Characterization of differences in immune responses during bolus and continuous infusion endotoxin challenges using mathematical modelling.

Endotoxin administration is commonly used to study the inflammatory response, and though traditionally given as a bolus injection, it can be administered as a continuous infusion over multiple hours. Several studies hypothesize that the latter better represents the prolonged and pronounced inflammation observed in conditions like sepsis. Yet very few experimental studies have administered endotoxin using both strategies, leaving significant gaps in determining the underlying mechanisms responsible for their differing immune responses. We used mathematical modelling to analyse cytokine data from two studies administering a 2 ng kg-1 dose of endotoxin, one as a bolus and the other as a continuous infusion over 4 h. Using our model, we simulated the dynamics of mean and subject-specific cytokine responses as well as the response to long-term endotoxin administration. Cytokine measurements revealed that the bolus injection led to significantly higher peaks for interleukin (IL)-8, while IL-10 reaches higher peaks during continuous administration. Moreover, the peak timing of all measured cytokines occurred later with continuous infusion. We identified three model parameters that significantly differed between the two administration methods. Monocyte activation of IL-10 was greater during the continuous infusion, while tumour necrosis factor α $ {\alpha} $ and IL-8 recovery rates were faster for the bolus injection. This suggests that a continuous infusion elicits a stronger, longer-lasting systemic reaction through increased stimulation of monocyte anti-inflammatory mediator production and decreased recovery of pro-inflammatory catalysts. Furthermore, the continuous infusion model exhibited prolonged inflammation with recurrent peaks resolving within 2 days during long-term (20-32 h) endotoxin administration.

Pain perception in healthy volunteers: effect of repeated exposure to experimental systemic inflammation.

We aimed to study the relationship between pain perception and cytokine release during systemic inflammation. We present a randomized crossover trial in healthy volunteers (n = 17) in 37 individual trials. Systemic inflammation was induced by an i.v. bolus of Escherichia coli LPS (2 ng/kg) on two separate trial days, with or without a nicotine patch applied 10 h previously. Pain perception at baseline, and 2 and 6 h after LPS was assessed by pressure algometry and tonic heat stimulation at an increasing temperature (45-48℃) during both trials. Compared with baseline, pain pressure threshold was reduced 2 and 6 h after LPS, while heat pain perception was accentuated at all testing temperatures after 2 but not 6 h. The magnitude of changes in pain perception did not correlate to cytokine release. No effect of transdermal nicotine or training status was observed. In conclusion, LPS administration in healthy human volunteers leads to reduction in pain pressure threshold and an increase in pain perception to heat stimuli, supporting a relationship between acute systemic inflammation and pain perception.

Central venous catheter (CVC) removal for patients of all ages with candidaemia.

BACKGROUND: Candida bloodstream infections most often affect those already suffering serious, potentially life-threatening conditions and often cause significant morbidity and mortality. Most affected persons have a central venous catheter (CVC) in place. The best CVC management in these cases has been widely debated in recent years, while the incidence of candidaemia has markedly increased. OBJECTIVES: The main purpose of this review is to examine the impact of removing versus retaining a CVC on mortality in adults and children with candidaemia who have a CVC in place. SEARCH METHODS: We searched the following databases from inception to 3 December 2015: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid SP), EMBASE (Ovid SP), the Commonwealth Agricultural Bureau (CAB), Web of Science and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We searched for missed, unreported and ongoing trials in trial registries and in reference lists of excluded articles. SELECTION CRITERIA: We searched for randomized controlled trials (RCTs) and quasi-RCTs involving adults and children with candidaemia and in which participants were randomized for removal of a CVC (the intervention under study), irrespective of publication status, date of publication, blinding status, outcomes published or language.However, two major factors make the conduct of RCTs in this population a difficult task: the large sample size required to document the impact of catheter removal in terms of overall mortality; and lack of economic interest from the industry in conducting such a trial. DATA COLLECTION AND ANALYSIS: Our primary outcome measure was mortality. Several secondary outcome measures such as required time for clearance of blood cultures for Candida species, frequency of persistent candidaemia, complications, duration of mechanical ventilation and length of stay in the intensive care unit (ICU) and in the hospital were planned, as were various subgroup and sensitivity analyses, according to our protocol. We assessed papers and abstracts for eligibility and resolved disagreements by discussion. However, we were not able to include any RCTs or quasi-RCTS in this review and, as a result, have carried out no meta-analyses. However, we have chosen to provide a brief overview of excluded observational studies. MAIN RESULTS: We found no RCT and thus no available data for evaluation of the primary outcome (mortality) nor secondary outcomes or adverse effects. Therefore, we conducted no statistical analysis.A total of 73 observational studies reported on various clinically relevant outcomes following catheter removal or catheter retention. Most of these excluded, observational studies reported a beneficial effect of catheter removal in patients with candidaemia. None of the observational studies reported results in favour of retaining a catheter. However, the observational studies were very heterogeneous with regards to population, pathogens and interventions. Furthermore, they suffered from confounding by indication and an overall high risk of bias. As a consequence, we are not able to provide recommendations or to draw firm conclusions because of the difficulties involved in interpreting the results of these observational studies (very low quality of evidence, GRADE - Grades of Recommendation, Assessment, Development and Evaluation Working Group). AUTHORS' CONCLUSIONS: Despite indications from observational studies in favour of early catheter removal, we found no eligible RCTs or quasi-RCTs to support these practices and therefore could draw no firm conclusions. At this stage, RCTs have provided no evidence to support the benefit of early or late catheter removal for survival or other important outcomes among patients with candidaemia; no evidence with regards to assessment of harm or benefit with prompt central venous catheter removal and subsequent re-insertion of new catheters to continue treatment; and no evidence on optimal timing of insertion of a new central venous catheter.

The incretin effect in critically ill patients: a case-control study.

INTRODUCTION: Patients admitted to the intensive care unit often develop hyperglycaemia, but the underlying mechanisms have not been fully described. The incretin effect is reduced in patients with type 2 diabetes. Type 2 diabetes and critical illness have phenotypical similarities, such as hyperglycaemia, insulin resistance and systemic inflammation. Previous studies have shown beneficial effects of exogenous glucagon-like peptide (GLP)-1 on glycaemia in critically ill patients, a phenomenon also seen in patients with type 2 diabetes. In this study, we hypothesised that the incretin effect, which is mediated by the incretin hormones GLP-1 and glucose-dependent insulinotropic peptide (GIP), is impaired in critically ill patients. METHODS: The incretin effect (i.e., the relative difference between the insulin response to oral and intravenous glucose administration) was investigated in a cross-sectional case-control study. Eight critically ill patients without diabetes admitted to a mixed intensive care unit and eight healthy control subjects without diabetes, matched at group level by age, sex and body mass index, were included in the study. All subjects underwent an oral glucose tolerance test (OGTT) followed by an intravenous glucose infusion (IVGI) on the next day to mimic the blood glucose profile from the OGTT. Blood glucose, serum insulin, serum C-peptide and plasma levels of GLP-1, GIP, glucagon and proinflammatory cytokines were measured intermittently. The incretin effect was calculated as the increase in insulin secretion during oral versus intravenous glucose administration in six patients. The groups were compared using either Student's t test or a mixed model of repeated measurements. RESULTS: Blood glucose levels were matched between the OGTT and the IVGI in both groups. Compared with control subjects, proinflammatory cytokines, tumour necrosis factor α and interleukin 6, were higher in patients than in control subjects. The endogenous response of GIP and glucagon, but not GLP-1, to the OGTT was greater in patients. The insulin response to the OGTT did not differ between groups, whereas the insulin response to the IVGI was higher in patients. Consequently, the calculated incretin effect was lower in patients (23 vs. 57%, p=0.003). CONCLUSIONS: In critically ill patients, the incretin effect was reduced. This resembles previous findings in patients with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01347801 . Registered on 2 May 2011.

Bench-to-bedside review: Challenges of diagnosis, care and prevention of central catheter-related bloodstream infections in children.

Central venous catheters (CVCs) are indispensable in modern pediatric medicine. CVCs provide secure vascular access, but are associated with a risk of severe complications, in particular bloodstream infection. We provide a review of the recent literature about the diagnostic and therapeutic challenges of catheter-related bloodstream infection (CRBSI) in children and its prevention. Variations in blood sampling and limitations in blood culturing interfere with accurate and timely diagnosis of CRBSI. Although novel molecular testing methods appear promising in overcoming some of the present diagnostic limitations of conventional blood sampling in children, they still need to solidly prove their accuracy and reliability in clinical practice. Standardized practices of catheter insertion and care remain the cornerstone of CRBSI prevention although their implementation in daily practice may be difficult. Technology such as CVC impregnation or catheter locking with antimicrobial substances has been shown less effective than anticipated. Despite encouraging results in CRBSI prevention among adults, the goal of zero infection in children is still not in range. More high-quality research is needed in the field of prevention, accurate and reliable diagnostic measures and effective treatment of CRBSI in children.

[No evidence of malicious effect of NSAID treatment on bone healing]. / Manglende evidens for skadelig effekt på knogleheling ved behandling med NSAID.

The use of NSAIDs for postoperative pain management following orthopaedic surgery or during conservative treatment of fractures is controversial. Experimental animal models suggest NSAIDs inhibit bone healing. In a review of the literature, there was no clinical evidence to support categorical discard of NSAID for postoperative pain relief in uncomplicated cases. However, NSAID should be considered a potentiel risk factor of impaired bone healing and avoided in patients with a high risk of pseudoarthrosis. Recommended daily doses should be respected and duration of treatment should be limited.