Population pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing regimens.

PURPOSE: This study aimed to characterize pharmacokinetics of intravenous and oral ciprofloxacin in children to optimize dosing scheme. METHODS: Children treated with ciprofloxacin were included. Pharmacokinetics were described using non-linear mixed-effect modelling and validated with an external dataset. Monte Carlo simulations investigated dosing regimens to achieve a target AUC0-24 h/MIC ratio ≥ 125. RESULTS: A total of 189 children (492 concentrations) were included. A two-compartment model with first-order absorption and elimination best described the data. An allometric model was used to describe bodyweight (BW) influence, and effects of estimated glomerular filtration rate (eGFR) and age were significant on ciprofloxacin clearance. CONCLUSION: The recommended IV dose of 10 mg/kg q8h, not exceeding 400 mg q8h, would achieve AUC0-24 h to successfully treat bacteria with MICs ≤ 0.25 (e.g. Salmonella, Escherichia coli, Proteus, Haemophilus, Enterobacter, and Klebsiella). A dose increase to 600 mg q8h in children > 40 kg and to 15 mg/kg q8h (max 400 mg q8h, max 600 mg q8h if augmented renal clearance, i.e., eGFR > 200 mL/min/1.73 m2) in children < 40 kg would be needed for the strains with highest MIC (16% of Pseudomonas aeruginosa and 47% of Staphylococcus aureus). The oral recommended dose of 20 mg/kg q12h (not exceeding 750 mg) would cover bacteria with MICs ≤ 0.125 but may be insufficient for bacteria with higher MIC and a dose increase according bodyweight and eGFR would be needed. These doses should be prospectively confirmed, and a therapeutic drug monitoring could be used to refine them individually.

[Echocardiographic assessment of myocardial function during His bundle and right ventricular pacing]. / Echokardiographische Beurteilung der myokardialen Funktion unter His-Bündel- und rechtsventrikulärer Schrittmacherstimulation.

INTRODUCTION: In patients with pacemaker (PM) therapy, His bundle stimulation (HBS) may lead to a more synchronous activation of the left ventricle (LV) than conventional right ventricular stimulation (RVS). In this study, we investigated to which extent this effect can be objectified by means of contemporary echocardiographic functional imaging. METHODS: In all, 15 RVS patients (6 women, mean age 76.6 ± 4.1 years) and 15 HBS patients (6 women, mean age 74.6 ± 3.7 years) underwent echocardiography with and without cardiac pacing. Besides LV end-diastolic volume (EDV), ejection fraction (EF), and global strain (GLS), we measured global and regional myocardial work and LV efficiency based on noninvasive pressure-strain loops. RESULTS: In all HBS patients, optimization of PM settings resulted in immediate changes in myocardial function parameters. With pacing, RVS patients showed a higher decrease in EF and GLS than HBS patients. Global LV work and LV work efficiency decreased significantly only in RVS patients. CONCLUSION: Changes in regional and global myocardial function can by proven and quantified by functional echocardiography. In patients under PM therapy, HBS shows functional advantages in comparison to conventional RVS.

[Apnea test for assessment of brain death under extracorporeal life support]. / Apnoetest beim irreversiblen Hirnfunktionsausfall unter extrakorporaler Zirkulation.

BACKGROUND: The fourth edition of the German guideline for the assessment of brain death, published in 2015 by the German Medical Council (Bundesärztekammer), emphasizes the importance of an apnea test. It is also now required under all circumstances of extracorporeal life support. OBJECTIVES: This article is an instruction for the guideline-conforming performance of an apnea test in general and also in cases of extracorporeal life support in different configurations. MATERIALS AND METHODS: A literature review was performed. CONCLUSIONS: The apnea test is an essential part of the bedside examination for the clinical diagnosis of brain death. It is required for all kinds of extracorporeal life support and can be easily performed without endangering the patient. More accurate recommendations for its performance should be considered for the next version of the German guideline for brain death assessment.

Assessing the efficacy and cost of detergents used in a primary care automated washer disinfector.

Background: Cleaning of re-usable medical devices is a critical control point in the decontamination cycle, although defined end-points of the process are controversial. Objective: Investigate cleaning efficacy and cost of different detergent classes in an automated washer disinfector (AWD) designed for dental practice. Methods: Loads comprised test soiled dental hand instruments in cassettes and extraction forceps. Residual protein assayed using the International standard method (ISO 15883-5:2005) 1% SDS elution with ortho-phthalaldehyde (OPA) or GBox technology (on instrument OPA analysis). Short (60 minutes) and long (97 minutes) AWD cycles were used with four different classes of detergents, tap water and reverse osmosis water. Results: SDS elution analysis (N = 612 instruments) demonstrated four detergents with both wash cycles achieved equivalent cleanliness levels and below a threshold of 200 µg protein/instrument. GBox methodology (N = 575) using UK Department of Health threshold of 5 µg/instrument side demonstrated that tap water performed with the greatest efficacy for all types of instruments and cycle types. Conclusions: Using International standard methodology, different detergent classes had equivalence in cleaning efficacy. Cheaper detergents used in this study performed with similar efficacy to more expensive solutions. Findings emphasise the importance of validating the detergent (type and concentration) for each AWD.

Reducing the risk of iatrogenic Creutzfeldt-Jakob disease by improving the cleaning of neurosurgical instruments.

BACKGROUND: In all, there have been 178 variant Creutzfeldt-Jakob disease (vCJD) patients diagnosed in the UK, with an estimated maximum 1:2000 carriage rate based on archived appendix and tonsil tissue, implying that infection may be rare but carriage relatively frequent. Previous workers have identified that maintenance of surgical instruments in a humid atmosphere after use and prior to cleaning assists cleaning efficacy. Recently the Department of Health/Advisory Committee on Dangerous Pathogens UK have recommended a surgical instrument cleanliness threshold post cleaning of <5 µg protein per instrument side. AIM: To quantify cleanliness of neurosurgical instruments and to investigate cost-effective measures for improved cleaning. METHODS: Two instrument protein quantification methods were used: one based on the International Standard (15883 series) using sodium dodecyl sulphate elution and ortho-phthalaldehyde reaction, and a second in-situ protein fluorescence detection system (ProReveal) providing results per instrument side. In-vitro investigation of the efficacy of some commercial and in-house pre-clean wetting agents was undertaken using artificial test soil and stainless steel discs under standard conditions. In-vivo evaluation of best-performing in-vitro agents was undertaken on craniotomy sets. FINDINGS: ProReveal technology demonstrated that 163 out of 187 (87%) neurosurgical instruments had <5 µg residual protein per instrument side. The use of proprietary National Health Service plastic bags and sterile water-soaked wound pads were equivalent in efficacy to commercial pre-cleaning wetting products and significantly less expensive. CONCLUSION: Although we demonstrate low in-situ protein levels on neurosurgical instruments and the beneficial effects of keeping instruments moist, other cleaning critical-control points such as instrument loading patterns should also be monitored.

Transoral laser microsurgery versus radiation therapy in the management of T1 and T2 laryngeal glottic carcinoma: which modality is cost-effective within the UK?

OBJECTIVES: To identify the most cost-effective treatment strategy in patients with early stage (T1 and T2) cancers of the laryngeal glottis. DESIGN: A Markov decision model populated using data from updated systematic reviews and meta-analyses, with attributable costs from NHS sources. Data on local control and mortality were obtained from updates of existing systematic reviews conducted for the NICE guideline on cancer of the upper aerodigestive tract. Procedure costs were sourced from NHS reference costs 2013/14 by applying tariffs associated with the appropriate health resource group code SETTING: The UK National Health Service. POPULATION: Patients with early stage (T1 and T2) cancers of the laryngeal glottis. INTERVENTIONS: Transoral laser microsurgery (TLM) and radiation therapy (RT). MAIN OUTCOME MEASURES: Total costs, incremental costs and quality adjusted life years (QALYs) over a 10-year time horizon. RESULTS: Radiation therapy as the initial treatment strategy was found to be more expensive (£2654 versus £623) and less effective (QALY reduction of 0.141 and 0.04 in T1a and T1b-T2 laryngeal cancers, respectively) than TLM. The dominance of TLM for T1a cancers was unchanged in most scenarios modelled in sensitivity analysis. For T1b-T2 laryngeal cancers, the result changed in numerous scenarios. In probabilistic sensitivity analysis, TLM was found to have a 71% and 58% probability of being cost-effective in T1a and T1b-T2 laryngeal cancers, respectively. CONCLUSIONS: Transoral laser microsurgery is a cost-effective strategy to adopt in the management of T1a laryngeal cancers. Uncertainty remains over the optimal strategy to adopt in T1b-T2 laryngeal cancers.

Prospective evaluation of comorbidity and psychosocial need in children and adolescents with anorectal malformations. Part 2: evaluation of psychosocial need.

PURPOSE: Only a few patients with anorectal malformations (ARM) have satisfactory bowel functions. Studies of ARM have reported psychosocial problems in up to 73% of patients. The aim of the current study was to document the psychosocial needs of patients with ARM. METHODS: Between June 2004 and September 2005, 44 patients with ARM were treated; the sample included 30 patients (23 males and 7 females) aged 4-17. To focus on potential psychosocial strain, a comprehensive grading system with a sophisticated perspective of continence, associated malformations, number of surgical interventions and postoperative complications was introduced. For psychosocial screening, the following instruments were used: German "Basis-Dokumentation" (BADO), Impact on Family Scale (IFS), the Strengths and Difficulties Questionnaire (SDQ). All families assessed their own psychosocial needs. An extensive psychosocial programme was provided. RESULTS: Twenty-three patients were suffering severe burden according to the comprehensive grading system. Nearly half of the families reported increased financial stress, and one-third reported emotional or hyperactivity problems of the child. More than 70% confirmed psychosocial need. CONCLUSIONS: Paediatric surgeons should promote psychosocial support for all patients who suffer severe forms of ARM or its numerous associated malformations as well as for patients undergoing numerous surgical interventions or having many postoperative complications.

[Essentials of prevention policy in Germany]. / Eckpunkte der Prävention in der Gesundheitspolitik.

Prevention has become a major task of German health policy. In light of decreasing birth rates and low ages for starting retirement, prevention can contribute to stabilizing the social system by helping to prevent the outburst of diseases, ensure early diagnosis, and facilitate better coping strategies. It can also help to postpone or prevent early retirement and nursing care. To utilize preventive potentials German health policy has initiated the German Forum on Prevention and Health Promotion and a Law on Prevention, which is being negotiated in the German Parliament at present. In order to strengthen prevention, a system will be created that is financed by health, pension, accident and nursing insurance providers together. There will be campaigns, initiation of behavioural changes and setting activities (as required and described by WHO). The system will be controlled by common goals and targets, quality standards and a reporting duty to monitor the efficiency. On the federal level there will be a foundation on prevention and health promotion by the social insurance for the purpose of coordination. The German Forum has existed for 3 years now being a voluntary joint venture of relevant actors in prevention. The aim is to work together and create synergies. At present it is working on four topics: healthy kindergarden and schools, health promotion in firms, healthy aging and organisation and law.

[Potentials of and approaches to prevention. Current developments in Germany]. / Potenziale und Ansätze der Prävention. Aktuelle Entwicklungen in Deutschland.

Prevention and health promotion are rewarding investments to stabilize our health security systems. They yield sustainable social and individual profit. This is precisely one of the explicitly declared aims of the government's coalition agreement of October 2002 - to upgrade and extend prevention and health promotion in Germany. The Federal Ministry of Health and Social Security is initiating measures and strategies to improve the framework for effective prevention and health promotion, for instance by initiating measures in the field of legislation and by establishing the German Platform for Prevention und Health Promotion.

Computerized system for outcomes-based antiemetic therapy in children.

OBJECTIVE: To introduce a computerized data collection system used for an outcomes-based approach to antiemetic therapy in children, and to present data collected with this system in support of a new antiemetic dosing regimen. METHODS: A validated nausea/vomiting survey was used to collect data on nausea severity (NSEV), vomiting severity (VSEV), daily activity interference (DAI), and the number of vomiting episodes. NSEV, VSEV, and DAI were rated as 0 = none to 3 = severe. All children and/or their parents were surveyed following the completion of each highly emetogenic chemotherapy regimen. This survey was computerized and transferred to a handheld data entry unit. Time and motion studies were performed to compare the time required to collect nausea/vomiting data and transfer the data to a computerized database with the hand-held system versus traditional paper (manual) surveys. The hand-held technology was used to collect survey data for children receiving a new antiemetic regimen (daily ondansetron and dexamethasone [OD]), which was then compared with data obtained with a previously employed regimen (thrice-daily ondansetron and daily methylprednisolone [OM]). Statistical analysis and a cost-effectiveness analysis (CEA) were performed to compare the two antiemetic regimens. RESULTS: The mean time required for total data entry with the manual system was 5.2 minutes per survey versus 2.4 minutes with the hand-held technology (p = 0.0026). A total of 376 nausea/vomiting surveys in 78 children receiving the OM antiemetic regimen were compared with 153 surveys in 38 children treated with the OD regimen. The mean survey scores were as follows: NSEV (1.2 vs. 0.8), VSEV (1.0 vs. 0.7), DAI (1.0 vs. 0.7), and number of vomiting episodes (4.3 vs. 2.1) for OM and OD, respectively; all were significantly lower with the OD regimen (p < 0.05). The percentage of patients with complete control of nausea and vomiting (19.2% vs. 39.2%) and good control (55.6% vs. 65.4%) were significantly greater with the OD regimen (p < 0.05). The CEA revealed that the OD resulted in a reduction of approximately $31 per patient for good protection and a $258 reduction for complete protection from nausea and vomiting. CONCLUSIONS: A computerized outcomes-based system aided by handheld technology allowed for more prompt and efficient collection of nausea/vomiting data. The OD antiemetic regimen was shown to be a more cost-effective alternative for children receiving severely emetogenic chemotherapy.

Inborn errors of metabolism: medical and administrative "orphans".

CONTEXT: Inborn errors of metabolism are genetic conditions that affect the normal biochemical functions of the body in any organ and at any age. More than 500 metabolic diseases are known; almost all are classified as orphan diseases under the US Food and Drug Administration guidelines (incidence < 200,000 persons) and each has its own requirements for diagnosis and treatment. Management of these complex, lifelong, multisystem disorders often requires a coordinated, multidisciplinary approach involving several subspecialists and which may include complex laboratory evaluations, genetic counseling, nutritional therapy, and unusual therapeutic approaches that have been used in only a small number of cases. RESULTS: Not infrequently, inborn errors of metabolism fall outside current standard diagnostic and treatment guidelines of managed care plans. This results in delays in diagnosis and appropriate management, with increased costs to patients and to society. CONCLUSIONS: Patients with inborn errors of metabolism should not be discriminated against and all health plans should specify that access to specialists and metabolic centers are a covered benefit of the plan. The acceptance of treatment guidelines, the development of international disease classification codes for the disorders, and the performance of cost-benefit analyses would all greatly facilitate this process. However, without recognition that these disorders require such services, and steps to provide them by the insurance industry, the care of children with metabolic disorders and other chronic diseases will continue to be a source of frustration and anger among the caregivers and the families they serve.

Assessment of the emetogenic potential of intrathecal chemotherapy and response to prophylactic treatment with ondansetron.

The purpose of this study was to document the emetogenic potential of intrathecal chemotherapy (IC) in children and to evaluate the efficacy of ondansetron in reducing nausea and vomiting with this chemotherapy treatment. Patients less than 18 years of age with acute lymphoblastic leukemia were eligible to participate in a survey project measuring the emetogenic potential of various chemotherapy treatments. Patients surveyed for 1 or more IC treatments were included in this report. The IC consisted of methotrexate, hydrocortisone and cytarabine, dosed according to patient age. A nausea/vomiting survey instrument was completed by each patient and/or parent following IC treatment. The instrument rated nausea, vomiting and daily activity interference (DAI) on a 4-point scale of 0 = none, 1 = mild, 2 = moderate and 3 = severe, and collected data on the number of vomiting and/or retching episodes in addition to the child's appetite following the chemotherapy treatment. When ondansetron was employed, it was administered in an i.v. infusion at a dose of 0.15 mg/kg before and after chemotherapy or as an oral dose of 4 mg or 8 mg before chemotherapy. Courses of IC without antiemetics were analyzed to determine the emetogenic potential of IC. For patients receiving IC both with and without ondansetron, courses were compared with each patient used as their own control to determine the influence of ondansetron upon survey responses. Statistical analysis consisted of nonparametric Friedman 2-way ANOVA for ordinal variables and a paired t-test for continuous variables. The binomial test was employed to analyze for differences between ondansetron and no antiemetic in the number of patients with complete control of both nausea and vomiting or vomiting alone. A total of 63 children with a mean age of 7.6 +/- 4.2 years were each studied on one or more occasions. Thirty-seven children were surveyed for 87 IC treatments without antiemetics (group I), and 17 children from this group were surveyed for 48 IC courses with i.v. ondansetron (group IA). An additional 18 children were subsequently surveyed for 39 IC courses with i.v. ondansetron (group II). Fifteen patients (7 of whom were members of group I) were surveyed following 33 IC courses with oral ondansetron (group III). The survey scores for group I patients were: nausea severity 1.3 +/- 1.1, vomiting severity 1.2 +/- 1.1, DAI 1.2 +/- 1.0 and mean number of emetic episodes 4.7 +/- 8.4. The mean appetite score was 1.5 +/- 1.1. For patients in group IA, nausea severity (0.8 +/- 0.9), vomiting severity (0.5 +/- 0.8), DAI (0.7 +/- 0.8), and the number of emetic episodes (1.4 +/- 2.8) were all significantly lower than with prior IC treatments without ondansetron. For complete protection, children receiving i.v. ondansetron had greater complete protection rates from both nausea and vomiting or vomiting alone than did patients receiving no antiemetic. Survey responses were also lower for patients receiving oral ondansetron, but insufficient control data did not allow for statistical analysis. IC results in mild to moderate nausea and vomiting in children. The emetogenic potential of IC is significantly reduced by i.v. ondansetron.

Preoperative assessment of the child with neuromuscular scoliosis.

The medical preoperative assessment of the child with neuromuscular scoliosis under consideration for spinal fusion is presented. Issues of the respiratory, gastrointestinal, cardiovascular, and hematologic systems as well as nutrition are reviewed. An outline of preoperative screening tests and a discussion of common medical issues should help the surgeon prepare the child with neuromuscular scoliosis for spinal reconstructive surgery.

The neonate with unexpected acidemia.

We attempted to determine the etiology and clinical significance of unexpected acidemia in otherwise healthy neonates. A retrospective review was performed of the umbilical cord pH in 11,203 deliveries performed at Denver General Hospital, with an umbilical artery pH < 7.13 (3 SD below the mean) selected as the definition of neonatal acidemia. Among those neonates weighing > 2.5 kg with umbilical artery pH < 7.13, 76 were expected to have acidemia because of signs of severe fetal distress. There were 59 neonates with unexpected acidemia, having umbilical artery pH < 7.13, with no definite etiology found. In 96% of cases of unexpected acidemia, the neonates were discharged with their mothers, while 84% of the expected cases went home with their mothers. In excess of $880,000 was spent performing routine umbilical blood pH determinations without any apparent clinical or legal benefit. Routine umbilical blood gas studies on all neonates does not appear to be indicated for either clinical or legal reasons.