[Multicenter analysis of tolerance and clinical safety of the extracellular MR contrast agent gadobenate dimeglumine (MultiHance)]. / Multizentrische Analyse der Verträglichkeit und klinischen Sicherheit des extrazellulären MR-Kontrastmittels Gadobenat-Dimeglumin (MultiHance).

PURPOSE: Retrospective analysis of the occurrence of adverse events and the diagnostic efficacy of a paramagnetic contrast agent with weak intermittent protein binding and high relaxivity. MATERIALS AND METHODS: Postmarketing surveillance studies for gadobenate dimeglumine (MultiHance, BRACCO Altana Pharma, Constance) were conducted in Germany between 1998 and 2006 and then retrospectively analyzed. Demographic data, relevant comorbidities, and allergies were recorded. The safety and tolerability of MultiHance were logged on a standardized data sheet. RESULTS: A total of 38,568 patients were included in the study. 829 patients (2.1%) had a known intolerance against contrast media. The examined regions included the central nervous system, the liver, and the vascular bed. The injection rate with automated injectors (n = 10456) varied between 1.0 und 3.0 ml/sec in 86.5% of patients. Adverse events totaled 1.2%. 11 patients (0.03%) experienced serious adverse events. The most frequent findings were nausea, vomiting and a feeling of warmth. CONCLUSION: MultiHance is a safe and very well tolerated contrast agent for magnetic resonance imaging (MRI) with a profile and frequency of adverse events similar to other extracellular MR contrast materials.

Randomized comparison of a nutrient-dense formula with an energy-supplemented formula for infants with faltering growth.

INTRODUCTION: The practice of supplementing standard infant formula with energy for infants with faltering growth has been widespread. This increases energy density but disturbs the protein : energy ratio, and increases risks of microbial contamination and errors in feed preparation. This study aimed to compare the effectiveness of a nutrient-dense formula (NDF) with an energy-supplemented formula (ESF) in infants with faltering growth. METHODS: In an open, parallel, randomized study, 49 infants with faltering growth were randomized to receive a NDF (4.2 kJ mL(-1)) or an ESF (4.2 kJ mL(-1)), for 6 weeks. Anthropometry, biochemistry, feed intake, stool and vomit frequency were collected. RESULTS: No significant differences in tolerance, feed volumes or energy intakes were recorded but the NDF group received 42% more protein and 15-40% more vitamins and minerals. Blood urea concentration in the ESF group fell by 50% over the trial period, suggesting a suboptimal protein : energy ratio in the ESF feed. The NDF group retained a normal mean blood urea concentration, a higher urinary potassium concentration and did not have the significant fall in length z-score seen in the ESF group. CONCLUSION: Increasing the energy content of normal infant formula without also increasing protein and micronutrients should not be practiced in infants with faltering growth.

Impact of nutrient density of nocturnal enteral feeds on appetite: a prospective, randomised crossover study.

OBJECTIVE: To determine whether the energy density of isocaloric nocturnal enteral feeds (NEF) influences daily nutrient intake in children. METHOD: In a 6 week, randomised, crossover trial, the impact on spontaneous nutrient intake of manipulating the energy density of two isocaloric overnight feeds (1.0 kcal/ml and 1.5 kcal/ml) was compared in a group of 32 children aged 1-10 years (or 8-25 kg body weight) on long term, overnight enteral feeding at home. Total daily oral energy, protein, fat and carbohydrate intake were assessed using 3 day food diaries. Anthropometric data were also recorded during the study. RESULTS: Spontaneous intakes of energy, protein, fat and carbohydrate from food were 20-30% greater when receiving the lower nutrient density feed (1 kcal/ml). This was due to a gender effect; males consumed twice as much protein from food than females and had slightly higher (but not significant) energy and fat intakes when on the larger volume feed. All children increased in weight, height and mid-upper arm circumference in the 6 week period. CONCLUSIONS: Children appear to tolerate and grow equally well, irrespective of the nutrient density and volume of NEF taken. However, it appears that children will consume a more energy and nutrient dense oral diet when given their NEF as a higher volume/lower nutrient density feed. This is particularly so for boys, while for girls the volume of NEF or feed concentration appeared to have no impact on quantity of oral diet taken. However, further blinded studies with larger subject numbers would be useful to support these findings.

Incidence of symptomatic vitamin D deficiency.

A survey of West Midlands paediatricians in 2001 identified 24 cases of symptomatic vitamin D deficiency in children less than 5 years of age. The overall incidence was 7.5 per 100,000 children per year with notable differences in incidence per ethnic group.

Protein substitute dosage in PKU: how much do young patients need?

BACKGROUND: The optimal dose of protein substitute has not been determined in children with phenylketonuria (PKU). AIM: To determine if a lower dose of protein substitute could achieve the same or better degree of blood phenylalanine control when compared to the dosage recommended by the UK MRC.(1) METHODS: In a six week randomised, crossover study, two doses of protein substitute (Protocol A: 2 g/kg/day of protein equivalent; Protocol B: 1.2 g/kg/day protein equivalent) were compared in 25 children with well controlled PKU aged 2-10 years (median 6 years). Each dose of protein substitute was taken for 14 days, with a 14 day washout period in between. Twice daily blood samples (fasting pre-breakfast and evening, at standard times) for plasma phenylalanine were taken on day 8-14 of each protocol. The median usual dose of protein substitute was 2.2 g/kg/day (range 1.5-3.1 g/kg/day). RESULTS: When compared with control values, median plasma phenylalanine on the low dose of protein substitute increased at pre-breakfast by 301 mumol/l (95% CI 215 to 386) and in the evening by 337 micromol/l (95% CI 248 to 431). On the high dose of protein substitute, plasma phenylalanine concentrations remained unchanged when compared to control values. However, wide variability was seen between subjects. CONCLUSIONS: A higher dosage of protein substitute appeared to contribute to lower blood phenylalanine concentrations in PKU, but it did have a variable and individual impact and may have been influenced by the carbohydrate (+/- fat) content of the protein substitute.

Current issues in the management of intestinal failure.

Successful long term parenteral nutrition has transformed the prognosis for children with irreversible intestinal failure in the last three decades, but has also highlighted the long term complications: intestinal failure associated liver disease; recurrent catheter sepsis; and impaired venous access. Recent advances in small bowel transplantation and non-transplant surgical techniques now offer hope of sustained survival in the future without parenteral nutrition.

Emergency department thrombolysis improves door to needle times.

OBJECTIVE: To identify the effect on door to needle (DTN) time of moving the site of thrombolysis delivery from the coronary care unit (CCU) to the emergency department (ED). To ascertain if moving the site of thrombolysis enables appropriate use of thrombolysis. DESIGN: Prospective cohort study. SETTING: CCU and ED of a 450 bed Scottish district general hospital without on-site primary angioplasty. PARTICIPANTS: Primary site for thrombolysis of patients presenting to the hospital with ST elevation MI (STEMI) moved from CCU to ED on 1 April 2000. Study patients who had a confirmed STEMI and/or received thrombolytic therapy before this date were defined as the pre-change group; those who were diagnosed as STEMI and/or received thrombolytic therapy after this date were defined as the post-change group. STATISTICAL ANALYSIS: Mann-Whitney test was used to compare medians and chi(2) test for categorical data. RESULTS: 1349 patients were discharged from CCU with a diagnosis of STEMI or received thrombolysis in the ED or CCU between April 1998 and April 2002. There were 632 patients in the pre-change group and 654 patients in the post-change group. Sixty three patients were excluded. Median DTN time for the pre-change group (321 thrombolysed patients) was 64 minutes and median DTN time for the post-change group (324 thrombolysed patients) was 35 minutes, a median difference of 25 minutes (95% CI for difference 20 to 29 minutes, p<0.0001, Mann-Whitney U test). A total of 37 patients were thrombolysed but did not have a final diagnosis of STEMI. CONCLUSION: A significant reduction in DTN times accompanied this change in practice in this hospital.

The role of platelet activating factor in a neonatal piglet model of necrotising enterocolitis.

BACKGROUND AND AIMS: Necrotising enterocolitis (NEC) is a potentially devastating disorder of preterm infants but its aetiology remains unclear. The aim of these studies was to develop a neonatal piglet model for NEC and to then use the model to investigate the role of platelet activating factor (PAF) in its pathogenesis. METHODS: Anaesthetised newborn piglets were divided into six groups: (i) controls, and groups subjected to (ii) hypoxia, (iii) lipopolysaccharide (LPS), (iv) hypoxia+LPS, (v) hypoxia+LPS and the PAF antagonist WEB 2170, and (vi) PAF. Arterial blood pressure (ABP), superior mesenteric artery blood flow (MBF), mesenteric vascular conductance (MVC), and arterial blood gases were recorded, and intestinal histology was evaluated. RESULTS: Exposure to LPS, hypoxia+LPS, or PAF all caused haemorrhagic intestinal lesions associated with varying degrees of intestinal injury. PAF caused a significant initial decrease in both MVC and MBF whereas hypoxia+LPS caused a significant late reduction in ABP and MBF with a trend towards a decrease in MVC. The effects of hypoxia+LPS on both haemodynamic changes and intestinal injury were ameliorated by WEB 2170. CONCLUSIONS: Administration of hypoxia and LPS or of PAF in the neonatal piglet induces haemodynamic changes and intestinal lesions that are consistent with NEC. These effects are ameliorated by prior administration of WEB 2170, indicating an important role for PAF in the pathogenesis of NEC.

Bacterial production of methylglyoxal: a survival strategy or death by misadventure?

The production of MG (methylglyoxal) in bacterial cells must be maintained in balance with the capacity for detoxification and protection against this electrophile. Excessive production of MG leads to cell death. Survival of exposure to MG is best understood in the Gram-negative bacteria. The major mechanism of protection is the spontaneous reaction of MG with GSH to form hemithiolacetal, followed by detoxification by the glyoxalase system leading to the production of D-lactate. The KefB and KefC glutathione-gated K(+) efflux systems are integrated with the activity of the glyoxalase system to regulate the cytoplasmic pH in response to exposure to electrophiles. Bacteria only produce MG when an imbalance occurs in metabolism. Operation of the MG bypass enables cells to adapt, such that balance is restored to metabolism. Excessive production of MG is an adaptive ploy, which, if it fails, has fatal consequences. On this basis one might define MG-induced loss of life as "death by misadventure" rather than suicide!

Administration of protein substitute and quality of control in phenylketonuria: a randomized study.

Uneven administration of an L-amino acid protein substitute is an important contributing factor in variability in plasma phenylalanine concentrations over the 24-hour period in patients with phenylketonuria under treatment. The aim of this study was to determine whether manipulating the timing of protein substitution would reduce variability in plasma phenylalanine over 24 h. Sixteen children (aged 1-11 years) with well-controlled phenylketonuria were entered into a randomized crossover study in which four protocols of the same daily dose of protein substitute administration were compared. In protocol A, three equal, divided doses were given with meals over 10 h; in protocol B, three equal doses over 14 h; in protocol C, four equal doses over 14 h; and in protocol D, six equal doses over 24 h (3 subjects only). Four-hourly skin puncture blood specimens were collected for 48 h in each study protocol. In protocols A, B and C, but not in protocol D, there was wide variability in 24 h plasma phenylalanine. The median daily differences (micromol/L) between highest and lowest phenylalanine concentrations were: for protocol A, 140; for protocol B, 100; for protocol C, 120; and for protocol D, 40. In protocol D, 97% of all phenylalanine concentrations were below 120 micromol/L and no concentration fell below 40 micromol/L. Administration of protein substitute overnight as well as during daytime produces stable and lower plasma phenylalanine concentrations and may lead to improved dietary phenylalanine tolerance.

Free use of fruits and vegetables in phenylketonuria.

This study aimed to evaluate systematically the effect of the free use of fruits and vegetables containing an intermediate amount of phenylalanine (51-100 mg/100 g) on the biochemical control in children with phenylketonuria (PKU). Fifteen subjects with PKU, with a median age of 6 years (range 1-24 years) were studied. In a three-part prospective 15-week study, subjects sequentially ate fruits and vegetables containing phenylalanine 0-50 mg/100 g for weeks 1 to 3; 51-75 mg/100 g for weeks 4 to 8; and 76-100 mg/100 g for weeks 9 to 15. Plasma phenylalanine concentrations were measured twice daily for three consecutive days in weeks 1, 3, 6, 8, 11, 13 and 15. A standard menu was followed on the blood sampling days. Daily dietary records of fruits and vegetables under study were kept throughout the trial. Control of phenylalanine concentrations was not adversely affected by the free use of fruits and vegetables containing 51-100 mg/100 g. Pre-breakfast median plasma concentrations were: weeks 1 to 3, 260 micromol/L (range 90-890); weeks 4 to 8, 255 micromol/L (range 130-920); and weeks 9 to 15, 278 micromol/L (range 30-880). Pre-evening meal median plasma phenylalanine concentrations were: weeks 1 to 3, 240 micromol/L (range 30-820); weeks 4 to 8, 210 micromol/L (40-880); and weeks 9 to 15, 238 micromol/L (range 20-880). These data suggest that free use of fruits and vegetables containing 51-75 mg/100 g poses no problem for children with PKU.

Are tablets a practical source of protein substitute in phenylketonuria?

BACKGROUND: A phenylalanine-free amino acid based protein substitute is necessary to provide the major source of protein in phenylketonuria (PKU). Protein substitutes in PKU are usually given as drinks. These are unpalatable and compliance is often poor. Tablets containing a suitable mixture of phenylalanine-free amino acids (Aminogran Food Supplement, UCB) are now available. AIMS: To compare the effectiveness and acceptability of these tablets with conventional protein substitute drinks. METHODS: Twenty one subjects with PKU, aged 8-25 years, participated in a randomised crossover study. During one phase, subjects received at least 40% of their protein substitute requirements from the amino acid tablets and the rest from their usual protein substitute tablets. During the other phase, they received their usual protein substitute. Each period lasted 12 weeks. Blood phenylalanine concentrations were measured at least once every two weeks and other plasma amino acids were measured at the beginning, at crossover, and at the end of the study. The subjects kept a diary of all protein substitute taken. RESULTS: Compliance appeared to be better with the new tablets than with patients' usual protein substitutes. Ninety per cent (18/20) recorded that they took the tablets as prescribed, compared with 65% (13/20) fully compliant with their usual protein substitute. Moreover, plasma phenyalanine was lower on the amino acid tablets, and the median difference in blood concentrations between the two groups was 46 micro mol/l (95% CI 14.8 to 89.0, p = 0.02). Tyrosine increased by a median of 16 micro mol/l daily on the amino acid tablets (95% CI 7.1 to 40.5, p = 0.01). Most subjects (70%) preferred incorporating the new tablets into their usual protein substitute regimen. CONCLUSIONS: Amino acid tablets are an effective and relatively popular protein substitute in older children, teenagers, and adults with PKU.

An observational study to evaluate micronutrient status during enteral feeding.

BACKGROUND: There are few data on the optimal micronutrient composition of paediatric enteral feeds. The recent European Directive on Foods for Special Medical Purposes (1999/21/EC) did not distinguish between the composition of adult and paediatric feeds. AIMS: To evaluate, in an open, observational study, the long term nutritional biochemistry of 12 children aged 1-6 years and/or 8-20 kg. METHODS: The children were receiving at least 50% of their estimated average requirement (EAR) for energy from paediatric enteral formulae: 1.0 kcal/ml (Nutrison Paediatric Standard) or 1.5 kcal/ml (Nutrison Paediatric Energy Plus). Venous blood samples for trace elements, vitamins, and minerals were taken at study entry and six months later. Parents kept three day food and feed records every month. RESULTS: Despite a median energy intake of only 75% EAR (range 52-158%), 67% (n = 8) achieved their reference nutrient intake (RNI) for all micronutrients. No significant micronutrient deficiencies were seen on blood analysis after six months. Eighty three per cent (n = 10) had vitamin B(12) and 92% (n = 11) had copper intake >150% RNI. Fifty eight per cent (n = 7) had high plasma B(12) (>733 micromol/l) and 75% (n = 9) had high serum copper (>22 micromol/l) concentrations. CONCLUSIONS: Children without excess losses maintain adequate micronutrient status on long term enteral feeding. Subjects had high blood concentrations of vitamin B(12) and copper, and had high dietary intakes of these micronutrients. We suggest that the maximum nutrient guidelines for paediatric enteral feeds should be more clearly defined.

Growth reference charts for use in the United Kingdom.

Since the introduction of new growth charts in the mid 1990s, there has been confusion about which charts should be used, with many districts using more than one version. Because of this uncertainty, an expert working party, the Growth Reference Review Group, was convened by the Royal College of Paediatrics and Child Health to provide guidance on the validity and comparability of the different charts currently in use. This paper describes the technical background to the construction and evaluation of growth charts and outlines the group's findings on the validity of each growth reference in relation to contemporary British children. The group concluded that for most clinical purposes the UK90 reference is superior and for many measures is the only usable reference that can be recommended, while the original Tanner-Whitehouse and the Gairdner-Pearson charts are no longer reliable for use at any age. After the age of 2 the revised Buckler-Tanner references are still suitable for assessing height. There are presently no reliable head circumference reference charts for use beyond infancy. The group propose that apart from refinements of chart design and layout, the new UK90 reference should now be "frozen", with any future revisions only undertaken after careful planning and widespread consultation.

Protected environments allow parallel evolution of a bacterial pathogen in a patient subjected to long-term antibiotic therapy.

Long-term antibiotic treatment offers a rare opportunity to study the evolution of bacteria within the same individual. The appearance of new variants has been suggested to take place via the selection of enhanced resistance in compartments of the body in which the antibiotic concentration is low. Laboratory models of protected compartments have elegantly demonstrated their potential in selecting novel variants. However, comparable data from patients have been rare. In this study, extended antibiotic therapy in a single patient suffering from multiple infected liver cysts has provided the opportunity to observe and analyse the molecular evolution of antibiotic resistance. Each isolate has the same basic ompC gene sequence that is distinct from other Escherichia coli isolates, which suggests that they derive from the same founder population. However, the isolates differ in their auxotrophic markers, in the pI values of their dominant beta-lactamase activities and in the mutations in the promoter region of the ampC gene leading to increased expression of the AmpC enzyme. The data provide strong evidence for a single focal infection expanding via parallel pathways of evolution to give a range of antibiotic-resistant isolates. These data suggest that the infected cysts provide numerous protected environments that are the foci for the separate development of distinct variants.