Optimal dosing of cefotaxime and desacetylcefotaxime for critically ill paediatric patients. Can we use microsampling?

OBJECTIVES: To describe the population pharmacokinetics of cefotaxime and desacetylcefotaxime in critically ill paediatric patients and provide dosing recommendations. We also sought to evaluate the use of capillary microsampling to facilitate data-rich blood sampling. METHODS: Patients were recruited into a pharmacokinetic study, with cefotaxime and desacetylcefotaxime concentrations from plasma samples collected at 0, 0.5, 2, 4 and 6 h used to develop a population pharmacokinetic model using Pmetrics. Monte Carlo dosing simulations were tested using a range of estimated glomerular filtration rates (60, 100, 170 and 200 mL/min/1.73 m2) and body weights (4, 10, 15, 20 and 40 kg) to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets, including 100% ƒT>MIC with an MIC breakpoint of 1 mg/L. RESULTS: Thirty-six patients (0.2-12 years) provided 160 conventional samples for inclusion in the model. The pharmacokinetics of cefotaxime and desacetylcefotaxime were best described using one-compartmental model with first-order elimination. The clearance and volume of distribution for cefotaxime were 12.8 L/h and 39.4 L, respectively. The clearance for desacetylcefotaxime was 10.5 L/h. Standard dosing of 50 mg/kg q6h was only able to achieve the PK/PD target of 100% ƒT>MIC in patients >10 kg and with impaired renal function or patients of 40 kg with normal renal function. CONCLUSIONS: Dosing recommendations support the use of extended or continuous infusion to achieve cefotaxime exposure suitable for bacterial killing in critically ill paediatric patients, including those with severe or deep-seated infection. An external validation of capillary microsampling demonstrated skin-prick sampling can facilitate data-rich pharmacokinetic studies.

Perioperative Cefazolin Prophylaxis in Pediatric Cardiac Surgery: A Prospective, Cohort Study.

BACKGROUND: This study's objective was to determine the effect of age, prolonged bypass, and hypothermia on serum cefazolin concentrations in children undergoing cardiac surgery. METHODS: A prospective, single-center, observational study was conducted, examining children undergoing cardiac surgery. Participants received cefazolin intravenously approximately 1 hour before skin incision, 3 hourly intraoperatively, and 8 hourly postoperatively. Blood samples were collected at 6 to 8 time points intraoperatively and at 6 time points in the first 24 hours postoperatively. Target unbound serum cefazolin concentrations were 2 mg/L. RESULTS: Sixty-eight patients were enrolled in the study, and 64 were included in the analysis. All maintained concentrations ≥ 2 mg/L throughout the operation. Nineteen patients (30%) did not maintain concentrations ≥ 2 mg/L in the first 24 hours after surgery. Older, larger children (P < .0001) were significantly less likely to achieve target unbound serum cefazolin concentrations. CONCLUSIONS: Intraoperative cefazolin concentrations reached the target concentration in all pediatric cardiac surgical cases. Postoperative cefazolin dosing appears to be insufficient to achieve minimum inhibitory concentrations in many patients.

Evaluation of low-volume plasma sampling for the analysis of meropenem in clinical samples.

Reducing the volume of blood sampled from neonatal or paediatric patients is important to facilitate research in a group that is under-represented in clinical studies. Not all patients have a cannula available for blood sampling, meaning there are real advantages in obtaining a blood microsample by skin prick. In this study, the results obtained from both capillary microsamples (CMS) and a microfluidic (MF)-CMS by skin prick are compared to conventional plasma sampled from an arterial catheter in a clinical bridging study. Six critically ill patients receiving meropenem were included with the incurred sample reanalysis test meeting the acceptance criteria for both CMS (n = 24 samples) and MF-CMS (n = 20 samples). Bland-Altman plots comparing MF-CMS to conventional arterial blood sampling revealed a difference of - 12.7 ± 22.1% (mean ± standard deviation (SD), and comparing CMS to conventional arterial blood sampling a difference of - 3.4 ± 17.0%. At - 12.7%, the bias between MF-CMS and conventional sampling is greater than the bias found with CMS, although within the limit of acceptability for analytical accuracy (that being ± 15%). Samples collected by skin prick and using CMS produced meropenem concentrations that were comparable to those obtained from conventional arterial catheter sampling. CMS samples were found to be stable when stored in the capillary tube for 24 h at 5 °C or for 4 h at room temperature.

Microsampling to support pharmacokinetic clinical studies in pediatrics.

BACKGROUND: Conventional sampling for pharmacokinetic clinical studies requires removal of large blood volumes from patients. This can result in a physiological/emotional burden for children. Microsampling to support pharmacokinetic clinical studies in pediatrics may reduce this burden. METHODS: Parents/guardians and bedside nurses completed a questionnaire describing their perception of the use of microsampling compared to conventional sampling to collect blood samples, based on their child's participation or their own role within a paired-sample pharmacokinetic clinical study. Responses were based on a seven-point Likert scale and were analyzed using frequency distributions. RESULTS: Fifty-one parents/guardians and seven bedside nurses completed a questionnaire. Parents/guardians (96%) and bedside nurses (100%) indicated that microsampling was highly acceptable and recommended as a method for collecting blood samples for pediatric patients. Responding to a question about the child indicating pain during the blood sampling procedure, 61% of parent/guardians reported no pain in their children, 14% remained neutral, and 26% reported that their child indicated pain; 71% of the bedside nurses slightly agreed that the children indicated pain. CONCLUSIONS: This study strongly suggests that parents/guardians and bedside nurses prefer microsampling to conventional sampling to conduct pediatric pharmacokinetic clinical studies. Employing microsampling may support increased participation by children in these studies. IMPACT: Pharmacokinetic clinical studies require the withdrawal of blood samples at multiple times during a dosing interval. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Microsampling offers an important opportunity for pharmacokinetic clinical studies in vulnerable patient populations, where smaller sample volumes can be collected. However, microsampling is not commonly used in clinical studies. Understanding the perceptions of parents/guardians and bedside nurses about microsampling may ascertain if this technique offers an improvement to conventional blood sample collection to perform pharmacokinetic clinical studies for pediatric patients.

Development and validation of a UHPLC-MS/MS method to measure cefotaxime and metabolite desacetylcefotaxime in blood plasma: a pilot study suitable for capillary microsampling in critically ill children.

Critical illness has been shown to affect the pharmacokinetics of antibiotics, which can lead to ineffective antibiotic exposure and the potential emergence of resistant bacteria. The lack of studies describing antibiotic pharmacokinetics in critically ill children has led to significant off-label dosing. This is, in part, due to the ethical and physiological challenges of removing frequent, large-volume samples from children. Capillary microsampling facilitates the collection of small volumes of blood samples to conduct clinical pharmacokinetic studies. A sensitive, rapid, and accurate ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) bioanalytical method to measure cefotaxime and desacetylcefotaxime in 2.8 µL of plasma was developed and validated. Plasma samples were treated with acetonitrile and analytes were separated using a Kinetex C8 (100 × 2.1 mm) column. The chromatographic separation was established using a gradient method, with the mobile phases consisting of acetonitrile and ammonium acetate. An electrospray ionization source interface operated in a positive mode for the multiple reaction monitoring MS/MS analysis of cefotaxime, desacetylcefotaxime, and deuterated cefotaxime (internal standard). The bioanalytical method using microsample volumes met requirements for method validation for both analytes. Cefotaxime had precision within ± 7.3% and accuracy within ± 5% (concentration range of 0.5 to 500 mg/L). Desacetylcefotaxime had precision within ± 9.5% and accuracy within ± 3.5% (concentration range of 0.2 to 10 mg/L). The bioanalytical method was applied for the quantification of cefotaxime and its metabolite to 20 capillary microsamples collected at five time points in one dosing interval from five critically ill children.

Uncertainty in Antibiotic Dosing in Critically Ill Neonate and Pediatric Patients: Can Microsampling Provide the Answers?

PURPOSE: With a decreasing supply of antibiotics that are effective against the pathogens that cause sepsis, it is critical that we learn to use currently available antibiotics optimally. Pharmacokinetic studies provide an evidence base from which we can optimize antibiotic dosing. However, these studies are challenging in critically ill neonate and pediatric patients due to the small blood volumes and associated risks and burden to the patient from taking blood. We investigate whether microsampling, that is, obtaining a biologic sample of low volume (<50 µL), can improve opportunities to conduct pharmacokinetic studies. METHODS: We performed a literature search to find relevant articles using the following search terms: sepsis, critically ill, severe infection, intensive care AND antibiotic, pharmacokinetic, p(a)ediatric, neonate. For microsampling, we performed a search using antibiotics AND dried blood spots OR dried plasma spots OR volumetric absorptive microsampling OR solid-phase microextraction OR capillary microsampling OR microsampling. Databases searched include Web of Knowledge, PubMed, and EMbase. FINDINGS: Of the 32 antibiotic pharmacokinetic studies performed on critically ill neonate or pediatric patients in this review, most of the authors identified changes to the pharmacokinetic properties in their patient group and recommended either further investigations into this patient population or therapeutic drug monitoring to ensure antibiotic doses are suitable. There remain considerable gaps in knowledge regarding the pharmacokinetic properties of antibiotics in critically ill pediatric patients. Implementing microsampling in an antibiotic pharmacokinetic study is contingent on the properties of the antibiotic, the pathophysiology of the patient (and how this can affect the microsample), and the location of the patient. A validation of the sampling technique is required before implementation. IMPLICATIONS: Current antibiotic regimens for critically ill neonate and pediatric patients are frequently suboptimal due to a poor understanding of altered pharmacokinetic properties. An assessment of the suitability of microsampling for pharmacokinetic studies in neonate and pediatric patients is recommended before wider use. The method of sampling, as well as the method of bioanalysis, also requires validation to ensure the data obtained reflect the true result.

Is there a role for microsampling in antibiotic pharmacokinetic studies?

INTRODUCTION: Clinical pharmacokinetic studies of antibiotics can establish evidence-based dosing regimens that improve the likelihood of eradicating the pathogen at the site of infection, reduce the potential for selection of resistant pathogens, and minimize harm to the patient. Innovations in small volume sampling (< 50 µL) or 'microsampling' may result in less-invasive sample collection, self-sampling and dried storage. Microsampling may open up opportunities in patient groups where sampling is challenging. AREAS COVERED: The challenges for implementation of microsampling to assure suitability of the results, include: acceptable study design, regulatory agency acceptance, and meeting bioanalytical validation requirements. This manuscript covers various microsampling methods, including dried blood/plasma spots, volumetric absorptive microsampling, capillary microsampling, plasma preparation technologies and solid-phase microextraction. EXPERT OPINION: The available analytical technology is being underutilized due to a lack of bridging studies and validated bioanalytical methods. These deficiencies represent major impediments to the application of microsampling to antibiotic pharmacokinetic studies. A conceptual framework for the assessment of the suitability of microsampling in clinical pharmacokinetic studies of antibiotics is provided. This model establishes a 'contingency approach' with consideration of the antibiotic and the type and location of the patient, as well as the more prescriptive bioanalytical validation protocols.

Comparison of Pediatric Severe Sepsis Managed in U.S. and European ICUs.

OBJECTIVES: Pediatric severe sepsis remains a significant global health problem without new therapies despite many multicenter clinical trials. We compared children managed with severe sepsis in European and U.S. PICUs to identify geographic variation, which may improve the design of future international studies. DESIGN: We conducted a secondary analysis of the Sepsis PRevalence, OUtcomes, and Therapies study. Data about PICU characteristics, patient demographics, therapies, and outcomes were compared. Multivariable regression models were used to determine adjusted differences in morbidity and mortality. SETTING: European and U.S. PICUs. PATIENTS: Children with severe sepsis managed in European and U.S. PICUs enrolled in the Sepsis PRevalence, OUtcomes, and Therapies study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: European PICUs had fewer beds (median, 11 vs 24; p < 0.001). European patients were younger (median, 1 vs 6 yr; p < 0.001), had higher severity of illness (median Pediatric Index of Mortality-3, 5.0 vs 3.8; p = 0.02), and were more often admitted from the ward (37% vs 24%). Invasive mechanical ventilation, central venous access, and vasoactive infusions were used more frequently in European patients (85% vs 68%, p = 0.002; 91% vs 82%, p = 0.05; and 71% vs 50%; p < 0.001, respectively). Raw morbidity and mortality outcomes were worse for European compared with U.S. patients, but after adjusting for patient characteristics, there were no significant differences in mortality, multiple organ dysfunction, disability at discharge, length of stay, or ventilator/vasoactive-free days. CONCLUSIONS: Children with severe sepsis admitted to European PICUs have higher severity of illness, are more likely to be admitted from hospital wards, and receive more intensive care therapies than in the United States. The lack of significant differences in morbidity and mortality after adjusting for patient characteristics suggests that the approach to care between regions, perhaps related to PICU bed availability, needs to be considered in the design of future international clinical trials in pediatric severe sepsis.

Pediatric Hematopoietic Stem Cell Transplant and Intensive Care: Have Things Changed?

OBJECTIVES: Mortality for pediatric patients who require intensive care posthematopoietic stem cell transplant still remains high. Previously at our institution, survival rates were 44% for patients who required mechanical ventilation posthematopoietic stem cell transplant. We conducted a review of patients to identify whether there has been any improvement in survival over the past 12 years and to identify any risk factors that contribute to mortality. DESIGN: Retrospective chart review. SETTING: PICU and hematopoietic stem cell transplant unit of a single tertiary children's hospital. PATIENTS: Children less than 18 years old undergoing hematopoietic stem cell transplant who required admission to the ICU between January 2000 and December 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 350 separate admissions to the ICU for 206 patients posthematopoietic stem cell transplant. Median Age was 9.3 years (range, 1-17 yr). Median time from hematopoietic stem cell transplant to admission was 35 days (interquartile range, 13-152 d), and 59% of patients were male. Survival to ICU discharge for all admissions was 75%, which equated to 57% of all patients. Of the admissions that required invasive mechanical ventilation, 48% survived to ICU discharge, with a survival to ICU discharge of 36% if there was more than one admission requiring mechanical ventilation. Survival to ICU discharge was 33% if renal replacement therapy was required. Mechanical ventilation, inotrope/vasopressor use, and number of organ dysfunction within an admission were predictors of mortality. Having an underlying malignant condition or an autologous hematopoietic stem cell transplant was associated with a more favorable outcome. CONCLUSIONS: This is the largest single-center series for pediatric patients who require intensive care posthematopoietic stem cell transplant and demonstrates that this group of patients still faces high mortality. There has been an improvement in survival for those patients who require renal replacement therapy and also for patients who require mechanical ventilation more than once; however, the need for mechanical ventilation still remains a significant predictor of mortality.

Isotonic versus hypotonic solutions for maintenance intravenous fluid administration in children.

BACKGROUND: Maintenance intravenous fluids are frequently used in hospitalised children who cannot maintain adequate hydration through enteral intake. Traditionally used hypotonic fluids have been associated with hyponatraemia and subsequent morbidity and mortality. Use of isotonic fluid has been proposed to reduce complications. OBJECTIVES: To establish and compare the risk of hyponatraemia by systematically reviewing studies where isotonic is compared with hypotonic intravenous fluid for maintenance purposes in children.Secondly, to compare the risk of hypernatraemia, the effect on mean serum sodium concentration and the rate of attributable adverse effects of both fluid types in children. SEARCH METHODS: We ran the search on 17 June 2013. We searched the Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE (OvidSP), Embase (OvidSP), and ISI Web of Science. We also searched clinical trials registers and screened reference lists. We updated this search in October 2014 but these results have not yet been incorporated. SELECTION CRITERIA: We included randomised controlled trials that compared isotonic versus hypotonic intravenous fluids for maintenance hydration in children. DATA COLLECTION AND ANALYSIS: At least two authors assessed and extracted data for each trial. We presented dichotomous outcomes as risk ratios (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean differences with 95% CIs. MAIN RESULTS: Ten studies met the inclusion criteria, with a total of 1106 patients. The majority of the studies were performed in surgical or intensive care populations (or both). There was considerable variation in the composition of intravenous fluid, particularly hypotonic fluid, used in the studies. There was a low risk of bias for most of the included studies. Ten studies provided data for our primary outcome, a total of 449 patients in the analysis received isotonic fluid, while 521 received hypotonic fluid. Those who received isotonic fluid had a substantially lower risk of hyponatraemia (17% versus 34%; RR 0.48; 95% CI 0.38 to 0.60, high quality evidence). It is unclear whether there is an increased risk of hypernatraemia when isotonic fluids are used (4% versus 3%; RR 1.24; 95% CI 0.65 to 2.38, nine studies, 937 participants, low quality evidence), although the absolute number of patients developing hypernatraemia was low. Most studies had safety restrictions included in their methodology, preventing detailed investigation of serious adverse events. AUTHORS' CONCLUSIONS: Isotonic intravenous maintenance fluids with sodium concentrations similar to that of plasma reduce the risk of hyponatraemia when compared with hypotonic intravenous fluids. These results apply for the first 24 hours of administration in a wide group of primarily surgical paediatric patients with varying severities of illness.

Oesophageal button battery injuries: think again.

We present the cases of two infants with complications following accidental button battery ingestion with delayed presentations to medical care. Both cases had button batteries recognized as oesophageal foreign bodies and removed appropriately but the time delay resulted in significant morbidity as they developed spinal erosion and tracheo-oesophageal fistula, respectively. Close follow up is required of all children with delayed removal of button batteries as the injury initiated by the battery can lead to a chronic inflammation with significant injury to the surrounding structures.

Sleep and adolescence. Do New Zealand teenagers get enough?

AIM: The objective of this study is to describe the sleep patterns of secondary school students in New Zealand. METHODS: This study uses data from a national secondary school youth health survey conducted in 2001. A total of 9567 students completed the survey with an overall response rate of 64.3%. Students were asked if they felt they got enough sleep and the numbers of sleep hours were estimated from self-reported bedtimes and awakening times during the week and weekend. RESULTS: A significant proportion (21%) of students reported not getting enough sleep. Inadequate sleep was more common among older students and female students of Maori and New Zealand European ethnicity. The average amount of sleep secondary school students report in New Zealand is 8 h and 40 min during the week and 9 h and 23 min during the weekend. There was a shift towards later bedtimes and fewer total sleep hours among older students. Increasing hours of extracurricular activities and employment were generally associated with less sleep, especially among students engaging in more than 5 h a day of these activities. CONCLUSIONS: Significant numbers of secondary school students report inadequate sleep. Given the importance of adequate sleep on healthy adolescent development, parents and health professionals should be wary of the amount of extracurricular activities that young people engage in, especially part-time employment and the potential negative impact it may have on the adequacy of their sleep.