Host defense against infection is based on two crucial mechanisms: the inflammatory response and the activation of coagulation. Platelets are involved in both hemostasis and immune response. These mechanisms work together in a complex and synchronous manner making the contribution of platelets of major importance in sepsis. This is a summary of the pathophysiology of sepsis-induced thrombocytopenia, microvascular consequences, platelet-endothelial cells and platelet–pathogens interactions. The critical role of platelets during sepsis and the therapeutic implications are also reviewed.

In the context of worldwide increasing antimicrobial resistance, good antimicrobial prescribing in more needed than ever; unfortunately, information available to clinicians often are insufficient to rely on. Biomarkers might provide help for decision-making and improve antibiotic management. The purpose of this expert panel review was to examine currently available literature on the potential role of biomarkers to improve antimicrobial prescribing, by answering three questions: 1) Which are the biomarkers available for this purpose?; 2) What is their potential role in the initiation of antibiotic therapy?; and 3) What is their role in the decision to stop antibiotic therapy? To answer these questions, studies reviewed were limited to recent clinical studies (<15 years), involving a substantial number of patients (>50) and restricted to controlled trials and meta-analyses for answering questions 2 and 3. With regard to the first question concerning routinely available biomarkers, which might be useful for antibiotic management of acute infections, these are currently limited to C-reactive protein (CRP) and procalcitonin (PCT). Other promising biomarkers that may prove useful in the near future but need to undergo more extensive clinical testing include sTREM-1, suPAR, ProADM, and Presepsin. New approaches to biomarkers of infections include point-of-care testing and genomics.

BackgroundThe cecal ligation and puncture (CLP) model, a gold standard in sepsis research, is associated with an important variability in mortality. While the number of punctures and needle size is well described in CLP animal studies, the length of cecal ligation is often not. The relationship between cecal ligation and survival in mice is briefly reported in the literature; therefore, we devised an investigation in mice of the consequences of three standardized cecal ligation lengths on mortality and the severity of the ensued sepsis.MethodsMale C57BL/6J mice underwent standardized CLP. The cecum was ligated at 5, 20, or 100 % of its total length and further perforated by a single 20-G puncture. Mortality was analyzed. We assessed blood lactate, serum creatinine levels, and serum cytokines (TNF-α, IL-1β, IL-6, and IL-10) after procedure in a control group and in ligated mice.ResultsMortality was directly related to ligation length: median survival was 24 h for the “100 %” group and 44 h for the “20 %” group. Blood lactate increased proportionally with the ligation length. At 6 h post-procedure, pro-inflammatory cytokines significantly increased in the ligated group with significantly higher serum levels of IL-6 in the 100 % group compared to the other ligated groups. The 20 % group exhibited the characteristics of septic shock with hypotension below 65 mmHg, pro-inflammatory balance, organ dysfunction, and hyperlactatemia.ConclusionsCecal ligation length appears to be a major limiting factor in the mouse CLP model. Thus, this experimental model should be performed with high consistency in future protocol designs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT? • It is well known that tobramycin given as an once daily dose according to the usual recommendations needs therapeutic drug monitoring by measurement of peak and trough concentrations. In the literature, there are only few published studies on the population pharmacokinetics of once daily tobramycin in critically ill patients. Glomerular filtration rate and bodyweight were identified as covariates contributing to the inter‐individual variability in the disposition of aminoglycosides. The study, by Peris‐Marti et al. [24], only evaluated the pharmacodynamic effectiveness of a 4 mg kg−1 dose of tobramycin given once daily in critically ill patients. The authors concluded with a simulation showing that for a theoretical MIC of 1 or 2 mg l−1, a 7 mg kg−1 dose was required. WHAT THIS STUDY ADDS? • Our results confirm the high variability of tobramycin disposition in intensive care patients and consequently the possible lack of effectiveness. • By using a population pharmacokinetic approach, two explicative covariates (height and Cockcroft creatinine clearance) added to a two‐compartment model with proportional error, explained much of the inter‐individual variability of tobramycin disposition in the critically ill patient population. • In a median ICU patient, simulations were performed at various dosage regimens and peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Drug monitoring is required to manage efficacy and toxicity. AIM The aim of this study was to evaluate the disposition of tobramycin (TOB) in critically ill patients (ICU) by a population pharmacokinetic approach, to determine the covariates involved, and to simulate tobramycin dosage regimens. METHODS Forty‐nine adult ICU patients received TOB (5 mg kg−1) once daily. NonMem modelling was performed on 32 patients. The 17 other patients were used for the qualification process by normalized prediction distribution error. Then Monte Carlo simulations (MCS) were performed. RESULTS A two‐compartment model with a proportional error best fitted the data. TOB total clearance (CLTOB) was significantly correlated with Cockcroft creatinine clearance (COCK) and height. TOB clearance was 4.8 ± 1.9 l h−1 (range 1.22–8.95), the volume of distribution of the central compartment was 24.7 ± 3.7 l (range 17.34–32.83) and that of the peripheral compartment and the inter‐compartmental clearance were 30.6 l and 4.74 l h−1, respectively. Only 29% of the patients presented a target AUC between 80 and 125 mg l–1 h and 61% were lower than 80 mg l−1 h. After considering COCK and height, MCS showed that only 50% of the population could achieve the target AUC for the 375 and 400 mg dosages. CONCLUSION Even after taking into account COCK and height, for strains with an MIC ≤ 1 mg l−1, MCS doses evidenced that peak and AUC pharmacodynamic targets could not be reached simultaneously in more than 45% of the ICU patient population. Combination therapy in addition to drug mo...

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BackgroundIn ICU patients with normal serum creatinine (SCr), a state of increased renal drug excretion has been described (creatinine clearance ≥130 ml/min/1.73 m2), and named augmented renal clearance (ARC). In ICU patients, the accuracy of GFR estimates is insufficient. However, in clinical practice, the physician has not at one’s disposal patient measured creatinine clearance (CrCl) when prescribing. The primary objective of this study was to assess the accuracy of 4 formulas to estimate GFR (Cockcroft-Gault (CG), Robert, sMDRD, and CKD-EPI formulas) with other covariates to detect ARC in ICU patients.MethodsWe enroled 360 consecutive ICU patients with normal SCr in this prospective observational study conducted in a primary teaching hospital. Comparisons between CrCl values and 4 estimated GFR (eGFR) formulas were estimated.ResultsIn these 360 patients, ARC was observed in 33 % of patients most of them trauma. Individual predictive values of equations were poor and the phenomenon increased in ARC subgroup. CG and CKD-EPI were more accurate to detect an ARC. Multivariable analysis showed that the best-fitting model included 3 factors independently correlated to ARC: trauma patients, cut-off values of age ≤58 years, and CKD-EPI more than 108 ml/min/1.73 m2.ConclusionsIn ICU patients with normal SCr, eGFR formulas are imprecise in assessing CrCl. If measured CrCl must be ideally used to detect modifications of the renal function, in clinical practice, age, reason for admission, and CKD-EPI could be used as screening tool to identify ARC.

In critically ill patients, therapeutic monitoring must be part of the routine, and knowledge of Cl(CR) value may be useful for the choice of adequate initial piperacillin dosing.

IntroductionThe aim of this study, performed in an intensive care unit (ICU) population with a normal serum creatinine, was to estimate urinary creatinine clearance (CLCR) in a population of polytrauma patients (PT) through a comparison with a population of non trauma patients (NPT).MethodsThis was a retrospective, observational study in a medical and surgical ICU in a university hospital. A total of 284 patients were consecutively included. Two different groups were studied: PT (n = 144) and NPT (n = 140). Within the second week after admission to the ICU, renal function was assessed using serum creatinine, 24 h urinary CLCR .ResultsAmong the 106 patients with a CLCR above 120 mL minute-1 1.73 m-2, 79 were PT and 27 NPT (P < 0.0001). Only 63 patients had a CLCR below 60 mL minute-1 1.73 m-2 with 15 PT and 48 NPT (P < 0.0001). Patients with CLCR greater than 120 mL minute-1. 1.73 m -2 were younger, had a lower SAPS II score and a higher male ratio as compared to those having CLCR lower than 120 mL minute-1. 1.73 m -2. Through a logistic regression analysis, age and trauma were the only factors independently correlated to CLCR.ConclusionsIn ICU patients with normal serum creatinine, CLCR, is higher in PT than in NPT. The measure of CLCR should be proposed as routine for PT patients in order to adjust dose regimen, especially for drugs with renal elimination.