Objective 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. Methods 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. Results 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. Conclusion 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.

Acute severe clinical deterioration of patients with cystic fibrosis (CF) may mandate endotracheal intubation. The benefits of intubation were evaluated by examining which pre‐admission parameters were associated with intensive care unit (ICU) outcome and assessing the potential benefits of intubation for survivors in terms of time from ICU discharge to death.

Purpose: 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.Methods: 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.Results: 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.Conclusions: 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. (C) 2013 Elsevier Inc. All rights reserved.

Background and objective: ARDS is characterized by bilateral pulmonary infiltrates and refractory hypoxemia attributed to V/Q mismatch. We used dynamic CT to characterize changes in lung composition, regional perfusion and tissue distribution in patients with ARDS in comparison with healthy subjects.Methods: The Fick principle was applied to serial attenuation measurements constructed from sequential CT images acquired during the passage of a bolus of iodinated contrast medium in healthy subjects (n = 3) and patients with ARDS (n = 11). Perfusion was calculated by the Mullani-Gould method and mapped throughout both lungs. Gradients of perfusion and tissue density against vertical height were constructed.Results: In comparison with normal individuals, the tissue component of lungs from patients with ARDS was significantly increased (P < 0.05). Blood fraction was unchanged. There was a discernable gradient in tissue density from non dependent to dependent regions in the patients with ARDS that was significantly different from controls. The proportion of perfusion applied to consolidated areas (i.e. shunt) correlated significantly (P < 0.05) with the severity of hypoxaemia.Conclusions: In patients with ARDS there are changes in both lung composition and the distribution of tissue and perfusion that may account in part for the physiological changes that define the syndrome.

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.

Burke-Gaffney, Anne PhD; Evans, Timothy W. FRCP; Quinlan, Gregory J. PhD Author Information

Endothelin-1 (ET-1) is a potent vasoconstrictor and co-mitogen for vascular smooth muscle and is implicated in pulmonary vascular remodeling and the development of pulmonary arterial hypertension. Vascular smooth muscle is an important source of ET-1. Here we demonstrate synergistic induction of preproET-1 message RNA and release of mature peptide by a combination of tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) in primary human pulmonary artery smooth muscle cells. This induction was prevented by pretreatment with the histone acetyltransferase inhibitor anacardic acid. TNFalpha induced a rapid and prolonged pattern of nuclear factor (NF)-kappaB p65 subunit activation and binding to the native preproET-1 promoter. In contrast, IFNgamma induced a delayed activation of interferon regulatory factor-1 without any effect on NF-kappaB p65 nuclear localization or consensus DNA binding. However, we found cooperative p65 binding and histone H4 acetylation at distinct kappaB sites in the preproET-1 promoter after stimulation with both TNFalpha and IFNgamma. This was associated with enhanced recruitment of RNA polymerase II to the ATG start site and read-through of the ET-1 coding region. Understanding such mechanisms is crucial in determining the key control points in ET-1 release. This has particular relevance to developing novel treatments targeted at the inflammatory component of pulmonary vascular remodeling.

I n this issue of Critical Care Medicine, Kahn et al (1) share the results of a national survey of adult practitioners regarding the regionalization of critical care services. Regionalization is defined as “categorizing hospitals by the level of critical care they can provide and then routinely transferring critically ill patients to high-level referral hospitals.” The authors describe physician attitudes toward regionalization, and identify barriers and potential solutions. Overall opinion was nearly evenly divided on whether regionalization of adult critical care would improve patient survival, with 52% in agreement. Physicians specializing in anesthesia critical care or surgical critical care were more in favor of regionalization, as were those who would likely receive patients under a regionalized system of care. The lack of consensus on the impact of regionalization on outcome is noteworthy, given the success of organized systems of care in other fields, such as emergency cardiac care, trauma, and neonatology. Likewise, specific conditions within adult critical care have recently been the target of regionalization strategies to improve outcome, such as the development of stroke centers and networks to facilitate early percutaneous coronary intervention for S-T segment elevation myocardial infarction (2, 3). The attitudes reflected in this survey may be related to the wide scope and heterogeneity of adult critical care services, which encompass cardiac, surgical, medical, and neurologic intensive care, among others. Adults who require intensive care admission may be cared for by a pulmonologist, surgeon, anesthesiologist, internist, or emergency physician in place of an intensivist, especially in a community setting. It is estimated that 4.4 million adults are admitted to one of approximately 6000 intensive care units each year in the United States (4). In contrast, there were an estimated 349 pediatric intensive care units (PICUs) in the United States as of 2001 (5). With few exceptions, a pediatric intensivist is typically involved in the care of all children in a PICU, often in collaboration with other pediatric subspecialists. In a recent large survey of PICU directors, 94% of pediatric critical care units had a pediatric intensivist as a member of the healthcare team (6). Regionalization of pediatric critical care services has been endorsed in a joint statement by the American College of Critical Care Medicine, Society of Critical Care Medicine, and the American Academy of Pediatrics (7). Despite this, there are no formal guidelines or regulations for regionalization of pediatric critical care by governmental agencies or professional societies. Although states may determine the number of licensed PICU beds within a specific institution, the transfer of patients is typically determined by agreements between sending and receiving facilities. Most hospitals without a PICU have policies defining a lower age limit for admission of older children to an adult intensive care unit, and specifying when children must be transferred to a higher level of care. To a certain degree, regionalization occurs by economic and logistic necessity, because PICUs are concentrated in tertiary facilities and pediatric intensivists are commonly affiliated with academic medical centers. The evidence that regionalization of pediatric critical care services improves patient outcome is based on observational studies showing that mortality for children in tertiary PICUs is lower than that in smaller facilities, and that staffing by pediatric intensivists reduces severityadjusted mortality for critically ill and injured children (8, 9). Although the number of PICUs is small in comparison with adult intensive care units, proliferation of PICUs has led to the concern for diluting the volume–outcome relationship; a large review of 16 hospitals demonstrated an impact of patient volume on mortality with an adjusted odds ratio of 0.95 for each change of 100 patients admitted (10). Is there evidence that regionalization of adult critical care services could improve outcome? The literature is replete with studies demonstrating the importance of the volume–outcome relationship for specific conditions or procedures, such as cardiac catheterization, carotid endarterectomy, and coronary artery bypass, among others (11–13). Within the field of adult critical care, there are several large case series to support the existence of a volume– outcome relationship. Investigators in Taiwan reported that patients with pneumonia treated by physicians with a high volume of experience had approximately half the mortality rate compared with those treated by physicians who treated a lower number of patients (14). Kahn et al demonstrated that adults requiring mechanical ventilation for nonsurgical conditions had a 37% reduction in the odds of death, if they were treated in a facility that cared for 400 ventilated patients per year as compared with one that ventilated 150 patients per year (15). The conclusion from the survey results by Kahn et al is sobering—in light of the existing evidence, the greatest barrier to regionalization of adult critical care seems to be the lack of conviction by intensive care providers that restructuring their system could improve patient outcome. In an ideal world, a healthcare system for critically ill patients would be designed to provide safe, high-quality patient care with excellent outcomes while operating at a high level of efficiency. Resources would be allocated to ensure that all patients had access to basic critical care services, while strategically deploying more limited or specialized assets to take advantage of the volume–outcome relationship and to promote cost effectiveness. An objective, evidencebased method to triage patients to facilities with appropriate resources would be used, and patients could be transferred using an organized system of critical care transport. *See also p. 2149.

The aim of perioperative haemodilution is to reduce loss of red blood cells during elective surgery. The oncotic and molecular characteristics of the various plasma substitutes employed determine how effectively normovolaemia is maintained, and their non-oncotic effects include alterations in microvascular perfusion. In the previous issue of Critical Care, Martini and colleagues assessed the effects of haemodilution with either polyethylene glycol (PEG)ylated albumin or a commercially available hydroxyethyl starch-based colloid in a hamster haemorrhage model. PEGylated albumin was superior to hydroxyethyl starch, as reflected by survival, haemodynamic parameters and assessment of the microcirculation using intravital microscopy.

The aim of perioperative haemodilution is to reduce loss of red blood cells during elective surgery. The oncotic and molecular characteristics of the various plasma substitutes employed determine how effectively normovolaemia is maintained, and their non-oncotic effects include alterations in microvascular perfusion. In the previous issue of Critical Care , Martini and colleagues assessed the effects of haemodilution with either polyethylene glycol (PEG)ylated albumin or a commercially available hydroxyethyl starch-based colloid in a hamster haemorrhage model. PEGylated albumin was superior to hydroxyethyl starch, as reflected by survival, haemodynamic parameters and assessment of the microcirculation using intravital microscopy.

International guidelines concerning the management of patients with sepsis, septic shock and multiple organ failure make no reference to the nature of the infecting organism. Indeed, most clinical signs of sepsis are nonspecific. In contrast, in vitro data suggest that there are mechanistic differences between bacterial, viral and fungal sepsis, and imply that pathogenetic differences may exist between subclasses such as Gram-negative and Gram-positive bacteria. These differences are reflected in different cytokine profiles and mortality rates associated with Gram-positive and Gram-negative sepsis in humans. They also suggest that putative anti-mediator therapies may act differently according to the nature of an infecting organism. Data from some clinical trials conducted in severe sepsis support this hypothesis. It is likely that potential new therapies targeting, for example, Toll-like receptor pathways will require knowledge of the infecting organism. The advent of new technologies that accelerate the identification of infectious agents and their antimicrobial sensitivities may allow better tailored anti-mediator therapies and administration of antibiotics with narrow spectra and known efficacy.

On the basis of the evidence available, the authors would suggest a decision making algorithm to determine the need for ICU admission postoperatively similar to that shown in Fig. 1. First, patients should quit smoking at least 1 month and preferably 2 months before surgery. Those over the age of 70 years should receive elective ICU admission. Second, those at increased risk of general anesthesia, as judged by ASA and performance status scores and cardiovascular risk assessment, should be prebooked into the ICU in the postoperative period. A ppo FEV1 of less than 44% should warrant additional monitoring rather than mandate ICU admission. Pre-existing fibrotic lung disease mandates ICU admission. Third, perioperatively, protective (low tidal volume) ventilatory strategies should be applied during one lung ventilation. Patients undergoing one lung ventilation, and especially those undergoing extensive lymphatic dissection, should be monitored closely for signs of ALI in the first 5 days postoperatively. This, together with any indication of postoperative complications such as POP, BPF or empyema, should mandate immediate transfer to the ICU.

Lipoteichoic acid (LTA), an immunostimulatory component of the cell walls of Gram positive bacteria, has pro-inflammatory effects in vitro and in vivo. However, one in vivo study concluded that LTA had no noticeable effects on leukocyte recruitment. In this study we investigated the effects of highly purified LTA, prepared by butanol extraction (Bu-LTA) at room temperature, on in vivo leukocyte adhesion. Using intravital microscopy we measured adhesion of leukocytes in mesenteric post-capillary venules of rats and mice. Topical superfusion of Bu-LTA (1μg/ml) in rats significantly (p<0.05) increased adhesion within 30min. By contrast, hot phenol-extracted LTA did not increase adhesion. Alkaline hydrolysis of Bu-LTA removed alanine residues and prevented adhesion. Also, pre-administration of anti-rat β2-integrin antibody abolished Bu-LTA-induced adhesion. Finally, intraperitoneal injection of Bu-LTA (100μg/ml) into mice also significantly (p<0.01) increased leukocyte adhesion measured at 60min. In conclusion, Bu-LTA with intact alanine residues promotes β2-integrin-dependent leukocyte adhesion in vivo.