There was a tendency for the ADRs to occur in overweight cisplatin synthesis patients (12/14), but this does not necessarily appear to be a result of higher doses used in this population. It could be explained by more overweight patients included in this evaluation. Several other factors, such as severity of illness and concomitant drug therapy, could have contributed in part to these ADRs [34]. The sparse availability of documented patient weights in previous, retrospective medical record review studies has precluded a thorough assessment of weight as a risk factor for ADRs [34]. This study does provide us with the inclination that the drugs we investigated in this study are high risk and susceptible to ADRs, irrespective of weight-based dosing selections.

Weight-based dosing strategies for vasoactive medications have been suggested based on the drugs’ pharmacokinetics. Since all inotropes and vasopressors, with the exception of milrinone, have short half-lives, fast onsets, and low volumes of distribution, the use of ideal body-weight (IBW) has been suggested for all weight-based vasoactive drugs [5]. Due to the frequent and rapid titration of these agents to a predetermined clinical effect, the lower starting dose provided by an ideal body weight-based dose seems to be a safer and reasonable strategy. While the package insert for vasoactive drugs has recommended weight-based dosing guidelines, these recommendations are not always abided by in real-world clinical practice and vary among institutions. The appropriate weight (actual, adjusted, or ideal) for the optimal dosing strategy in special populations (e.

g., obese patients) remains unknown. Of note, the vasoactive drugs were in the dosing ranges provided by the package inserts regardless of weight classification [11�C16]. The three ADRs seen in our study with the vasoactives (two with dobutamine, one with norepinephrine) occurred in a morbidly obese, an underweight, and an overweight individual. In each case, the doses identified were below the respective recommended maximum dose. Unfortunately, a recommendation for optimal weight-based vasoactive dosing strategies remains elusive in overweight populations.Heparin was another ��high-risk�� medication associated with variable and inappropriate dosing strategies. In our study, heparin was dosed outside the recommendations in the package insert for all weight categories except in ��underweight�� patients [17].

Heparin, an anticoagulant with a volume of distribution approximating blood volume (40�C70mL/kg), is not fully distributed into adipose tissue. Optimal dosing in obesity continues to challenge clinicians. Although these patients tend to have a greater Drug_discovery total body mass, this may not always translate into increased lean body mass compared to normal weight individuals. Dosing based on IBW risks subtherapeutic concentrations while using actual body weight (ABW) risks supratherapeutic concentrations [35, 36].

The relationship between the PCT kinetics and the appropriateness of the first-line antibiotic therapy was investigated through the comparison of the ��PCT values. A multivariate analysis was conducted besides following the same rules as described previously.The diagnosis accuracy of ��PCT and SOFA for the distinction between survivors and nonsurvivors was then expressed as the area under the corresponding receiver operating characteristic curve.P < 0.05 was considered statistically significant for all analyses. STATA software was used for all analyses (College Station, TX, USA).ResultsPatients' characteristicsBetween 1 May 2005 and 31 June 2007, 319 patients presented with sepsis on admission to the ICU or during their stay in our ICU.

Among these patients, 29 were excluded because the required PCT dosages were not available, 26 were excluded because fungi were isolated, 71 were excluded because bacterial cultures remained sterile and 13 were excluded because appropriate antibiotics had been given within the 48 hours preceding the onset of sepsis. The remaining 180 patients were considered eligible for further analysis.The main baseline characteristics of the included patients are presented in Table Table1.1. The main source of infection was found to be the lung (51.7%). In more than one-half of the cases of sepsis included, the diagnosis was bacteremia (56.1%). Gram-negative bacteria and Gram-positive bacteria were isolated in the same proportions (48.3% and 43.9% of all isolates, respectively). Gram-negative bacteria of the enterobacteriacae family were the most frequently isolated (32.

8% of all isolates). Gram-positive sepsis was mainly caused by Staphylococcus aureus and Streptococcus spp. (17.2% and 22.2%, respectively). The sepsis was polymicrobial in 7.8% of cases. Septic shock was present in 41.2% of the episodes.Table 1Baseline characteristics of patients with bacterial sepsis, appropriateness of first-line empirical antibiotic therapy, and outcomeAppropriateness of empirical first-line antibiotic therapyOne-quarter of the patients were given inappropriate antibiotics within the first 24 hours of sepsis management (Table (Table1).1). The proportion of Gram-negative bacteria isolated was significantly higher in patients who did not receive appropriate antibiotics than in those who did (60.0% vs. 44.5%, respectively; P = 0.

04), whereas no difference existed in terms of severity of the disease as assessed by the SAPS II on admission as well AV-951 as the D1 SOFA score.Even though the magnitude of the PCT elevation between D1 and D2 seemed larger in patients who were given inappropriate empirical antibiotic therapy than in those who received active molecules, we failed to demonstrate any statistically significant difference (Table (Table2).2). In contrast, the PCT variation was significantly different between D2 and D3 (that is, ��PCT D2�CD3) (P < 0.

Furthermore, selleck chemical the improvement of plasma L-arginine over the first 2 to 4 days was not significantly correlated with change in microvascular reactivity. These findings suggest that NO production and endothelial function in sepsis are influenced by other factors in addition to circulating L-arginine. Such factors may include an increase in competitive inhibitors of NOS, such as asymmetric dimethylarginine [44]; deficiency of NOS cofactors such as tetrahydrobiopterin; NO quenching by microvascular reactive oxygen intermediates [45]; and the enhanced local expression and activity of endothelial cell arginase [46]. The observation of higher microvascular reactivity in males compared with females is an unexpected finding; previous studies have found better microvascular function in females than males, both in non-inflammatory states [47] and in response to infusion of lipopolysaccharide [48].

However, gender-specific microvascular function has not previously been reported in sepsis.The marked hypoargininaemia, which we found in subjects with sepsis, supports the hypothesis that L-arginine is decreased in sepsis, independent of trauma [27]. This finding is strengthened by the fact that we only included subjects within 24 to 36 hours of admission, with standardised sepsis criteria and with more than 90% having community-acquired sepsis.Targeting tissue oxygen delivery [49] or the splanchnic microcirculation [50] as resuscitation goals in sepsis have not been shown to improve outcomes.

What, then, is the significance of monitoring the microvascular endothelium in sepsis? Endothelial cells have multiple roles in sepsis pathophysiology, including the regulation of microcirculatory vasomotor tone and the regulation of coagulation, immune and inflammatory responses and microvascular barrier function. Preliminary studies aimed at increasing endothelial NO bioavailability in sepsis have shown promising results [51] and the interventions which have been demonstrated to improve outcomes in sepsis (activated protein C [52], early goal directed therapy [53] and intensive insulin therapy [54]) could all potentially be mediated, at least in part, via attenuation of endothelial cell dysfunction [55]. Thus, monitoring of microvascular and endothelial function are likely to be important components of future trials of adjunctive treatments in sepsis.

Our study has several potential limitations. Baseline blood flow measurements were not available, and it is possible that the apparent decrease in reactive hyperaemia in sepsis is an artefact of marked baseline vasodilatation. This Entinostat could potentially limit the subjects’ ability to respond to ischaemia by increased blood flow, because they already have near-maximal vasodilatation. This is unlikely to be the case because baseline forearm blood flow in septic subjects has been found to be normal or decreased by multiple investigators [6,7,10,56].

Samples were …DiscussionPatients suffering from infections done seem to react individually to a similar insult. This capability to combat an infection is thought to be at least in part influenced by genetic factors [23]. Despite important advances in the understanding of the pathophysiological processes leading to sepsis and septic shock [4,24,25], knowledge on the role of genetic factors contributing to sepsis susceptibility has not yet translated into improved outcome [26,27].In the first part of this study we were able to show an association between the risk of severe infections and a combination of genetic variants in sequential molecules of the LPS-sensor consisting of TLR4 and its adaptor TIRAP/Mal.

The presence of TLR4 mutations in combination with TIRAP/Mal variants – either homozygous or heterozygous – resulted in a statistically significant increase in the risk of severe infections. Despite the fact that the number of patients carrying these mutations is low, we found intriguingly low serum levels of pro-inflammatory cytokines in double-mutant individuals in a second cohort (Group II). Additionally we found that monocytes of these patients show decreased cytokine production upon stimulation with LPS. One might speculate that moderate defects in TLR4 and TIRAP/Mal function may accumulate to induce significant alterations of TLR4 dependent signals. However, clinical outcome data in this cohort could not support the findings with regard to sepsis severity. One reason for this discrepancy could be that the second cohort consisted of more severely ill patients already suffering from infections caused by highly resistant Gram-negative pathogens.

Moreover, other confounding factors may influence those effects such as preexisting conditions, type of infection in surgical patients or causing microrganisms. As the innate immune response to bacterial infection has to be mounted early and effectively, genetic influence on cytokine response in infection may determine effectiveness of bacterial killing [28].Supporting our results, it has been recently found that severe sepsis and septic shock is associated with decreased expression of TLR4 on host immune cells [29]. Thus, a lack in TLR4 signaling may be associated with a worse outcome of disease, which also correlates Dacomitinib with the recent findings suggesting that immunosuppression caused by negative regulators of TLR signaling are associated with sepsis mortality [30].To further differentiate whether the observed lack in inducibility of cytokines depended on the type of inflammation, either bacterial infection or sterile inflammatory stimulus, we also assessed postoperative cytokine response following cardiac surgery (Group III).

Study monitors: Caroline Tournegros, Loic Ferrand, Nadira Kaddour, Boris Berthe, Samir Bekkhouche, Sylvain Anselme.
Pulmonary edema is characterized by the abnormal accumulation of fluid in the extravascular space of the lungs and is a common finding in critically ill patients [1]. This pathological condition may develop due to an increase in the pulmonary capillary permeability (acute lung injury (ALI), acute respiratory distress syndrome (ARDS)), an increase in the pulmonary capillary hydrostatic pressure (hydrostatic or cardiogenic pulmonary edema), or both [2]. Pulmonary edema can be detected by clinical evaluation of factors such as patients’ history, physical findings, and routine laboratory examinations, and is confirmed by the presence of bilateral pulmonary infiltration on chest radiography [2,3]. However, interpretation of these factors is often limited by a certain degree of subjectivity that might cause inter-observer variation even among experts, particularly in critically ill patients [4-6]. Moreover, intensive care physicians may find it difficult to determine the cause of the extravascular lung water (EVLW) increase [7].In 1994 the American Thoracic Society and the European Society of Intensive Care Medicine co-published the proceedings of a consensus conference on ARDS, and defined ALI and ARDS as an American-European Consensus Conference (AECC) definition [8,9].

73 m-2). Through a logistic regression analysis, only two factors (age and trauma patients) remained significantly correlated with a CLCR above normal and for a moderate renal impairment. In the current selleck inhibitor results, 12% of elderly patients (over 65 years) have a CLCR greater than 120 mL minute-1 1.73 m-2. The impact of age on CLCR is well known and this parameter was, therefore, introduced in the formulas estimating CLCR (Cockcroft-Gault, Robert and simplified MDRD) [13-15]. The decrease in glomerular filtration, the involution of nephronic units and the reduction of the renal blood flow explain the high frequency of renal impairement in elderly patients. However, it should be kept in mind that glomerular ageing is correlated to age in only two-thirds of the patients, and this phenomenon accounts for the inaccuracy of the CLCR estimated by calculated formulae [20].

Current evidence suggests that PT (mainly, young patients without significant comorbidities) present with a CLCR increase. However, this phenomenon as received little attention in the literature, and dose modification are therefore rarely considered. The present results clearly demonstrate for the first time that trauma is a major factor for CLCR increase. Several factors may explain this increase in CLCR in PT patients. First, urinary creatinine excretion may be involved in such a phenomenon. A higher creatinine urinary excretion was observed in PT compared with NPT patients whereas serum creatinine was similar in both groups. However, the higher creatinine urinary excretion observed in PT patients was within a normal range.

Serum protein variations may impact our results. However, all the patients had a serum protein value between 50 and 55 gL-1. It is, therefore, very unlikely that serum protein variations interfere with the present results. Also, regarding hemodynamics, CLCR were studied and measured at a steady state in both groups (that is, distant from the admittance). It should be noted that our patients were hemodynamically stable at the time of data collection with no sign of dehydration. Although interference due to some cephalosporin has been described when the creatininemia was measured by using the Jaffe method [21]; no changes in this parameter were observed during the overall period of the study. Sepsis can also reduce creatinine production as described in mice [22].

Moreover, in critically-ill patients, a positive fluid balance may lead to underestimation of the severity of AKI and delay the recognition of a 50% relative increase in sCr [23]. Finally, it should be hypothesized Dacomitinib that humoral and inflammatory mechanisms encountered after severe trauma [24] or burn [1] are involved in the observed CLCR increase.The present study encountered some limitations. Increased CLCR is related with enhanced renal elimination of circulating drugs.