.

Association between Preoperative Plasma sRAGE Levels and Recovery from Cardiac Surgery

Background. The receptor for advanced glycation end products (RAGE) is an inflammation-perpetuating receptor, and soluble RAGE (sRAGE) is a marker of cellular RAGE expression. This study investigated whether raised plasma levels prior to surgery of sRAGE or S100A8/A9 (a RAGE ligand) were associated with longer duration of hospital care in patients undergoing cardiac surgery necessitating cardiopulmonary bypass. Methods. Patients (n = 130) undergoing elective cardiac surgery were enrolled prospectively. Plasma sRAGE and S100A8/A9 concentrations were measured before and 2 h after surgery. Results. Preoperative plasma sRAGE increased significantly (P < 0.0001) from 1.06 ng/mL (IQR, 0.72–1.76) to 1.93 ng/mL (IQR, 1.14–2.63) 2 h postoperatively. Plasma S100A8/9 was also significantly (P < 0.0001) higher 2 h postoperatively (2.37 μg/mL, IQR, 1.81–3.05) compared to pre-operative levels (0.41 μg/mL, IQR, 0.2–0.65). Preoperative sRAGE, but not S100A8/A9, was positively and significantly correlated with duration of critical illness (r = 0.3, P = 0.0007) and length of hospital stay (LOS; r = 0.31, P < 0.0005). Multivariate binary logistic regression showed preoperative sRAGE to be, statistically, an independent predictor of greater than median duration of critical illness (odds ratio 16.6, P = 0.014) and to be, statistically, the strongest independent predictor of hospital LOS. Conclusion. Higher preoperative plasma sRAGE levels were associated with prolonged duration of care in adults undergoing cardiac surgery requiring cardiopulmonary bypass.

Balancing professional tension and deciding upon the status of death: Making end-of-life decisions in intensive care units

This study investigated how intensivists make decisions regarding withholding and withdrawing treatment for patients at the end of their lives. This involved completing in-depth interviews from two sites of the South of England, United Kingdom by twelve intensivists. The data collected by these intensivists were analysed using thematic analysis. This resulted in the identification of three themes: intensivists’ role, treatment effectiveness, and patients’ best interest. Transcending these were two overarching themes relating to the balance between quantity and quality of life, and the intensivists’ sense of responsibility versus burden. The results are considered in terms of making sense of death and the role of beliefs in the decision-making process.

sRAGE: A useful biomarker in acute lung injury?

Numerous studies of putative biomarkers in patients with acute lung injury (ALI) have been conducted to date, but none has proved worthy of entering routine clinical practice, largely because they have shown no clear advantage over clinical predictors (1, 2). Furthermore, the exemplar biomarker for ALI would be biologically plausible, sensitive, and highly specific, adding prognostic information independent of existing systems. The marker should also vary in proportion to the severity of injury and reflect the effects of therapeutic intervention. Conceivably, it would identify subgroups of patients who would benefit from specific therapies targeted at relevant pathogenetic pathways. Ideally, it would be inexpensive and rapidly quantified in a highly reproducible fashion. In this context, a prospective study published in this issue of Critical Care Medicine by Jabaudon et al (3) investigates whether the soluble form of the receptor for advanced glycation end products (sRAGE), is a valuable biomarker in patients with ALI regardless of whether it was associated with severe sepsis or septic shock.

Clinical solutions: not always what they seem?

Brenner and colleagues [1], in their article published in Critical Care, showed elevated levels of the reactive carbonyl species (RCS) methylglyoxal (MG) in the circulation of patients with septic shock. We commend the authors’ bravery in launching this molecule into a field well-populated with biomarkers and where clinical diagnosis persists as the ‘gold standard’ [2]. The authors hypothesised that MG accumulation resulted from metabolic dysregulation and oxidative stress associated with septic shock. Impairment of MG detoxification was also proposed as a contributory factor. However, whether MG was, at least in part, inadvertently administered during routine clinical care appears not to have been considered. Some clinical solutions, such as peritoneal dialysis fluid, are known to contain MG and other RCS [3,4]. Bearing in mind that patients with septic shock, managed on intensive care units, typically receive large volumes of intravenous fluids and, in due course, enteral (and parenteral) nutrition, could these solutions not also be a source of MG and other RCS? Also, 25% of the septic shock patients in Benner and colleagues’ study [1] had acute liver failure, and such patients often require infusions of high concentration dextrose, a further potential source of RCS. Given the growing awareness that clinical solutions are not always what they seem, we would suggest that measurements of MG and other RCS levels in solutions administered to patients with sepsis could be a helpful and perhaps an illuminative and valuable addition not only to this study but to the sepsis shock/intensive care field in general.