Developing a Method for Quantifying Meropenem in Children-Volumetric Adsorptive Microsampling Versus Plasma Sampling.

BACKGROUND: Meropenem is a carbapenem antibiotic often used in pediatric intensive care units due to its broad spectrum of activity. Therapeutic drug monitoring (TDM) is a useful tool to increase the effectiveness of meropenem by adjusting the dose based on plasma levels; however, the relatively large sample volume required for TDM can limit its use in children. Therefore, this study aimed to determine meropenem concentrations and consequently perform TDM effectively using the smallest possible sample volume. Volumetric absorptive microsampling (VAMS) is a sampling technology developed to collect a small, precise volume of blood. For the applicability of VAMS in TDM, plasma concentrations must be reliably calculated from whole blood (WB) collected by VAMS. METHODS: VAMS technology using 10 µL of WB was evaluated and compared with EDTA-plasma sampling. High-performance liquid chromatography with UV detection was applied to quantify meropenem in VAMS and plasma samples after the removal of proteins by precipitation. Ertapenem was used as the internal standard. Samples were collected simultaneously from critically ill children receiving meropenem using VAMS and traditional sampling. RESULTS: It was found that no consistent factor could be determined to calculate meropenem plasma concentrations from the WB, indicating that VAMS was not reliable in the TDM of meropenem. Therefore, to reduce the required sample amount in pediatric patients, a method for quantifying meropenem from 50 µL of plasma with a lower limit of quantification of 1 mg/L was developed and successfully validated. CONCLUSIONS: A simple, reliable, and low-cost method was established using high-performance liquid chromatography-UV to determine the concentration of meropenem in 50 µL of plasma. VAMS using WB does not seem to be suitable for TDM of meropenem.

Feasibility, efficacy, and safety of ultrasound-guided axillary plexus blockade in pediatric patients with epidermolysis bullosa dystrophica.

BACKGROUND: In patients suffering from epidermolysis bullosa dystrophica (DEB), the most severe form of epidermolysis bullosa, trauma or friction cause separation of the skin from underlying tissue with consecutive painful blisters, scarifications, contractures, and pseudosyndactyly. To retain functionality of the hands surgical procedures are necessary. Anesthesia is challenging as difficult airways make general anesthesia risky. Regional anesthesia is considered controversial in patients with EB as accidental subcutaneous injections can cause severe blisters. As ultrasound-guided procedures became standard of care this might have changed however. AIM: In this case series, we describe feasibility, efficacy, and safety of ultrasound-guided plexus axillaris block in DEB patients undergoing hand surgery. METHOD: We performed a retrospective analysis of the charts of all children with DEB undergoing hand surgery under plexus axillaris block and sedation between 2009 and 2013 in our institution. RESULTS: Nineteen procedures in nine children were performed. Induction of anesthesia (securing monitoring, sedation, plexus block) took a mean time of 34 min. Perioperative analgesia was adequate in all procedures. No complications such as airway incidents, conversion to general anesthesia, movement during surgery, incomplete block, or formation of new blisters were seen. CONCLUSION: Ultrasound-guided plexus axillaris block in DEB patients undergoing hand surgery in our institution has been feasible, effective, and safe.

Pros and cons of etomidate--more discussion than evidence?

PURPOSE OF REVIEW: To evaluate the most recent publications in the long-lived debate over the use of etomidate in critically ill septic and trauma patients. RECENT FINDINGS: Virtually without controversy is the hemodynamic stability after its use for induction of anesthesia on the one hand, and its negative effect on steroid synthesis on the other. The rating of the relative importance of both phenomena for the outcome of patients is however a highly controversial issue. We will discuss the most recent publications for two patient groups: trauma and critically ill septic patients. New meta-analyses and smaller studies have been published and might help us to weigh pros and cons in our patients. Sufficiently powered randomized controlled trials remain absent. The question whether supplemented corticosteroids after etomidate improve outcome is answered negatively by two recent studies. SUMMARY: A single dose of etomidate supplies good intubation conditions with hemodynamic stability, but increases the risk for adrenal insufficiency. The relative importance of these characteristics for the patients' outcome remains controversial, as there is a lack of direct evidence. According to the principle 'nihil nocere', reasoning argues against its use, especially in septic patients or in those at major risk to develop septic complications (e.g. trauma patients).

Tight glycemic control protects the myocardium and reduces inflammation in neonatal heart surgery.

BACKGROUND: Neonatal cardiac surgery evokes hyperglycemia and a systemic inflammatory response. Hyperglycemia is associated with intensified inflammation and adverse outcome in critically ill children and in pediatric cardiac surgery. Recently we demonstrated that tight glycemic control (TGC) reduced morbidity and mortality of critically ill children. Experimental data suggest that insulin protects the myocardium in the setting of ischemia-reperfusion injury, but this benefit could be blunted by coinciding hyperglycemia. We hypothesized that insulin-titrated TGC, initiated prior to myocardial ischemia and reperfusion, protects the myocardium and attenuates the inflammatory response after neonatal cardiac surgery. METHODS: This is a prospective randomized study at a university hospital. Fourteen neonates were randomized to intraoperative and postoperative conventional insulin therapy or TGC. Study endpoints were effects on myocardial damage and function; inflammation, endothelial activation, and clinical outcome parameters. RESULTS: Tight glycemic control significantly reduced circulating levels of cardiac troponin-I (p = 0.009), heart fatty acid-binding protein (p = 0.01), B-type natriuretic peptide (p = 0.002), and the need for vasoactive support (p = 0.008). The TGC suppressed the rise of the proinflammatory cytokines interleukin-6 (p = 0.02) and interleukin-8 (p = 0.05), and reduced the postoperative increase in C-reactive protein (p = 0.04). Myocardial concentrations of Akt, endothelial nitric-oxide synthase, and their phosphorylated forms were not different between groups. CONCLUSIONS: In neonates undergoing cardiac surgery, intraoperative and postoperative TGC protects the myocardium and reduces the inflammatory response. This appears not to be mediated by an early, direct insulin signaling effect, but may rather be due to independent effects of preventing hyperglycemia during reperfusion.

Phase 1 study of combination treatment with PTK 787/ZK 222584 and cetuximab for patients with advanced solid tumors: safety, pharmacokinetics, pharmacodynamics analysis.

INTRODUCTION: PTK/ZK is a small-molecule inhibitor of all three vascular endothelial growth factor (VEGF) receptors, platelet-derived growth factor receptor, colony-stimulating factor 1 receptor, and cytokine stem cell factor receptor. Cetuximab is a monoclonal antibody against epidermal growth factor (EGF) receptor. Combining inhibition of VEGF and EGF signaling might act additive or synergistically. METHODS: In phase 1 design, patients with advanced solid tumors were treated with PTK/ZK daily (cohort 1, 750 mg once daily; cohort 2, 1250 mg once daily; cohort 3, 250 mg [morning] and 500 mg [evening]; and cohort 4, 500 mg [morning] and 750 mg [evening]) in combination with cetuximab 250 mg/m(2) weekly in cycles of 28 days in cohorts of three patients. Toxicity was evaluated conform the Common Terminology Criteria for Adverse Events classification 3.0. Pharmacokinetics and pharmacodynamics consisting of circulating endothelial (progenitor) cell (CE[P]C) analysis by flow cytometry were performed. RESULTS: Safety and tolerability was evaluated in 16 patients. The most frequently reported adverse events were acne, dry skin, fatigue, nausea, dizziness, vomiting, headache, and diarrhea. One dose-limiting toxicity occurred in cohort 3 consisting of a grade 3 transaminitis. Pharmacokinetic analysis revealed no significant changes in PTK/ZK exposure on coadministration with cetuximab and in bioavailability at equivalent total daily doses. Biomarker analysis showed no significant change in the number of CE(P)Cs during treatment. One of 14 evaluable patients showed a partial response for at least 11.5 months, and 7 patients (50%) stable disease for at least 2 months. CONCLUSIONS: This study shows that the combination of PTK/ZK and cetuximab is well tolerated with only slightly overlapping toxicity profiles and has antitumor activity.

Hypoglycemia aggravates critical illness-induced neurocognitive dysfunction.

OBJECTIVE Tight glycemic control (TGC) in critically ill patients is associated with an increased risk of hypoglycemia. Whether those short episodes of hypoglycemia are associated with adverse morbidity and mortality is a matter of discussion. Using a case-control study design, we investigated whether hypoglycemia under TGC causes permanent neurocognitive dysfunction in patients surviving critical illness. RESEARCH DESIGN AND METHODS From our patient data management system, we identified adult survivors treated for >72 h in our surgical intensive care unit (ICU) between 2004 and 2007 (n = 4,635) without a history of neurocognitive dysfunction or structural brain abnormalities who experienced at least one episode of hypoglycemia during treatment (hypo group) (n = 37). For each hypo group patient, one patient stringently matched for demographic- and disease-related data were identified as a control subject. We performed a battery of neuropsychological tests investigating five areas of cognitive functioning in both groups at least 1 year after ICU discharge. Test results were compared with data from healthy control subjects and between groups. RESULTS Critical illness caused neurocognitive dysfunction in all tested domains in both groups. The dysfunction was aggravated in hypo group patients in one domain, namely that of visuospatial skills (P < 0.01). Besides hypoglycemia, both hyperglycemia (r = -0.322; P = 0.005) and fluctuations of blood glucose (r = -0.309; P = 0.008) were associated with worse test results in this domain. CONCLUSIONS Hypoglycemia was found to aggravate critical illness-induced neurocognitive dysfunction to a limited, but significant, extent; however, an impact of hyperglycemia and fluctuations of blood glucose on neurocognitive function cannot be excluded.

Intensive insulin therapy for patients in paediatric intensive care: a prospective, randomised controlled study.

BACKGROUND: Critically ill infants and children often develop hyperglycaemia, which is associated with adverse outcome; however, whether lowering blood glucose concentrations to age-adjusted normal fasting values improves outcome is unknown. We investigated the effect of targeting age-adjusted normoglycaemia with insulin infusion in critically ill infants and children on outcome. METHODS: In a prospective, randomised controlled study, we enrolled 700 critically ill patients, 317 infants (aged <1 year) and 383 children (aged >or=1 year), who were admitted to the paediatric intensive care unit (PICU) of the University Hospital of Leuven, Belgium. Patients were randomly assigned by blinded envelopes to target blood glucose concentrations of 2.8-4.4 mmol/L in infants and 3.9-5.6 mmol/L in children with insulin infusion throughout PICU stay (intensive group [n=349]), or to insulin infusion only to prevent blood glucose from exceeding 11.9 mmol/L (conventional group [n=351]). Patients and laboratory staff were blinded to treatment allocation. Primary endpoints were duration of PICU stay and inflammation. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00214916. FINDINGS: Mean blood glucose concentrations were lower in the intensive group than in the conventional group (infants: 4.8 [SD 1.2] mmol/L vs 6.4 [1.2] mmol/L, p<0.0001; children: 5.3 [1.1] mmol/L vs 8.2 [3.3] mmol/L, p<0.0001). Hypoglycaemia (defined as blood glucose median) stay in PICU was 132 (38%) in the intensive group versus 165 (47%) in the conventional group (p=0.013). Nine (3%) patients died in the intensively treated group versus 20 (6%) in the conventional group (p=0.038). INTERPRETATION: Targeting of blood glucose concentrations to age-adjusted normal fasting concentrations improved short-term outcome of patients in PICU. The effect on long-term survival, morbidity, and neurocognitive development needs to be investigated. FUNDING: Research Foundation (Belgium); Research Fund of the University of Leuven (Belgium) and the EU Information Society Technologies Integrated project "CLINICIP"; and Institute for Science and Technology (Belgium).

Clinical benefits of tight glycaemic control: focus on the paediatric patient.

Hyperglycaemia and glucose variability occur frequently during critical illness or after major surgery in children and are associated with worse outcome. Association does not necessarily imply causality however, and the question whether tight glycaemic control (TGC) with insulin infusion improves morbidity and mortality can only be answered by randomised controlled trials (RCTs). Currently, only one single-centre RCT exists, proving the concept of TGC in critically ill children. Attenuation of inflammation and reduction of secondary infections, decreased prolonged stay in intensive care and reduced dependency on haemodynamic support were accomplished, despite a substantial increased incidence of biochemical hypoglycaemia. Before universal implementation in paediatric intensive care both long-term effects on outcome and development and issues regarding optimal levels of blood glucose control need to be cleared in multicentre prospective RCTs. Technological improvement might be helpful in optimising blood glucose control.

Serial lactate measurements using microdialysis of interstitial fluid do not correlate with plasma lactate in children after cardiac surgery.

OBJECTIVES: Serial postoperative blood lactate (BL) concentrations have been shown to predict outcome of children after congenital heart surgery (CHS), and interventions aimed at lowering lactate can improve the outcome of these children. The cumulative blood loss for diagnostic purposes, such as repetitive arterial blood sampling in the intensive care unit, contributes, especially in small children, to anemia. Techniques to limit blood loss can therefore be of use. Microdialysis is a technique to monitor tissue chemistry in various clinical settings, and we hypothesized that it may be a valuable alternative for frequent blood sampling to monitor lactate in children after CHS. METHODS: Fifteen children with a mean age of 40 months (range, 4-118 months) were prospectively enrolled after CHS. A CMA double lumen microdialysis catheter was inserted into the subcutaneous adipose tissue of the abdominal wall and infused with an isotone mannitol 5% solution at 1 microL/min via the inlet tubing. Microdialysate fluid was collected every hour for 48 hrs and stored at -80 degrees C for lactate determination (interstitial fluid lactate, IFL). Every hour arterial blood was taken for lactate determination. Individual profiles, correlation coefficient, and Bland-Altman analysis were used to compare BL and IFL results. RESULTS: There were no complications with the microdialysis technique. All patients were discharged alive from hospital. Six hundred twenty paired samples were analyzed. Mean recovery of microdialysate fluid was 84%. Median (interquartile range) was 0.95 (0.70-1.15) mmol/L for BL and 1.13 (0.86-1.48) mmol/L for IFL (p < 0.0001). Individual profiles showed that IFL follows changes in BL in some, but not all children. With this study, we could not explain this discrepancy. The correlation between BL and IFL was poor (r = .77 (p < 0.0001) r = .59). Bland-Altman analysis confirmed the insufficient performance of the current microdialysis-based procedure compared with BL. CONCLUSION: Serial lactate measurements in microdialysis fluid of subcutaneous adipose tissue are feasible, but cannot be used as a reliable interchangeable method for plasma lactate analysis in children after CHS at this time. Whether this technique has its own place in the assessment of the overall hemodynamic status and tissue perfusion in children after CHS needs to be addressed in future studies.

Clinical and pharmacologic study of the novel prodrug delimotecan (MEN 4901/T-0128) in patients with solid tumors.

PURPOSE: To investigate i.v. administration of delimotecan (MEN 4901/T-0128), a carboxymethyldextran polymer prodrug of the active camptothecin derivative T-2513, and to assess the maximum tolerated dose, safety profile, clinical pharmacology, and antitumor activity of delimotecan and metabolites. EXPERIMENTAL DESIGN: Patients with solid tumors refractory to standard therapy received i.v. delimotecan as 3-hour infusion once every 6 weeks. The starting dose was 150 mg/m2, followed by an accelerated dose escalation with at least one patient per dose level. The pharmacokinetics of delimotecan, T-2513, and its metabolites, SN-38, SN-38G, T-1335, T-0055, and T-3921, were assessed in plasma and urine, and their pharmacodynamics were determined by measuring the effect of the treatment on hematologic and nonhematologic toxicity. RESULTS: Twenty-two patients received 35 courses. Dose-limiting toxicities were observed at 5,400 mg/m2 (n = 1), 3,600 mg/m2 (n = 1), and 2,400 mg/m2 (n = 2). The dose level of 1,800 mg/m2 was determined as maximum tolerated dose. Two partial responses were observed in patients with anal cancer (1800 mg/m2) and head and neck cancer (2400 mg/m2). Delimotecan had a long terminal half-life of 109 h, and relatively high exposures to T-2513 and SN-38 were obtained. The percentage decrease in WBC and absolute neutrophil count significantly correlated with the dose of delimotecan. CONCLUSIONS: Based on its preliminary antitumor activity, safety profile, and pharmacokinetic profile, we recommend to evaluate delimotecan given as 3-hour infusion once every 6 weeks at a dose level of 1,800 mg/m2 in a phase II study.

The importance of strict blood glucose control with insulin therapy in the intensive care unit.

Two randomised controlled trials have shown that maintenance of blood glucose levels below 110 mg/dl with intensive insulin therapy reduces mortality and morbidity of surgical and medical critically ill patients. An absolute reduction in the risk of death of 3-4 % is expected in intention-to-treat analysis, but the survival benefit increases when treatment is continued for at least a few days. Future studies set up to confirm the survival benefit and assign it as statistically significant in an intention-to-treat medical patient population should be adequately powered with inclusion of at least 5000 patients. For the observed benefits of intensive insulin therapy strict maintenance of normoglycaemia is primordial, whereas glycaemia-independent actions of insulin have minor, organ-specific impact. Pathophysiological mechanisms underlying the clinical effects are currently being unravelled further and might help to find new strategies for further improving outcome. Implementation of a strict glycemic control protocol in the intensive care unit is feasible and cost-effective, but asks for careful consideration of some practical aspects, such as prevention of hypoglycaemia, training of nurses and selection of accurate blood glucose measurement tools. Continuous blood glucose monitoring devices and closed-loop systems are under development and might be of great benefit to overcome these issues.

Successful treatment with rituximab of lymphoproliferative disorder in a child after cardiac transplantation.

Post-transplantation lymphoproliferative disorders (PTLDs) are life-threatening complications. We report the case of a 7-year-old girl in whom a lymphoproliferative disorder developed more than 2 years after cardiac transplantation. The patient was taking ganciclovir for Epstein-Barr virus hepatitis at the time the PTLD occurred. Rituximab, an anti-CD20 monoclonal antibody, given in the presence of reduced immunosuppression therapy, resulted in a complete response of the PTLD. The Epstein-Barr viral load in the peripheral blood, which was extremely high at diagnosis, dropped promptly and remained below the detection threshold 11 months after completion of therapy. We observed complete depletion of B lymphocytes until 7 months after rituximab therapy, which was associated with an important decrease in immunoglobulin levels.