Thomas Gaillard

Iron is essential for living

Iron as an element is a double-edged sword, essential for living but also potentially toxic through the generation of oxidative stress. The recent study by Chen and colleagues in Critical Care reminds us of this elegantly. In a mouse model of acute lung injury, they showed that silencing hepcidin (the master regulator of iron metabolism) locally in airway epithelial cells aggravates lung injury by increasing the release of iron from alveolar macrophages, which in turn enhances pulmonary bacterial growth and reduces the macrophages’ killing properties. This work underscores that hepcidin acts not only systematically (as a hormone) but also locally for iron metabolism regulation. This opens areas of research for sepsis treatment but also for iron deficiency or anaemia treatment, since the local and systemic iron regulation appear to be independent.

Transitioning from routine to on-demand test ordering in intensive care units: a prospective, multicentre, interventional study

interaction correlated with a positive change in their impact factor from their first adoption of Twitter to date. Recognizing that correlation does not imply causation, we examined this perceived relationship. Seven of 25 (28%) indexed anaesthesia journals have a Twitter account. We correlated Twitter presence, user/content interaction and validated metrics of social-media influence (Klout and BirdSong scores) with the journal’s current impact factor. We also looked at the change in impact factor since Twitter adoption by each journal and the number of article citations (Fig. 1). Comparison was made with the change in impact factor of anaesthesia journals without Twitter accounts over the same period. An active Twitter account with a high Klout score directlycorrelated with higher journal impact factor (P=0.034) and with a greater number of article citations (P=0.016) than journals not embracing social media. A highly-performing Twitter account was also associated with an increase in impact factor in the period after Twitter adoption (P=0.01), while journals without a social media presence, on average, saw a net stasis or decline in their impact factor. Twitter offers a unique platform for fast dissemination and discussion of the latest publications in anaesthesia. With smartphones and tablet devices allowing constant access to social media, anaesthetists communicate via social media to discuss journal publications and respond to journal editors. To encourage further adoption by our academic journals, we share our observations of a positive correlation between journal editorial interaction on Twitter and a subsequent increase in journal impact factor. Journals which did not actively embrace Twitter as a 21st-century Letter to (and from) the Editor saw a net stasis or even decline in impact factor.

Population pharmacokinetics of daptomycin in critically ill patients with various degrees of renal impairment

Objectives The objective of this study was to characterize the pharmacokinetics of unbound and total concentrations of daptomycin in infected ICU patients with various degrees of renal impairment. From these results, the probability of attaining antimicrobial efficacy and the risks of toxicity were assessed. Methods Twenty-four ICU patients with various renal functions and requiring treatment of complicated skin and soft-tissue infections, bacteraemia, or endocarditis with daptomycin were recruited. Daptomycin (Cubicin®) at 10 mg/kg was administered every 24 h for patients with creatinine clearance (CLCR) ≥30 mL/min and every 48 h for patients with CLCR <30 mL/min. Total and unbound plasma concentrations and urine concentrations of daptomycin were analysed simultaneously following a population pharmacokinetic approach. Simulations were conducted to estimate the probability of attaining efficacy (unbound AUCu/MIC >40 or >80) or toxicity (Cmin >24.3 mg/L) targets. Results Exposure to unbound daptomycin increased when the renal function decreased, thus increasing the probability of reaching the efficacy targets, but also the risk of toxicity. Modifications of the unbound fraction (fu) of daptomycin did not affect the pharmacokinetics of unbound daptomycin, but did affect the pharmacokinetics of total daptomycin. Conclusions Daptomycin at 10 mg/kg q24h allowed efficacy pharmacokinetic/pharmacodynamic targets for ICU patients with CLCR ≥30 mL/min to be reached. For patients with CLCR <30 mL/min, halving the rate of drug administration, i.e. 10 mg/kg q48h, was sufficient to reach these targets. No adverse events were observed, but the toxicity of the 10 mg/kg q24h dosing regimen should be further assessed, particularly for patients with altered renal function.

Iron deficiency without anemia is responsible for decreased left ventricular function and reduced mitochondrial complex I activity in a mouse model

BACKGROUND Iron deficiency (ID), with or without anemia, is frequent in heart failure patients, and iron supplementation improves patient condition. However, the link between ID (independently of anemia) and cardiac function is poorly understood, but could be explained by an impaired mitochondrial metabolism. Our aim was to explore this hypothesis in a mouse model. METHODS AND RESULTS We developed a mouse model of ID without anemia, using a blood withdrawal followed by 3-weeks low iron diet. ID was confirmed by low spleen, liver and heart iron contents and the repression of HAMP gene coding for hepcidin. ID was corrected by a single ferric carboxymaltose (FCM) injection (ID + FCM mice). Hemoglobin levels were similar in ID, ID + FCM and control mice. ID mice had impaired physical performances and left ventricular function (echocardiography). Mitochondrial complex I activity of cardiomyocytes was significantly decreased in ID mice, but not complexes II, III and IV activities. ID + FCM mice had improved physical performance, cardiac function and complex I activity compared to ID mice. Using BN-PAGE, we did not observe complex I disassembly, but a reduced quantity of the whole enzyme complex I in ID mice, that was restored in ID + FCM mice. CONCLUSIONS ID, independently of anemia, is responsible for a decreased left ventricular function, through a reduction in mitochondrial complex I activity, probably secondary to a decrease in complex I quantity. These abnormalities are reversed after iron treatment, and may explain, at least in part, the benefit of iron supplementation in heart failure patients with ID.

Anemia of the Critically Ill Patient: Pathophysiology, Lessons from Animal Models

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1789 Abstract Children with intestinal failure are often dependent on long-term central venous catheters for delivery of all or a portion of their fluid and caloric requirements. Unfortunately, they are at high risk for catheter-associated complications, most commonly infection. Catheterrelated bloodstream infections (CRBSI) can be difficult to treat and can lead to systemic sepsis and critical illness in this patient population. This chapter discusses the role for ethanol lock therapy (ELT) in both the prevention and treatment of CRBSI in children with intestinal failure. The safety and efficacy of this therapy is discussed and the details for use in the pediatric population are provided.