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The epidemiology of acute kidney injury (AKI) after cardiac surgery depends on the definition used. Our aims were to evaluate the Risk/Injury/Failure/Loss/End-stage (RIFLE) criteria, the AKI Network (AKIN) classification, and the Kidney Disease: Improving Global Outcomes (KDIGO) classification for AKI post–cardiac surgery and to compare the outcome of patients on renal replacement therapy (RRT) with historical data. Retrospective analysis of 1881 adults who had cardiac surgery between May 2006 and April 2008 and determination of the maximum AKI stage according to the AKIN, RIFLE, and KDIGO classifications. The incidence of AKI using the AKIN and RIFLE criteria was 25.9% and 24.9%, respectively, but individual patients were classified differently. The area under the receiver operating characteristic curve for hospital mortality was significantly higher using the AKIN compared with the RIFLE criteria (0.86 vs 0.78, P = .0009). Incidence and outcome of AKI according to the AKIN and KDIGO classification were identical. The percentage of patients who received RRT was 6.2% compared with 2.7% in 1989 to 1990. The associated hospital mortality fell from 82.9% in 1989 to 1990 to 15.6% in 2006 to 2008. The AKIN classification correlated better with mortality than did the RIFLE criteria. Mortality of patients needing RRT after cardiac surgery has improved significantly during the last 20 years.

Background The 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. Purpose The 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. Methods MEDLINE was searched (1990–2010) and relevant literature collected and reviewed. Results and conclusion RAGE 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.

Endothelial dysfunction associated with systemic inflammation can contribute to organ injury/failure following cardiac surgery requiring cardiopulmonary bypass (CPB). Roundabout protein 4 (Robo4), an endothelial-expressed transmembrane receptor and regulator of cell activation, is an important inhibitor of endothelial hyper-permeability. We investigated the hypothesis that plasma levels of Robo4 are indicative of organ injury, in particular acute kidney injury (AKI), after cardiac surgery. Patients (n = 32) undergoing elective cardiac surgery with CPB were enrolled, prospectively. Plasma Robo4 concentrations were measured pre-, 2 and 24 h post-operatively, using a commercially available ELISA. Plasma and endothelial markers of inflammation [interleukin (IL) -6, -8, -10: von Willibrand factor (vWF) and angiopoeitin-2 (Ang-2)] and the AKI marker, neutrophil gelatinase-associated lipocalin (NGAL), were also measured by ELISA. Plasma Robo4 increased significantly (p<0.001) from pre-operative levels of 2515 ± 904 pg/ml to 4473 ± 1915 pg/ml, 2 h after surgery; and returned to basal levels (2682 ± 979 pg/ml) by 24 h. Plasma cytokines, vWF and NGAL also increased 2 h post-operatively and remained elevated at 24 h. Ang-2 increased 24 h post-operatively, only. There was a positive, significant correlation (r = 0.385, p = 0.0298) between Robo-4 and IL-10, but not other cytokines, 2 h post-operatively. Whilst raised Robo4 did not correlate with indices of lung dysfunction or other biomarkers of endothelial activation; there was a positive, significant correlation between raised (2 h) plasma NGAL and Robo4 (r = 0.4322, p = 0.0135). When patients were classed as AKI or non-AKI either using NGAL cut-off of 150 ng/ml, or the AKI Network (AKIN) clinical classification; plasma Robo4 was significantly higher (p = 0.0073 and 0.003, respectively) in AKI vs. non-AKI patients (NGAL cut-off: 5350 ± 2191 ng/ml, n = 16 vs. 3595 ± 1068 pg/ml, n = 16; AKIN: 6546 pg/ml, IQR 5025-8079, n = 6; vs. 3727 pg/ml, IQR 1962-3727, n = 26) subjects. Plasma Robo4 levels are increased, transiently, following cardiac surgery requiring CPB; and higher levels in patients with AKI suggest a link between endothelial dysregulation and onset of AKI.

The therapeutic promise of nitric oxide (NO), a potent vasodilator, remains uncertain for adults, and licensed indications are restricted to pediatric practice. This review considers the biologic actions of inhaled nitric oxide, the clinical indications for its administration in adults, and an assessment of its potential therapeutic development. This review considers the biologic actions of inhaled nitric oxide, the clinical indications for its administration in adults, and an assessment of its potential therapeutic development. Background and Historical Perspective Nitric oxide was largely regarded as a toxic pollutant until 1987, when its biologic similarities to endothelium-derived relaxing factor were demonstrated. 1 Subsequently, nitric oxide and endothelium-derived relaxing factor were considered a single entity, modulating vascular tone through the stimulated formation of cyclic guanosine 3',5'-monophosphate (Figure 1). 2 Endogenous nitric oxide is formed from the semiessential amino acid L-arginine by one of three (neural, inducible, and endothelial) isoforms of nitric oxide synthase. The physiologic role of endogenous nitric oxide was first shown when an infusion of an inhibitor of all forms of nitric oxide synthase in healthy volunteers . . .

Improved patient survival and increasingly complex surgery have expanded the requirement for specialist care for patients with adult congenital heart disease (ACHD). Despite the recent publications of management guidelines for ACHD, data concerning optimal patterns of care in the peri-operative/critical care period of this challenging population are sparse. The aims of the current study were to therefore to determine the pattern of intensive care unit (ICU) management, resource utilisation and predictors of mortality in critically ill ACHD patients. Data were collected prospectively for patients with ACHD stratified for complexity of disease admitted to the ICU of a tertiary cardiothoracic centre (1997-2002). Multivariate analysis of pre-operative indices as predictors of mortality was performed. Of 342 ACHD admissions (total mortality 4.4%, simple 0%, moderate/complex 10.6%), the requirement for specialist investigations and interventions was high, reflected in ICU admission costs per patient (simple $5391+/-130, moderate $13218+/-261, complex $30074+/-689). Standard severity of illness scoring systems did not accurately predict mortality; however, abnormal pre-operative thyroid function (p=0.0048), creatinine (p=0.0032) and bilirubin (p=0.0021) were highly predictive of mortality. Peri-operative mortality in patients with ACHD is low overall but varies with disease complexity. Such patients have a high requirement for specialist ICU investigation/intervention. Although standard severity of illness scoring is unhelpful, simple pre-operative parameters may predict peri-operative mortality. These findings reflect the requirement for specialist care, and have implications for planning service provision, training and operative consent in ACHD patients.

Purpose To investigate differences in cytokine/chemokine release in response to lipoteichoic acid (LTA) or lipopolysaccharide (LPS) and contributing cellular mechanisms, in order to improve understanding of the pathogenesis of sepsis. Methods Levels of cytokines/chemokines were measured in plasma and peritoneal lavage fluid of 10-week-old male mice (C57/B16) following intraperitoneal injection of LTA or LPS (250 µg), and in supernatants of murine J774.2 cells, immortalised blood monocytes, or isolated human monocytes treated with LTA or LPS (0–10 µg/ml). The role of cytokine/chemokine messenger RNA (mRNA) stability versus nuclear factor-kappaB (NF-κB) and activator protein-1 (AP-1) in mediating cytokine/chemokine release in J774 cells was also assessed. Results In mice, plasma levels of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, interleukin (IL)-10, interferon (IFN)-γ and tumour necrosis factor-alpha (TNF-α) and peritoneal lavage fluid levels of KC, MIP-2 and TNF-α increased significantly 1 h after LPS. Only KC and MIP-2 levels increased 1 h after LTA. LPS-treated (10 μg/ml) J774 cells released MIP-2, IL-10, IFN-γ and TNF-α but not KC (24 h), whereas cells treated with 10 μg/ml LTA released only MIP-2. LPS-stimulated human monocytes released IL-10 and IL-8 (24 h); by contrast, LTA-treated cells released only IL-8. LPS and LTA activated NF-κB and AP-1 in J774 cells. The protein synthesis inhibitor cycloheximide abolished LPS-induced IL-10 mRNA expression and increased LTA- and LPS-induced mRNA for MIP-2 in J774 cells. Conclusion LTA and LPS, at clinically relevant concentrations, induced differential cytokine/chemokine release in vitro and in vivo, via effects distal to activation of NF-κB/AP-1 that might include chromatin remodelling or mRNA stability.

We investigated whether plasma levels of the inflammation marker S100A8/A9, could predict acute kidney injury (AKI) onset in patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB). Plasma levels of S100A8/A9 and other neutrophil cytosolic proteins were measured in 39 patients pre- and immediately post-CPB. All markers increased significantly post-CPB with S100A8/A9, S100A12 and myeloperoxidase levels significantly higher in patients who developed AKI within 7 days. S100A8/A9 had good prognostic utility for AKI, with an area under the receiver operating characteristic curve of 0.81 (95% CI: 0.676-0.949) and a cut-off value of 10.6 μg/ml (85.7% sensitivity and 75% specificity) irrespective of age. Plasma S100A8/A9 levels immediately after cardiac surgery, can predict onset of AKI, irrespective of age.

Purpose To establish the relationship between plasma levels of thioredoxin (Trx) and macrophage migration inhibitory factor (MIF) in systemic inflammatory stress syndrome (SIRS)/sepsis. Methods Enzyme-linked immunosorbent assay measurements of Trx, MIF, IL-6, -8, and -10 and enzyme-linked fluorescent assay determination of procalcitonin (PCT) in plasma from patients with SIRS/sepsis, neutropenic sepsis, healthy volunteers and pre-oesophagectomy patients. Results Thioredoxin was significantly higher in SIRS/sepsis patients [101.3 ng ml −1 , interquartile range (IQR) 68.7–155.6, n  = 32] compared with that in healthy controls (49.5 ng ml −1 , IQR 31.4–71.1, P  < 0.001, n  = 17) or pre-oesophagectomy patients (40.5 ng ml −1 , IQR 36.9–63.2, P  < 0.01, n  = 7), but was not raised in neutropenics ( n  = 5). MIF levels were also significantly higher in SIRS/sepsis patients (12.1 ng ml −1 , IQR 9.5–15.5, n  = 35), but not in the neutropenic group, when compared with healthy controls (9.3 ng ml −1 , IQR 7.3–10.7, P  < 0.01, n  = 20). Trx levels correlated, positively, with MIF levels and APACHE II scores. Plasma levels of IL-6, -8 and -10 and PCT increased significantly in patients with SIRS/sepsis ( P  < 0.001) and with neutropenic sepsis, but did not correlate with Trx or MIF levels. Conclusion Plasma levels of Trx, MIF, IL-6, -8, -10 and PCT were raised in patients with SIRS/sepsis. Comparisons between mediators suggest a unique correlation of Trx with MIF. Moreover, Trx and MIF differed from cytokines and PCT in that levels were significantly lower in patients with neutropenia compared with the main SIRS/sepsis group. By contrast, IL-8 and PCT levels were significantly greater in the neutropenic patient group. The link between MIF and Trx highlighted in this study has implications for future investigations into the pathogenesis of SIRS/sepsis.

Multiple organ dysfunction syndrome is the commonest reason for sepsis-associated mortality. In the 40 years since it was first described understanding of its pathophysiology has improved, and novel methodologies for monitoring and severity of illness scoring have emerged. These, together with the development of systematic strategies for managing organ dysfunction in sepsis, and potentially effective new therapeutic interventions, should assist in reducing sepsis-associated mortality. These historical developments are discussed, and the reader is directed to these references for further guidance.