High unbound flucloxacillin fraction in critically ill patients.

OBJECTIVES: To describe the unbound and total flucloxacillin pharmacokinetics in critically ill patients and to define optimal dosing strategies. PATIENTS AND METHODS: Observational multicentre study including a total of 33 adult ICU patients receiving flucloxacillin, given as intermittent or continuous infusion. Pharmacokinetic sampling was performed on two occasions on two different days. Total and unbound flucloxacillin concentrations were measured and analysed using non-linear mixed-effects modelling. Serum albumin was added as covariate on the maximum binding capacity and endogenous creatinine clearance (CLCR) as covariate for renal function. Monte Carlo simulations were performed to predict the unbound flucloxacillin concentrations for different dosing strategies and different categories of endogenous CLCR. RESULTS: The measured unbound concentrations ranged from 0.2 to 110 mg/L and the observed unbound fraction varied between 7.0% and 71.7%. An integral two-compartmental linear pharmacokinetic model based on total and unbound concentrations was developed. A dose of 12 g/24 h was sufficient for 99.9% of the population to achieve a concentration of >2.5 mg/L (100% fT>5×MIC, MIC = 0.5 mg/L). CONCLUSIONS: Critically ill patients show higher unbound flucloxacillin fractions and concentrations than previously thought. Consequently, the risk of subtherapeutic exposure is low.

Phenylephrine impairs host defence mechanisms to infection: a combined laboratory study in mice and translational human study.

BACKGROUND: Immunosuppression after surgery is associated with postoperative complications, mediated in part by catecholamines that exert anti-inflammatory effects via the ß-adrenergic receptor. Phenylephrine, generally regarded as a selective α-adrenergic agonist, is frequently used to treat perioperative hypotension. However, phenylephrine may impair host defence through ß-adrenergic affinity. METHODS: Human leukocytes were stimulated with lipopolysaccharide (LPS) in the presence or absence of phenylephrine and α- and ß-adrenergic antagonists. C57BL/6J male mice received continuous infusion of phenylephrine (30-50 µg kg-1 min-1 i.v.) or saline via micro-osmotic pumps, before LPS administration (5 mg kg-1 i.v.) or caecal ligation and puncture (CLP). Twenty healthy males were randomised to a 5 h infusion of phenylephrine (0.5 µg kg-1 min-1) or saline before receiving LPS (2 ng kg-1 i.v.). RESULTS: In vitro, phenylephrine enhanced LPS-induced production of the anti-inflammatory cytokine interleukin (IL)-10 (maximum augmentation of 93%) while attenuating the release of pro-inflammatory mediators. These effects were reversed by pre-incubation with ß-antagonists, but not α-antagonists. Plasma IL-10 levels were higher in LPS-challenged mice infused with phenylephrine, whereas pro-inflammatory mediators were reduced. Phenylephrine infusion increased bacterial counts after CLP in peritoneal fluid (+42%, P=0.0069), spleen (+59%, P=0.04), and liver (+35%, P=0.09). In healthy volunteers, phenylephrine enhanced the LPS-induced IL-10 response (+76%, P=0.0008) while attenuating plasma concentrations of pro-inflammatory mediators including IL-8 (-15%, P=0.03). CONCLUSIONS: Phenylephrine exerts potent anti-inflammatory effects, possibly involving the ß-adrenoreceptor. Phenylephrine promotes bacterial outgrowth after surgical peritonitis. Phenylephrine may therefore compromise host defence in surgical patients and increase susceptibility towards infection. CLINICAL TRIAL REGISTRATION: NCT02675868 (Clinicaltrials.gov).

Norepinephrine Dysregulates the Immune Response and Compromises Host Defense during Sepsis.

Rationale: Sepsis is characterized by a dysregulated immune response to infection. Norepinephrine, the cornerstone vasopressor used in septic shock, may contribute to immune dysregulation and impact host defense.Objectives: To investigate effects of norepinephrine and the alternative vasopressor vasopressin on the immune response and host defense.Methods: Leukocytes from six to nine donors were stimulated in the presence or absence of norepinephrine and vasopressin. A total of 190 C57BL/6J mice received a continuous infusion of norepinephrine or vasopressin via microosmotic pumps and were challenged with LPS or underwent cecal ligation and puncture. Thirty healthy volunteers were randomized to a 5-hour infusion of norepinephrine, vasopressin, or saline and intravenously challenged with LPS. The relationship between the norepinephrine infusion rate and the use of ß-blockers and plasma cytokines was assessed in 195 patients with septic shock.Measurements and Main Results: Norepinephrine attenuated the production of proinflammatory mediators and reactive oxygen species and augmented antiinflammatory IL-10 production both in vitro and in LPS-challenged mice. Norepinephrine infusion during cecal ligation and puncture resulted in increased bacterial dissemination to the spleen, liver, and blood. In LPS-challenged volunteers, norepinephrine enhanced plasma IL-10 concentrations and attenuated the release of the proinflammatory cytokine IFN-γ-induced protein 10. Vasopressin exerted no immunomodulatory effects across these experimental setups. In patients, higher norepinephrine infusion rates were correlated with a more antiinflammatory cytokine balance, whereas ß-blocker use was associated with a more proinflammatory cytokine balance.Conclusions: Norepinephrine dysregulates the immune response in mice and humans and compromises host defense. Therefore, it may significantly contribute to sepsis-induced immunoparalysis, whereas vasopressin does not have untoward immunologic effects.

Development and validation of an admission prediction tool for emergency departments in the Netherlands.

OBJECTIVE: Early prediction of admission has the potential to reduce length of stay in the ED. The aim of this study is to create a computerised tool to predict admission probability. METHODS: The prediction rule was derived from data on all patients who visited the ED of the Rijnstate Hospital over two random weeks. Performing a multivariate logistic regression analysis factors associated with hospitalisation were explored. Using these data, a model was developed to predict admission probability. Prospective validation was performed at Rijnstate Hospital and in two regional hospitals with different baseline admission rates. The model was converted into a computerised tool that reported the admission probability for any patient at the time of triage. RESULTS: Data from 1261 visits were included in the derivation of the rule. Four contributing factors for admission that could be determined at triage were identified: age, triage category, arrival mode and main symptom. Prospective validation showed that this model reliably predicts hospital admission in two community hospitals (area under the curve (AUC) 0.87, 95% CI 0.85 to 0.89) and in an academic hospital (AUC 0.76, 95% CI 0.72 to 0.80). In the community hospitals, using a cut-off of 80% for admission probability resulted in the highest number of true positives (actual admissions) with the greatest specificity (positive predictive value (PPV): 89.6, 95% CI 84.5 to 93.6; negative predictive value (NPV): 70.3, 95% CI 67.6 to 72.9). For the academic hospital, with a higher admission rate, a 90% probability was a better cut-off (PPV: 83.0, 95% CI 73.8 to 90.0; NPV: 59.3, 95% CI 54.2 to 64.2). CONCLUSION: Admission probability for ED patients can be calculated using a prediction tool. Further research must show whether using this tool can improve patient flow in the ED.

Motives for self-referral to the emergency department: a systematic review of the literature.

BACKGROUND: In several western countries patients' use of Emergency Departments (EDs) is increasing. A substantial number of patients is self-referred, but does not need emergency care. In order to have more influence on unnecessary self-referral, it is essential to know why patients visit the ED without referral. The goal of this systematic review therefore is to explore what motivates self-referred patients in those countries to visit the ED. METHODS: Recommendations from the PRISMA were used to search and analyze the literature. The following databases; PUBMED, MEDLINE, EMBASE, CINAHL and Cochrane Library, were systematically searched from inception up to the first of February 2015. The reference lists of the included articles were screened for additional relevant articles. All studies that reported on the motives of self-referred patients to visit an ED were selected. The reasons for self-referral were categorized into seven main themes: health concerns, expected investigations; convenience of the ED; lesser accessibility of primary care; no confidence in general practitioner/primary care; advice from others and financial considerations. A random-effects meta-analysis was performed. RESULTS: Thirty publications were identified from the literature studied. The most reported themes for self-referral were 'health concerns' and 'expected investigations': 36% (95% Confidence Interval 23-50%) and 35% (95% CI 20-51%) respectively. Financial considerations most often played a role in the United States with a reported percentage of 33% versus 4% in other countries (p < 0.001). CONCLUSIONS: Worldwide, the most important reasons to self-refer to an ED are health concerns and expected investigations. Financial considerations mainly play a role in the United States.

Inferring Human Activity Recognition with Ambient Sound on Wireless Sensor Nodes.

A wireless sensor network that consists of nodes with a sound sensor can be used to obtain context awareness in home environments. However, the limited processing power of wireless nodes offers a challenge when extracting features from the signal, and subsequently, classifying the source. Although multiple papers can be found on different methods of sound classification, none of these are aimed at limited hardware or take the efficiency of the algorithms into account. In this paper, we compare and evaluate several classification methods on a real sensor platform using different feature types and classifiers, in order to find an approach that results in a good classifier that can run on limited hardware. To be as realistic as possible, we trained our classifiers using sound waves from many different sources. We conclude that despite the fact that the classifiers are often of low quality due to the highly restricted hardware resources, sufficient performance can be achieved when (1) the window length for our classifiers is increased, and (2) if we apply a two-step approach that uses a refined classification after a global classification has been performed.

Altered Micafungin Pharmacokinetics in Intensive Care Unit Patients.

Micafungin is considered an important agent for the treatment of invasive fungal infections in the intensive care unit (ICU). Little is known on the pharmacokinetics of micafungin. We investigated micafungin pharmacokinetics (PK) in ICU patients and set out to explore the parameters that influence micafungin plasma concentrations. ICU patients receiving 100 mg of intravenous micafungin once daily for suspected or proven fungal infection or as prophylaxis were eligible. Daily trough concentrations and PK curves (days 3 and 7) were collected. Pharmacokinetic analysis was performed using a standard two-stage approach. Twenty patients from the ICUs of four hospitals were evaluated. On day 3 (n = 20), the median (interquartile range [IQR]) area under the concentration-time curve from 0 to 24 h (AUC0-24) was 78.6 (65.3 to 94.1) mg · h/liter, the maximum concentration of drug in serum (Cmax) was 7.2 (5.4 to 9.2) mg/liter, the concentration 24 h after dosing (C24) was 1.55 (1.4 to 3.1) mg/liter, the volume of distribution (V) was 25.6 (21.3 to 29.1) liters, the clearance (CL) was 1.3 (1.1 to 1.5) liters/h, and the elimination half-life (t1/2) was 13.7 (12.2 to 15.5) h. The pharmacokinetic parameters on day 7 (n = 12) were not significantly different from those on day 3. Daily trough concentrations (day 3 to the end of therapy) showed moderate interindividual (57.9%) and limited intraindividual variability (12.9%). No covariates of the influence on micafungin exposure were identified. Micafungin was considered safe and well tolerated. We performed the first PK study with very intensive sampling on multiple occasions in ICU patients, which aided in resolving micafungin PK. Strikingly, micafungin exposure in our cohort of ICU patients was lower than that in healthy volunteers but not significantly different from that of other reference populations. The clinical consequence of these findings must be investigated in a pharmacokinetic-pharmacodynamic (PK-PD) study incorporating outcome in a larger cohort. (This study is registered at ClinicalTrials.gov under registration no. NCT01783379.).

Large variation in anti-factor Xa levels with nadroparin as thromboprophylaxis in COVID-19 and non-COVID-19 critically ill patients.

PURPOSE: Critically ill COVID-19 and non-COVID-19 patients receive thromboprophylaxis with the LMWH nadroparin. Whether a standard dosage is adequate in attaining the target anti-FXa levels (0.20-0.50 IU/ml) in these groups is unknown. METHODS: This study was a prospective, observational study in the ICU of a large general teaching hospital in the Netherlands. COVID-19 and non-COVID-19 patients admitted to the ICU who received LMWH in a prophylactic dosage of 2850 IU, 5700 IU or 11400 IU subcutaneously were eligible for the study. Anti-FXa levels were determined 4 h after administration. Relevant laboratory parameters, prespecified co-variates and clinical data were extracted from the electronic health record system. The primary goal was to evaluate anti-FXa levels in critically ill patients on a prophylactic dosage of nadroparin. The second goal was to investigate whether covariates had an influence on anti-FXa levels. RESULTS: A total of 62 patients were included in the analysis. In the COVID-19 group and non-COVID-19 group, 29 (96%) and 12 patients (38%) reached anti-FXa levels above 0.20 IU/ml, respectively. In the non-COVID-19 group, 63% of the patients had anti-FXA levels below the target range. When adjusted for nadroparin dosage a significant relation was found between body weight and the anti-FXa level (p = 0.013). CONCLUSION: A standard nadroparin dosage of 2850 IU sc in the critically ill patient is not sufficient to attain target anti-FXa levels in the majority of the studied patient group. We suggest a standard higher dosage in combination with body-weight dependent dosing as it leads to better exposure to nadroparin. CLINICAL TRIALS REGISTRATION: Retrospectively registered, ClinicalTrials.gov ID NTC 05926518 g, date of registration 06/01/23, unique ID 2020/1725.

High unbound fraction of valproic acid in a hypoalbuminemic critically ill patient on renal replacement therapy.

OBJECTIVE: To describe a hypoalbuminemic critically ill patient with subtherapeutic total valproic acid serum concentrations but unbound valproic acid concentrations within normal limits. CASE SUMMARY: During an intensive care unit admission, a 61-year-old woman with urosepsis and multiorgan dysfunction syndrome developed tonic-clonic seizures with respiratory failure, and tracheal intubation was performed. An intravenous loading dose of valproic acid 1500 mg (25 mg/kg) was administered and therapy was continued with valproic acid 750 mg (12.5 mg/kg) twice daily. Because of progressive renal failure, continuous venovenous hemofiltration was started on day 3 of valproic acid therapy. On day 7 of valproic acid therapy, routine testing of serum valproic acid trough concentration returned as undetectable. Subsequent determinations of trough serum concentrations of total valproic acid showed values below the therapeutic range. Data from a full pharmacokinetic curve (multiple blood samples during a dosing interval) showed that the free fraction of valproic acid was >60%. Although total valproic acid concentrations were still low, the unbound concentrations were considered therapeutic. Serum albumin was 1.2 g/dL on the multiple sampling day. DISCUSSION: The patient's hypoalbuminemia probably explains the remarkably high free fraction of valproic acid. Our hypothesis is that the low albumin level was associated with high plasma clearance of valproic acid, leading to extremely low total drug concentrations. To our knowledge, this high percentage of free valproic acid has not been previously described. CONCLUSIONS: Health-care professionals should be aware of the need of early determination of both total and free fraction valproic acid serum concentrations in hypoalbuminemic critically ill patients. Increasing the dose of valproic acid purely based on total valproic acid serum concentrations in this patient population should be avoided.

Plasma apolipoprotein CI correlates with increased survival in patients with severe sepsis.

OBJECTIVE: We recently reported that apolipoprotein CI (apoCI) protects against the development of murine bacterial sepsis. We now examined the time course of plasma apoCI levels in survivors and non-survivors of severe sepsis. DESIGN: Prospective study in patients meeting predefined criteria for severe sepsis. SETTING: University hospital intensive care unit. PATIENTS AND PARTICIPANTS: Seventeen patients with severe sepsis. INTERVENTIONS: In each patient, serial blood samples for determination of total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, apoCI, apoAI, apoB, and apoCIII protein as well as clinical outcome data were collected over 30 days. MEASUREMENTS AND RESULTS: Upon hospitalization, apoCI levels were approximately 5 times lower than normal values in septic patients, i.e. median 1.34 [interquartile range (IQR) 0.82-2.16] mg/dl. ApoCI gradually increased to median values of 5.51 (IQR 3.64-6.97) mg/dl on day 28. At day 0, apoCI levels tended to be lower in non-survivors than in survivors. Remarkably, apoCI levels remained low in non-survivors, whereas apoCI levels gradually increased to normal levels in survivors. This difference was significant and remained so after adjustment for lipoprotein core lipids. No such effect between survivors and non-survivors could be detected for lipoprotein lipids or for apoAI, apoB, and apoCIII after lipid adjustment. CONCLUSIONS: Plasma apoCI levels are markedly decreased in patients with severe sepsis. ApoCI levels were higher in survivors, even after adjustment for lipid levels, and recovered progressively to normal levels. In contrast, apoCI levels remained low in non-survivors. Therefore, a high plasma apoCI level predicts survival in patients with severe sepsis.

Introducing copayments in the emergency department would deter appropriate visits in the Netherlands.

OBJECTIVE: To determine what the effects of introduction of copayments for self-referred emergency department (ED) visits would be in the Netherlands and at what amount patients would turn to a GP before visiting an ED. METHODS: This questionnaire study was carried out in the ED of the Rijnstate Hospital, a community teaching hospital in the Netherlands. In the Netherlands, a deductible excess system is in use and this study investigated the effects of a copayment for self-referred patients (SRPs) on top of the deductible excess. A questionnaire was developed and handed out to SRPs. RESULTS: A total of 433 SRPs were included; their average age was 33.1 years and 63% were male. With a copayment of &OV0556;100, 47% of SRPs would choose to visit their GP instead of the ED. A further increase in the copayment amount is largely ineffective in reducing the number of self-referred ED visits. The higher the household income and education level and the more urgent the triage category, the larger the copayment patients are willing to pay. There is no significant relation between appropriateness and the amount of copayment that patients are willing to pay and we found no specific copayment level that resulted in reducing mainly inappropriate ED visits. CONCLUSION: With a copayment of &OV0556;100, 47% of the SRPs would choose to visit their GP instead of the ED. There was no specific copayment level that resulted in reducing mainly inappropriate ED visits.

A Bayesian decision-support system for diagnosing ventilator-associated pneumonia.

OBJECTIVE: To determine the diagnostic performance of a Bayesian Decision-Support System (BDSS) for ventilator-associated pneumonia (VAP). DESIGN: A previously developed BDSS, automatically obtaining patient data from patient information systems, provides likelihood predictions of VAP. In a prospectively studied cohort of 872 ICU patients, VAP was diagnosed by two infectious-disease specialists using a decision tree (reference diagnosis). After internal validation daily BDSS predictions were compared with the reference diagnosis. For data analysis two approaches were pursued: using BDSS predictions (a) for all 9422 patient days, and (b) only for the 238 days with presumed respiratory tract infections (RTI) according to the responsible physicians. MEASUREMENTS AND RESULTS: 157 (66%) of 238 days with presumed RTI fulfilled criteria for VAP. In approach (a), median daily BDSS likelihood predictions for days with and without VAP were 77% [Interquartile range (IQR) = 56-91%] and 14% [IQR 5-42%, p < 0.001, Mann-Whitney U-test (MWU)], respectively. In receiver operating characteristics (ROC) analysis, optimal BDSS cut-off point for VAP was 46%, and with this cut-off point positive predictive value (PPV) and negative predictive value (NPV) were 6.1 and 99.6%, respectively [AUC = 0.857 (95% CI 0.827-0.888)]. In approach (b), optimal cut-off for VAP was 78%, and with this cut-off point PPV and NPV were 86 and 66%, respectively [AUC = 0.846 (95% CI 0.794-0.899)]. CONCLUSIONS: As compared with the reference diagnosis, the BDSS had good test characteristics for diagnosing VAP, and might become a useful tool for assisting ICU physicians, both for routinely daily assessment and in patients clinically suspected of having VAP. Empirical validation of its performance is now warranted.

Why patients self-refer to the Emergency Department: A qualitative interview study.

RATIONALE, AIMS, AND OBJECTIVES: There have been multiple studies investigating reasons for patients to self-refer to the Emergency Department (ED). The majority made use of questionnaires and excluded patients with urgent conditions. The goal of this qualitative study is to explore what motives patients have to self-refer to an ED, also including patients in urgent triage categories. METHODS: In a large teaching hospital in the Netherlands, a qualitative interview study focusing on reasons for self-referring to the ED was performed. Self-referred patients were included until no new reasons for attending the ED were found. Exclusion criteria were as follows: not mentally able to be interviewed or not speaking Dutch. Patients who were in need of urgent care were treated first, before being asked to participate. Interviews followed a predefined topic guide. Practicing cyclic analysis, the interview topic guide was modified during the inclusion period. Interviews were recorded on an audio recorder, transcribed verbatim, and anonymized. Two investigators independently coded the information and combined the codes into meaningful clusters. Subsequently, these were categorized into themes to build a framework of reasons for self-referral to the ED. Characteristic quotes were used to illustrate the acquired theoretical framework. RESULTS: Thirty self-referred patients were interviewed. Most of the participants were male (63%), with a mean age of 46 years. Two main themes emerged from the interviews that are pertinent to the patients' decisions to attend the ED: (1) health concerns and (2) practical issues. CONCLUSIONS: This study found that there are 2 clearly distinctive reasons for self-referral to the ED: health concerns or practical motives. Self-referral because of practical motives is probably most suitable for strategies that aim to reduce inappropriate ED visits.

Population Pharmacokinetic Model and Pharmacokinetic Target Attainment of Micafungin in Intensive Care Unit Patients.

OBJECTIVE: To study the pharmacokinetics of micafungin in intensive care patients and assess pharmacokinetic (PK) target attainment for various dosing strategies. METHODS: Micafungin PK data from 20 intensive care unit patients were available. A population-PK model was developed. Various dosing regimens were simulated: licensed regimens (I) 100 mg daily; (II) 100 mg daily with 200 mg from day 5; and adapted regimens 200 mg on day 1 followed by (III) 100 mg daily; (IV) 150 mg daily; and (V) 200 mg daily. Target attainment based on a clinical PK target for Candida as well as non-Candida parapsilosis infections was assessed for relevant minimum inhibitory concentrations [MICs] (Clinical and Laboratory Standards Institute). Parameter uncertainty was taken into account in simulations. RESULTS: A two-compartment model best fitted the data. Clearance was 1.10 (root square error 8%) L/h and V 1 and V 2 were 17.6 (root square error 14%) and 3.63 (root square error 8%) L, respectively. Median area under the concentration-time curve over 24 h (interquartile range) on day 14 for regimens I-V were 91 (67-122), 183 (135-244), 91 (67-122), 137 (101-183) and 183 (135-244) mg h/L, respectively, for a typical patient of 70 kg. For the MIC/area under the concentration-time curve >3000 target (all Candida spp.), PK target attainment was >91% on day 14 (MIC 0.016 mg/L epidemiological cut-off) for all of the dosing regimens but decreased to (I) 44%, (II) 91%, (III) 44%, (IV) 78% and (V) 91% for MIC 0.032 mg/L. For the MIC/area under the concentration-time curve >5000 target (non-C. parapsilosis spp.), PK target attainment varied between 62 and 96% on day 14 for MIC 0.016. CONCLUSIONS: The licensed micafungin maintenance dose results in adequate exposure based on our simulations with a clinical PK target for Candida infections but only 62% of patients reach the target for non-C. parapsilosis. In the case of pathogens with an attenuated micafungin MIC, patients may benefit from dose escalation to 200 mg daily. This encourages future study.

Self-referrals in a Dutch Emergency Department: how appropriate are they?

OBJECTIVE: Self-referred visits account for an average of 30% of all Emergency Department (ED) visits in the Netherlands. Some of these are considered inappropriate, because patients receive care that a GP can provide. Worldwide, studies have used various methods to determine the proportion of inappropriate visits by self-referred patients, resulting in diverging percentages. The aim of this study was to find a reliable percentage of appropriate visits to the ED by self-referred patients in the Netherlands. METHODS: This observational, prospective study was performed in the ED of a hospital in the Netherlands. Data were collected on all self-referred patients in four separate months over 1 year. The appropriateness of an ED visit was determined at two time points: first, after primary assessment of the patient, using predefined criteria, and second the moment the patient left the ED, on the basis of the diagnosis and treatment received. Finally, the perspective of the patients was taken into account using a questionnaire. RESULTS: In 4 months 3196 self-referred patients were included. In all, 1862 (58.8%) visits were classified as appropriate according to the predefined criteria. When the second time point was taken into consideration, 48.1% of the patients had a secondary care diagnosis and/or needed secondary care treatment, classifying their visits as appropriate. According to the opinion of the patients 76.7% classified their visit as appropriate. CONCLUSION: The percentage of appropriate ED visits by self-referred patients in the Netherlands ranges from 48.1 to 58.8%, as determined using two different methods.

Dose Reduction of Caspofungin in Intensive Care Unit Patients with Child Pugh B Will Result in Suboptimal Exposure.

BACKGROUND AND OBJECTIVES: Caspofungin is an echinocandin antifungal agent used as first-line therapy for the treatment of invasive candidiasis. The maintenance dose is adapted to body weight (BW) or liver function (Child-Pugh score B or C). We aimed to study the pharmacokinetics of caspofungin and assess pharmacokinetic target attainment for various dosing strategies. METHODS: Caspofungin pharmacokinetic data from 21 intensive care unit (ICU) patients was available. A population pharmacokinetic model was developed. Various dosing regimens (loading dose/maintenance dose) were simulated: licensed regimens (I) 70/50 mg (for BW <80 kg) or 70/70 mg (for BW >80 kg); and (II) 70/35 mg (for Child-Pugh score B); and adapted regimens (III) 100/50 mg (for Child-Pugh score B); (IV) 100/70 mg; and (V) 100/100 mg. Target attainment based on a preclinical pharmacokinetic target for Candida albicans was assessed for relevant minimal inhibitory concentrations (MICs). RESULTS: A two-compartment model best fitted the data. Clearance was 0.55 L/h and the apparent volumes of distribution in the central and peripheral compartments were 8.9 and 5.0 L, respectively. The median area under the plasma concentration-time curve from time zero to 24 h on day 14 for regimens I-V were 105, 65, 93, 130, and 186 mg·h/L, respectively. Pharmacokinetic target attainment was 100 % (MIC 0.03 µg/mL) irrespective of dosing regimen but decreased to (I) 47 %, (II) 14 %, (III) 36 %, (IV) 69 %, and (V) 94 % for MIC 0.125 µg/mL. CONCLUSION: The caspofungin maintenance dose should not be reduced in non-cirrhotic ICU patients based on the Child-Pugh score if this classification is driven by hypoalbuminemia as it results in significantly lower exposure. A higher maintenance dose of 70 mg in ICU patients results in target attainment of >90 % of the ICU patients with species with an MIC of up to 0.125 µg/mL.

Plasma vascular endothelial growth factor in severe sepsis.

Vascular endothelial growth factor (VEGF) is a potent vascular permeability factor. The development of capillary leak is common in septic patients, and several sepsis-associated mediators may induce VEGF production. The potential role of VEGF during sepsis has not been studied to date. The aim of the study was first to assess whether circulating VEGF levels increase during sepsis, and second, to examine whether plasma VEGF levels are associated with disease severity. VEGF levels were measured in serial plasma samples of 18 patients with severe sepsis and in 40 healthy controls. VEGF levels were correlated to clinical signs and symptoms. VEGF levels were significantly elevated in sepsis patients compared with healthy controls (134 vs. 55 pg/mL; P <0.001). Serum albumin levels used as an indirect measure of vascular leak were decreased in septic patients. Increased plasma VEGF levels at study entry were correlated to severity of multiple organ dysfunction during the course of disease (Pearson correlation coefficient r=0.75; P=0.001). Moreover, maximum VEGF levels in nonsurvivors were significantly higher than those in survivors (P=0.018). These data show that plasma VEGF levels are elevated during severe sepsis. Furthermore, our data indicate that plasma VEGF levels are associated with disease severity and mortality. Further study of the potential role of VEGF in the development of sepsis-associated capillary leak is indicated.

Self-referrals in the emergency department: reasons why patients attend the emergency department without consulting a general practitioner first-a questionnaire study.

BACKGROUND: To influence self-referral, it is crucial to know a patient's motives to directly visit the emergency department (ED). The goal of this study is to examine motives for self-referral to the ED and compare these motives in relation to appropriateness. METHODS: All self-referred patients visiting the ED of a Dutch hospital over four separate months in a 1-year period were included. Patients were handed questionnaires that included questions on their reasons to visit the ED directly and where they would seek medical help next time. Additionally, the motives of patients that either appropriately or inappropriately visited the ED were compared. In a previous study on the same patient cohort, the appropriateness of the ED visits was determined using predefined criteria. RESULTS: A total of 3196 self-referred patients were included, and 48.9 % completed the questionnaires. The majority of patients (28.0 %) attended the ED without a referral because they thought they would get help faster; the next reason was the easier access to radiologic and laboratory investigations (answered by 23.8 %); and the third was the symptoms were considered too severe to visit a general practitioner (GP) (answered by 22.7 %). The majority (78.5 %) would attend the ED the next time they are faced with similar symptoms. Appropriate visits were significantly more seen in females, elderly, and patients in higher triage categories. Patients who expect investigations are necessary, think their symptoms are too severe to visit a GP, or would return to the ED next time were more often appropriately visiting the ED. CONCLUSIONS: The choice of patients to self-refer to an ED is often an explicate decision. Patients are looking for specialist help and want fast and easy access to radiologic and laboratory investigations. Even though the primary care network is well developed in the Netherlands, the reasons for self-referral are similar to the reasons found in previous literature based in other countries. Patients who visit the ED because of health concerns visit the ED more often appropriately than patients visiting for practical reasons.

[Ceftriaxone-induced immune haemolytic anaemia and multi-organ failure]. / Hemolyse en multiorgaanfalen door ceftriaxon.

BACKGROUND: Drug-induced immune haemolytic anaemia (DIIHA) is caused by various drugs or their metabolites. Cephalosporins are associated with haemolytic anaemia but multi-organ failure is rarely described. CASE DESCRIPTION: We report the case of a 57-year-old female who was diagnosed with neuroborreliosis and treated with ceftriaxone. The patient developed severe DIIHA. Massive intravascular haemolysis led to shock and acute renal failure, necessitating mechanical ventilation and dialysis. Treatment with ceftriaxone was discontinued and glucocorticoids were prescribed. The patient recovered slowly but fully. CONCLUSION: Ceftriaxone-induced immune haemolytic anaemia is a rare but potentially fatal condition.